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Frontiers | Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities

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REVIEW article 

Front. Med. , 08 April 2024

Sec. Precision Medicine 

Volume 11 - 2024 |  [ https://doi.org/10.3389/fmed.2024.1365183 ](https://doi.org/10.3389/fmed.2024.1365183)

This article is part of the Research Topic Precision Treatments for Patients with Obesity [View all 6 articles](https://www.frontiersin.org/research-topics/52268/precision-treatments-for-patients-with-obesity/articles)

# Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities

[![\\r\\nRiccardo Sarzani,](https://loop.frontiersin.org/images/profile/887470/74)Riccardo Sarzani](https://loop.frontiersin.org/people/887470)1,2![Matteo Landolfo,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Matteo Landolfo1,2![Chiara Di Pentima](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Chiara Di Pentima1![Beatrice Ortensi,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Beatrice Ortensi1,2![Paolo Falcioni,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Paolo Falcioni1,2![Lucia Sabbatini,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Lucia Sabbatini1,2![Adriano Massacesi,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Adriano Massacesi1,2![Ilaria Rampino,](https://loop.frontiersin.org/cdn/images/profile/default_32.jpg)Ilaria Rampino1,2[![Francesco Spannella,
](https://loop.frontiersin.org/images/profile/1903474/74)Francesco Spannella](https://loop.frontiersin.org/people/1903474)1,2*[![Federico Giulietti](https://loop.frontiersin.org/images/profile/1910504/74)Federico Giulietti](https://loop.frontiersin.org/people/1910504)1

  * 1Internal Medicine and Geriatrics, European Society of Hypertension (ESH) "Hypertension Excellence Centre", Societa Italiana per lo Studio dell'Aterosclerosi (SISA) LIPIGEN Centre, IRCCS INRCA, Ancona, Italy
  * 2Centre for Obesity, Department of Clinical and Molecular Sciences, University "Politecnica delle Marche", Ancona, Italy



Obesity is a multifactorial chronic disease characterized by an excess of adipose tissue, affecting people of all ages. In the last 40 years, the incidence of overweight and obesity almost tripled worldwide. The accumulation of "visceral" adipose tissue increases with aging, leading to several cardio-metabolic consequences: from increased blood pressure to overt arterial hypertension, from insulin-resistance to overt type 2 diabetes mellitus (T2DM), dyslipidemia, chronic kidney disease (CKD), and obstructive sleep apnea. The increasing use of innovative drugs, namely glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2-i), is changing the management of obesity and its related cardiovascular complications significantly. These drugs, first considered only for T2DM treatment, are now used in overweight patients with visceral adiposity or obese patients, as obesity is no longer just a risk factor but a critical condition at the basis of common metabolic, cardiovascular, and renal diseases. An adipocentric vision and approach should become the cornerstone of visceral overweight and obesity integrated management and treatment, reducing and avoiding the onset of obesity-related multiple risk factors and their clinical complications. According to recent progress in basic and clinical research on adiposity, this narrative review aims to contribute to a novel clinical approach focusing on pathophysiological and therapeutic insights.

## Introduction

Obesity is a chronic multifactorial disease characterized by an excessive accumulation of adipose tissue, affecting people of all ages. The World Health Organization (WHO), as well as the World Obesity Federation (WOF) and the World Heart Federation (WHF), defined obesity as a chronic relapsing disease with a body mass index (BMI) ≥ 30 kg/m2 (1). Over the last four decades, the global incidence of overweight (BMI ≥ 25 kg/m2) and obesity has nearly tripled (2). The WHO predicted that 18% of men and 21% of women will be affected by obesity in 2025, while 40% of the global population will be overweight (3). Recent evidence correlated almost 4 million deaths to obesity and its cardiovascular (CV) complications (4). Life expectancy decreases proportionally with increasing BMI, starting from 25 kg/m2 and even more from 27 kg/m2 (5). Increased body weight also correlates with a marked increase in healthcare costs. The average annual healthcare cost of an obese adult doubles that of a normal-weight adult in the U.S.A. ($5,010 vs. $2,504) (6).

Genetic, environmental, psychological, socio-economic, and cultural factors contribute to obesity, which may arise at different ages (7, 8). The rare and severe early-onset monogenic forms of obesity led to the identification of major pathophysiological pathways involved in the development of the more common polygenic obesity (9), which is the main focus of this review. The foundation for overweight and obesity development lies in an excessive and disproportionate caloric intake compared to energy expenditure, leading to an accumulation of calories excess in the form of triglycerides stored in the adipocytes that undergo pathological hypertrophy and possibly also hyperplasia (10).

The distribution of excessive adipose tissue is also essential to determine the obesity-related CV and metabolic risk. Individuals with an excessive amount of visceral adipose tissue (VAT), primarily localized intra-abdominally, in the mediastinum, the epicardium, the neck, and even the tongue are at higher CV and metabolic risk than individuals with subcutaneous accumulation of adipose tissue (i.e., in the femoral-gluteal area) (11). Visceral obesity is an independent risk factor for CV disease and mortality (nearly 60% of all CV deaths occur in obese subjects) (4, 12, 13). Indeed, visceral obesity is often associated with several CV and metabolic risk factors, such as arterial hypertension (nocturnal or sustained), metabolic syndrome, insulin resistance, impaired glucose metabolism, type 2 diabetes mellitus (T2DM), dyslipidemia and steatosis/steatohepatitis (4) and their complications, in terms of major CV events, such as acute myocardial infarction and heart failure (often with preserved ejection fraction, HFpEF), atrial fibrillation (AF) and ventricular arrhythmias, stroke, but also chronic kidney disease (CKD), respiratory diseases, such as obstructive sleep apnea syndrome (OSAS), and all-cause mortality (14).

In this regard, we are facing a new era in the pharmacological treatment of obesity and its complications. Among the newer and available drugs, both the glucagon-like peptide-1 receptor agonists (GLP1-RA) and the sodium-glucose cotransporter-2 inhibitors (SGLT2-i) can improve metabolic and CV risk factors by reducing body weight and acting on associated pathophysiological derangements.

This narrative review will range from pathophysiological aspects of obesity, mainly related to excess VAT and its clinical consequences, to the current and future therapeutic approaches of obesity-related CV and metabolic diseases. This paper aims to promote an integrated clinical approach and therapeutic strategy to face the different aspects of obesity-related CV and metabolic complications, beginning from the highly prevalent body overweight, in which the presence of a VAT excess, that we denominate here "visceral overweight," should never be disregarded, or considered only a mere "amplifier" of CV risk.

## Brief overview of obesity pathophysiology and its cardiovascular and metabolic consequences

We can consider the dietary-polygenic type of obesity as the prototype of a disease in which a polygenic predisposition is coupled with multiple environmental factors, among which an excessive caloric intake with food and beverages coupled with the reduced metabolic rate or, more commonly, the scarce physical activity prevail (15). The genes predisposing to obesity are also widespread in countries with a shortage of food intake; however, this polygenic background helps improving survival without any pathological weight gain. In contrast, whenever food availability is excessive, "emotional" eating and junk food-related gratification can be driven by polygenic traits and are often worsened by a sedentary lifestyle, resulting unavoidably in overweight and obesity.

Monogenic obesity has an early onset in life and severe clinical features (9). Thanks to research on monogenic forms of obesity, derangements in the central nervous system (CNS) pathways have been recognized, especially regarding changes in leptin (LEP) and its receptor (LEPR). Each gene mutation involving these pathways can lead to uncontrolled food intake and obesity development. Leptin is produced by adipose tissue, secondary to its abundance, and is connected to the path centered on melanocortin (MSH, largely α-MSH): hypothalamic neurons in the arcuate nucleus that express pro-opiomelanocortin (POMC) and the agouti-related protein (AGRP) also express LEPR, which binds circulating LEP that reflects the fat amount. POMC neurons, via the MSH component of POMC, interact with neurons that express the melanocortin receptor type 4 (MC4R) in the arcuate and paraventricular nuclei of the hypothalamus, which controls appetite and sense of satiety (Figure 1).

Figure 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g001.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g001.jpg)

**Figure 1**. Effect of leptin in the central nervous system and hypothalamic circuits regulating hunger, satiety, and energy expenditure. POMC, pro-opiomelanocortin; PCSK1, proprotein convertase subtilisin/kexin type 1; MSH, Melanocyte Stimulating Hormone; MC4R, melanocortin receptor type 4; BDNF, brain-derived neurotrophic factor.

On the contrary, AGRP acts as an antagonist of the MC4R and stimulates increased food intake. Every mutation of genes encoding for these neuronal circuits often simulates leptin deficiency and leads to hyperphagia and severe obesity. Human leptin analogs are available and very effective for treating rare leptin gene mutations and deficiency cases. Setmelanotide, a selective MC4R agonist, has recently been approved by the FDA for the treatment of rare forms of monogenic obesity characterized by LEPR or proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency, a pivotal enzyme to process POMC into α-MSH that stimulates MC4R (and MC3R) to reduce food intake (9).

Adipose tissue also acts as an endocrine organ affecting the circulating levels of several other hormones: it can secrete not only adipokines (i.e., adiponectin) but also proteins (angiotensinogen) and peptides (angiotensin II), contributing to the overactivation of the renin-angiotensin-aldosterone system (RAAS) and obesity-related hypertension (see below for details) and it can seize and degrade cardiac natriuretic peptides (NPs) by a glucose/insulin-dependent pathway leading to the over-expression of their clearance receptor (NPRC) (16). The lower biological activity of NPs on adipocytes, due to the higher expression of NPRC stimulated by overeating (especially rapidly absorbable sugars), lowers the well-known lipolytic and "browning" activities of NPs, resulting in less beige and brown adipocytes, those rich in mitochondria and ATP-burning heat-producing uncoupling protein 1 (UCP-1), thus contributing to reduced basal metabolism (16, 17). Furthermore, higher VAT is associated with adipocyte hypertrophy, known to be linked with increased insulin resistance, cellular stress and consequent necrosis followed by macrophage recruitment and increased inflammation with the releasing of pro-inflammatory cytokines such as tumor-necrosis-factor alpha (TNFα) and interleukin-6 (IL-6) that contribute to low-grade chronic inflammation and joint obesity-related CV and metabolic complications (10). Adipose tissue in obesity is also associated with capillary rarefaction and reduced delivery of oxygen and nutrients, leading to increased hypoxia-inducible factors and fibrosis (18). Microcirculation dysfunction and rarefaction are hallmarks of arterial hypertension, and some of the findings in obese patients are due to a chronic increase in blood pressure (BP).

Fat accumulation and distribution are also sex- and age-related (19). Excessive subcutaneous fat depots with typical female gluteal and thigh localization usually comprise smaller adipocytes with fewer metabolic abnormalities, identifying a particular phenotype of obese patients, defined as "metabolically healthy obese" (MHO). However, it is an apparent oxymoron nowadays (20, 21). Indeed, MHO patients may already have chronic heart damage (increased interstitial tissue/fibrosis volume and changes in systolic and diastolic functions) predisposing to HFpEF, the most common HF phenotype in the obese population (22) (see below for details). As highlighted in recent literature, the "obesity paradox" described in some clinical contexts, especially in older adults, in whom lean muscle mass is progressively replaced by fat mass, led to the misconception of a possible "_healthy (or even benign)_ " obesity. This concept needs to be revised, also through the help of newer anthropometric and metabolic indices more sensitive and specific than BMI, such as the waist-to-height ratio, which has a stronger association with central adiposity-related complications and that should be more frequently used in clinical studies as well as in daily clinical practice (23, 24).

The excess of visceral triglycerides "spillover" can also result in direct lipotoxicity and contribute to chronic organ damage. In the liver, for example, hyperinsulinemia due to visceral obesity-related insulin resistance stimulates the production and accumulation of triglycerides, promoting hepatic steatosis and lipotoxicity, potentially evolving into non-alcoholic steatohepatitis that can progress up to cirrhosis and hepatic cancer (25). These liver changes, also known as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), are considered expressions of metabolic syndrome-related organ damage and are independently associated with increased mortality for CV events (26). A recent "Consensus Statement" involving several scientific societies has proposed a revised nomenclature and classification, defining these alterations as "metabolic dysfunction-associated steatotic liver disease" (MASLD), associating this clinical feature with at least one of the five critical cardiometabolic risk factors (27).

## Obesity, high-normal blood pressure, and arterial hypertension

It is estimated that about three out of four cases of essential arterial hypertension are caused by overweight and obesity (28). Although many genetic and environmental factors contribute to the increase in BP, hypertension is strikingly more prevalent in obese than in normal-weight individuals. In obese hypertensive patients, apart from an excessive dietary salt intake with an average of 10 g/day (29), excessive adipose tissue, especially VAT, is directly involved in the chronic hyperactivation of the sympathetic nervous system (SNS) (30). There is a glomerular hyperfiltration in obesity, which is often coupled with increased tubular sodium reabsorption (31), thus contributing to systemic arterial hypertension and chronic kidney damage. Visceral fat is associated with a "within normal range" increase in plasma aldosterone concentrations, supported by the production of adipokines and angiotensinogen, a fundamental component of the RAAS. This form of "inappropriate secondary hyperaldosteronism" (renin values are inappropriately normal in obese hypertensive despite salt intake and high BP) further favors greater sodium reabsorption, especially at the level of the distal tubule (32). Noteworthy, obese individuals have high serum levels of very low-density lipoprotein (VLDL) cholesterol that induces aldosterone synthesis partly mediated by phospholipase D (PLD) and its enzymatic cascade (33). This obesity-related and VLDL-related alteration of the RAAS, despite the excessive dietary salt intake, maintains mineralocorticoid activity above the overall median values in hypertensive obese patients. Thus, in obese subjects, the aldosterone release and plasma concentrations are set at higher levels than those necessary to maintain BP, leading to inappropriate aldosterone levels (despite they are usually in the "normal" range). In the hypertensive obese, this dysregulation leads to an "escape" from the inhibition of aldosterone secretion during ACE-inhibitors (ACE-I) and AT1 angiotensin receptor blockers (ARBs) therapy (34), which is coupled with an increase in pulse pressure, nighttime BP and cardiac damage (35). In daily clinical practice, the renin-to-aldosterone-ratio (RAR), which is the reciprocal of the ratio that is commonly used to screen for primary aldosteronism (aldosterone-to-renin-ratio, ARR), has been proposed to assess the efficacy of RAAS antagonism, showing the real-life effectiveness of ACE-I or ARBs therapy. A higher RAR was associated with a better 24 h-BP control, especially during night-time (35). Higher RAR values indicate an adequate blockade of the RAAS and, therefore, an adequate therapeutic adherence to ACE-I or ARBs because the increased renin activity is the expression of a reduced negative AT1 feedback on renin secretion together with a lower angiotensin II-dependent aldosterone secretion. On the contrary, lower RAR values can be due to poor adherence or insufficient efficacy/dosage of the drug used, and in the setting of overweight and obese patients highlight a more significant "escape" from the inhibitory action of ACE-I and ARBs, with relative secondary hyperaldosteronism.

Obesity might also lead to hypertension by VAT expansion through mechanical kidney compression and RAAS activation, as visceral perivascular adipose tissue has paracrine effects on the vascular wall, regulating inflammation and RAAS activation (18). Another key pathophysiological mechanism of hypertension development in obese individuals is the impaired blood concentrations, metabolism, and activity of cardiac NPs (ANP and BNP) that exert their activities by binding the NP receptor A (NPRA), which is mainly expressed in the kidney, adipose tissue, adrenal gland, heart, and vascular smooth muscle (32, 36). Both ANP and BNP antagonize the RAAS at multiple levels, decreasing systemic BP but increasing renal perfusion and natriuresis due to a direct proximal tubular inhibition mechanism that leads to macula densa activation followed by afferent arteriole vasodilation and renin secretion inhibition (37). Obese hypertensive patients have reduced plasma NP levels compared to overweight and normal-weight patients. This is primarily due to increased NP clearance mediated by the NPRC overexpression (38, 39), driven by hyperinsulinemia secondary to insulin resistance. Also, the glomerular hyperfiltration in obese subjects (glomerular filtration rate and creatinine clearance increase by 0.7 ml/kg in severe obesity) can lead to an increased renal clearance of NT-proBNP. In addition to NP deficit, other essential determinants of hyperfiltration in obese patients include sodium intake, BP and meat protein consumption. In this context, a new formula for the estimation of creatinine clearance has been proposed in obesity (40).

Conversely, both natriuresis and diuresis associated with fasting-induced BP reduction are thought to result from reduced NPRC expression in adipose tissue (41). Indeed, fasting exerts a specific tissue and gene suppression of the NPRC gene in adipose tissue that seems to be followed by an increase in the biological activity of ANP. In this regard, a drastic decrease in NPRC messenger RNA levels in brown and white adipose tissue has been found, although NPRA expression in adipose tissue is constant or tends to increase (42). Accordingly, ANP infusion was found to have a greater efficacy after a low-calorie diet in obese hypertensive patients (43).

Obese hypertensive patients are, therefore, characterized by a "natriuretic handicap" due to increased degradation and reduced NP biological activity coupled with increased RAAS activity, increased SNS activity and a higher intake of dietary salt. The "swollen feeling," often reported by obese patients (especially by females), together with leg edemas even in the absence of HF or reduced renal glomerular filtration rate, may be due to the imbalance of sodium and water handling, as well as impaired lipid metabolism, inevitably leading to an increase in BP up to arterial hypertension.

These pathophysiological considerations are also relevant for the HF diagnosis, often a common sequelae of visceral adiposity accumulation and uncontrolled hypertension (44). Since obesity reduces the overall levels of different types of circulating cardiac NPs, even those not taken up by NPRC, the European Society of Cardiology (ESC) has recently proposed different cut-offs for the HF diagnosis in obese patients: a cut-off reduced by 25% when BMI is between 30 and 35 kg/m2, a cut-off reduced by 30% when BMI is between 35 and 40 kg/m2, and a cut-off reduced by 40% when BMI is over 40 kg/m2 (45). These proposed lower cut-offs are being validated in clinical practice.

## Obesity, impaired glucose handling and type 2 diabetes mellitus

One of the most relevant complications related to excessive adiposity is T2DM. Obese patients have a 6.7 times greater risk of developing glucose intolerance and a 4.9 times greater risk of developing T2DM compared to normal-weight patients (46). Despite the well-known T2DM polygenic predisposition, it is estimated that up to 80% of patients would not develop diabetes in the absence of overweight or obesity, which are the primary substrates for insulin resistance and T2DM. In hypertrophic VAT infiltrated by macrophages, inflammatory cytokines (TNFα and IL-6) and reduced adiponectin production [the only well-known "protective adipokine" exerting anti-atherogenic, anti-diabetic, and anti-inflammatory effects (47)] contribute to decreased insulin sensitivity or insulin resistance, leading to dysregulation of glucose handling by the insulin-sensitive tissues. The sedentary lifestyle also contributes to insulin resistance through sarcopenia, leading to a vicious circle that the prediabetic obese generally fails to break, resulting in chronic severe consequences. In clinical practice, overweight/obese patients affected by T2DM were still overweight at the end of several trials based on lifestyle intervention with long follow-up periods, such as the Look AHEAD trial, in which the very modest average weight loss was insufficient to reduce CV outcomes (48). At the same time, a _post-hoc_ analysis of the same trial showed that the minority of patients who reached at least 10% weight loss significantly reduced the primary endpoint (49). T2DM in overweight/obese patients is always preceded by a long history of prediabetes, which is often a part of the "metabolic syndrome" driven by insulin resistance, also associated with NAFLD and other well-defined and known metabolic and CV risk conditions. The incidence and prevalence of atherosclerosis and CV events are, therefore, increased even before the diagnosis of overt T2DM (50, 51). The homeostasis model assessment-insulin resistance (HOMA-IR) index, derived from fasting serum glucose and insulin, and the Triglyceride-Glucose (TyG) Index, derived from fasting blood glucose and triglycerides, are the most used indexes to estimate insulin resistance in clinical practice and can help to detect the obese at higher risk of having T2DM (52, 53). Noteworthy, when both familial and polygenic predispositions for T2DM are present, the progression to T2DM is almost unavoidable in this adipocentric clinical setting.

## Obesity and dyslipidemia

Obese patients usually have increased circulating VLDL remnants and atherogenic non-high-density lipoprotein (non-HDL) cholesterol. At the same time, high serum triglycerides levels (with also higher postprandial peaks), low circulating HDL levels and increased concentration of the more atherogenic "small and dense" low-density-lipoprotein (LDL) are expected in obesity (54). The enlarged VAT mass exposes the liver, through the portal circulation, to higher levels of free fatty acids (FFA) that impair hepatic lipid and carbohydrate metabolism, especially in the postprandial phase. The increased FFA flux may contribute to the dysregulation of liver metabolism with consequent steatosis and excessive production and secretion of VLDL richer in triglycerides (55). More in-depth, obesity-related hypertriglyceridemia and atherogenic dyslipidemia are the result of induced gene transcription of acyl-coenzyme A hepatic synthetase due to the increasing inflow of FFA to the liver, concurring to hypertriglyceridemia by excessively synthesizing triglycerides, and of the reduced VLDL catabolism in the circulation (56). In addition to these common atherogenic dyslipidemias, visceral overweight and obesity, if concomitant metabolic syndrome or T2DM are also present, can cause severe hypertriglyceridemia with an increased risk of acute pancreatitis, especially in the presence of a predisposing genetic setting and/or excessive intake of carbohydrates, alcohol, and some drugs (57). The consequences mentioned above of abnormal adiposity are graphically summarized in Figure 2.

Figure 2

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g002.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g002.jpg)

**Figure 2**. The adipocentric vision of the more common cardio-metabolic and renal conditions. T2DM, Type 2 Diabetes Mellitus.

## Obesity and other relevant cardiometabolic risk factors

_Aging_ is characterized by insulin secretion deficiency due to a decreased function of pancreatic beta cells coupled with increased insulin resistance (58). The beta cells' senescence and reduced sensitivity to glucose significantly increase the risk of T2DM. Aging is also associated with ectopic lipid deposition, a pro-inflammatory milieu ("inflammageing"), mitochondrial dysfunction, and accumulation of reactive oxygen species with increased oxidative stress and sarcopenia.

_Sarcopenia_ in older obese is particularly relevant because it is associated with reduced production of musclin, a peptide similar to the NPs, but able to selectively block the NPRC, thus increasing NPs levels and their positive biological activities. Notably, the sarcopenic reduction of musclin facilitates the onset of HF (37). Furthermore, older obese often suffer from osteoarticular diseases, thus contributing to even lower levels of physical activity.

_Cigarette smoking_ , a CV risk multiplier, causes pro-atherogenic and inflammatory damage. In daily clinical practice, the fixed-dose combination of naltrexone and bupropion, a drug combination approved for weight management, could be helpful in obese smokers because of the positive effects of bupropion on tobacco dependence symptoms after withdrawal. However, it is essential to note that bupropion therapy requires proper monitoring of arterial BP, given its slight hypertensive effect (59).

_Obstructive sleep apnea syndrome (OSAS)_ increases the risk of CV events, mainly stroke. While sleeping, upper airways collapse with subsequent intermittent hypoxia and hypercapnia (60). Such alterations determine the activation of the SNS, endothelial system dysfunction and reduction of the physiological nocturnal BP dip, contributing at first to nocturnal hypertension and then to sustained and drug-resistant hypertension (61). OSAS is a widespread condition in obesity, contributing to the onset and progression of CV risk factors and diseases (62).

_Peripheral arterial disease (PAD)_ is a highly prevalent condition whenever obesity is complicated with T2DM and arterial hypertension. Macrovascular and microvascular arterial damage (both atherosclerosis and arteriosclerosis) can be easily detected in retinal, cerebral, cardiac, lower limbs and other arterial districts (63, 64). Documented PAD is equivalent to previous CV events such as myocardial infarction, predisposing to further new ones and therefore requiring a reduction of LDL cholesterol below 55 mg/dL or even below 40 mg/dL using combinations of proven to be effective lipid-lowering drugs (statins, ezetimibe, bempedoic acid, PCSK9 inhibitors, and inclisiran).

_Dementia_ development is favored by obesity together with aging, mainly because of its link with higher BP and T2DM. Moreover, adipokines secreted by the excess adipose tissue significantly impact the CNS by increasing leptin resistance (65) and insulin resistance (66). A recent study confirmed the association of brain aging with common CV risk factors, including excessive body weight (67). The adequate control of the obesity-related risk factors to prevent irreversible cerebral consequences should be a priority.

## Global cardiovascular risk assessment in obesity

An individual global CV risk assessment is mandatory for overweight and obese patients. However, the evaluation of the overall CV risk in the obese using the European Society of Cardiology (ESC) endorsed Systematic Coronary Risk Estimation (SCORE2 and its counterpart for older patients SCORE2-OP) models and charts (68) is still not widely used in daily clinical practice. Therefore, easy-to-use multilanguage web-apps (e.g., [www.humtelemed.it](http://www.humtelemed.it)) have been developed to help less experienced physicians to assess CV risk adequately. Furthermore, a specific tool has recently been developed in diabetic patients (the SCORE2-diabetes), that allows a more accurate assessment of the CV risk in this population (69). Apart from using these models and charts in primary prevention, assessing CV risk in a patient with visceral obesity could be pretty complex. Considering all the adiposity-related complications reminds the opening of a modern version of the mythical "Pandora's Jar" (Figure 3), which at present, among the non-transmissible diseases, mainly contains visceral obesity and its CV and metabolic complications, such as increased insulin resistance and T2DM, atherogenic dyslipidemia, altered natriuresis with increased BP and arterial hypertension, glomerular hyperfiltration leading to CKD, increased gluconeogenesis, steatosis and hepatic lipotoxicity with steatohepatitis, and ultimately major CV events and CV death.

Figure 3

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g003.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g003.jpg)

**Figure 3**. Visceral obesity: the Pandora's Jar of the twenty-first century. T2DM, Type 2 Diabetes Mellitus.

## Evaluation of obesity in clinical practice: low-cost clinical tools to improve phenotyping

Estimating VAT amount can unmask normal-weight individuals (according to BMI) who may have metabolic syndrome and, therefore, be classified as metabolically obese normal-weight patients. On the contrary, the so-called MHO phenotype meets the BMI values for obesity, but does not have the clinical features of metabolic syndrome, not even insulin resistance. Although it is not a benign condition, MHO individuals usually have larger fat storage capacity in subcutaneous tissue, lower visceral and ectopic fat levels, less liver steatosis, and a lower degree of systemic inflammation (70). Whereas, short-term cross-sectional studies suggest that MHO men and women are not at increased risk of CV disease, longitudinal studies indicate that this phenotype may not be benign and that this group is at higher risk for increased carotid artery intima-media thickness, coronary calcification, impaired vasoreactivity, and other CV events, as well as all-cause mortality (71). However, they do not usually manifest associated comorbidities, such as prediabetes, dyslipidemia, or hypertension. Therefore, clinicians should view MHO as a transient or intermediary state that, in many cases, may progress over time to an evident unhealthy obesity phenotype. Reduced cardiorespiratory fitness might be related to MHO. Cardiorespiratory fitness lowers the risk of all-cause mortality for metabolically unhealthy individuals with obesity and those with and without the MHO phenotype, suggesting that including the evaluation of cardiorespiratory fitness along with BMI and waist circumference may improve the assessment of risk status (10). Recent evidence further downgraded the benign nature of MHO, showing increased extracellular components and myocardial fibrosis with subclinical alterations of both systolic and diastolic function, the seeds of the development of HFpEF (22).

Several methods are available for evaluating and phenotyping obesity and its associated cardiometabolic risk. The distribution and amount of adipose tissue can accurately be assessed using imaging such as magnetic resonance (MRI) and computed tomography (CT) that represent the "gold standards." However, these ideal methods of VAT evaluations in overweight and obesity are usually performed only for research purposes in small groups of selected patients. Non-invasive methods, such as bioimpedentiometry, dual energy X-ray absorptiometry (DEXA) or total body 3D scanners, are useful to identify body fat percentage and distribution (72, 73), although even these tools are not widely available and cost-efficient on large scales. Overall, the quality of anthropometric measurements is of fundamental importance. Nowadays, waist circumference (WC) is still the most used method to estimate visceral obesity (74, 75). The waist-to-hip ratio is another traditional tool to describe visceral obesity (76), whereas extensive recent studies showed that the waist-to-height ratio should be preferred (23, 77). Indeed, an "obesity survival paradox" has been reported in HF patients, especially in older adults: obese subjects might have better outcomes and lower mortality risk compared with normal weight in the setting of HFrEF. However, this spurious result was not confirmed when the data were adjusted for waist-to-height ratio. Both BMI and waist-to-height ratio showed that greater adiposity is associated with a higher risk of the primary outcome and HF hospitalization, with more robust evidence for waist-to-height ratio (24). In addition, the association between BMI (and potentially any other anthropometric index) and outcome in patients with HFrEF is also confounded by the relationship between adiposity and NPs levels, which are typically lower in obesity (45). BMI should be replaced in patients with HFrEF and daily clinical practice because alternative anthropometric measurements showed a more precise association between greater adiposity and a higher risk of HF hospitalization. Regardless of the anthropometric index, greater adiposity was associated with worse symptoms and health-related quality of life (24). These measurements could also demonstrate a link between adiposity and mortality in the older population (78).

The frequent association between visceral adiposity, hepatic steatosis and dyslipidemia with increased circulating triglycerides due to increased synthesis and/or reduced catabolism of VLDL introduced the so-called "hypertriglyceridemic waist" phenotype, in which the increased abdominal circumference (90 cm in men and 85 cm in women, lower values than the standard criteria for the diagnosis of metabolic syndrome) is coupled with hypertriglyceridemia (2 mmol/L or 177 mg/dl in men and 1.5 mmol/L or 133 mg/dl in women). The hypertriglyceridemic waist phenotype is binary (presence or absence), so it cannot be used as a continuous variable to evaluate its correlation with visceral adipose tissue; in any case, the presence of hypertriglyceridemic waist phenotype is associated with a 75-85% probability of increased amount of visceral adipose tissue (79, 80).

Using fasting triglyceridemia (TG) and glycemia in the TyG index, a reliable insulin-resistance and metabolic syndrome marker and an independent predictor of CV events has been tested (81, 82). TyG index is calculated with the following formula: ln [fasting triglycerides (mg/dl) fasting plasma glucose (mg/dl)/2]. TyG index below 4.5 is considered normal in both men and women. TG-to-HDL-C ratio is also used in clinical practice. Recent studies showed that an increased TG-to-HDL-C ratio is associated with a higher prevalence of pre-hypertension and arterial hypertension, even in normoglycemic individuals, despite the TyG index turning out to be more accurate. High levels of both these indices strongly correlate with an increased global CV risk, and this association was partly mediated by increased prevalence of dyslipidemia, T2DM, and hypertension (81). The metabolic score for insulin resistance (METS-IR) estimates the cardiometabolic risk in healthy and at-risk subjects, representing a promising screening for insulin resistance. It is calculated with the following formula: ln [2 FPG (fasting plasma glucose) (mg/dl) + fasting TG (mg/dl)] BMI (kg/m2)/ln [HDL-C (mg/dl)]. Recent studies showed that the METS-IR score might be a valid indicator of overall CV risk. It may predict the risk of coronary calcification (and therefore the CV risk) in asymptomatic patients without obvious CV pathologies (83, 84).

In addition to waist-to-height ratio, other indexes that take into consideration both anthropometric and metabolic parameters together, have been validated and disseminated in clinical practice. These tools are easily applicable and useful to identify a "functional" excess of visceral adiposity even in overweight patients. The visceral adiposity index (VAI) has been recently developed. It is an empirical-mathematical gender-specific model based on simple anthropometric (BMI and WC) and functional parameters (TG and HDL-C) indicative of fat distribution and function. It was found to be a marker of cardiometabolic risk and has a strong independent association with CV and cerebrovascular events (85). Another helpful tool is the lipid accumulation product (LAP) index calculated from WC and TG, which strongly indicates insulin resistance, metabolic syndrome, T2DM, and NAFLD (86). Recently, a novel score (METS-VF) was developed to estimate VAT by combining the METS-IR, waist-to-height ratio, age and sex, showing a better performance compared to other VAT surrogate formulas and the ability to predict incident T2DM and hypertension (87).

In conclusion, these low-cost bio-anthropometric indexes should be applied more widely in clinical practice, especially to characterize overweight or obese non-diabetic individuals with a high prevalence of metabolic syndrome, prediabetes, pre-hypertension and arterial hypertension. The improvement in phenotyping will allow the detection of patients at higher metabolic and CV risk, thus needing more focused and intense treatment. Clinicians should become more confident with adiposity evaluation through these usual and novel anthropometric measurements and formulas. An adipocentric-guided clinical evaluation should focus more on a broader use of these indexes.

## Cardiometabolic effects of weight loss

Weight loss in obesity is linked to a multitude of positive consequences on CV and metabolic health. Losing weight improves insulin resistance, which is completely reversible in the early stages, thus preventing the development of T2DM. More considerable weight loss can also lead to T2DM vanishing. It also reduces systolic BP by at least one mmHg per kg of weight loss (88). In many cases, especially in younger individuals with high-normal BP or stage 1 arterial hypertension, normotension can still be achieved by only losing weight (49). It is important to remember that an average reduction of 2 mmHg in the medium-long term corresponds to a 10% risk reduction of stroke and a 7% risk reduction of ischemic heart disease (89, 90), stressing the role of weight loss as a therapeutic strategy to reduce BP and CV disease burden. Cardiac overload is also reduced by weight loss, thus avoiding or slowing the development and progression of HF. Weight loss also improves sleep quality by reducing the severity of OSAS, leading to improvement in night-time BP profiles. Weight loss reduces circulating lipids, especially non-HDL cholesterol and triglycerides. These improvements in circulating lipids can also lead to a reduction in liver steatosis. All the above changes benefit CV and renal health, reducing glomerular hyperfiltration and albuminuria and slowing down the reduction of kidney function (91).

## Treatment of visceral overweight and obesity: an adipose-related approach between established therapies and newest pharmacological interventions

Lifestyle changes, including nutrition/behavioral interventions, have been and still are the first step in the clinical management of overweight and obesity (92). However, it means not only more physical activity and diet, but also acting concretely on the individual familial and social background to build a supportive environment allowing the patient to maintain a healthy lifestyle as long as possible (55). Early education at school, population-based messages about physical activity, healthy foods and early care, and worksite health promotion programs are all valuable strategies still not efficaciously implemented in many countries (70). In the overweight or obese older subjects, diet and lifestyle should modulate weight loss to avoid losing muscle mass. Unless CKD is present, a caloric deficit of ~500 kcal/day with at least 1,000-1,200 kcal/day with 1gr/Kg of protein has been suggested (93). Nevertheless, many studies showed a substantial failure of the several proposed diets and lifestyle approaches in the long term (years) because individuals tend to regain all the weight and adiposity lost. This is particularly true outside the clinical trials, where the patients are usually closely followed, given that in real life, worldwide overweight and obesity have not only been reduced by decades of predicated lifestyle changes but are instead increasing steadily in both incidence and prevalence.

Lifestyle approaches to treat obesity have been recently summarized in several guidelines, and we did not address this topic in this conceptual review. Instead, we will focus on effective surgical and pharmacological treatments that are now available, making lifestyle changes more effective and long-lasting.

In treated overweight and obese patients with VAT, beyond the percentage weight loss, the novel cardiometabolic indexes of visceral "functional" adiposity, such as the above mentioned LAP, VAI or METS-VT, can be easily monitored in clinical practice and could be good efficacy parameters to take into consideration. Given the global effects of weight loss, even the clinical indexes, such as accurate BP measurements or glycated hemoglobin, can be used as well.

## Bariatric surgery

We chose to present the relevance of bariatric surgery first because of its conceptual significance, given that it proved the critical role played by excessive caloric intake and adiposity in determining T2DM, dyslipidemias, hypertension, and CV diseases and, on the other hand, the beneficial effects of weight loss linked to surgery. Bariatric surgery is a therapeutic option generally reserved for severe obesity who failed non-pharmacological and pharmacological approaches. It has been, so far, the only therapeutic strategy that proved to be effective for the most severe forms of obesity, leading to significant weight loss with improvement or even remission of its related complications. The most used procedures in bariatric surgery are sleeve gastrectomy, gastric bypass and intragastric balloon, which are indicated especially in class II and III obese after accurate clinical assessment, including psychological aspects. Arterial hypertension, T2DM and dyslipidemia generally improve significantly or can even resolve after bariatric surgery (94). All the baseline anthropometric parameters, such as body weight, BMI, WC, and abdominal excessive adipose tissue measurements significantly improved 3 months after surgery. A decrease in extra-abdominal adipose tissue (especially the cardiac one) was also documented. Moreover, bariatric surgery led to more remarkable percentage changes in all anthropometric "adipose" measurements compared to diet and exercise (95). Despite its demonstrated benefits in patients with severe obesity, bariatric surgery is still an underused therapeutic option performed only in a small number of selected severely obese patients because of its costs and possible complications related to surgical procedures (3).

## Pharmacological treatment of obesity

There are several medications approved and available for clinical use in overweight and obese patients. The fixed-dose combination of phentermine/topiramate was not approved for clinical use in the European Union. These drugs are described below, from the older ones in availability to the incoming ones.

_Orlistat_ is a selective inhibitor of pancreatic lipase. It reduces dietary fats' absorption, resulting in increased fecal excretion. A moderately low-calorie and a lower-fat diet should always be combined. It is indicated for the treatment of obese patients with a BMI > 30 kg/m2 or overweight patients with a BMI > 28 kg/m2 and associated risk factors and has been approved at a dose of 120 mg three times daily by both EMA and FDA (also as over-the-counter drug). The prevalent bowel side effects strongly reduce the adherence and persistence to treatment. Indeed, the daily losses of fatty, orange-colored and malodorous liquid stools usually create discomfort on the one hand. On the other hand, however, it can be used as an "index" of the dietary fat intake, thus encouraging adherence to a low-calorie diet with reduced fat content to decrease the amount of fat excretion and the burden of side effects.

_Bupropion/Naltrexone_ is a fixed-dose drug combination approved for obesity treatment. Bupropion is a dopamine and norepinephrine reuptake inhibitor used effectively for the treatment of depression and for tobacco smoking cessation (59). Naltrexone is an opioid receptor antagonist used to treat alcohol and opiate dependence. Pro-opiomelanocortin (POMC) neurons are powerfully stimulated by dopamine and norepinephrine. This combination would determine a dopamine-mediated stimulation of the hypothalamus, thanks to the reuptake inhibition due to bupropion, to produce more POMC and more MSH, leading to greater MC4R activation, with decreased appetite and increased satiety. Specifically, naltrexone would reduce the effects of beta-endorphin by blocking opioid receptors that inhibit POMC secretion, diminishing the desire and the search for certain foods and the consequent pleasure in consuming them. This combination was approved in the early 2010's by EMA and FDA and is indicated, in addition to a low-calorie diet and physical activity, for weight management in adult patients with an initial BMI of 30 kg/m2 (96). It could also be used starting from a BMI of 27-30 kg/m2 in the presence of at least one weight-related comorbidity, such as prediabetes or T2DM, or when GLP1-RA are not tolerated. However, there is no data regarding CV safety (no CV outcome studies published), and bupropion can increase both BP and heart rate (97, 98). From phase III studies, the combination of bupropion/naltrexone appeared to increase systolic and diastolic BP of up to 3 mmHg compared to placebo (99) due to the increase in norepinephrine caused by bupropion. However, BP levels would appear to decrease after 56 weeks of persistence on treatment. In any case, any BP reduction linked to weight loss was absent. A 4-6% reduction in body weight compared to placebo was only obtained at the maximum dosage, with common side effects such as nausea, headache, and constipation (97, 98). Therefore, this association is not indicated in obese with high-normal BP or hypertension. Otherwise, if the subject is on effective antihypertensive therapy and other obesity treatment cannot be tolerated, this combination can be considered to lose weight.

_Liraglutide_ is still the only GLP1-RA approved for the treatment of weight loss in most countries. In patients not affected by T2DM, the drug is generally not reimbursed by national health systems, such as in Italy. At the dose of 3 mg/day, it is indicated in adult patients with BMI ≥ 30 kg/m2 or in adult patients with BMI ≥ 27 kg/m2 in the presence of at least one weight-related comorbidity, such as prediabetes or T2DM, hypertension, dyslipidemia or OSAS. In one of the SCALE studies, performed in non-diabetic patients without any drugs that could significantly impact weight loss/gain (obesity and prediabetes study), liraglutide 3 mg reduced weight in 63% of the subjects during 56 weeks, with 14.4% of patients that lost 15% of their weight, starting from an average BMI of 38.3 kg/m2 (100, 101). Weight loss was mainly mediated by reduced appetite and calorie intake rather than increased energy expenditure and was accompanied by a significant reduction in BMI and abdominal circumference. A decrease in both systolic and diastolic BP, blood glucose concentration, VLDL and triglycerides, and PCR has been observed, while on the contrary, adiponectin increased as expected (101, 102).

The side effects of liraglutide, mainly consisting of moderate nausea, vomiting or diarrhea, are generally mild, usually dose-dependent, transient and self-limiting, and this is the reason why this drug should always be started at lower doses. Severe adverse events occurred in 6.2% of patients treated with liraglutide and in 5% of patients treated with placebo, events unrelated to the drug. Gallbladder stones and cholecystitis occurred with a slightly higher frequency in the liraglutide group, and this side effect was noticed in several other weight loss trials (103, 104), as they are linked to weight loss itself in the obese and not so much to the drug (105). Indeed, the lower food intake and weight loss may lead to altered production and bile secretion coupled with a reduction in gallbladder emptying that might contribute to increased symptomatic gallstones in patients treated with liraglutide (106).

_Semaglutide_ was found to be very effective in reducing body weight in non-diabetic obese patients taking 2.4 mg of the drug in the STEP studies. STEP-1 study enrolled a total of 1961 obese non-diabetic adult patients with a BMI > 30 kg/m2 or a BMI > 27 kg/m2 coupled with at least one obesity-related comorbidity (hypertension, dyslipidemia, CV disease, obstructive sleep apnea), showing an average decrease of 15.3% in body weight in the group treated for 68 weeks with 2.4 mg (starting from 0.25 mg and then titrated) of semaglutide associated with a healthy lifestyle, compared to 2.6% body weight loss in the placebo group (107, 108). In addition, the STEP-1 study showed a net decrease in inflammatory markers, BP, blood lipids and glycosylated hemoglobin. The STEP 3 study enrolled 611 patients always treated with 2.4 mg of semaglutide (titrated from 0.25 mg) in association with a targeted behavioral therapy, showing a 17.6% weight loss compared to a 5% weight loss in the placebo group (109). These data were subsequently confirmed by the STEP-4 study that enrolled 902 patients, demonstrating an average reduction of 14.8% in body weight in the treated group. Moreover, this study found a marked average decrease in the abdominal circumference (−9.7 cm) and systolic arterial BP (−3.9 mmHg) coupled with an improvement in the physical function score (secondary endpoints). Despite gastrointestinal side effects in 49% of the study population, only 2.4% of treated patients stopped the drug (110). During the following years, several studies confirmed a weight loss between 7 and 11%. In addition, semaglutide has been compared in recent studies with liraglutide in non-diabetic obese, showing that the association with a healthy diet and a healthy lifestyle leads to a more marked reduction in body weight than liraglutide. In the recently published STEP-HFpEF trial, 529 obese (mean BMI 37 kg/m2) hypertensive (82%) non-diabetic older adults (mean age 69 years) with HFpEF were randomized to semaglutide 2.4 mg vs. placebo for 52 weeks (111). The primary composite endpoint, a better Kansas City Cardiomyopathy Questionnaire score and a significant weight loss (-13.3%), was obtained with semaglutide compared to placebo (112). Furthermore, an improved 6-min walking distance and a 21% reduction in NT-proBNP levels confirmed that excessive weight plays a crucial role in HFpEF and the reduction of hemodynamic load also by a significant BP decrease (−4.9 mmHg) may be of great benefit in these patients. Moreover, semaglutide showed the ability to improve NASH, with no worsening of fibrosis in NASH patients, leading to reduced serum transaminase, liver fat content and liver stiffness (113, 114).

The SELECT trial, a landmark study in paving the way for a new real-life adipocentric approach to CV disease, enrolled 17,604 adults aged 45 years or older with overweight or obesity and established CV disease with no prior history of diabetes mellitus and showed a significant reduction (−20%) in major CV events (MACE) in patients taking semaglutide 2.4 mg vs. placebo. The study's primary endpoint was defined as the composite outcome of the first occurrence of MACE (defined as CV death, non-fatal myocardial infarction or stroke). The three primary endpoint components contributed to the MACE reduction (115).

Semaglutide is also available for oral administration once daily through the development of a particular technology that involves the co-formulation of semaglutide with an absorption booster, the sodium salcaprozate [Sodium N-(8-(2-hydroxybenzyl-Amino) caprylate] (SNAC). In the PIONEER-6 trial (116), oral semaglutide was found to be not inferior, but not superior to placebo, in the primary CV outcome, and a further study (SOUL trial) on 9,642 subjects aiming at proving the effectiveness of oral semaglutide compared to placebo in reducing the CV outcome is currently ongoing (117). Real-world data is emerging on its safety and efficacy in lowering glycated hemoglobin, BMI, and BP (118). Oral semaglutide at 14 mg showed a similar BP lowering of 2 mmHg as subcutaneous semaglutide at 1 mg, an amount of reduction that can already justify a reduction in CV events and mortality (119). Also, after 6 months of treatment, it reduced fatty liver index and VAT, preserving fat-free and skeletal muscle mass, evaluated with bioimpedentiometry (120). Thanks to their weight loss properties, which involve all the body's adipose tissue deposits (119), GLP1-RA improves all CV risk factors, such as BP and lipid profile (121). A novel, potent preventive approach to CV disease will be based on a substantial weight loss strategy achievable only when a GLP1-RA is associated with lifestyle modifications.

_Tirzepatide_ is a dual GLP1 and GIP (glucose-dependent insulinotropic peptide, formerly called gastric inhibitory peptide) receptor agonist recently approved for obesity treatment in both the U.S.A. and Europe. Regarding pharmacodynamics, tirzepatide couples the activation of the GLP1-RA to the effect on the GIP receptor, which is responsible for most of the action in stimulating insulin secretion (122). The phase III SURMOUNT-1 trial studied the efficacy and safety profile of 10 or 15 mg tirzepatide in patients not affected by T2DM treated for 72 weeks, showing a significant decrease in both body weight and abdominal circumference. Indeed, after 24 weeks of treatment with the maximum dosage of the drug, it led to a 17% average reduction of the abdominal circumference, a 34% reduction of the total fat mass, a 0.5 points average reduction of glycosylated hemoglobin, a 28% average reduction of circulating triglycerides and an 8-mmHg average reduction of systolic BP (123). In addition, more than 95% of the patients who entered the study with prediabetes had normoglycemia by the end of the study. These data are highly significant to demonstrate further how excessive calorie intake and adiposity are primary factors in determining the leading CV and metabolic complications of overweight and obesity, especially prediabetes/T2DM and hypertension, that may resolve with an appropriate weight loss. Given its five-day half-life, tirzepatide is administered subcutaneously once a week, as well as semaglutide. Similarly, side effects (mainly nausea, diarrhea, and constipation) were modest and transient and occurred with increasing doses. Patients on tirzepatide were found to have a higher prevalence of cholecystitis than patients on a placebo. Still, this evidence appears to be related to obesity itself and the lower food intake coupled with a more rapid weight loss in obese patients rather than a direct effect of the drug (124). The results of the SURPASS-CVOT trial are expected in 2024 (125). This randomized, double-blind phase III study is enrolling participants with T2DM and atherosclerotic CV disease. It aims at evaluating the CV outcomes of the therapy with tirzepatide by assessing the non-inferiority and superiority of this drug compared to the GLP1-RA dulaglutide. The expectations for this new molecule are high, and the scientific community worldwide already speaks of a revolutionary drug from the metabolic point of view, especially for its superior effectiveness in inducing weight loss. Another CV outcome-focused trial in obese patients not affected by T2DM should end in 2027 (SURMOUNT MMO), evaluating the effect of tirzepatide on morbidity and mortality reduction in established CV disease. In the meantime, the weight loss found in the SURMOUNT-3 and SURMOUNT-4 trials in a combined total of 1,249 randomized adults adds positive results to the data previously reported from more than 3,400 patients randomized in SURMOUNT-1 and SURMOUNT-2 trials. In the SURMOUNT-3 trial, tirzepatide titration to a 10-/15 mg weekly dose, coupled with intensive lifestyle management, showed a 21% average reduction in body weight after 72 weeks from randomization, compared to a 3.3% average increase in body weight among controls (126). The 94% of patients on tirzepatide achieved at least a 5% weight loss. The SURMOUNT-4 assessed a tirzepatide discontinuation, highlighting that those who received tirzepatide continuously for 88 weeks (the 36-week run-in phase plus the 52-week randomized phase) had an overall 26% average weight loss from baseline. Conversely, the group that switched to placebo had an average weight gain of 14.8% (127). Among the predictive factors for a ≥15% weight loss, there were higher tirzepatide dose, female sex, white or Asian race, younger age, undergoing treatment with metformin, better glycemic control (based on lower glycated hemoglobin and lower fasting serum glucose) and lower non-HDL cholesterol level (128). In T2DM patients treated with basal insulin, tirzepatide showed a better lowering of glycated hemoglobin and fewer hypoglycemia episodes than prandial insulin (129), proving an excellent alternative. The findings from this trial pointed out the highest level of weight loss observed in the SURMOUNT program and the importance of ongoing tirzepatide treatment to maintain weight loss.

It is evident, summarizing the results obtained from these novel drug therapies for obesity, that these can be addressed as real "adipocentric" drugs able to reduce any metabolic and CV risk factor along with weight and visceral adiposity. In this perspective, today's primary goal is to raise awareness of the adipocentric nature of the CV and metabolic diseases affecting overweight and obese patients, aiming at setting up an effective combined non-pharmacological treatment coupled with the substantial and unprecedented help of these novel pharmacological weapons. At this point, clinicians should not only treat the obesity-related serious consequences but should aim at preventing them, mainly through early and intensive management of overweight and obesity. Effective treatment of overweight and obesity with the new adipocentric drugs, primarily directed toward those with higher CV risk in which a "multi-specialist" approach and treatment would be necessary, will lead to better patient health and lower global cost burden.

_Other incretin mimetics_ , such as the once-daily oral non-peptide GLP1-RA orforglipron tested in phase II trials in patients with and without T2DM, are under investigation. It reported a reduction of up to 2.1% of glycated hemoglobin and a decrease in mean body weight at week 26 of up to 10.1 kg in T2DM patients (130). In comparison, a weight reduction of at least 10% by week 36 was observed in up to 75% of patients at a dose of 45 mg in non-diabetic obese patients with related improvement in their cardiometabolic measures (131). Two dual agonists of both GLP-1 and glucagon receptors, pemvidutide (NCT05295875) and survodutide (NCT06077864, NCT06066515), produced significant weight loss and other cardiometabolic benefits in preliminary randomized trials and are in development, especially for the treatment of obesity and NASH (132, 133). Lastly, retatrutide is supported by phase 2 trials. It is a triple G agonist, a single peptide that activates GLP-1, GIP, and glucagon receptors. Thanks to the activation of the glucagon receptor with its catabolic effects (adipose lipolysis, food intake reduction, slower gastric emptying, and increased energy expenditure), while the two systems counterbalance the hyperglycemic effect, it managed to achieve a 24% weight loss over 48 weeks at the highest dose (12 mg) in obese patients without T2DM (134). This weight loss was associated with improved BP and glycated hemoglobin levels, fasting glucose, insulin, total and LDL cholesterol and triglycerides. However, 16% of subjects have discontinued the drug at the highest dose for adverse events, mainly due to nausea and non-serious gastrointestinal effects (134, 135). The main drugs available to treat obesity and their main clinical characteristics are summarized in Table 1.

Table 1

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-t001.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-t001.jpg)

**Table 1**. Main characteristics of the pharmacological treatments against obesity.

Overall, the changes in anthropometric and cardiometabolic parameters in obese patients under pharmacological treatment are usually variable. This well-known variability can depend on genetic or social factors, but it likely mainly depends on a large variability in diet and lifestyle adherence. The novel pharmaceutical approaches, especially those based on GLP1-RA if well-tollerated can reduce such variability by improving adherence to diet. Current evidence on the new anti-obesity drugs found a magnitude of weight loss almost comparable to bariatric surgery in some cases, varying on the basis of the molecule used, with a weight loss plateau after 12-18 months (136). However, their benefits partly regress after withdrawal, as demonstrated by the SURMOUNT-4 trial (127), supporting the hypothesis of the need for their chronic use. This is also the reason for a need of a guided lifestyle approach that should be undertaken in these patients, together with the introduction of the anti-obesity drug, in order to maintain weight loss in the long term (136). Real-life studies on large populations and of longer duration will be able to provide us with further information in the coming years.

## Pharmacological treatment of obese patients affected by T2DM

Recently published guidelines went into detail regarding the critical importance of excessive adiposity in the genesis and management of most cases of T2DM. The first essential therapeutic intervention is a low-carbohydrate and low-calorie diet subdivided into smaller meals and coupled with an increase in physical activity. Still, new drugs are already a valuable resource for managing obese T2DM patients with promising and lasting results. Treatments of obesity associated with T2DM could be effectively evaluated and managed according to the most recent internationally published guidelines (69, 137, 138). Therefore, in this conceptual review, we will deal only with some pivotal concepts that are still often disregarded even in the specialistic setting. Beyond glycemic control, the new therapies are focused on CV disease and CKD prevention.

In managing obese patients affected by T2DM, the GLP1-RAs have recently gained a key spot, given their effectiveness in weight reduction. In 2020, the American Association of Clinical Endocrinologists and American College of Endocrinology (AACE/ACE) Consensus Statement had already recommended the use of GLP1-RAs and SGLT2-i independently of glycaemic control and as the first choice, especially in the presence of atherosclerotic CV disease, in patients at high risk of CV events, in patients with stage 3-4 CKD, and patients affected by HFrEF (139). The Kidney Disease Improving Global Outcomes (KDIGO) 2022 Guidelines in patients affected by T2DM and CKD with an estimated glomerular filtration rate (eGFR) between 60 and 30 ml/min and/or albuminuria recommended SGLT2-i as the first choice, and GLP1-RA in addition as second choice (140). The most recent 2023 ESC Guidelines on Cardiovascular Disease Prevention in patients with T2DM strongly advised first obtaining adequate weight loss using GLP1-RA (69).

Any reduction of ventricular wall stress, like that resulting from weight loss and the consequent decrease in blood volume and BP during GLP1-RA treatment, is also accompanied by a reduction in circulating NT-proBNP levels, as a measure of a reduced NPs secretion from the heart (141) because there is a very rapid resetting of cardiac NPs secretion and their clearance. Moreover, GLP1-RA, thanks to the weight loss, indirectly facilitates sodium elimination by improving NPs action through lower food intake and then reduced expression of NPRC that is insulin/glucose dependent in adipocytes (16).

Benefits of weight loss, mainly due to reduced caloric intake, have already been described above for semaglutide and liraglutide (142-144). Liraglutide treatment in patients with T2DM was accompanied by lower CV mortality and lower all-cause mortality in the landmarking LEADER study (144). Several studies on semaglutide in T2DM (SUSTAIN 1-5) demonstrated its effectiveness at 0.5 and 1 mg daily doses in reducing body weight and glycated hemoglobin (142, 145-148). The SUSTAIN-6 CV outcome study showed a 26% reduction in the overall risk of death from CV causes, non-fatal acute myocardial infarction, or non-fatal stroke (149). The significant decrease in body weight, BP and glycated hemoglobin accompanied a 36% reduction in the risk of new nephropathy or renal function worsening, resulting in excellent metabolic, CV and renal benefits (150).

Another GLP1-RA approved for T2DM therapy is dulaglutide, which has a homology of about 90% with native human GLP1 and resistance to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV) and large dimensions that slow its absorption and reduce its clearance at the renal level. A soluble formulation with a half-life of 4.7 days is administered once a week subcutaneously. The long-term study on CV outcomes (REWIND) (151) recruited a different T2DM population than previous CV outcome studies with GLP1-RA. Indeed, only 31.5% of the study participants had a history of CV disease known at the time of recruitment. Most patients presented only CV risk factors or subclinical vascular damage and were in primary prevention. The dulaglutide group maintained better glycemic control and lower levels of some CV risk factors compared to placebo throughout the follow-up. A possible more significant effect on stroke was observed compared to non-fatal myocardial infarction, and the nephroprotective effect was confirmed (151). Similarly, the dual GLP1 and GIP receptor agonist, tirzepatide, will be essential in managing patients with obesity and T2DM. Many patients taking tirzepatide lost 10% or more of their body weight, a threshold value effectively associated with greater metabolic and CV benefits. Other GLP1-RA agonists, dual (GLP-1 and GIP) and triple (GLP-1, GIP and glucagon) receptor agonists, are also in an advanced phase of clinical development and testing in clinical trials and will be available soon (134, 152).

Other key classes of molecules for the treatment of obese patients with T2DM are SGLT2-i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin, and sotagliflozin), "hybrid" and "dual" diuretics able to inhibit the RAAS, unlike the other available and "classic" diuretics (153). They act on the proximal tubule of the nephron, promoting natriuresis and glycosuria with osmotic diuresis. The inhibition of the SGLT2 cotransporter leads to reduced proximal reabsorption of glucose and sodium chloride, just as NPs do. The sensor of the macula densa, the Na/K/2Cl cotransporter, perceives an increased amount of sodium (but especially senses chlorine), interpreting this as glomerular hyperfiltration and/or increased sodium chloride in the body. This results in an increased release of the nucleotides ATP and ADP from the macula, which rapidly catabolize to the nucleoside adenosine at the vascular pole of the glomerulus of the same nephron, with stimulation of type 1 adenosine receptors and subsequent direct vasoconstriction of the afferent arteriole together with a reduced release of renin from the granular smooth muscle cells of the same afferent arteriole (Figure 4). Importantly, this will also lead to lower local production of angiotensin I and lower arrival of angiotensin II to the efferent arteriole, which is rapidly produced by the local ACE present throughout the glomerular endothelium, resulting in less vasoconstriction of the efferent arteriole and lower glomerular hyperfiltration in obese. The term "double" diuretic applied to SGLT2-i is due to the natriuretic and osmotic diuretic effects. The term "hybrid" is related precisely to the ability of this molecule to reduce RAAS activity, behaving in the opposite way to loop diuretics (that block the macula densa sensor) or distal convolute tubule thiazide diuretics (153). Moreover, SGLT2 blockade is linked to inhibition of the Na-H-exchanger NHE3 with further natriuresis (154). These characteristics also determine their effectiveness in reducing BP by lowering distal tubule sodium reabsorption due to the lower renin activity. In comparison, ARBs and ACE inhibitors, especially at the low dosages commonly used in clinical practice, cannot completely counteract the "intra-nephron" effects of locally produced angiotensin II, which can also be produced by renin-formed angiotensin I via alternative routes to ACE. In addition, ARBs and ACE inhibitors stimulate renin secretion from the afferent arteriole because they hinder inhibiting its secretion via the angiotensin II-dependent negative feedback. Noteworthy, in obese patients, an "escape" from the effects of ACE inhibitors or ARBs on the control of aldosterone secretion can be observed, possibly also due to the simultaneous enhanced renin activity (34). The ability of SGLT2-i to reduce plasma volume and body sodium without stimulating the intrarenal RAAS, except for an increase in system RAAS in an early acute phase due to the rapid lowering of plasma volume, with consequent BP lowering, produces a reduction of cardiac afterload. Due to the consequences of SGLT2 cotransporter inhibition, there will be significant cardio- and renal-protective benefits that have revolutionized therapies in these fields irrespective of the presence of T2DM (155). In addition, this drug class leads the patient to lose about 70 grams of glucose per day (280 kcal), facilitating weight loss in overweight or obese patients with a documented reduction of VAT. Dapagliflozin facilitates an average weight loss of up to a maximum of 6.4% and reduces glycated hemoglobin by 1%, allowing an average reduction of at least 18 IU of insulin. In the DECLARE study, in which diabetic patients were also obese (mean BMI 32.1 kg/m2), no increased risk of severe hypoglycemia was observed with dapagliflozin therapy compared with placebo. Thanks to its features, dapagliflozin led to a reduction in HF hospitalizations and mortality in patients with HF regardless of ejection fraction (156). Several observational data indicated how SGLT2-i decreased the sodium concentration in interstitial fluid with a consequent interstitial fluid clearance without changing the intravascular volume by osmotic diuresis (157). Dapagliflozin slowed renal function decline over the years by up to 28% in diabetic patients with diabetic nephropathy. The DELIVER study also found its benefits in patients with HF and preserved ejection fraction (158). In the DAPA CKD trial, dapagliflozin was found to reduce the risk of end-stage renal disease (ESRD) by 50%, also reducing the risk of progression of renal damage and death from renal or CV causes, when used in patients with CKD regardless of the presence or absence of DM (159). The same outcomes were also found for empagliflozin regarding HF patients with preserved and reduced ejection fraction and patients with CKD (160-162). Regarding Canagliflozin, the CANVAS study, conducted in T2DM patients with CV disease or high CV risk, aimed to demonstrate the safety and CV efficacy of the drug. The results showed a reduction in CV events in patients treated with canagliflozin compared to the placebo group but an increased risk of metatarsal or toe amputation (163). In the CREDENCE trial, canagliflozin was given to T2DM patients with CKD, reducing renal and CV events (163, 164). Using canagliflozin, as expected based on the class effects of SGLT2-i, resulted in an initial drop of eGFR with subsequent stabilization and longer-term renal protection. At the same time, canagliflozin was very effective in lowering systolic BP, thus reducing the need for further medications to lower BP in already treated hypertensive patients (165). These three gliflozins have demonstrated very similar and very positive metabolic, CV, and renal effects, even in patients not affected by T2DM, but only empagliflozin and dapagliflozin to date have the clinical indication for CKD and HF with reduced or preserved ejection fraction, regardless the presence of T2DM. The safety of such therapies is not a particular concern, and to limit their most common predictable side effects (urinary tract infections), patients are only requested to stay well-hydrated and maintain good genital hygiene after each urination.

Figure 4

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g004.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g004.jpg)

**Figure 4**. Activation of the macula densa by SGLT2 inhibitors and consequences on glomerular hemodynamics and renal protection. SGLT2, sodium-glucose cotransporter-2; ATP, adenosine triphosphate; ADP, adenosine diphosphate; ADO, adenosine.

## Pharmacological treatment of obese patients affected by arterial hypertension

Overweight or obese patients who are also affected by arterial hypertension usually need antihypertensive combination strategies to obtain proper 24-h coverage (90, 166). First-choice drugs are ARBs or ACE-I, preferably used at the highest dosages (167). For example, in the DROP study (168) on hypertensive obese patients with T2DM and microalbuminuria, the most effective dosage of valsartan, both for BP control and for microalbuminuria reduction, was 640 mg per day (considering the maximum available dosage in a single pill is 320 mg). Irbesartan has obtained excellent dosage-dependent results regarding nephroprotection in diabetic patients with microalbuminuria. The IRMA-2 study on 590 hypertensive patients with T2DM showed that irbesartan can prevent progression to overt nephropathy (169). The IDNT study, conducted on 1,715 hypertensive with T2DM and proteinuria with advanced stages of nephropathy, showed that irbesartan at 300 mg, compared with amlodipine, can protect against the risk of ESRD or death (170). The REIN study, conducted with ACE-I in chronic but non-diabetic nephrotic patients, showed unequivocally that the renal protective effect of ramipril was absent in people with normal BMI and was instead maximum in obese people both for progression of renal damage and for proteinuria (171).

In most of the obese patients, to obtain an adequate BP control, diuretic therapy is usually needed. The combination of ACE-I or ARBs with thiazide or thiazide-like diuretics down to about an eGFR of 30 ml/min/1,73 m2 or the use of loop diuretics (torasemide is preferable over furosemide due to its longer half-life and its higher bioavailability after oral intake) when eGFR <30 ml/min/1,73 m2 is useful and often necessary to control BP in obese hypertensives (166, 172). Diuretics help excrete the excess dietary sodium, whereas ARBs or ACE-I reduce the unwanted effects of the consequent diuretic-mediated RAAS stimulation (172). In clinical practice, to increase treatment adherence, single-pill fixed-dose triple combinations of ARB or ACE-I plus a thiazide diuretic (or the thiazide-like indapamide) and amlodipine are available, such as two combinations containing an ACE-I (perindopril or ramipril) and two combinations containing an ARB (olmesartan or valsartan). Amlodipine blocks the L-type calcium channels found mainly in the glomerular afferent arteriole and, unfortunately, could favor glomerular hyperfiltration in obese patients. Antagonists of the RAAS should always counterbalance the action of diuretics or direct vasodilators such as amlodipine. Otherwise, there could be an increase in diuresis with nocturia, reduced nephroprotective effect, and postural oedema. An amlodipine-based monotherapy could lead to significant peripheral oedema due to a vasodilating direct impact, so an association with a RAAS blocker should be preferred to reduce this unpleasant but avoidable effect (173). Lercanidipine can be used as an alternative to amlodipine, for a more balanced dilation of the efferent arterioles due to L-type and T-type calcium channel blockade. The latest version of the European Society of Hypertension (ESH) Guidelines emphasized how single-pill double or triple-fixed-dose combinations with a diuretic can resolve the efficacy problem frequently found in obese hypertensives, thus increasing therapeutic adherence (90).

Beta-1 selective or super-selective adrenergic blockers such as bisoprolol or nebivolol can help maintain the heart rate <70 bpm in sedentary obese patients. Beta-1 blockers help reduce renin secretion after beta-1 adrenergic stimulation by sympathetic nerves on the renin-secreting cells of the afferent glomerular arteriole.

Obese patients affected by arterial hypertension may also need a mineralocorticoid receptor antagonist (MRA; e.g., canrenone) to obtain adequate control of 24-h BP due to the above-explained "escape" phenomenon and the persistent inappropriate secretion of aldosterone despite the use of ACE-I or ARBs in the overweight/obese subjects (34). For an effective and complete 24-h BP control, these subjects, especially if with low RAR values, are the best candidates for MRA or the "new" aldosterone synthase inhibitor (174, 175) (i.e., baxdrostat and lorundrostat). Classic MRAs, such as canrenone, are usually considered as a fourth choice in obese hypertensive patients uncontrolled by a triple therapy with an ACE-I or ARB, a thiazide (or thiazide-like) diuretic and a calcium channel blocker (CCB) (90). Recent studies on finerenone (a non-steroidal antagonist of the mineralocorticoid receptor) found that it can reduce and maintain systolic BP 3 mmHg lower approximately, and, likely, even more on 24 h or at night (not evaluated in published trials). It can reduce both renal and CV damage in patients with diabetic nephropathy who are usually obese, lowering the risk of kidney damage and HF hospitalization (176). This novel aldosterone antagonist, studied for target organ protection, might be particularly valuable in obesity-related hypertension.

The association of antihypertensive therapy (ACE-I or ARB plus a CCB) with an SGLT2-i has broad implications, together or in alternative to "classical" diuretic treatment, in reducing BP and increasing at the same time the cardiorenal protection with clinical indications regardless the presence of T2DM. In this setting, a recent substudy of the SURMOUNT-1 (177) was conducted on 494 overweight and obese (BMI ≥ 27 Kg/m2) non-diabetic hypertensive patients to assess the impact of different doses of tirzepatide on BP profiles evaluated with ambulatory BP monitoring (ABPM). After 36 weeks, reductions in 24-h systolic and diastolic BP were dose-dependent and consistent across subgroups of participants stratified by clinically relevant confounders, including age, sex, BMI, and hypertension-related factors. This study demonstrates that tirzepatide improves 24-h BP in obesity-related hypertension. Even night-time systolic BP, which is often poorly controlled in overweight and obese patients, being a stronger predictor of CV and all-cause death than daytime and 24-h systolic BP, was also significantly reduced by tirzepatide. Furthermore, correlation and mediation analyses indicated that these effects of tirzepatide on BP are independent of weight loss, therefore, adding a GLP1-RA, or a double GLP1/GIP-RA, in overweight/obese non-diabetic hypertensive patients could be the ultimate fundamental improvement in BP management and relative target organ protection.

## General considerations on drug therapy for cardiometabolic prevention in the obese patient

Evidence-based therapies for CV risk reduction are still not adequately implemented in clinical practice, even in obese patients affected by T2DM with proven CV damage. In a recent study of Italian specialized centers on diabetes care, only 26.8% of T2DM patients at high CV risk were treated with high-intensity statin therapy, only 3.9% with GLP1-RA and only 2.8% with SGLT2-i. It was a fact that only 3.6% of patients requiring all three treatment classes received such prescriptions, while 42.6% received no prescriptions (178). Beyond and regardless of obesity, there is still too much therapeutic inertia to the prescription of drugs that have proved to be safe and effective in reducing mortality from CV events (56). For example, statins proved to be safe and preventive even in patients affected by NAFLD and NASH, reducing the risk of both cirrhosis and hepatocellular carcinoma in obese subjects (179).

An adiposity-centered approach to overweight and obesity will open a new era in the treatment of the main consequences of chronic excessive adiposity, such as arterial hypertension, T2DM, CKD, and HF. The two recently introduced therapies, GLP1-RA and SGLT2-i, are fundamental in the management of obese patients, especially in the presence of multiple CV risk factors and/or cardio-renal damage. We believe that overweight patients defined by BMI criteria need to improve their diet and lifestyle first, but if they suffer from comorbidities, such as metabolic syndrome, prediabetes and hypertension and are not able to lose weight or ameliorate their risk profile through diet and lifestyle alone, anti-obesity drugs, especially GLP1-RA, can already have a role in therapy. The robust evidence mentioned in our review showed that losing adiposity with the help of GLP1-RA can ameliorate all the cardiometabolic risk factors, corroborating the standard therapies for hypertension, dyslipidemia and diabetes thus improving the chances to reach therapeutic goals more easily. Until a few years ago, it was challenging for a patient affected by obesity and T2DM to reach back a condition of euglycemia by losing 10-20% of his body weight, also improving dyslipidemia, hypertension and OSAS. This condition was steadily achieved only with bariatric surgery, keeping in mind all the costs and the possible related complications. This novel pharmacological approach based on these drugs, previously limited to T2DM patients only, opens new perspectives. The use of these drugs leading to weight loss and exerting diuretic action may also help simplify the burden of the antihypertensive therapy, leading to a more considerable reduction of CV risk at the same time. In addition, the use of these drugs in the early stages of metabolic impairments, such as in prediabetes and/or metabolic syndrome, where insulin resistance is present without overt organ damage yet, will even prevent the progression to diabetes and chronic kidney and heart damage. Indeed, GLP1-RA and SGLT2-i in the early phases counteract renal hyperfiltration and the consequent glomerular sclerosis and/or microalbuminuria with progressive loss of nephrons as well as chronic BP-related conditions leading to macro- and micro-vascular arterial damage, cardiac and cerebral ischemic events, and HFpEF. CV outcome studies have confirmed the efficacy of both GLP1-RA and SGLT2-i in reducing CV and renal events and mortality in obese with or without T2DM.

Nowadays, in many countries, such as Italy, among the GLP1-RA, only liraglutide is indicated (but not reimbursed by the national health system) in non-diabetic obese patients with high CV risk. However, semaglutide is likely to get the approval for the same indication, with the advantage of a single weekly administration. On the other hand, SGLT2-i are indicated and reimbursed not only in T2DM patients but also in HF patients with reduced or preserved EF, as well as in CKD patients, regardless of the presence of T2DM.

## Conclusion

The pathophysiological and clinical concept of "adipocentrism" in managing obesity-related conditions should lead to a therapeutic strategy to reduce body weight and improve BP, lipids, and glucose levels. It should be planned as soon as possible, applying what we named "adipocentric approach." After decades of lifestyle-only interventions as an "ancillary" treatment that often failed to reach the desired outcomes, especially in the medium and long term, the availability of innovative drugs is likely to change radically the management of obesity and its related complications. In the light of this novel therapeutic era, for the obese affected by arterial hypertension as a practical example, we propose an adipocentric modification of the historical figure of Irvine Page by introducing novel therapeutic combinations for the treatment of obese hypertensive patients, also considering the expected associations with T2DM, CKD, and HF (Figure 5).

Figure 5

[ ![www.frontiersin.org](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g005.jpg) ](https://www.frontiersin.org/files/Articles/1365183/fmed-11-1365183-HTML/image_m/fmed-11-1365183-g005.jpg)

**Figure 5**. Possible drug associations for the hypertensive obese patient with or without impaired glucose metabolism and/or cardio-renal organ damage. The continuous lines indicate proved safe and effective associations whereas intermittent lines indicate less tested or less indicated associations. GLP-1, glucagon like peptide-1; SGLT2, sodium-glucose cotransporter-2; ARB, angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitors; CCB, calcium channel blocker.

Soon, the combination of GLP1-RA and SGLT2-i is likely to become the first choice for the treatment of obese patients, even with high-normal BP and prediabetes (and/or metabolic syndrome). In obese patients affected by arterial hypertension, adding a GLP1-RA and an SGLT2-i on top of a RAAS antagonist and the often-needed diuretic can provide effective metabolic, CV, and renal protection, especially in the presence of subclinical or clinical target organ damage. Furthermore, lipid-lowering treatments for primary and secondary CV prevention should be frequently associated, keeping in mind that the use of the novel obesity-centered therapeutic strategies in the background is likely to facilitate the achievement of the therapeutic goals for LDL values (i.e., LDL cholesterol below 70 or below 55 mg/dL in high and very high-risk patients, respectively) with less pharmacological intensity (lower dosages and/or lower number of lipid-lowering drugs needed).

In conclusion, an adipocentric approach aiming at treating early and intensively, especially the VAT excess, rather than waiting for the dangerous adiposity-related CV and metabolic comorbidities to develop, may facilitate a more effective reduction of CV, cerebrovascular, and renal events in most overweight and obese patients. Global healthcare costs are also likely to be consistently reduced.

## Author contributions

RS: Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. ML: Data curation, Formal analysis, Investigation, Software, Supervision, Writing - original draft, Writing - review & editing. CD: Data curation, Investigation, Supervision, Visualization, Writing - original draft, Writing - review & editing. BO: Data curation, Investigation, Writing - original draft, Writing - review & editing. PF: Data curation, Investigation, Writing - original draft, Writing - review & editing. LS: Data curation, Investigation, Writing - original draft, Writing - review & editing. AM: Data curation, Investigation, Writing - original draft, Writing - review & editing. IR: Data curation, Investigation, Writing - original draft, Writing - review & editing. FS: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing. FG: Conceptualization, Data curation, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing.

## Funding

This work was partly supported by the Italian Health Ministry (Ricerca Corrente to IRCCS INRCA). This research was also supported by "Politecnica delle Marche" University (Ricerca di Ateneo to Prof. Riccardo Sarzani).

## Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

## Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: obesity, visceral adiposity, hypertension, type 2 diabetes mellitus, adipocentric, GLP-1 receptor agonists, SGLT2-inhibitors, cardiometabolic complications

Citation: Sarzani R, Landolfo M, Di Pentima C, Ortensi B, Falcioni P, Sabbatini L, Massacesi A, Rampino I, Spannella F and Giulietti F (2024) Adipocentric origin of the common cardiometabolic complications of obesity in the young up to the very old: pathophysiology and new therapeutic opportunities. _Front. Med._ 11:1365183. doi: 10.3389/fmed.2024.1365183

Received: 03 January 2024; Accepted: 26 March 2024;  
Published: 08 April 2024.

Edited by:

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Copyright (C) 2024 Sarzani, Landolfo, Di Pentima, Ortensi, Falcioni, Sabbatini, Massacesi, Rampino, Spannella and Giulietti. This is an open-access article distributed under the terms of the [Creative Commons Attribution License (CC BY)](http://creativecommons.org/licenses/by/4.0/). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Francesco Spannella, Zi5zcGFubmVsbGFAdW5pdnBtLml0

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Table of contents

  * Abstract
  * Introduction
  * Brief overview of obesity pathophysiology and its cardiovascular and metabolic consequences
  * Obesity, high-normal blood pressure, and arterial hypertension
  * Obesity, impaired glucose handling and type 2 diabetes mellitus
  * Obesity and dyslipidemia
  * Obesity and other relevant cardiometabolic risk factors
  * Global cardiovascular risk assessment in obesity
  * Evaluation of obesity in clinical practice: low-cost clinical tools to improve phenotyping
  * Cardiometabolic effects of weight loss
  * Treatment of visceral overweight and obesity: an adipose-related approach between established therapies and newest pharmacological interventions
  * Bariatric surgery
  * Pharmacological treatment of obesity
  * Pharmacological treatment of obese patients affected by T2DM
  * Pharmacological treatment of obese patients affected by arterial hypertension
  * General considerations on drug therapy for cardiometabolic prevention in the obese patient
  * Conclusion
  * Author contributions
  * Funding
  * Conflict of interest
  * Publisher's note
  * References



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Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes - Endotext - NCBI Bookshelf

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# Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes

Kenneth R. Feingold, MD.

Author Information and Affiliations

Kenneth R. Feingold, MD

Emeritus Professor of Medicine, University of California, San Francisco

Email: [ude.fscu@dlognief.htennek](mailto:dev@null)

Corresponding author.

Last Update: September 11, 2024.

## ABSTRACT

While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with Type 2 diabetes (T2DM) will require medications to achieve and maintain glycemic control. The purpose of this chapter is to provide the healthcare practitioner with an overview of the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists. In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and pramlintide can be administered by injection. Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action. A variety of fixed combinations of 2 agents are available in the US and in many other countries. In this chapter we discuss the administration, mechanism of action, effect on glycemic control, other benefits, side effects, and the contraindications of the use of these glucose lowering drugs. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, [WWW.ENDOTEXT.ORG](http://www.endotext.org/).

## INTRODUCTION

While lifestyle changes such as dietary modification and increased physical activity can be very effective in improving glycemic control, over the long-term most individuals with Type 2 diabetes (T2DM ) will require medications to achieve and maintain glycemic control (1). The purpose of this chapter is to provide the healthcare practitioner with detailed information on the existing oral and injectable (non-insulin) pharmacological options available for the treatment of patients with T2DM. The use of these drugs to treat diabetes during pregnancy, in children and adolescents, and for the prevention of diabetes are discussed in other Endotext chapters (2-4). For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Emily Schroeder in Endotext (5).

Currently, there are ten classes of orally available pharmacological agents to treat T2DM: 1) sulfonylureas, 2) meglitinides, 3) metformin (a biguanide), 4) thiazolidinediones (TZDs), 5) alpha glucosidase inhibitors, 6) dipeptidyl peptidase IV (DPP-4) inhibitors, 7) bile acid sequestrants, 8) dopamine agonists, 9) sodium-glucose transport protein 2 (SGLT2) inhibitors and 10) oral glucagon like peptide 1 (GLP-1) receptor agonists ([Table 1](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab/?report=objectonly)) (6-8). In addition, glucagon like peptide 1 (GLP-1) receptor agonists, dual GLP-1 receptor and GIP receptor agonists, and pramlintide can be administered by injection ([Table 2](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab_1/?report=objectonly)) (6-8).

### Table 1. 

Currently Available (USA) Oral Hypoglycemic Drugs to Treat Type 2 Diabetes

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab/?report=objectonly)

  
General Class  
Compound/Brand Name| Generic Available| Dose Range| Cost  
---|---|---|---  
**1 st Generation Sulfonylureas**  
Chlorpropamide/ Diabinese| Yes| 100-750mg qd| Low  
Tolazamide/ Tolinase| Yes| 100mg qd to 500mg bid| Low  
Tolbutamide/ Orinase| Yes| 500mg qd to 1000mg tid with meals| Low  
Acetohexamide/ Dymelor| Yes| 250mg qd to 750mg bid| Low  
**2nd Generation Sulfonylureas**  
Glyburide (Glibenclamide)/ Diabeta, Glynase| Yes| 2.5mg qd to 10mg bid| Low  
Glipizide/ Glucotrol, Glucotrol XL| Yes| 2.5mg qd to 20mg bid| Low  
Glimepiride/ Amaryl| Yes| 0.5mg to 8mg qd| Low  
Gliclazide/ Diamicron| Yes| 40mg qd to 160mg bid| Low  
**Meglitinides**  
Repaglinide/ Prandin| Yes| 0.5mg to 4 mg with meals. Max 16mg/day| Low  
Nateglinide/ Starlix| Yes| 60-120mg tid with meals| Low  
**Biguanide**  
Metformin/ Glucophage, Glucophage XR| Yes| 500-2500mg qd or tid depending upon preparation| Low  
**Thiazolidinediones (TZDs)**  
Rosiglitazone/ Avandia| Yes| 4-8mg qd| High  
Pioglitazone/ Actos| Yes| 15-45mg qd| Low  
**Alpha-glucosidase inhibitors**  
Acarbose/ Precose| Yes| 25-100mg tid with meals| Low  
Miglitol/ Glyset| Yes| 25-100mg tid with meals| High  
Voglibose/ Basen, Voglib| Yes| 0.2mg tid with meals|   
**Dipeptidyl peptidase-IV (DPP-4) inhibitors**  
Alogliptin/ Nesina| Yes| 25mg qd| High  
Linagliptin/ Tradjenta| No| 5mg qd| High  
Sitagliptin/ Januvia| No| 25-100mg qd| High  
Saxagliptin/ Onglyza| No| 2.5-5mg qd| High  
Vildagliptin/ Galvus| No| 50mg qd|   
**Bile Acid Sequestrant**  
Colesevelam/ Welchol| No| 1875mg bid or 3.75-gram packet or bar qd| High  
**Dopamine Agonist**  
Bromocriptine/ Cycloset| No| 0.8 - 4.8mg qAM| High  
**Sodium-glucose co-transporter-2 (SGLT2) inhibitors**  
Canagliflozin/ Invokana| No| 100-300mg qd| High  
Dapagliflozin/ Farxiga| No| 5-10mg qd| High  
Empagliflozin/ Jardiance| No| 10-25mg qd| High  
Ertugliflozin/ Stelgatro| No| 5-15mg qd| High  
**Oral glucagon like peptide 1 (GLP-1) receptor agonists**  
Semaglutide/ Rybelsus| No| 7-14mg qd| High  
  
### Table 2. 

Currently Available (USA) Injectable Hypoglycemic Drugs to Treat Type 2 Diabetes

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab_1/?report=objectonly)

  
General Class  
Compound/Brand Name| Generic Available| Dose Range| Cost  
---|---|---|---  
**GLP-1 Receptor Agonist**  
  
Exenatide/ Byetta| No| 5-10mcg bid| High  
Exenatide/ Bydureon| No| 2mg once weekly| High  
Liraglutide/ Victoza| No| 0.6-1.8mg qd**| High  
Albiglutide/ Tanzeum*| No| 30-50mg once weekly| High  
Dulaglutide/ Trulicity| No| 0.75-4.5mg once weekly| High  
Lixisenatide/ Adlyxin| No| 10-20mcg qd| High  
Semaglutide/ Ozempic| No| 0.25-2.0mg once weekly| High  
**Dual GLP-1 Receptor/GIP Receptor Agonists**  
Tirzepatide/ Mounjaro| No| 5mg-15mg once weekly| High  
**Amylin Mimetic**  
Pramlintide/ Symlin| No| 15-120mcg tid with meals| High  
  
*
    

Withdrawn from market.

Medications from these distinct classes of pharmaceutical agents may be used as treatment by themselves (monotherapy) or in a combination of 2 or more drugs from multiple classes with different mechanisms of action (6-8). A variety of fixed combination of 2 agents are available in the US and in many other countries (examples shown in [Table 3](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.oral_pharmacologi/?report=objectonly)). There are even combinations that contains 3 drugs (Qternmet XR which contains dapagliflozin, saxagliptin, and metformin and Trijardy XR which contains empagliflozin, linagliptin, and metformin). Additionally, there are combinations of GLP-1 receptor agonists and insulin ([Table 3](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.oral_pharmacologi/?report=objectonly)). These combination products may be useful and attractive to the patient, as they provide multiple drugs in a single tablet or injection, offering convenience and increased compliance. In the US, they also enable patients to receive two medications for a single medical insurance co-payment. Most importantly, the addition of a second drug results in an additive improvement in glycemic control. When a patient is on drug A if drug B is added to drug A, there is an improvement in glycemic control. This concept can be extended by the addition of a third drug C, and even a fourth drug D ([Figure 1](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F1/?report=objectonly)).

### Table 3. 

Oral Pharmacological Fixed Combination Therapies to Treat Type 2 Diabetes

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.oral_pharmacologi/?report=objectonly)

Drug 1| Drug 2| Brand Name| Generic  
---|---|---|---  
Glyburide| Metformin|  [Glucovance](http://packageinserts.bms.com/pi/pi_glucovance.pdf) _(discontinued by manufacturer: generic available)_ | Yes  
Glipizide| Metformin| [Metaglip](https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/021460s007lbl.pdf) (discontinued by manufacturer; generic available)| Yes  
Glimepiride| Pioglitazone|  [Duetact](https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/021925s010s011lbl.pdf) | Yes  
Glimepiride| Rosiglitazone|  [Avandaryl](https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Avandaryl/pdf/AVANDARYL-PI-MG.PDF) | Yes  
Sitagliptin| Metformin|  [Janumet](https://www.merck.com/product/usa/pi_circulars/j/janumet/janumet_pi.pdf) | No  
Saxagliptin| Metformin|  [Kombiglyze XR](http://www.azpicentral.com/kombiglyze-xr/pi_kombiglyze_xr.pdf) | No  
Pioglitazone| Metformin|  [ACTOSplus Met](http://general.takedapharm.com/content/file.aspx?filetypecode=actoplusmetpi&cacheRandomizer=8c0b2ada-9d0a-49e9-b409-865fe4c65920) _; ACTOSplus Met XR_ | Yes  
Repaglinide| Metformin|  [PrandiMet](https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022386s007lbl.pdf) | Yes  
Rosiglitazone| Metformin|  [Avandamet](https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Avandamet/pdf/AVANDAMET-PI-MG.PDF) | Yes  
Linagliptin| Metformin|  [Jentadueto](http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Jentadueto/Jentadueto.pdf) | No  
Alogliptin| Metformin|  [Kazano](http://general.takedapharm.com/content/file.aspx?FileTypeCode=KAZANOPI&cacheRandomizer=4b6c6e32-1d4c-4a5c-873b-04c3d9baa465) | Yes  
Alogliptin| Pioglitazone|  [Oseni](http://general.takedapharm.com/content/file.aspx?filetypecode=OSENIPI&cacheRandomizer=547fb1f5-6b01-4b66-97e0-18512e576fa2) | No  
Canagliflozin| Metformin|  [Invokamet](https://www.invokanahcp.com/invokamet/dosing-prescribing) | No  
Dapagliflozin| Metformin|  [Xigduo XR](http://www.azpicentral.com/xigduo/pi_xigduoxr.pdf) | No  
Dapagliflozin| Saxagliptin| Qtern| No  
Empagliflozin| Linagliptin|  [Glyxambi](http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Glyxambi/Glyxambi.pdf) | No  
Empagliflozin| Metformin|  [Synjardy](http://docs.boehringer-ingelheim.com/Prescribing%20Information/PIs/Synjardy/Synjardy.pdf) | No  
Ertugliflozin| Metformin| Segluromet| No  
Ertugliflozin| Sitagliptin| Steglujan| No  
Lixisenatide| Glargine Insulin| Soliqua| No  
Liraglutide| Degludec Insulin| Xultophy| No  
  
![Figure 1. . Efficacy When Oral Agents are Used as Add-On Therapy.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image001.jpg)

### Figure 1. 

Efficacy When Oral Agents are Used as Add-On Therapy. When a patient is on drug A and they are changed to drug B, C, or D, often no improvement in glucose control will be seen. However, if drug B is added to drug A, there is an improvement. This concept can often be extended by the addition of a third drug (C), or even a fourth drug (D). There is decreasing benefit for each additional drug as the baseline A1c level decreases. Note that there is limited data on the use of 4 drug combinations.

## OVERVIEW OF DRUGS

There are a number of different abnormalities that contribute to the hyperglycemia that occurs in patients with T2DM (9). Therefore, the drugs used to treat patients with T2DM can have a number of different mechanisms by which they lower glucose levels. [Figure 2](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F2/?report=objectonly) shows the various sites of action of the pharmacological therapies for the treatment of T2DM.

![Figure 2. . Sites of Action of Pharmacological Therapies for the Treatment of Type 2 Diabetes.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image002.jpg)

### Figure 2. 

Sites of Action of Pharmacological Therapies for the Treatment of Type 2 Diabetes.

A broad overview of the most commonly used drugs to treat T2DM is shown in [Table 4](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.benefits_and_side/?report=objectonly) and the effect of drugs on blood lipid levels is shown in [Table 5](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glucose/?report=objectonly).

### Table 4. 

Benefits and Side Effects of Commonly Used Drugs

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.benefits_and_side/?report=objectonly)

Drugs| Ability to Lower Glucose| Risk of Hypoglycemia| Weight Change| Effect on ASCVD| Effect on Heart Failure| Effect on Renal Disease  
---|---|---|---|---|---|---  
2nd Generation SU| High| Yes| Increase| Neutral| Neutral| Neutral  
Metformin| High| No| Neutral- modest weight loss| Potential Benefit| Neutral| Neutral  
TZDs| High| No| Increase| Potential Benefit (Pioglitazone)| Increased| Neutral  
DPP-4 inhibitors| Intermediate| No| Neutral| Neutral| Potential Increase (saxagliptin and alogliptin)| Neutral  
SGLT2 inhibitors| Immediate| No| Decrease| Potential Benefit| Benefit| Benefit-  
Reduced progression of renal failure  
GLP-1 receptor agonists| High| No| Decrease| Benefit| Benefit| Benefit- Reduced progression of renal failure  
  
### Table 5. 

Effect of Glucose Lowering Drugs on Lipid Levels*

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glucose/?report=objectonly)

Metformin| Modestly decrease triglycerides and LDL-C  
---|---  
Sulfonylureas| No effect  
DPP4 inhibitors| Decrease postprandial triglycerides  
GLP1 analogues| Decrease fasting and postprandial triglycerides  
Acarbose| Decrease postprandial triglycerides  
Pioglitazone  
Rosiglitazone| Decrease triglycerides and increase HDL-C. Small increase LDL-C but a decrease in small dense LDL  
SGLT2 inhibitors| Small increase in LDL-C and HDL-C  
Colesevelam| Decrease LDL-C. May increase triglycerides  
Bromocriptine-QR| Decrease triglycerides  
Insulin| No effect  
  
*
    

These effects are beyond benefits of glucose lowering.

Bloomgarden et al reported results from a meta-regression analysis of 61 clinical trials evaluating the efficacy of the five major classes of oral anti-hyperglycemic agents (10). The results demonstrated that there is a strong direct correlation between baseline A1c level and the magnitude of the decrease in fasting glucose and A1c induced by these drugs (i.e., significantly greater reductions in both fasting plasma glucose and A1c were observed in groups with higher baseline A1c levels). Thus, expectations for the overall magnitude of effect from a given agent might be modest when treating patients whose baseline A1c is <7.5-8.0% while in patients with elevated A1c levels the effect of drug therapy may be more robust ([figure 3](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F3/?report=objectonly)). A separate meta-analysis of 59 clinical studies reached similar conclusions (11). These results indicate that comparing efficacies among different anti-diabetic medications is challenging, when the baseline HbA1c is different in the studies being compared.

Additionally, the population of patients studied can impact the efficacy of a particular class of drug. For example, patients with limited beta cell function will have a decreased response to sulfonylurea drugs as these agents work via stimulating insulin secretion by the beta cells while TZDs are most effective in patients with insulin resistance. Another example would be the decrease in efficacy of SGLT2 inhibitors lowering A1c levels in patients with decreased renal function. A recent trial demonstrated that in individuals with a BMI > 30 pioglitazone reduced HbA1c levels better than sitagliptin while in individuals with a BMI < 30 sitagliptin was more effective (12). In individuals with an eGFR > 90 canagliflozin lowered HbA1c better than sitagliptin while in individuals with an eGFR between 60-90 sitagliptin was more effective (12). These results demonstrate that certain patient characteristics will influence the response to treatment with specific drugs indicating the ability to target drug therapy for the specific patient. Additionally, the variation in response of patients makes it difficult to compare the glucose lowering effects of different hypoglycemic drugs except in direct head-to-head comparison studies.

![Figure 3. . Relationship between baseline A1c level and the observed reduction in A1c with oral anti-hyperglycemic medications.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image003.jpg)

### Figure 3. 

Relationship between baseline A1c level and the observed reduction in A1c with oral anti-hyperglycemic medications. Irrespective of drug class, the baseline glycemic control markedly influences the overall magnitude of efficacy. Data from Bloomgarden et al, [Table 1](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab/?report=objectonly) (10).

A recent model-based meta-analysis was used to compare glycemic control between a large number of drugs adjusted for important differences between studies, including duration of treatment, baseline A1c, and drug dosages (13). In this analysis 229 studies with 121,914 patients were utilized. [Table 6](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly) shows the estimated decrease in A1c levels for different drugs in patients that are drug naive with an A1c of 8% and a weight of 90kg after 26 weeks of treatment. If one averages the effect on A1c of the highest doses for each drug in a specific drug class the reductions in A1c for each class of drug are metformin 1.09%, sulfonylureas 1.0%, TZDs 0.95%, DPP-4 inhibitors 0.66%, SGLT2 inhibitors 0.83%, and GLP-1 receptor agonists 1.24%. These data and the individual data for each drug in [table 6](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly) provides a rough estimate of the efficacy of various drugs and drug classes in lowering A1c levels. One should note that within a drug class there may be differences in the ability of different drugs to lower A1c levels. This is particularly true with the GLP-1 receptor agonist drugs. For additional information there is a website that provides updated comparisons of various agents to treat patients with T2DM (<https://www.comparediabetesdrugs.com/>). This website shows the effect of glucose lowering drugs on A1c levels, change in weight, and hypoglycemia.

### Table 6. 

Estimated Efficacy of Hypoglycemic Drugs Available in US (13)

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly)

Drug| A1c % Decrease| Drug| A1c % Decrease  
---|---|---|---  
Metformin 2000mg| 1.01| Dulaglutide 0.75| 1.18  
Metformin 2550mg| 1.09| Dulaglutide 1.5mg| 1.36  
Glipizide 5-20mg| 0.86| Exenatide 10ug BID| 0.86  
Glyburide 1.25-20mg| 1.17| Exenatide 2mg QW| 1.16  
Glimepiride 1-8mg| 0.97| Exenatide 2mg QWS| 1.14  
Pioglitazone 15mg| 0.62| Liraglutide 0.6mg| 0.88  
Pioglitazone 30mg| 0.85| Liraglutide 1.2mg| 1.13  
Pioglitazone 45mg| 0.98| Liraglutide 1.8mg| 1.25  
Rosiglitazone 4mg| 0.67| Lixisenatide 10ug| 0.44  
Rosiglitazone 8mg| 0.91| Lixisenatide 20ug| 0.66  
Canagliflozin 100mg| 0.84| Semaglutide 0.5mg| 1.43  
Canagliflozin 300mg| 1.01| Semaglutide 1.0mg| 1.77  
Dapagliflozin 5mg| 0.65| Alogliptin 12.5mg| 0.58  
Dapagliflozin 10mg| 0.73| Alogliptin 25mg| 0.66  
Empagliflozin 10mg| 0.69| Linagliptin 5mg| 0.59  
Empagliflozin 25mg| 0.77| Saxagliptin 2.5mg| 0.59  
Ertugliflozin 5mg| 0.73| Saxagliptin 5mg| 0.67  
Ertugliflozin 15mg| 0.81| Sitagliptin 100mg| 0.72  
  
    

The decreases in A1c are modeled for drug naive patients with an A1c of 8% and a weight of 90kg after 26 weeks of treatment.

The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) Study randomized approximately 5,000 patients with relatively recent onset of T2DM (4.2 years) on metformin therapy to sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, or insulin (14). The primary outcome was the time to primary failure defined as an A1c ≥ 7% over an anticipated mean observation period of 5 years The results as expected demonstrated that the GLP-1 receptor agonist liraglutide was more effective than the sulfonylurea glimepiride and the DPP4 inhibitor sitagliptin in maintaining the A1c < 7% (GLP1 receptor agonist better than sulfonylurea better than DPP-4 inhibitor) (15). Liraglutide and glargine insulin were similarly effective in lowering A1c levels (15). Significantly the majority of patients regardless of drug assignment did not have an A1c level less than 7% (Glargine 67.4%, Glimepiride 72.4%, Liraglutide 68.2%, Sitagliptin 77.4%) demonstrating the progressive nature of diabetes and the difficulty in maintaining good glycemic control. It should be noted that the SGLT2 inhibitors and TZD drugs were not included in this study. The incidences of microvascular complications (renal disease and neuropathy) and death were not different among the four treatment groups (16). There was a suggestion of a decrease in cardiovascular disease in the liraglutide treated group (16,17).

## SULFONYLUREAS

### Introduction

Sulfonylureas were developed in the 1950s and have been widely used in the treatment of patients with T2DM (18,19). First generation sulfonylureas (acetohexamide, chlorpropamide, tolazamide, and tolbutamide) possess a lower binding affinity for the ATP-sensitive potassium channel, their molecular target (vide infra), and thus require higher doses to achieve efficacy (see [table 1](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.currently_availab/?report=objectonly)) (18,19). These first-generation sulfonylureas are currently rarely used. Subsequently, in the 1980s 2nd generation sulfonylureas including glyburide (glibenclamide), glipizide, gliclazide, and glimepiride were developed and are now widely used (18). The 2nd generation sulfonylureas are much more potent compounds (~100-fold). Sulfonylureas can be used as monotherapy or in combination with any other class of oral diabetic medications except meglitinides because they lower glucose levels by a similar mechanism of action (18,20).

Key characteristics of the different sulfonylureas are shown in [Table 7](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.key_characteristi/?report=objectonly) (18). Of clinical importance is the duration of action, which varies with the rate of hepatic metabolism and the hypoglycemic activity of drug metabolites. Drugs with a long duration of action are more likely to cause severe and prolonged hypoglycemia whereas short acting drugs need to be given multiple times per day (18). Additionally, drugs that are metabolized to active agents (for example glyburide) are also more likely to cause hypoglycemia (18). Most sulfonylureas are metabolized in the liver and are to some extent excreted by the kidney; therefore, hepatic and/or renal impairment increases the risk of hypoglycemia (18).

### Table 7. 

Key Characteristics of Sulfonylureas

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.key_characteristi/?report=objectonly)

  
Drug| Duration of action| Metabolites| Excretion  
---|---|---|---  
Tolbutamide| 6-12 h| Inactive| Kidney  
Chlorpropamide| 60 h| Active or unchanged| Kidney  
Tolazamide| 12-24 h| Inactive| Kidney  
Glipizide| 12-24 h| Inactive| Kidney 80%  
Feces 20%  
Glipizide ER| >24 h| Inactive| Kidney 80%  
Feces 20%  
Glyburide| 16-24 h| Inactive or weakly active| Kidney 50%  
Micronized glyburide| 12-24 h| Inactive or weakly active| Kidney 50%  
Feces 50%  
Glimepiride| 24 h| Inactive or weakly active| Kidney 60%  
Feces 40%  
  
### Administration

Sulfonylureas should be taken 30 minutes before meals starting with a low dose with an increase in dosage until desired glycemic control has been achieved. In patients with a high risk of severe hypoglycemia a very low-dose can be the initial therapy while in patients with very high A1c levels one can initiate therapy at a higher dose.

The recommended starting dose of glipizide is 5 mg approximately 30 minutes before breakfast. Geriatric patients or those with liver or renal disease or other risk factors for severe hypoglycemia can be started on 2.5 mg. Patients with very high A1c levels may be started on a higher dose. Based on the glucose response the dose can be increased weekly by 2.5-5 mg. If a once-a-day dose is not satisfactory or the patient requires more than 15 mg per day one can give the drug before breakfast and dinner. The maximum daily dose is 40 mg per day.

The usual starting dose of extended-release glipizide is 5 mg per day with breakfast. Those patients who are at high risk of hypoglycemia may be started at a lower dose. The dose can be increased based on glucose or A1c measurements. The maximum dose is 20 mg per day.

The usual starting dose of glyburide is 2.5 to 5 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 1.25 mg per day. The dose should be increased weekly by 2.5 mg based on the glucose response. The maximum dose per day is 20 mg.

The usual starting dose of micronized glyburide is 1.5 to 3 mg daily with breakfast or the first main meal. Patients at high risk for hypoglycemia should be started on 0.75 mg per day. The dose should be increased weekly by 1.5 mg based on the glucose response. The maximum dose per day is 12 mg.

The recommended starting dose of glimepiride is 1 or 2 mg once daily. Patients at increased risk for hypoglycemia should be started on 1 mg once daily. The dose should be increased every 1-2 weeks in increments of 1 or 2 mg based upon the patient's glycemic response. The maximum dose is 8 mg per day.

The recommended starting dose of gliclazide is 40 - 80mg once daily. Patients at increased risk for hypoglycemia should be started on 40 mg once daily. The dose should be increased every 1-2 weeks in increments of 40 or 80 mg based upon the patient's glycemic response. The maximum dose is 160mg twice a day.

### Mechanism of Action

Sulfonylureas are insulin secretagogues and lower blood glucose levels by directly stimulating glucose independent insulin secretion by the pancreatic beta cells (18,20). Through the concerted efforts of GLUT2 (the high Km glucose transporter), glucokinase (the enzyme that phosphorylates glucose), and glucose metabolism, pancreatic beta cells sense blood glucose levels and secrete the appropriate amount of insulin in response (21,22). Glucose metabolism leads to ATP generation and increases the intracellular ratio of ATP/ADP, which results in the closure of the ATP-sensitive potassium channel on the plasma membrane (18,21,23). Closure of this channel depolarizes the membrane and triggers the opening of voltage-sensitive calcium channels, leading to the rapid influx of calcium (18,24). Increased intracellular calcium causes an alteration in the cytoskeleton and stimulates translocation of insulin-containing secretory granules to the plasma membrane and the secretion of insulin ([Figure 4](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F4/?report=objectonly)) (18).

![Figure 4. . Mechanism by which glucose, sulfonylureas, and meglitinides stimulate insulin secretion by the beta cells.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image004.jpg)

### Figure 4. 

Mechanism by which glucose, sulfonylureas, and meglitinides stimulate insulin secretion by the beta cells.

The KATP channel is comprised of two subunits, both of which are required for the channel to be functional (24). One subunit contains the cytoplasmic binding sites for both sulfonylureas and ATP, and is designated as the sulfonylurea receptor type 1 (SUR1). The other subunit is the potassium channel, which acts as the pore-forming subunit (24). Either an increase in the ATP/ADP ratio or ligand binding by sulfonylureas or meglitinides to SUR1 results in the closure of the KATP channel and insulin secretion (19,24). Studies comparing sulfonylureas and non-sulfonylurea insulin secretagogues have identified several distinct binding sites on the SUR1 that cause channel closure. Some sites exhibit high affinity for sulfonylureas, while other sites exhibit high affinity for meglitinides.

In addition to binding to SUR1, sulfonylureas also bind to Epac2, a protein activated by cAMP (18). Sulfonylurea-stimulated insulin secretion was reduced both in vitro and in vivo in mice lacking Epac2, indicating that Epac2 also plays a role in sulfonylurea induced insulin secretion (25).

In addition to inducing insulin secretion sulfonylureas have other effects that could play a role in lowering blood glucose levels (18). Specifically, sulfonylureas have been shown to decrease hepatic insulin clearance, inhibit glucagon secretion from pancreatic alpha-cells (this may be secondary to increasing insulin secretion), and enhance insulin sensitivity in peripheral tissues (this may be partially due to lowering glucose levels and reducing glucotoxicity) (18). The contribution and importance of these additional effects in mediating the glucose lowering effects of sulfonylureas is uncertain.

### Glycemic Efficacy

When used at maximally effective doses, results from well-controlled clinical trials have not indicated a marked superiority of one 2nd generation sulfonylurea over another in improving glycemic control (26). Similarly, 2nd generation sulfonylureas exhibit similar clinical efficacy compared to the 1st generation agents (26). Sulfonylureas do not have a linear dose-response relationship and the majority of the A1C reduction occurs at half maximum dosage. The effect of sulfonylureas as monotherapy or when added to metformin therapy on A1c levels varies but typically results in reductions in A1c of approximately 0.50-1.5% (13,19,20,27,28). If A1c levels are very high decreases in the range of 1.5- 2.0% may be seen (19,20,26). Patients with a short duration of diabetes with residual beta cell function (high C-peptide levels) are likely to be most responsive to sulfonylurea therapy (26). Overtime many patients on sulfonylureas require additional therapies (secondary failure). In the ADOPT study, after 5 years 34% of the patients on glyburide monotherapy had fasting glucose levels > 180 mg/dl (i.e., secondary failure) (29). Similarly, in the United Kingdom Prospective Diabetes Study (UKPDS), only 34% of patients attained an A1c <7% at 6 years treated with sulfonylureas (glyburide or chlorpropamide) and this number declined to 24% at 9 years (18). This lack of durability of sulfonylurea therapy is likely to due to beta cell exhaustion. In addition, the weight gain induced by sulfonylurea therapy may also adversely affect glycemic control.

The results of the GRADE study, which compared glargine insulin, glimepiride, liraglutide, and sitagliptin added to metformin, were discussed earlier in the section entitled "OVERVIEW OF DRUGS".

### Other Effects

#### CARDIOVASCULAR DISEASE

Based on the University Group Diabetes Project (UGDP) sulfonylureas carry a "black box" warning regarding cardiovascular disease (30,31). However, the U.K. Prospective Diabetes Study Group (UKPDS) studied a large number of newly diagnosed patients with T2DM at risk for cardiovascular disease. In this study improved glycemic control with sulfonylureas reduced cardiovascular disease by approximately 16%, which just missed being statistically significant (p=0.052) (32). In the UKPDS, A1c was reduced by approximately 0.9% and the 16% reduction in cardiovascular disease was in the range predicted based on epidemiological studies. Thus, the reduction in cardiovascular events was likely due to improvements in glycemic control and not a direct benefit of sulfonylurea treatment. In support of this conjecture is that in the UKPDS, insulin treatment resulted in a similar decrease in A1c levels and reduction in cardiovascular events (32). Additionally, a large randomized cardiovascular outcome study (Carolina Study) reported that linagliptin, a DPP-4 inhibitor, and glimepiride, a sulfonylurea, had similar effects on cardiovascular events (hazard ratio 0.98) (33). Taken together these results suggest that sulfonylureas have a neutral effect on cardiovascular disease.

### Side Effects

#### HYPOGLYCEMIA

The major side effect of sulfonylurea treatment is hypoglycemia, which is more likely to occur and is more severe with long- acting sulfonylureas (18,19). In the UKPDS severe hypoglycemia, defined by need for third-party assistance, occurred each year in 0.4-0.6/100 patients treated with a sulfonylurea while non-severe hypoglycemia was seen in 7.9/100 persons treated with a sulfonylurea (34). Other studies have found even higher rates of severe hypoglycemia with 20-40% of patients receiving sulfonylureas having hypoglycemia and severe hypoglycemia (requiring third-party assistance) occurring in 1-7% of patients (20,34). With continuous glucose monitoring 30% of well controlled patients with T2DM had episodes of hypoglycemia that were often asymptomatic and nocturnal (35). Of great concern these hypoglycemic events were associated with EKG changes, particularly QTc prolongation (35). Other studies have also observed a very high rate of hypoglycemia in patients with T2DM treated with sulfonylureas when monitored using continuous glucose monitoring (36).

Hypoglycemia typically occurs after periods of fasting or exercise. In light of this hypoglycemic risk, initiation of treatment with sulfonylureas should be at the lowest recommended dose and the dose slowly increased in patients with modestly elevated A1c levels. Older patients (> age 65) and patients with hepatic or renal disease are more likely to experience frequent and severe hypoglycemic reactions, particularly if the goals of therapy aim for inappropriately tight glycemic control (18). Many clinicians avoid the use of long acting sulfonylureas (glyburide) in these high-risk patients as glyburide has a higher risk of hypoglycemia compared to other sulfonylureas (37).

#### WEIGHT GAIN

In the UKPDS, sulfonylurea treatment caused a net weight gain of approximately 3 kg, which occurred during the first 3-4 years of treatment and then stabilized (19,32). Other studies have similarly observed weight gain with sulfonylurea treatment (26).

#### FIRST GENERATION SIDE EFFECTS

Chlorpropamide can induce hyponatremia and water retention due to inappropriate secretion of antidiuretic hormone (ADH) (18). In addition, tolbutamide and chlorpropamide, in certain susceptible individuals, is associated with alcohol-induced flushing (18). Because of an increased risk of side effects 1st generation sulfonylureas are seldom used.

#### RARE SIDE EFFECTS

Intrahepatic cholestasis and allergic skin reactions, including photosensitivity and erythroderma may rarely occur (Package insert).

### Contraindications and Drug Interactions

Sulfonylureas are best avoided in patients with a sulfa allergy who experienced prior severe allergic reactions (Package insert). Otherwise, cross-reactivity between antibacterial and nonantibacterial sulfonamide agents is rare.

In renal failure, the dose of the sulfonylurea agent will require adjustment based on glucose monitoring to avoid hypoglycemia (18). Because it is metabolized primarily in the liver without the formation of active metabolites, glipizide is the preferred sulfonylurea in patients with renal disease (38).

In the elderly, long acting sulfonylureas, such as glyburide, glimepiride and chlorpropamide are not recommended (39).

Sulfonylureas can cause hemolytic anemia in patients with glucose 6-phosphate dehydrogenase (G6PD) deficiency and therefore should be used with caution in such patients (Package insert).

Certain drugs may enhance the glucose-lowering effects of sulfonylureas by inhibition of their hepatic metabolism (antifungals and monoamine oxidase inhibitors), displacing them from binding to plasma proteins (coumarins, NSAIDs, and sulfonamides), or inhibiting their excretion (probenecid) (20).

### Summary

While the ability of sulfonylureas to improve glycemic control is robust, the risk of hypoglycemia and weight gain reduce the desirability of this drug class. Additionally, the shorter durability of effectiveness is also a limiting factor. In patients at high risk for the occurrence of severe hypoglycemic reactions or in patients who are obese, using drugs other than sulfonylureas to treat T2DM is indicated if possible. Similarly, in patients with atherosclerotic cardiovascular disease, heart failure, or at high risk for cardiovascular disease or renal disease other hypoglycemic drugs have important advantages. Nevertheless, because sulfonylureas are generic drugs and very inexpensive, they continue to be used and play a role in the management of patients with T2DM.

### Table 8. 

Summary of the Advantages and Disadvantages of Sulfonylureas

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_the_ad/?report=objectonly)

Advantages| Disadvantages  
---|---  
Inexpensive| Hypoglycemia  
Rapid acting| Weight gain  
Once a day administration possible| Limited durability  
Long history of use| Need to titrate dose  
  
## MEGLINATIDES

### Introduction

The meglitinides are non-sulfonylurea insulin secretagogues characterized by a very rapid onset and abbreviated duration of action (20,40). Repaglinide (Prandin), a benzoic acid derivative introduced in 1998, was the first member of the meglitinide class. Nateglinide (Starlix) is a derivative of the amino acid D-phenylalanine and was introduced to the market in 2001. Unlike sulfonylureas, repaglinide and nateglinide stimulation of insulin secretion is dependent on the presence of glucose (40,41). As glucose levels decrease, insulin secretion decreases, which reduces the risk of hypoglycemia compared with sulfonylureas.

Meglitinides are rapidly absorbed with maximum serum concentrations generally attained within 1 hour and then quickly metabolized by the liver cytochrome CYP3A4 and CYP2C8 pathways, producing inactive metabolites, resulting in a plasma half-life of around 1 h (20). This rapid onset and short duration of action results in the ability of this class of drugs to predominantly reduce postprandial glucose levels (40). Because of the rapid onset and short duration of action meglitinides are given 1-30 minutes prior to meals. The drug should not be administered if the patient is going to skip the meal.

The pharmacokinetics of meglitinides differ with nateglinide having a faster onset and shorter duration of action than repaglinide (41). Nateglinide stimulates early insulin release faster and to a greater extent than repaglinide with insulin levels returning to baseline levels more rapidly (40,41).

### Administration

The recommended starting dose of nateglinide is 120 mg three times per day before meals (1-30 minutes). In patients who are near their glycemic goal when treatment is initiated the recommended starting dose of nateglinide is 60 mg three times per day before meals. The maximum dose of nateglinide is 120 mg three times per day before meals.

The recommended starting dose of repaglinide for patients whose A1c is less than 8% is 0.5 mg before each meal (1-30 minutes). For patients whose A1c is 8% or greater the starting dose is 1 or 2 mg orally before each meal. The patient's dose should be doubled up to 4mg with each meal until satisfactory glycemic control is achieved (should wait one week between increasing dose). The maximum daily dose is 16 mg per day.

### Mechanism of Action

Meglitinides bind to a different site on SUR1 in β cells that is separate from the sulfonylurea binding site ([Figure 4](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F4/?report=objectonly)) (20,40). The effect of meglitinide binding is similar to the effect of sulfonylureas with binding resulting in the closure of the KATP channel leading to cell depolarization and calcium influx resulting in insulin secretion (20,40,41). However, the relatively rapid onset and short duration of action of meglitinides suits their use as prandial glucose-lowering agents (20,40).

### Glycemic Efficacy

Studies have shown that A1c reductions are similar to, or slightly less, than those observed with sulfonylurea or metformin treatment when meglitinides are used as monotherapy (20,40). In studies comparing repaglinide monotherapy with sulfonylurea or metformin therapy the decrease in A1c was similar (40,42). In contrast, a study comparing nateglinide with metformin demonstrated that metformin was more effective in lowering A1c levels (43). In a randomized trial comparing repaglinide and nateglinide in patients with T2DM previously treated with diet and exercise, repaglinide was more effective in lowering A1c levels (1.57% vs. 1.04%) (44). While postprandial glucose levels were similar repaglinide was more effective in reducing fasting glucose levels, probably due to its longer duration of action. These clinical findings can be incorporated into clinical decision making. For example, if the main issue for the patient is postprandial hyperglycemia, and fasting glucoses are near normal, an agent, such as nateglinide, that has a limited effect on the fasting glucose would be ideal. However, if one needs reductions in both fasting and postprandial glucose levels a longer acting agent such as repaglinide is a better choice.

### Other Effects

#### CARDIOVASCULAR DISEASE

The Navigator study was a double-blind, randomized clinical trial in 9,306 individuals with impaired glucose tolerance and either cardiovascular disease or cardiovascular risk factors who received nateglinide (up to 60 mg three times daily) or placebo (45). After 5 years, nateglinide administration did not alter the incidence of cardiovascular outcomes suggesting that meglitinides do not have adverse or beneficial cardiovascular effects. The effect of meglitinides on cardiovascular disease has not been studies in patients with T2DM.

### Side Effects

Similar to sulfonylureas, meglitinides can cause hypoglycemia but the risk of severe hypoglycemia is less (20,40,42). The incidence of hypoglycemia is lower with nateglinide than for repaglinide and nateglinide is less likely to cause severe hypoglycemia (20). In one study, the occurrence of symptomatic hypoglycemia was 2% for nateglinide and 7% for repaglinide (41). Weight gain is also a common side effect of meglitinides (approximately 1-3 kg) with nateglinide leading to less weight gain than repaglinide (20,41).

### Contraindications and Drug Interactions

Because meglitinides are metabolized by the liver these drugs should be used cautiously in patients with impaired liver function (Package insert).

Drugs that inhibit CYP3A4 (for example ketoconazole, itraconazole and erythromycin) or CYP2C8 (for example trimethoprim, gemfibrozil and montelukast) can result in the increased activity of meglitinides enhancing the risk of hypoglycemia and should be avoided if possible (42).

### Summary

Meglitinides can be useful drugs when there is a need to specifically lower postprandial glucose levels (i.e., patients with fasting glucose in desired range but elevated post meal glucose levels). Additionally, because of their short duration of action meglitinides can be useful in patients who eat erratically as this class of drugs can be given only before meals and the duration of action will match the postprandial increase in glucose. The risk of severe hypoglycemia and weight gain is less than sulfonylureas but still must be considered in patients treated with meglitinides. The development of drugs that do not cause weight gain or severe hypoglycemia and lower postprandial glucose levels have resulted in the limited use of meglitinides.

### Table 9. 

Summary of the Advantages and Disadvantages of Meglitinides

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_the_ad_1/?report=objectonly)

Advantages| Disadvantages  
---|---  
Decrease postprandial glucose| Hypoglycemia  
Flexible dosing| Weight gain  
Relatively inexpensive| Frequent dosing  
Short action allowing for missing meals| Need to titrate dose  
  
## METFORMIN

### Introduction

Metformin (Glucophage) is a synthetic analog of the natural product guanidine (20). Since its initial clinical use over 50 years ago, metformin has surpassed the sulfonylureas as the most widely prescribed oral agent for T2DM throughout the world because of its proven efficacy on glycemic control as monotherapy and in combination with many other available agents (20). The widespread acceptance of metformin evolved after the realization that lactic acidosis was not a major problem in individuals with normal renal function. Phenformin, a structural analog of metformin, was previously withdrawn from the market in many countries due its propensity to induce lactic acidosis (20).

### Administration

The usual starting dose of metformin is 500 mg twice a day with meals. After 1-2 weeks the dose can be increased to 1500 mg per day (750 mg twice a day or 500 mg in AM and 1000 mg in PM). After another 1-2 weeks the dose can be increased to 1000 mg twice a day. The slow increase in dosage is to reduce GI side effects and the dose should not be increased if GI side effects are occurring. The maximum dose is 2550 mg per day which can be given as 850 mg three times per day with meals but most patients are treated with 1000 mg twice a day with breakfast and dinner.

The usual starting dose of metformin extended release is 500 mg with the evening meal (largest meal). The dose can be increased by 500 mg weekly depending upon tolerability. The maximum dose is 2000 mg with the evening meal.

Note the dose of metformin may need to be adjusted based on renal function (discussed below).

Metformin should be temporarily discontinued when patients are unable to eat or drink. Metformin is seldom used in hospitalized patients.

### Mechanism of Action

Metformin decreases hepatic glucose production and improves hepatic insulin sensitivity but has only a modest impact on peripheral insulin-mediated glucose uptake (i.e., insulin resistance), which is likely due to a reduction in hyperglycemia, triglycerides, and free fatty acid levels (46,47). Hyperinsulinemia is reduced and the decrease in hepatic glucose production results in a decrease in fasting glucose levels (20). In addition, metformin also increases intestinal glucose utilization and stimulates GLP-1 secretion (46,47). Insulin secretion is not increased (20). The cellular and molecular mechanisms that account for these changes are not definitively understood.

#### LIVER

There are several lines of evidence indicating that the liver plays an important role in metformin's ability to improve glycemic control (46). In humans and rodents, metformin is concentrated in the liver and blocking the uptake of metformin into the liver in mice prevents the ability of metformin to lower blood glucose levels (46,47). As noted above tracer studies in humans show that metformin lowers hepatic glucose production and increases hepatic insulin sensitivity (46). There are a number of proposed mechanisms by which metformin alters hepatic metabolism (46).

1) Metformin inhibits mitochondrial ATP production by inhibition of Complex I of the respiratory chain and/or inhibiting mitochondrial glycerophosphate dehydrogenase, which is required to carry reducing equivalents from the cytoplasm into the mitochondria for re-oxidation (46,47). The decrease in ATP production could decrease hepatic gluconeogenesis (47). This also leads to an increase in AMP.

2) Metformin increases hepatic AMP levels and AMP is a potent allosteric inhibitor of fructose 1,6-bisphosphatase, a key enzyme in gluconeogenesis (47). In addition, high AMP levels inhibit adenylate cyclase reducing cyclic AMP formation in response to glucagon, which also decreases glycogenolysis and gluconeogenesis (i.e., decreases glucagon activity) (47). The increase in AMP also activates AMP-activated protein kinase.

3) Metformin activates AMP-activated protein kinase, which activates catabolic pathways leading to decreased gluconeogenesis, decreased fatty acid synthesis, and increased fatty acid oxidation (46,47). The changes in fatty acid metabolism are thought to account for the improvement in hepatic insulin sensitivity and the decrease in serum triglyceride levels (46).

4) Metformin inhibits glycerol-3-phosphate dehydrogenase increasing the cytosolic redox state resulting in a decreased conversion of glycerol and lactate to glucose (48).

#### INTESTINE

Several lines of evidence indicate that the intestine plays an important role in explaining metformin's ability to lower blood glucose levels. First, a decrease in hepatic glucose production can only partially account for the decrease in blood glucose (46). Second, in humans with loss-of-function variants in SLC22A1, which decrease the uptake of metformin into the liver, the ability of metformin to lower A1c levels is not impaired (46). Finally, a delayed-release metformin that is retained in the gut, with minimal systemic absorption, is as effective at lowering blood glucose as the standard metformin formulation in patients with T2DM (46,49). There are a number of proposed mechanisms for how the intestine accounts for the beneficial effects of metformin.

1) Metformin increases anaerobic glucose metabolism in the intestine resulting in increased intestinal glucose utilization and decreased glucose uptake into the circulation (46). This is likely due to the inhibition of mitochondrial ATP production described above. The increased utilization of glucose by anaerobic metabolism could contribute to metformin induced weight loss.

2) Metformin increases GLP-1 secretion, which could increase insulin secretion and decrease glucagon secretion (46). The increase in GLP-1 could also contribute to the weight loss or weight neutral effects of metformin.

3) Metformin alters the intestinal microbiome, which could alter glucose metabolism (46,50).

It is clear that there are multiple potential mechanisms by which metformin can improve glucose metabolism and further studies are required to elucidate the relative importance and contribution of these proposed mechanisms and others yet to be identified.

### Glycemic Efficacy

Metformin is often used as the initial therapy in patients with diabetes in conjunction with lifestyle changes (6,7). The typical reduction in A1c with metformin therapy is in the range of 1 to 2.0% (20,51). The decrease in A1c induced by metformin is independent of age, weight, and diabetes duration as long as some residual β-cell function remains (20). One retrospective study has reported that African-Americans have a greater decrease in A1c with metformin compared to Caucasians (52). The effect of immediate release and extended release metformin on A1c levels is similar (53). In head-to-head trials, metformin has been shown to produce equivalent reductions in A1c as sulfonylureas and thiazolidinediones but is more potent than DPP-4 inhibitors (51).

The durability of glycemic control with metformin is more prolonged than with sulfonylureas but shorter than with TZDs (29). After 5 years of monotherapy, 15% of individuals on rosiglitazone therapy, 21% of individuals on metformin therapy, and 34% of individuals on glyburide (glibenclamide) therapy had fasting glucose levels above the acceptable range (29). The ability to maintain an A1c <7% was 57 months with rosiglitazone, 45 months with metformin, and 33 months with glyburide (glibenclamide) (29).

In addition to the ability to improve glycemic control in monotherapy, metformin in combination with sulfonylureas, meglinitides, TZDs, DPP-4 inhibitors, SGLT-2 inhibitors, insulin, and GLP-1 receptor agonists lowers A1c levels and often allows for patients to achieve their A1c goals (51). As shown in [Table 3](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.oral_pharmacologi/?report=objectonly) there are a large number of combination tablets that include metformin with other glucose lowering drugs.

Hypoglycemia does not occur with metformin monotherapy (51). Hypoglycemia may occur with metformin during concomitant use with other glucose-lowering agents such as sulfonylureas and insulin.

### Other Effects

#### WEIGHT

Metformin is weight neutral or can sometimes result in a modest weight loss (up to 4 kg) (51). When used in combination with sulfonylureas or insulin it blunts the weight gain induced by these agents.

#### LIPIDS

Metformin decreases serum triglyceride levels and LDL-C levels without altering HDL-C (54,55). In a meta-analysis of 37 trials with 2,891 patients, metformin decreased triglycerides by 11.4mg/dl when compared with control treatment (p=0.003) (54). In an analysis of 24 trials with 1,867 patients, metformin decreased LDL-C by 8.4mg/dl compared to control treatment (p<0.001) (54). In contrast, metformin did not significantly alter HDL-C levels (54). It should be noted that in the Diabetes Prevention Program 3,234 individuals with impaired glucose metabolism were randomized to placebo, intensive lifestyle, or metformin therapy (56). In the metformin therapy group no significant changes were noted in triglyceride, LDL-C, or HDL-C levels compared to the placebo group. Thus, metformin may have small effects on lipid levels.

#### CARDIOVASCULAR DISEASE

In the UKPDS, metformin, while producing a similar improvement in glycemic control as insulin or sulfonylureas, markedly reduced cardiovascular disease by approximately 40% (57). In the ten-year follow-up the patients randomized to metformin in the UKPDS continued to show a reduction in MI and all-cause mortality (58). Two other small randomized controlled trials have also demonstrated cardiovascular benefits with metformin therapy. A study by Kooy et al compared the effect of adding metformin or placebo in overweight or obese patients already on insulin therapy (59). After a mean follow-up of 4.3 years this study observed a reduction in macrovascular events (HR 0.61 CI- 0.40-0.94, p=0.02), which was partially accounted for by metformin's beneficial effects on weight. In this study the difference in A1c between the metformin and placebo group was only 0.3%. Hong et al randomized non-obese patients with coronary artery disease to glipizide vs. metformin therapy for three years (60). A1c levels were similar, but there was a marked reduction in cardiovascular events in the metformin treated group (HR 0.54 CI 0.30- 0.90, p=0.026). These results suggest that metformin may reduce cardiovascular disease and that this effect is not due to improving glucose control. Metformin decreases weight or prevents weight gain and lowers lipid levels and these or other non-glucose effects may account for the beneficial effects on cardiovascular disease. Larger cardiovascular outcome studies are required to definitively demonstrate a beneficial effect of metformin on cardiovascular disease.

#### POLYCYSTIC OVARY SYNDROME (PCOS)

In patients with PCOS metformin lowers serum androgen levels, increases ovulations, and improves menstrual frequency (61). Metformin may also be associated with weight loss in some women with PCOS (61). Metformin combined with clomiphene may be the best combination in obese women with PCOS to improve fertility (61). For a detailed discussion of the treatment of PCOS see the chapter on polycystic ovary syndrome in Endotext (61).

#### CANCER

Multiple epidemiological studies have demonstrated an association between metformin treatment and a reduced cancer incidence and mortality (62,63). Treatment with metformin has been associated with a decreased risk of breast, colon, liver, pancreas, prostate, endometrium and lung cancer and marked reductions in cancer-specific mortality for colon, lung and early-stage prostate cancer and improvements in survival for breast, colon, endometrial, ovarian, liver, lung, prostate and pancreatic cancer (62,63). A wide variety of different mechanisms have been proposed that could account for metformin's anti-tumor effects providing biological plausibility (63). However, data from large randomized controlled trials have not yet definitively demonstrated whether metformin can prevent the development of cancer or is useful in the treatment of cancer (62-65). Further studies are required to elucidate the potential role of metformin in oncology.

### Side Effects

#### GASTROINTESTINAL

The most common side effects of metformin are diarrhea, nausea, and/or abdominal discomfort, which can occur in up to 50% of patients (20,51). These side effects are usually mild and disappear with continued drug administration. The GI side effects are dose-related and slow titration to allow for tolerance can reduce the occurrence of these symptoms (51). Administrating metformin three times a day with meals instead of twice a day may also reduce GI side effects. A small number of patients cannot tolerate the drug, even at low doses (51). Extended-release metformin [metformin XR]) causes fewer GI symptoms and can be used in patients who do not tolerate immediate release metformin (51).

Studies have shown that reduced function of plasma membrane monoamine transporter or organic cation transporter 1 leads to an increase in metformin GI side effects (66,67). Use of drugs that inhibit organic cation transporter 1 activity (including tricyclic antidepressants, citalopram, proton-pump inhibitors, verapamil, diltiazem, doxazosin, spironolactone, clopidogrel, rosiglitazone, quinine, tramadol and codeine) increased intolerance to metformin (66).

#### LACTIC ACIDOSIS

A very rare complication of metformin therapy is lactic acidosis (51). This complication was much more common with phenformin therapy, the initial biguanide, and the risk with metformin is estimated to be 20 times less (51). The estimated incidence of metformin-associated lactic acidosis is 3-10 per 100,000 person-years (51). This is a potentially lethal complication of metformin therapy that typically occurs when renal dysfunction results in very high blood metformin levels, which inhibit mitochondrial function resulting in the overproduction of lactate (51). In addition to renal disorders other risk factors for metformin associated lactic acidosis include sepsis, cardiogenic shock, hepatic impairment, congestive heart failure, and alcoholism (51). In some circumstances the lactic acidosis observed in patients treated with metformin may not be due to metformin but rather to underlying clinical disorders such as severe sepsis.

#### VITAMIN B12 DEFICIENCY

Studies have demonstrated that vitamin B12 malabsorption is a side effect of metformin therapy (51). A randomized controlled trial showed that metformin 850 mg three times per day for over 4 years resulted in a 19% decrease in B12 levels compared to placebo (68). Moreover, 9.9% of patients treated with metformin developed vitamin B12 deficiency (<150 pmol/l) vs. only 2.7% in the placebo group (68). The Diabetes Prevention Program Outcomes Study also demonstrated an increased risk of B12 deficiency with long term metformin use (69). It is now recommended that periodic testing of vitamin B12 levels should be considered in patients on long-term metformin therapy, particularly in the setting of anemia or neuropathy (70).

#### OVULATION AND PREGNANCY

As discussed above in the polycystic ovary section, treatment of premenopausal women with PCOS with metformin may induce ovulation and thereby result in unplanned pregnancies. In premenopausal anovulatory women started on metformin one needs to discuss the need for contraception.

### Contraindications and Drug Interactions

Metformin is contraindicated in patients with advanced kidney or liver disease, acute unstable congestive heart failure, conditions marked by decreased perfusion or hemodynamic instability, major alcohol abuse, or conditions characterized by acidosis (51). Metformin therapy should be suspended during serious illness or surgical procedures. Metformin is seldom used in hospitalized patients.

#### RENAL DISEASE

A major contraindication to the use of metformin is renal disease (51). Metformin is not metabolized and is excreted intact by the kidneys and therefore kidney function is a major determinant of blood metformin levels. eGFR should be obtained prior to initiating therapy. In patients with renal dysfunction or at risk for developing renal dysfunction eGFR should be obtained more frequently. In patients with a eGFR < 30 mL/min/1.73 m2 metformin therapy is contraindicated (51). In patients with an eGFR between 30-60mL/min/1.73 m2 metformin can be used but one should consider using lower doses (51). In patients with eGFR < 45mL/min/1.73 m2 the author typically uses ½ the maximal dose of metformin. In patients with labile renal disease, especially if frequent deteriorations in kidney function occur, metformin is best avoided.

#### IODINATED CONTRAST STUDIES

FDA guidelines indicate that metformin use should be withheld before iodinated contrast procedures if a) the eGFR is 30-60 mL/min/1.73 m2, b) in the setting of liver disease, alcoholism, or heart failure, or c) if intra-arterial contrast is used. The eGFR should be checked 48 hours later and metformin restarted if renal function remains stable.

#### DRUG INTERACTIONS

Carbonic anhydrase inhibitors, such as topiramate or acetazolamide, can decrease serum bicarbonate levels and induce a non-anion gap, hyperchloremic metabolic acidosis. Concomitant use of these drugs with metformin may increase the risk for lactic acidosis (Package Insert).

Certain drugs, such as ranolazine, vandetanib, dolutegravir, and cimetidine, may interfere with common renal tubular transport systems that are involved in the renal elimination of metformin and therefore can increase systemic exposure to metformin and may increase the risk for lactic acidosis (Package Insert).

### Summary

Metformin is a commonly used as the first drug for the treatment of diabetes because of excellent efficacy, an outstanding safety profile, low cost, and a long history of use without significant problems.

### Table 10. 

Summary of the Advantages and Disadvantages of Metformin

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_the_ad_2/?report=objectonly)

Advantages| Disadvantages  
---|---  
Inexpensive| GI side effects  
No hypoglycemia| B12 deficiency  
Once a day administration possible| Lactic acidosis (very rare)  
Long history of use| Need to monitor renal function  
No weight gain and maybe weight loss|   
May decrease cardiovascular disease|   
  
## THIAZOLIDINEDIONES (TZDS)

### Introduction

Troglitazone (Rezulin), pioglitazone (Actos), and rosiglitazone (Avandia) are members of the thiazolidinedione (TZD) class of insulin sensitizing compounds that activate PPAR gamma (20,71). Troglitazone was withdrawn from the US, European, and Japanese markets in 2000 due to an idiosyncratic hepatic reaction leading to hepatic failure and death in some patients (20,71). This idiosyncratic hepatic reaction has not occurred with pioglitazone or rosiglitazone (71). TZDs decrease insulin resistance and thereby enhance the biological response to endogenously produced insulin, as well as exogenous insulin (71).

### Administration

Initiate pioglitazone at 15 mg or 30 mg once a day with or without food. Use 15 mg in patients where there is concern of fluid retention. If there is inadequate glycemic control, the dose can be increased in 15 mg increments up to a maximum of 45 mg once daily.

Initiate rosiglitazone at 4 mg once a day with or without food. If there is inadequate glycemic control, the dose can be increased to a maximum of 8 mg once daily.

Because the maximum effect of TZDs on glycemic control may take 10-14 weeks one should wait 12 weeks before deciding whether to increase the dose of TZDs.

### Mechanism of Action

The primary effect of pioglitazone and rosiglitazone is the reduction of insulin resistance resulting in an improvement of insulin sensitivity (20,71,72). Pioglitazone and rosiglitazone are selective agonists for the PPAR gamma receptor, a member of the super-family of nuclear hormone receptors that function as ligand-activated transcription factors (71,72). In the absence of ligand, PPARs bind as hetero-dimers with the 9-cis retinoic acid receptor (RXR) and a multi-component co-repressor complex to a specific response element (PPRE) within the promoter region of their target genes (71,72). Once PPAR gamma is activated by ligand, the co-repressor complex dissociates allowing the PPAR-RXR heterodimer to associate with a multi-component co-activator complex resulting in an increased rate of gene transcription (71,72). Additionally, PPAR gamma can repress target gene expression by negative feedback on other signal transduction pathways, such as the nuclear factor kB (NF-kB) signaling pathway, in a DNA binding independent manner (71). The target genes of PPAR gamma include those involved in the regulation of lipid and carbohydrate metabolism and inflammation (71,72).

PPAR gamma is highly expressed in adipose tissue while its expression in skeletal muscle is low (71,72). In the liver PPAR gamma expression is low but increases in obesity and thus in obese individuals it is possible that TZDs directly affect the liver (73). It is likely that the primary effects of TZDs are on adipose tissue, followed by secondary benefits on other target tissues of insulin (71). TZDs promote fatty acid uptake and storage in adipose tissue resulting in a decrease in circulating fatty acids and a decrease in fat accumulation in liver, muscle, and pancreas leading to the protection of these tissues from the harmful metabolic effects of higher levels of fatty acids (20,71). This decrease in fat accumulation in liver and muscle leads to an improvement in insulin action and the decrease in the pancreas may improve insulin secretion. Additionally, PPAR gamma agonists increase the expression and circulating levels of adiponectin, an adipocyte-derived protein with insulin sensitizing activity (71). A decrease in the gene expression of other adipokines involved in induction of insulin resistance, such as TNF-alpha, resistin, etc. are likely to also contribute to the improvement in insulin resistance that occurs with TZDs (71). Finally, the activation of PPAR gamma in other tissues may contribute to the beneficial effects of TZDs.

### Glycemic Efficacy

Pioglitazone and rosiglitazone decrease A1c levels to a similar degree as metformin and sulfonylurea therapy (typically a 1.0-1.5% decrease in A1c) (20,71). The decreases in fasting plasma glucose were observed as early as the second week of therapy but maximal decreases occurred after 10-14 weeks (20,74). This differs from other hypoglycemic drugs where the maximal effect occurs more rapidly. TZDs lower both fasting and postprandial glucose levels (71). TZDs are more effective in improving glycemic control in patients with marked insulin resistance (75).

TZDs are effective in combination with other hypoglycemic drugs including insulin (20,41,74). TZDs do not cause hypoglycemia when used as monotherapy or in combination with metformin (20,41). In combination with insulin or insulin secretagogues, TZDs can potentiate hypoglycemia. If hypoglycemia occurs one needs to adjust the dose of insulin or insulin secretagogues.

The durability of glycemic control with TZDs is more prolonged than with either sulfonylureas or metformin (18). After 5 years of monotherapy, 15% of individuals on rosiglitazone, 21% of individuals on metformin, and 34% of individuals on glyburide (glibenclamide) had fasting glucose levels above the acceptable range (18). The ability to maintain an A1c <7% was 57 months with rosiglitazone, 45 months with metformin, and 33 months with glyburide (glibenclamide) (18). Similar results were observed when pioglitazone therapy was compared to sulfonylurea therapy (76). After 2-years of therapy 47.8% of pioglitazone-treated patients and only 37.0% of sulfonylurea-treated patients maintained an A1c <8%. Studies have shown that TZDs improve and preserve beta cell function, which may account for their better durability (77-79).

### Other Beneficial Effects

#### PROTEINURIA

A meta-analysis of 15 studies (5 with rosiglitazone and 10 with pioglitazone) involving 2,860 patients demonstrated that TZDs decreased urinary albumin excretion in patients without albuminuria, in patients with microalbuminuria, and in patients with proteinuria (80).

#### BLOOD PRESSURE

TZDs modestly lower BP. In a review of 37 studies TZDs lowered systolic BP by 4.70 mm Hg and diastolic BP by 3.79 mm Hg (81).

#### LIPIDS

The effect of TZDs on lipids depends on which agent is used. Rosiglitazone increases serum LDL cholesterol levels, increases HDL cholesterol levels, and only decreases serum triglycerides if the baseline triglyceride levels are high [66]. In contrast, pioglitazone has less impact on LDL cholesterol levels, but increases HDL cholesterol levels, and decreases serum triglyceride levels (82). In the PROactive study, a large randomized cardiovascular outcome study, pioglitazone decreased triglyceride levels by approximately 10%, increased HDL-C levels by approximately 10%, and increased LDL-C by 1-4% (83). It should be noted that reductions in the small dense LDL subfraction and an increase in the large buoyant LDL subfraction are seen with both TZDs (82). Treatment with pioglitazone for 12 weeks resulted in a significant increase in the ability of HDL to facilitate the efflux of cholesterol from cells (84).

In a randomized head-to-head trial, it was shown that pioglitazone decreased serum triglyceride levels and increased serum HDL cholesterol levels to a greater degree than rosiglitazone treatment (85,86). Additionally, pioglitazone increased LDL cholesterol levels less than rosiglitazone. In contrast to the differences in lipid parameters, both rosiglitazone and pioglitazone decreased A1c and C-reactive protein to a similar extent. The mechanism by which pioglitazone induces more favorable changes in lipid levels than rosiglitazone is unclear, but differential actions of ligands for nuclear hormone receptors are well described.

#### CARDIOVASCULAR DISEASE

Studies with pioglitazone have suggested a beneficial effect on cardiovascular disease. The PROactive study was a randomized controlled trial that examined the effect of pioglitazone vs. placebo over a 3-year period in patients with T2DM and pre-existing macrovascular disease (87). With regard to the primary endpoint (a composite of all-cause mortality, non-fatal myocardial infarction including silent MI, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle), there was a 10% reduction in events in the pioglitazone group but this difference was not statistically significant (p=0.095). It should be noted that both leg revascularization and leg amputations are not typical primary end points in cardiovascular disease trials and these could be affected by pioglitazone induced edema. When one focuses on standard cardiovascular disease endpoints, the pioglitazone treated group did demonstrate a 16% reduction in the main secondary endpoint (composite of all-cause mortality, non-fatal myocardial infarction, and stroke) that was statistically significant (p=0.027). In the pioglitazone treated group, blood pressure, A1c, triglyceride, and HDL cholesterol levels were all improved compared to the placebo group making it very likely that the mechanism by which pioglitazone decreased vascular events was multifactorial.

The IRIS trial was a multicenter, double-blind trial that randomly assigned 3,876 patients with insulin resistance but without diabetes and a recent ischemic stroke or TIA to treatment with either pioglitazone or placebo (88). After 4.8 years, the primary outcome of fatal or nonfatal stroke or myocardial infarction occurred in 9.0% of the pioglitazone group and 11.8% of the placebo group (hazard ratio 0.76; P=0.007). All components of the primary outcome were reduced in the pioglitazone treated group. Additionally, in the subgroup of patients with "prediabetes" pioglitazone therapy also reduced cardiovascular events (89). Fasting glucose, fasting triglycerides, and systolic and diastolic blood pressure were lower while HDL cholesterol and LDL cholesterol levels were higher in the pioglitazone group than in the placebo group. Although this study excluded patients with diabetes the results are consistent with and support the results of a protective effect of pioglitazone observed in the PROactive study.

In contrast to the above results, a study compared the effect of pioglitazone vs. sulfonylurea on cardiovascular disease and did not observe a reduction in events with pioglitazone treatment (TOSCA.IT) (90). Patients with T2DM (n= 3,028), inadequately controlled with metformin monotherapy (2-3 g per day), were randomized to pioglitazone or sulfonylurea and followed for a median of 57 months. Only 11% of the participants had a previous cardiovascular event. The primary outcome was a composite of first occurrence of all-cause death, non-fatal myocardial infarction, non-fatal stroke, or urgent coronary revascularization and occurred in 6.8% of the patients treated with pioglitazone and 7.2% of the patients treated with a sulfonylurea (HR 0.96; NS). Limitations of this study are the small number of events likely due to low-risk population studied and the relatively small number of participants. Additionally, 28% of the subjects randomized to pioglitazone prematurely discontinued the medication. Thus, the results of this study should be interpreted with caution. Additionally, it should be noted that when patients in this study were analyzed based on the risk of developing cardiovascular disease those at high risk had a marked reduction in events when treated with pioglitazone compared to the sulfonylurea (91).

Further support for the beneficial effects of pioglitazone on atherosclerosis is provided by studies that have examined the effect of pioglitazone on carotid intima-medial thickness. Both the Chicago and Pioneer studies demonstrated favorable effects on carotid intima-medial thickness in patients treated with pioglitazone compared to patients treated with sulfonylureas (92,93). Additionally, in patients with "prediabetes" pioglitazone also slowed the progression of carotid intima-medial thickness (94). Similarly, Periscope, a study that measured atheroma volume by intravascular ultrasonography, also demonstrated less atherosclerosis in the pioglitazone treated group compared to patients treated with sulfonylureas (95).

There are a large number of potential mechanisms by which pioglitazone might reduce cardiovascular disease ([Table 11](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_pioglit/?report=objectonly)) (79). In addition to altering risk factors pioglitazone has direct anti-atherogenic effects on the arterial wall that could reduce cardiovascular disease (79).

### Table 11. 

Effect of Pioglitazone on Cardiovascular Risk Factors

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_pioglit/?report=objectonly)

Cardiovascular Risk Factor| Effect of Pioglitazone  
---|---  
Visceral Obesity| Decreases  
Hypertension| Lowers BP  
High Triglycerides| Lower TG  
Low HDL cholesterol| Increases HDL cholesterol  
Small dense LDL| Converts small LDL to large LDL  
Endothelial dysfunction| Improves  
Hyperglycemia| Lowers A1c  
Inflammation| Lowers CRP  
PAI-1| Lower PAI-1  
Insulin resistance| Reduces  
Hyperinsulinemia| Lowers insulin levels  
  
While the data from a variety of different types of studies strongly suggests that pioglitazone is anti-atherogenic, the results with rosiglitazone are different. Several meta-analyses of small and short-duration rosiglitazone trials suggested that rosiglitazone was associated with an increased risk of adverse cardiovascular outcomes (96,97). However, the final results of the RECORD study, a randomized trial that was specifically designed to compare the effect of rosiglitazone vs. either metformin or sulfonylurea therapy as a second oral drug in those receiving either metformin or a sulfonylurea on cardiovascular events, have been published and did not reveal a difference in cardiovascular disease death, myocardial infarctions, or stroke (98,99). Similarly, an analysis of patients on rosiglitazone in the BARI 2D trial also did not suggest an increase or decrease in cardiovascular events in the patients treated with rosiglitazone (100).

Thus, while the available data indicate that pioglitazone is anti-atherogenic, the data for rosiglitazone suggests a neutral effect. Whether these differences between pioglitazone and rosiglitazone are accounted for by their differential effects on lipid levels or other factors is unknown.

#### METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Studies have shown that pioglitazone has beneficial effects on MASLD and MASH (101). In an early study 55 patients with impaired glucose tolerance or T2DM and liver biopsy-confirmed MASH were randomized to pioglitazone 45 mg/day or placebo (102). After 6 months of therapy liver enzymes improved and hepatic fat decreased, measured by magnetic resonance spectroscopy. Moreover, histologic findings improved including steatosis (P=0.003), ballooning necrosis (P=0.02), and inflammation (P=0.008). However, fibrosis was unchanged. A more recent study randomized 101 patients with prediabetes or T2DM and biopsy-proven MASH to pioglitazone 45 mg/day or placebo for 18 months (103). The primary outcome was a reduction of at least 2 points in the MASLD activity score in 2 histologic categories without worsening of fibrosis. Pioglitazone treatment resulted in 58% of patients achieving the primary outcome vs. only 17% of the placebo group (p<0.001) and 51% had resolution of MASH compared to 19% of the placebo group (p<0.001). Moreover, pioglitazone treatment improved the fibrosis score.

A meta-analysis of 8 randomized controlled trials (5 using pioglitazone and 3 using rosiglitazone) with 516 patients with biopsy-proven MASH reported that TZD treatment was associated with improved advanced fibrosis (OR, 3.15; P = .01), fibrosis of any stage (OR, 1.66; P = .01), and MASH resolution (OR, 3.22; P < .001) (104). Similar results were observed in patients with and without diabetes. Pioglitazone was more effective in improving MASH than rosiglitazone.

These studies demonstrate that pioglitazone has beneficial effects on MASLD and MASH. Whether this will result in improved clinical outcomes will require additional studies. TZDs are not FDA approved for the treatment of MASLD or MASH.

#### POLYCYSTIC OVARY SYNDROME

TZDs by improving insulin sensitivity decrease circulating androgen levels, improve ovulation rates, and improve glucose tolerance in patients with PCOS (61). Small trials have shown some benefit of TZDs for the treatment of infertility, usually in conjunction with clomiphene (61). Concerns regarding toxicity have limited the use of TZDs for the treatment of PCOS but if a patient has diabetes and TZDs are chosen for treating the diabetes one can anticipate beneficial effects on the PCOS.

### Side Effects

#### WEIGHT GAIN

TZDs lead to an increase in body weight of 2 to 3 kg for every 1 percent decrease in A1c levels (71). In some studies patients gained over 4 kg during a 26-week study (71). Weight gain to a similar degree occurred in monotherapy studies and in studies where TZDs were added to metformin, sulfonylureas, or insulin (71). However, in combination with an SGLT2 inhibitor or a GLP-1 receptor agonist the weight gain was blunted or prevented (105,106). In the ADOPT trial weight gain was greater with TZD therapy than with glyburide therapy (2.5 kg over 5 years) (29). The weight gain induced by TZDs is dose related and can be minimized by using low doses (107).

The TZD induced increase in body weight is due to an expansion of the subcutaneous fat depot whereas the mass of visceral fat remains unchanged or even decreases (71). While weight increases, waist circumference typically remains stable. Stimulation of PPAR gamma in subcutaneous adipocytes stimulates lipid accumulation (72). Fluid retention as discussed below may also contribute to the increase in weight.

#### FLUID RETENTION

Edema has been reported in 3.0 to 7.5% of patients treated with the TZDs compared with 1.0 to 2.5% in patients on placebo or treated with other oral antidiabetic therapy (108). The increase in fluid retention is dose related. The risk of developing edema is greatest when a TZD is used in combination with insulin (108). The occurrence of edema is reduced when a TZD is used in combination with an SGLT2 inhibitor (105).

TZD induced edema responds poorly to treatment with thiazide and loop diuretics but responds to diuretics that effect the distal tubules such as spironolactone, triamterene, and amiloride (107). Additionally, edema improves when TZD treatment is discontinued (108). The increased fluid retention can lead to an increase in plasma volume resulting in a modest decrease in hemoglobin levels (2-4%) (107).

The increase in fluid retention is likely due to TZDs activating PPAR gamma in the renal tubules leading to the increased expression of the epithelial Na(+) channel resulting in the increased resorption of sodium (109). TZDs have been shown to decrease urine sodium excretion and to increase plasma renin and aldosterone levels (110).

#### CONGESTIVE HEART FAILURE (CHF)

In a meta-analysis of seven studies with a total of 10,040 participants with 641 CHF events, pioglitazone treatment increased the risk of developing CHF by 33% (RR 1.33, 95% CI 1.14-1.54) (111). Another meta-analysis found that pioglitazone was associated with a 51% increased risk of CHF while rosiglitazone was associated with a 173% increase (112). In the RECORD trial, the rosiglitazone group had an increased rate of severe episodes of CHF resulting in hospital admission or death (OR 2.10, p = 0.001) (98). Similarly, in the PROactive trial, the pioglitazone group also had increased rates of CHF (6% vs. 4%, p = 0.007) (87). Patients treated with TZDs have a higher risk for CHF development if they have a history of cardiovascular disease (107). Interestingly, TZD-associated CHF has not been linked with increased mortality (87,113).

Although TZDs are associated with worsening of CHF or CHF development, they are not associated with adverse effects on cardiac function or structure (107). It is thought that the CHF is mainly due to fluid retention rather than TZDs inducing primarily cardiac dysfunction (107).

#### OSTEOPOROSIS

Large randomized trials have shown that TZDs increase fracture risk, particularly in women. In the ADOPT study, which compared rosiglitazone, metformin, and glyburide, there was no difference in the incidence of fractures in men (114). However, fractures in women at 5 years was increased in the group treated with rosiglitazone (rosiglitazone 15.1%, metformin 7.3%, and glyburide 7.7%) (114). The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and were seen predominantly in the lower and upper limbs (114). In the PROactive study there was a higher rate of bone fractures in females treated with pioglitazone vs. placebo (5.1% vs 2.5%) (115). In the RECORD trial upper and distal lower limb fracture rates were increased mainly in women in the rosiglitazone treatment group (98). Hip and femur fracture were not increased with rosiglitazone treatment (98). In the IRIS trial an increased risk of fracture was seen in both males and females (men 9.4% vs 5.2%; HR, 1.83; women 14.9% vs 11.6%; HR, 1.32) (116). In a meta-analysis of 22 randomized controlled trials with 24,544 participants with 896 fracture cases there was a significantly increased incidence of fracture in women (OR=1.94; P<0.001), but not in men (OR=1.02; P=0.83) treated with TZDs (117). The risk of a fracture was similar with rosiglitazone and pioglitazone treatment and appeared to be similar for participants aged <60 years old and older than ≥60 years of age (117). Of note, in the ACCORD trial the risk of fractures in the women treated with rosiglitazone decreased after discontinuing rosiglitazone therapy (118).

In mice, TZDs suppress bone formation and increase bone resorption resulting in decreased bone mass (85). Additionally, TZD administration in mice results in the massive accumulation of adipocytes in the bone marrow cavity (85). In a meta-analysis of 14 trials with 1,734 participants, treatment with TZDs for 3 to 24 months decreased bone mineral density measured by DEXA at the lumbar spine (difference -1.1%; p < 0.0001), total hip (-1.0%; p < 0.0001) and forearm (-0.9%; p = 0.007) (117). In five studies TZD therapy was discontinued and after 24-52 weeks there was no increase in bone mineral density indicating no restoration of bone mineral density with cessation of TZD treatment (117). In an observation study each year of TZD use was associated with greater bone loss at the whole body (additional loss of -0.61% per year), lumbar spine (-1.23% per year), and trochanter (-0.65% per year) in women, but not in men (119).The effect of TZD treatment on bone turnover markers varied considerably between individual studies (117). This reduction in bone mass induced by TZD treatment could contribute to the increase in fractures but it is possible that changes in the microarchitecture of bone also plays a role.

#### BLADDER CANCER

In preclinical studies pioglitazone administration increased bladder cancer in male rats but not in female rats or in mice, dogs, or monkeys (120). In the PROactive study there was a nonsignificant increase in the number of patients who developed bladder cancer (16 vs 6, p = 0.069) (87). In a number of instances, the development of bladder cancer could not plausibly be related to treatment due to the temporal sequence of drug exposure and cancer diagnosis. After eliminating these patients there were six patients with bladder cancer in the pioglitazone group and three patients in the placebo group (87). After 10 years of follow-up, bladder cancer was reported in 0.8% of patients (n = 14) in the pioglitazone versus 1.2% (n = 21) in the placebo group (relative risk 0.65) during the follow-up period (121). In the IRIS study bladder cancer occurred in 12 patients in the pioglitazone group and in 8 in the placebo group (P=0.37) (88). Thus, in large randomized trials the data do not definitively support that pioglitazone significantly increases the risk of bladder cancer. The short duration of the randomized studies and infrequent occurrence of bladder cancer make interpretation of these studies difficult.

Because of the preclinical data the FDA requested that the manufacturer of pioglitazone initiate a prospective study to examine the relationship between pioglitazone and bladder cancer. This 10-year study of 193,099 persons did not find any statistically significant association between pioglitazone treatment and bladder cancer (122). Additionally, in a multinational cohort of 1.01 million patients with T2DM there was no evidence for any association between cumulative exposure to pioglitazone and bladder cancer in men or women after adjustment for age, calendar year, diabetes duration, smoking, and any ever use of pioglitazone (123). Similarly, no association was observed between rosiglitazone and bladder cancer in men or women (123). In a careful review of 23 epidemiological studies Davidson concluded that there was little evidence that pioglitazone increased the risk of bladder cancer (120). The FDA still warns about the possibility of bladder cancer with pioglitazone use and recommends that pioglitazone not be used in diabetic patients with active bladder cancer or history of bladder cancer (package insert).

#### MACULA EDEMA

Macular edema has been reported in patients taking TZDs (124,125). Patients may present with blurred vision or decreased visual acuity or be diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at the time macular edema was diagnosed (125). Some patients had improvement in their macular edema after discontinuation of the TZD (125).

#### OVULATION AND PREGNANCY

As discussed above in the polycystic ovary section, TZD treatment of premenopausal women with PCOS may induce ovulation and thereby result in unplanned pregnancies. In premenopausal anovulatory women started on a TZD one needs to discuss the need for contraception.

### Contraindications and Drug Interactions

TZDs are contraindicated in patients with NYHA Class III or IV heart failure. Pioglitazone should not be used in diabetic patients with active bladder cancer or history of bladder cancer.

Strong CYP2C8 inhibitors (e.g., gemfibrozil) increase pioglitazone and rosiglitazone concentrations and one should limit pioglitazone dose to 15 mg daily (package insert).

### Summary

TZDs are effective drugs in improving glycemic control and have significant benefits on disorders that occur commonly in patients with T2DM (cardiovascular disease, NAFLD/NASH, PCOS). Unfortunately, TZDs also have serious side effects, such as edema, CHF, osteoporosis, and weight gain, that limit their use. Clinicians need to balance the advantages and disadvantages of TZDs for the individual patient.

### Table 12. 

The Advantages and Disadvantages of Thiazolidinediones

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.the_advantages_an/?report=objectonly)

Advantages| Disadvantages  
---|---  
Once a day administration| Edema  
Reduces CVD (pioglitazone)| Heart failure  
Durable Effect| Weight gain  
Reduces MASLD| Osteoporosis  
No hypoglycemia| Bladder cancer (pioglitazone)?  
Relatively inexpensive| Macula edema?  
No dose adjustment for renal disease| Small increase in LDLc  
Increase HDL-C and decrease triglycerides|   
  
## ALPHA-GLUCOSIDASE INHIBITORS

### Introduction

Acarbose (Precose, Glucobay), miglitol (Glycet), and voglibose (Basen, Voglib) are members of the α-glucosidase inhibitor class of oral anti-hyperglycemic compounds that were introduced in the 1990s (20).

### Administration

The recommended starting dosage of acarbose and miglitol is 25 mg given orally three times daily at the start of each meal. The dose of acarbose and miglitol can be adjusted at 4 to 8-week intervals based on one-hour postprandial glucose or A1c levels, and on tolerance. The dosage can be increased from 25 mg tid with meals to 50 mg tid with meals. The maximum dose is 100 mg tid with meals. Note that the dose can be varied based on the amount of carbohydrate in the meal. In some patients one can initiate therapy once a day with the largest meal.

### Mechanism of Action

Alpha-glucosidase inhibitors are competitive, reversible inhibitors of pancreatic α-amylase and membrane-bound intestinal α-glucosidase hydrolase enzymes (20,126). Inhibiting these enzymes prevents the metabolism of disaccharides and oligosaccharides into monosaccharides delaying carbohydrate digestion and absorption (20,126). Carbohydrate absorption occurs more distally in the intestine reducing the postprandial increase in glucose and lowering postprandial insulin levels (20,126). Acarbose and miglitol have minimal inhibitory activity against lactase and consequently will not prevent the increase in plasma glucose following the ingestion of milk or cause lactose intolerance (package insert). In addition to effecting carbohydrate absorption, alpha-glucosidase inhibitors increase postprandial GLP-1 secretion and reduce glucose-dependent insulinotropic polypeptide (GIP) secretion (20).

### Glycemic Efficacy

The typical decrease in A1c levels is relatively modest with alpha-glucosidase inhibitors (0.5-1.0%) (41,126,127). The decrease in A1c is predominantly due to decreases in post meal glucose levels and alpha-glucosidase inhibitors have only modest effects on fasting glucose levels (20,126,127). Alpha-glucosidase inhibitors can be combined with other hypoglycemic drugs with additive effects and are particularly useful to lower postprandial glucose levels (41,126). Alpha-glucosidase inhibitors are most effective in patients who ingest a high carbohydrate diet and for this reason have been widely used and very effective in Asian populations (20).

These drugs do not cause weight gain and hypoglycemia is uncommon (20,41,127). If a patient experiences hypoglycemia while taking an alpha-glucosidase inhibitor in combination with insulin or sulfonylureas the patient should be instructed to use glucose (gel, tablets, etc.) as alpha-glucosidase inhibitors will prevent the breakdown of sucrose and delay glucose absorption resulting in a failure to quickly correct hypoglycemia. Severe hypoglycemia may require intravenous glucose or intramuscular glucagon administration.

### Other Effects

#### CARDIOVASCULAR DISEASE

In the STOP-NIDDM trial 1,429 subjects with impaired glucose tolerance were randomized to placebo vs. acarbose and followed for 3.3 years (128). In the acarbose group a 49% relative risk reduction in the development of cardiovascular events was observed (hazard ratio 0.51; P =0.03). Among cardiovascular events, the major reduction was in the risk of myocardial infarction (HR 0.09; P =0.02). In a smaller trial, 135 patients hospitalized for the acute coronary syndrome who were newly diagnosed with IGT were randomly assigned to acarbose or placebo (129). During a mean follow-up of 2.3 years the risk of recurrent major adverse cardiovascular event was decreased significantly in the acarbose group compared with the control group (26.7% versus 46.9%, P < 0.05).

Despite these favorable observations a large trial failed to demonstrate a beneficial effect of acarbose in Chinese patients with impaired glucose tolerance (ACE trial) (130). In a randomized trial acarbose vs. placebo was compared in 6,522 patients with coronary heart disease and impaired glucose tolerance. The primary outcome was cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospital admission for unstable angina, and hospital admission for heart failure and patients were followed for a median of 5 years. The primary outcome was similar in the acarbose and placebo groups (hazard ratio 0.98; p=0.73). No significant differences were seen for death from any cause, cardiovascular death, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, hospital admission for unstable angina, hospital admission for heart failure, or impaired renal function.

Thus, whether acarbose favorably affects cardiovascular disease in patients at high risk for developing diabetes is uncertain. Moreover, the effect of acarbose on cardiovascular disease in patients with diabetes is unknown.

#### WEIGHT

Acarbose is may result in a very small decrease in weight (0.4kg) (131).

### Side Effects

Gastrointestinal side effects of alpha-glucosidase inhibitors include flatulence, abdominal discomfort, and diarrhea and are very commonly encountered (20,41,127). These side effects can lead to the inability to tolerate these drugs. A high carbohydrate diet may worsen the GI adverse effects. Over time the GI symptoms tend to decrease as the intestines adapt (126). GI side effects are due to the mechanism of action of alpha-glucosidase inhibitors (126). The inhibition of carbohydrate digestion in the small intestine leads to the delivery of undigested carbohydrates to the large intestine where microorganisms metabolize them into short-chain fatty acids, methane, carbon dioxide, and hydrogen, that can cause abdominal discomfort, increased flatulence, and diarrhea (126).

Acarbose, particularly at doses in excess of 50 mg tid, may give rise to elevations of serum transaminases and, in rare instances, hyperbilirubinemia. It is recommended that serum transaminase levels be checked every 3 months during the first year of treatment with acarbose and periodically thereafter. If elevated transaminases are observed, a reduction in dosage or withdrawal of therapy may be indicated, particularly if the elevations persist (package insert).

### Contraindications and Drug Interactions

Acarbose and miglitol are contraindicated in patients with inflammatory bowel disease, colonic ulceration, intestinal obstruction or those predisposed to intestinal obstruction, patients with chronic intestinal disease, or conditions that will be worsened by the increased gas formation in the intestine (41) (package insert). Acarbose is contraindicated in patients with cirrhosis (package insert).

Acarbose and miglitol should not be used in patients with a creatinine > 2 mg/dl (package insert).

### Summary

Alpha-glucosidase inhibitors are excellent drugs for lowering postprandial glucose levels. Unfortunately, because of their GI side effects many patients are unable to tolerate these drugs. Additionally, the need for three times a day administration makes it difficult for patients to comply with these drugs.

### Table 13. 

Advantages and Disadvantages of Alpha-Glucosidase Inhibitors

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di/?report=objectonly)

Advantages| Disadvantages  
---|---  
No hypoglycemia| GI side effects  
Weight neutral| Frequent dosing schedule  
Decreases postprandial glucose| Avoid if renal disease (creatinine> 2mg/dL  
Relatively inexpensive| Limited glucose lowering effect  
  
## SODIUM-GLUCOSE TRANSPORT PROTEIN 2 (SGLT2) INHIBITORS

### Introduction

There are currently five SGLT2 inhibitors available (Canagliflozin/ Invokana; Dapagliflozin/ Farxiga; Empagliflozin/Jardiance; Ertugliflozin/ Stelgatro; Bexagliflozin/ Brenzavvy) (132). These drugs are very similar and there are only a few differences between these agents.

### Administration

The recommended starting dose of canagliflozin is 100 mg once daily, taken before the first meal of the day. In patients tolerating canagliflozin 100 mg once daily who have an eGFR of 60 mL/min/1.73 m2 or greater and require additional glycemic control, the dose can be increased to 300 mg once daily.

The recommended starting dose of dapagliflozin is 5 mg once daily, taken in the morning, with or without food. In patients tolerating dapagliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 10 mg once daily.

The recommended starting dose of empagliflozin is 10 mg once daily in the morning, taken with or without food. In patients tolerating empagliflozin, the dose may be increased to 25 mg.

The recommended starting dose of ertugliflozin is 5 mg once daily, taken in the morning, with or without food. In patients tolerating ertugliflozin 5 mg once daily who require additional glycemic control, the dose can be increased to 15 mg once daily.

The recommended starting dose of bexagliflozin is 20 mg once daily, taken in the morning, with or without food.

Before initiating SGLT2 inhibitor therapy one should assess renal function and volume status. The dose of SGLT2 inhibitors may need to be adjusted based on renal function (see below).

### Mechanism of Action

SGLT2 is a low-affinity, high-capacity glucose transporter in the proximal tubules of the kidneys, which is responsible for the reabsorption of the majority of the filtered glucose (approximately 90%) entering the tubules (20,133). SGLT1, which is predominantly expressed in the intestines is also expressed in the kidneys, is a high-affinity, low-capacity glucose transporter in the proximal tubules, which makes a minor contribution to the reabsorption of filtered glucose (approximately 10%) (20,133). SGLT 1 and 2 transporters are capable of reabsorbing virtually all the filtered glucose when blood glucose levels are less than approximately 180mg/dL. When blood glucose levels are greater than approximately 180mg/dL, glucose begins to appear in the urine (i.e., glycosuria). The higher the blood glucose level the greater the quantity of glucose in the urine. Patients with T2DM express a greater number of SGLT2 transporters in the proximal tubule than do healthy individuals and hence glucose reabsorption from the glomerular filtrate is increased in patients with diabetes and glycosuria occurs at a higher blood glucose level (typically approximately 220mg/dl (134).

Inhibition of SGLT2 by drugs results in glycosuria and can lead to the excretion of 60-90 grams of glucose in the urine per day ([Figure 5](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F5/?report=objectonly)) (20). The amount of glucose excreted in the urine can vary considerably depending on renal function and the degree of hyperglycemia (20). Decreased renal function results in a decrease in filtered glucose and less glucose in the urine while high blood glucose levels increase filtered glucose and increases the loss of glucose in the urine (20). The ability of the inhibition of SGLT2 to lower blood glucose levels is not dependent on insulin action and hence is not affected by insulin levels or insulin resistance (20). As will be discussed below many of the non-glucose lowering benefits and side effects of SGLT2 inhibitors can be explained by the increase in glucose excretion in the urine. It should be recognized that glycosuria results in an osmotic diuresis. Additionally, because the SGLT2 transporters also facilitate the reabsorption of sodium from the filtrate there is also the loss of sodium in the urine.

![Figure 5. . Effect of SGLT2 Inhibitors on the Kidney.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image005.jpg)

### Figure 5. 

Effect of SGLT2 Inhibitors on the Kidney.

### Glycemic Efficacy

A meta-analysis of 66 randomized trials found that SGLT2 inhibitors decreased A1c levels by 0.4 to 1.1% (135). In comparison to other hypoglycemic drugs, it was found that SGLT‐2 inhibitors showed a greater efficacy than DPP‐4 inhibitors and similar or slightly less efficacy compared to metformin and TZDs (13,135). Sulfonylureas appeared to be superior to SGLT‐2 inhibitors at 12 weeks, but at 24- and 52-weeks efficacy was similar or slightly lower (13,135). However, SGLT‐2 inhibitors produced a greater reduction in HbA1c than sulfonylureas at 104 weeks perhaps due to the lack of durability of sulfonylurea therapy discussed earlier (135). The A1c lowering ability of the different SGLT2 inhibitors is similar but A1c is reduced to a slightly greater extent by high-dose canagliflozin, which is probably a result of its additional action of inhibiting SGLT1 in the intestine decreasing dietary glucose absorption (132,133,135). SGLT2 inhibitors when used as an add-on therapy to metformin, insulin, thiazolidinediones, DPP-4 inhibitors, GLP-1 receptor agonists, sulfonylureas, or metformin ± DPP-4 inhibitor were similarly effective in reducing A1c levels as when used in monotherapy (20,133). The efficacy of SGLT2 inhibitors is dependent on renal function and as renal function decreases the ability of these drugs to lower A1c levels diminishes (20,133). SGLT2 inhibitors lower both fasting and postprandial glucose levels (133). In monotherapy SGLT2 inhibitors have a low risk of causing hypoglycemia but in combinations with insulin or sulfonylureas may potentiate the development of hypoglycemia (20). In patients in good glycemic control, one often decreases the insulin or sulfonylurea dose when initiating therapy with an SGLT2 inhibitor. If glucose levels are very high SGLT2 inhibitors can result in marked polyuria and nocturia that leads to uncomfortable symptoms and therefore many clinicians do not initiate SGLT2 inhibitor therapy in patients with high HbA1c levels until glucose control is in a more reasonable range.

### Other Effects

#### WEIGHT

SGLT2 inhibitors lead to weight loss (20,133). In general patient's lose approximately 1- 3 kg on these drugs (20,132,133). SGLT2 inhibitor-induced weight loss results primarily from a decrease in fat mass, including reductions in visceral and subcutaneous adipose tissue (133). The weight loss is due to the loss of glucose in the urine, which represents the loss of calories (133,136). The excretion of 50 grams of glucose in the urine is equivalent to the loss of 225 calories (50-grams X 4.5 calories per gram of glucose). However, the amount of glucose lost in the urine should result in a greater weight loss than is typically observed and a compensatory increase in food intake blunts the weight loss (136). There are likely to be other homeostatic mechanisms that also play a role in limiting weight loss with SGLT2 inhibitors.

#### GLUCOSE MONITORING

Monitoring glycemic control with 1,5-AG assay is not accurate as measurements of 1,5-AG are unreliable in patients taking SGLT2 inhibitors.

#### BLOOD PRESSURE

SGLT2 inhibitors decrease systolic BP by approximately 3-6 mmHg and diastolic BP by approximately 2-3 mmHg (20,133). Patients with poorly controlled BP at baseline experience the largest reduction in BP (132). SGLT2 inhibitors lower BP by promoting an osmotic diuresis and decreasing intravascular volume (133). Weight loss may also contribute to the decrease in BP.

#### LIPID LEVELS

SGLT2 inhibitors cause a small increase in LDL and HDL cholesterol levels. In the EMPA-REG outcome study, described in detail below, LDL cholesterol levels were increased by 2-4 mg/dL and HDL cholesterol by 2-3 mg/dL in the group treated with empagliflozin (137). Similarly, in the CANVAS outcome study, discussed in detail below, LDL cholesterol and HDL cholesterol were also marginally increased in the canagliflozin treated group (LDL cholesterol 4-5 mg/dL and HDL cholesterol 2-3 mg/dL) (138). In a meta-analysis of 43 randomized trials with 22,528 patient's triglyceride levels were decreased by 2 mg/dL (139). In a meta-analysis of 48 randomized controlled trials SGLT2 inhibitors significantly increased LDL-C (3.8mg/dl, p < 0.00001), HDL-C (2.3mg/dl, p < 0.00001), and decreased triglyceride levels (8.8mg/dl, p < 0.00001) (140). It is unlikely that these small changes in LDL-C, HDL-C, and triglyceride levels are of clinical significance. The mechanism for these increases in LDL and HDL cholesterol is unknown but could be due to a decrease in plasma volume. The decrease in triglycerides might be secondary to weight loss.

#### URIC ACID

SGLT2 inhibitors lower blood uric acid levels (141). This decrease is due to an increase in uric acid excretion by the kidneys. In an observational study 47,905 individuals receiving an SGLT2 inhibitor and 183,303 receiving a DPP4 inhibitor it was observed that the incidence of gout was 20.26 per 1000 patient-years for SGLT2 inhibitor users and 24.30 per 1000 patient-years for DPP4 inhibitor users (142). A similar study found that a gout flare was lower among SGLT2 inhibitor users than DPP-4 inhibitor users (52.4 vs. 79.7 events per 1000 person-years) (143). Additionally, an observations study found that the incidence of gout was lower among SGLT2i initiators than sulfonylurea initiators (HR 0.62; 95% CI, 0.48-0.80) (144).

#### CARDIOVASCULAR

There have been numerous large randomized studies of the effect of SGLT2 inhibitors on cardiovascular events published (others are in progress).

##### EMPA-REG Outcome Trial

In this study, 7,020 patients with established cardiovascular disease and T2DM were randomly assigned to receive 10 mg or 25 mg of empagliflozin or placebo once daily and were followed for 3.1 years (137). In the combined empagliflozin treated groups there was a statistically significant 14% reduction in the primary outcome (death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). As compared with placebo, empagliflozin treatment did not result in a significant difference in the occurrence of non-fatal myocardial infarction or strokes. However, empagliflozin resulted in a significantly lower risk of death from cardiovascular causes (HR 0.62), death from any cause (HR 0.68), and hospitalization for heart failure (HR 0.65). The beneficial effects of empagliflozin were noted to occur very rapidly and the beneficial effects on heart failure appeared to be the dominant effect compared to effects on atherosclerotic events. Decreases in cardiovascular outcomes and mortality with empagliflozin occurred across the range of cardiovascular risk (145). Additionally, the reduction in hospitalizations for heart failure and cardiovascular death were observed both in patients with and without heart failure at baseline (146).

##### CANVAS Trial

The effects of placebo vs. canagliflozin 100mg or 300mg per day were determined in two combined trials involving a total of 10,142 participants with T2DM and high cardiovascular risk (approximately 70% of patients had established cardiovascular disease) (138). The primary outcome was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke and the mean follow-up was 188 weeks. The primary outcome was reduced in the canagliflozin group (HR 0.86; P=0.02). The effect of canagliflozin on the primary outcome was similar in people with chronic kidney disease and those with preserved kidney function (147). Death from any cause (HR 0.87; 95% CI 0.74-1.01) and death from cardiovascular disease (HR 0.87; 95% CI 0.72-1.06) were reduced but were not statistically significant. Similarly, canagliflozin treatment did not result in a significant difference in non-fatal strokes or non-fatal myocardial infarctions. As seen with empagliflozin, hospitalization for heart failure was markedly reduced (HR 0.67; 95% CI 0.52-0.87) and this beneficial effect occurred rapidly.

##### CREDENCE Trial

In a second canagliflozin trial that focused on patients with kidney disease, a decrease in cardiovascular events was also observed (148). In this double-blind trial 4,401 patients with chronic kidney disease and T2DM were randomized to canagliflozin 100mg per day or placebo and followed for a median of 2.62 years. All the patients had an eGFR of 30 to <90 ml per minute per 1.73 m2 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000). In this trial hospitalization for heart failure was reduced by 39%. The relative benefits of canagliflozin for cardiovascular outcomes was similar in individuals across the spectrum of eGFR levels (149)

##### DECLARE-TIMI 58 Trial

The effect of dapagliflozin on cardiovascular events has been reported (150). 17,160 patients with T2DM, including 10,186 without atherosclerotic cardiovascular disease, were randomized to dapagliflozin 10mg per day or placebo and followed for a median of 4.2 years. The primary outcome was a composite of major adverse cardiovascular events (MACE), defined as cardiovascular death, myocardial infarction, or ischemic stroke. Dapagliflozin did not result in a lower rate of major adverse cardiovascular events (8.8% in the dapagliflozin group and 9.4% in the placebo group; HR 0.93; P=0.17) but did result in a lower rate of cardiovascular death or hospitalization for heart failure (4.9% vs. 5.8%; HR 0.83; P=0.005), which reflected a lower rate of hospitalization for heart failure (HR 0.73; 95% CI 0.61 to 0.88). Interestingly, in the patients with a history of a previous MI dapagliflozin reduced the risk of a MACE (HR 0.84; P=0.039), whereas there was no effect in patients without a previous MI (151). Dapagliflozin reduced the risk of heart failure in patients with and without a history of heart failure but the benefit was greater in patients with a history of heart failure (with heart failure HR 0.62; 95% CI 0.45-0.86; without heart failure HR 0.88; 95% CI 0.74-1.03) (152). Dapagliflozin also reduced the risk of heart failure in patients without a history of atherosclerotic cardiovascular disease (153).

##### VERTIS CV

Patients with atherosclerotic cardiovascular disease and T2DM were randomized to ertugliflozin 5mg (n=2752), 15mg (2747), or placebo (n=2747) and the primary composite outcome of cardiovascular death and non-fatal MI or stroke was determined after a mean duration of follow-up of 3.5 years (154). This trial did not demonstrate a significant difference in the primary endpoint (MACE) nor any components of the primary endpoint. However, heart failure hospitalizations were significantly reduced by 30% in the patients treated with ertugliflozin (HR 0.70; CI 0.54-0.90). The benefits on heart failure were observed in both patients with a history of heart failure (decreased 37%) and patients without a history of heart failure (decreased 21%) (155).

##### DAPA HF Trial

In this trial 4,744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to receive either dapagliflozin 10 mg once daily or placebo for a median of 18.2 months (156). The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death. Of note only approximately 45% of the patients had T2DM. Treatment with dapagliflozin reduced the primary outcome (HR 0.74; 95% CI 0.65 to 0.85; P<0.001), heart failure (HR 0.70; 95% CI 0.59 to 0.83), and death from cardiovascular disease (HR 0.82; 95% CI 0.69 to 0.98). Symptoms of heart failure were also improved with dapagliflozin treatment. Additionally, dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death (157). The benefits of dapagliflozin were similar in patients with and without T2DM (158). This study demonstrates that an SGLT2 inhibitor is beneficial in patients with pre-existing heart failure and this occurs in both patients with and without T2DM.

##### EMPEROR-Reduced Trial

In this trial 3,730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to empagliflozin 10 mg once daily or placebo for a median of 16 months (159). The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. Approximately 50% of the patients had T2DM. Treatment with empagliflozin reduced the primary outcome (HR 0.75; 95% CI 0.65 to 0.86; P<0.001) and hospitalization for heart failure (HR 0.69; 95% CI 0.59 to 0.81) but did not reduce cardiovascular death (HR 0.92; 95% CI 0.75 to 1.12). The beneficial effects were observed in patients with and without diabetes. This study is concordant with the results observed in the DAPA HF trial and demonstrates that SGLT2 inhibitors are beneficial in patients with pre-existing heart failure and this occurs in both patients with and without diabetes. Notably, the beneficial effects of empagliflozin on heart failure decreased when the drug was stopped indicating that therapy needs to be continued (160)

##### DAPA CKD Trial

This trial randomized 4,304 participants with an eGFR of 25 to 75 ml/min/1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio 200 to 5000 mg/g to receive dapagliflozin 10 mg daily or placebo for a median of 2.4 years (161). Approximately 67% of the patients had diabetes. The composite of death from cardiovascular causes or hospitalization for heart failure was decreased in the dapagliflozin group (HR 0.71; 95% CI 0.55-0.92).

##### EMPEROR-Preserved Trial

This trial randomized 5,988 patients with heart failure with an ejection fraction of >40% to treatment with placebo or empagliflozin 10 mg daily (162). Empagliflozin decreased the combined risk of cardiovascular death, hospitalization for heart failure, or an emergency or urgent heart failure visit by 23% (HR 0.77; P<0.0001). Moreover, this benefit occurred rapidly reaching statistical significance at 18 days after randomization. The benefit of empagliflozin was similar in patients with an ejection fraction of >40% to <50% and 50% to <60%, but was attenuated at higher ejection fractions. These results indicate that SGLT2 inhibitors are beneficial even in patients with a preserved ejection fraction.

##### Deliver Trial

This trial randomized 6,263 patients with heart failure and a left ventricular ejection fraction greater than 40% to receive dapagliflozin 10 mg once daily or placebo (163). Treatment with dapagliflozin reduced the risk of hospitalization for heart failure by 18% (HR 0.82; P<0.001). Similar benefit was seen in patients with and without diabetes. Additionally, in patients with a left ventricular ejection fraction greater than 60% or those with a left ventricular ejection fraction of less than 60% the results were similar. These results confirm the results of the EMPEROR Preserved Trial described above and further suggest that even patients with heart failure and an ejection fraction greater than 60% will benefit from SGLT2 inhibitors.

##### EMPACT-MI Trial

Patients hospitalized for an acute myocardial infarction were randomized to empagliflozin 10 mg daily (n=3260) or placebo (n=3262) for a median follow-up of 17.9 months (164). Patients were at high risk of heart failure with evidence of newly developed left ventricular ejection fraction <45% or signs or symptoms of congestion plus other factors such as age > 65 years or older, a newly developed ejection fraction < than 35%, T2DM, or an GFR < than 60. Approximately 32% of the participants were diabetic. The composite primary end point of hospitalization for heart failure or death from any cause occurred in 8.2% in the empagliflozin group and 9.1% in the placebo group (HR 0.90; 95% CI 0.76 to 1.06; P=0.21). Death from any cause was similar in both groups but first hospitalization for heart failure occurred in 3.6% in the empagliflozin group and in 4.7% in the placebo group (HR 0.77; 95% CI, 0.60 to 0.98). Total heart failure events were reduced by 33% (risk ratio 0.67; 95% CI 0.51- 0.89; P=0.006) and the decrease was similar in patients with and without diabetes (165). This study demonstrates that initiating SLT2 inhibitor therapy during hospitalization for a myocardial infarction will reduce the occurrence of heart failure in high-risk patients.

##### Summary

Thus, a large number of randomized trials of SGLT2 inhibitors demonstrated a robust decrease in heart failure with SGLT2 inhibitor therapy ([table 14](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_effect/?report=objectonly)) without a consistent strong effect on myocardial infarctions or strokes (166-168). In a meta-analysis of eight of these trials (not including Emperor Preserved or the Deliver Trial) with 59,747 patients it was observed that SGLT2 inhibitors reduced the risk of all-cause mortality (HR 0.84; 95% CI 0.78-0.91), cardiovascular mortality (HR 0.84; 95% CI 0.76-0.93), hospitalization for heart failure (HR 0.69; 95% CI 0.64-0.74), and myocardial infarction (HR 0.91; 95% CI 0.84-0.99), but there was no significant effect on the risk of stroke (HR 0.98; 95% CI 0.86-1.11) (167). The reduction in heart failure was seen in patients with and without diabetes, patients with renal disease, and patients with and without a history of heart failure. The Emperor Preserved and Deliver trial demonstrated that patients with a preserved ejection fraction also benefit from treatment with a SGLT2 inhibitor. Finally, the EMPULSE trial demonstrated that starting empagliflozin during the hospitalization for heart failure was beneficial (169) while the EMPACT-MI Trial demonstrated that starting empagliflozin in patients hospitalized for a myocardial infarction who were at high risk for heart failure also reduced the risk of developing heart failure (164,165).

### Table 14. 

Summary of Effect of SGLT2 Inhibitors on Heart Failure

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_effect/?report=objectonly)

| Number| Prior Heart Failure| Mean Follow-up (years)| Hazard Ratio* (95% CI)| P value  
---|---|---|---|---|---  
EMPA-REG  
Empagliflozin| 7,020| 10.1%| 3.1| 0.65  
(0.05-0.85)| 0.002  
CANVAS  
Canagliflozin| 10,142| 14.4%| 3.6| 0.67  
(0.52-0.87)| \--  
DECLARE-TIMI 58  
Dapagliflozin| 17,160| 10.0%| 4.2| 0.73  
(0.61-0.88)| 0.0007  
VERTIS-CV  
Ertugliflozin| 8,246| 23.7%| 3.0| 0.70  
(0.54-0.90)| 0.006  
CREDENCE  
Canagliflozin| 4,401| 14.8%| 2.6| 0.61  
(0.47-0.80| 0.001  
DAPA-HF  
Dapagliflozin| 4,774| 100%| 1.5| 0.70  
(0.59-0.83)| 0.001  
EMPEROR  
Empagliflozin| 3,730| 100%| 1.3| 0.69  
(0.59-0.81)| <0.001  
EMPEROR Preserved| 5,988| 100%| 2.2| 0.73  
(0.61 to 0.88)| <0.001  
DAPA-CKD| 4,304| 11%| 2.4| 0.71**  
(0.55-0.92)| <0.009  
  
    

Modified from reference (167).

*
    

Hospitalization for Heart Failure.

** 
    

Hospitalization for Heart Failure and death from cardiovascular disease.

A meta-analysis of the effect of SGLT2 inhibitors on patients with diabetes (n= 74,437) and various other disorders (ASCVD, heart failure, and chronic renal disease) is shown in [table 15](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.the_decrease_in_k/?report=objectonly) (168). In patients with diabetes with or without ASCVD, heart failure, or chronic renal disease SGLT2 inhibitors reduced the risk of heart failure and decreased cardiovascular death (the decrease in cardiovascular death was not statistically significant in patients without ASCVD and without heart failure). These results indicate that treatment with an SGLT2 inhibitors will be beneficial in a wide spectrum of patients with diabetes.

### Table 15. 

The Decrease in Key Outcomes in Patients with Diabetes Treated with SGLT2 Inhibitors

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.the_decrease_in_k/?report=objectonly)

| First Hospitalization for Heart Failure| Cardiovascular Death  
---|---|---  
Overall| 28%| 15%  
With ASCVD| 29%| 17%  
Without ASCVD| 37%| 5%*  
With Chronic Kidney Disease| 34%| 17%  
Without Chronic Kidney Disease| 27%| 22%  
With Heart Failure| 28%| 14%  
Without Heart Failure| 28%| 13%*  
  
    

Modified from reference (168).

*
    

not statistically significant.

The mechanisms accounting for the beneficial effects of SGLT2 inhibitors on heart failure are uncertain (170). Glycemic control was better in the SGLT2 inhibitor treated patients but it is doubtful that this modest decrease in glucose could account for the observed results (additionally benefit in non-diabetics makes a glucose effect very unlikely). SGLT2 inhibitor treatment was associated with small reductions in weight, waist circumference, uric acid level, and systolic and diastolic blood pressure, with no increase in heart rate and small increases in both LDL and HDL cholesterol. Whether these changes played a role in reducing events remains to be determined but it is unlikely that these play a major role as other treatments that effect these factors do not markedly diminish the risk of heart failure events. It is possible that hemodynamic changes secondary to the osmotic diuresis induced by SGLT2 inhibitors contributed to the beneficial effects. In an analysis of the EMPA-REG OUTCOME trial, the change in hematocrit (~3% increase), corresponding to ~7% reduction in plasma volume, accounted for approximately 50% of the benefit of the drug on cardiovascular death (171). Additionally, SGLT2 inhibitors increase free fatty acid levels and glucagon secretion, which promotes the production of ketone bodies such as beta-hydroxybutyrate that are utilized by the heart for energy production (172). It is possible that this alternative source of energy could be protective for heart function. Finally, there may be direct effects of SGLT2 inhibition on myocardial and renal metabolism (170,173,174). Further studies are required to better elucidate the mechanism of the beneficial effects of SGLT2 inhibitors on heart failure.

#### RENAL DISEASE

The large randomized SGLT2 inhibitor cardiovascular outcome trials described above also examined the effect of these drugs on renal disease.

##### EMPA-REG Outcome Trial

The effect of empagliflozin on renal outcomes was studied in 4,124 patients with T2DM who were randomized to empagliflozin (10 mg or 25 mg) or placebo (175). The prespecified outcomes were progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease, and incident albuminuria. Worsening nephropathy occurred in 12.7% of patients in the empagliflozin group and in 18.8% of patients in the placebo group, a relative risk reduction of 39% (P<0.001). Progression to macroalbuminuria was reduced 38%, doubling of serum creatinine by 44%, and initiation of renal replacement therapy by 55% (all statistically significant). The renal benefit was seen regardless of baseline eGFR, occurring in individuals with an eGFR as low as 30 mL/min/1.73 m2. While empagliflozin caused an initial decrease in eGFR over the long term eGFR decreased in the placebo group at a more rapid rate than the empagliflozin group. Additionally, patients treated with empagliflozin were more likely to convert from microalbuminuria to normoalbuminuria (HR 1.43; p<0.0001) or from macroalbuminuria to microalbuminuria or normoalbuminuria (HR 1.82; p<0.0001), and were less likely to experience a sustained deterioration from normoalbuminuria to microalbuminuria or macroalbuminuria (HR 0.84; p=0.0077) (176).

##### CANVAS Trial

Similar to the results seen with empagliflozin, canagliflozin has also been shown to decrease renal disease. 10,142 participants with T2DM and high cardiovascular risk were randomly assigned to receive canagliflozin or placebo and were followed for a mean of 188.2 weeks (138). Progression of albuminuria occurred less frequently in the canagliflozin group (HR 0.73; 95% CI 0.67 to 0.79). In addition, regression of albuminuria also occurred more frequently in the canagliflozin group (HR 1.70; 95% CI 1.51 to 1.91). Most importantly, the composite outcome of sustained 40% reduction in eGFR, the need for renal-replacement therapy, or death from renal causes occurred less frequently in the canagliflozin group (HR 0.60; 95% CI 0.47 to 0.77). Annual eGFR decline was slower (slope difference between groups 1.2 mL/min/1.73 m2 per year, 95% CI 1.0-1.4) and mean urinary albumin creatinine ratio was 18% lower (95% CI 16-20) in participants treated with canagliflozin than in those treated with placebo (177). The benefits of canagliflozin on renal disease occurred across a wide spectrum of eGFR ranging from 30-45 to ≥90 and in patients with moderate and severe albuminuria (147,178).

##### CREDENCE Trial

The CREDENCE Trial focused on patients with renal disease. In a double-blind trial 4,401 patients with T2DM and chronic kidney disease were randomized to canagliflozin or placebo and followed for a median of 2.62 years (148). All the patients had an eGFR of 30 to <90 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin-angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. The primary outcome was 30% lower in the canagliflozin group (HR 0.70; P = 0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was 34% lower (HR 0.66; P<0.001), and the relative risk of end-stage kidney disease was 32% lower (HR 0.68; P = 0.002). Benefits were seen regardless of baseline eGFR.

##### DECLARE-TIMI 58 Trial

In this trial of 17,160 participants a secondary outcome was a renal composite outcome defined as a sustained decrease of 40% or more in eGFR to < 60, new end-stage renal disease, or death from renal or cardiovascular causes (150). As seen in the other SGLT2 inhibitor studies there was a decrease in the development of renal disease with the incidence of the renal outcome 4.3% in the dapagliflozin group vs. 5.6% in the placebo group (HR 0.76; 95% CI 0.67 to 0.87). Excluding death from cardiovascular causes as part of the composite endpoint, the reduction in renal events was even more impressive (HR 0.53 p<0.0001) (179). The risk of end-stage renal disease or renal death was lower in the dapagliflozin group than in the placebo group (HR 0.41; p=0.012) (179).

##### VERTIS CV Trial

In VERTIS CV trial the renal composite end point of renal death, dialysis/transplant, or doubling of serum creatinine was reduced but not statistically significant in the ertugliflozin treated group (HR 0.81; CI 0.63-1.04) (154).

##### DAPA-HF Trial

In this trial 4,744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to receive either dapagliflozin 10 mg once daily) or placebo for a median of 18.2 months (156). The renal outcome was a composite outcome of a reduction of 50% or more in the estimated GFR sustained for at least 28 days, end-stage renal disease, or death from renal causes. End-stage renal disease was defined as an eGFR of <15, long-term dialysis, or kidney transplantation. There was a trend towards benefit with dapagliflozin treatment that was not statistically significant due to a small number of events (HR 0.71; 95% CI 0.44 to 1.16).

##### EMPEROR-Reduced Trial

In this trial 3,730 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less were randomized to empagliflozin 10 mg once daily or placebo for a median of 16 months (159). The annual rate of decline in the eGFR was decreased in the empagliflozin group compared to the placebo group (-0.55 vs. -2.28 ml per minute per 1.73 m2 of body-surface area per year, P<0.001). Additionally, a composite renal outcome (chronic dialysis or renal transplantation or a profound, sustained reduction in the eGFR) was decreased in the empagliflozin group (HR 0.50; 95% CI 0.32 to 0.77).

##### DAPA-CKD Trial

In this trial 4,304 individuals with and without diabetes with an eGFR of 25 to 75 and a urinary albumin-to-creatinine ratio of 200 to 5000mg/g were randomized to dapagliflozin 10 mg/day or placebo for a median of 2.4 years (this study was stopped early by the data monitoring board) (161). The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes and this was reduced by 39% in the dapagliflozin group (HR 0.61; 95% CI 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19). All of the components of this primary outcome were decreased in the dapagliflozin group. A sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was reduced by 44% in the dapagliflozin group (HR 0.56; P<0.001). In the subgroup of patients with Stage 4 chronic kidney disease (eGFR< 30) the benefits of dapagliflozin were similar to those described above indicating that even in patients with severe renal disease dapagliflozin is beneficial (180) Finally, the benefits of dapagliflozin were similar in participants with T2DM (36% decrease) and in those without T2DM (50% decrease). Thus, similar to the CREDENCE trial, this trial demonstrates that dapagliflozin decreases renal disease progression in patients with pre-existing renal disease. Moreover, this benefit is seen in patients with and without T2DM. Finally, benefit was observed in the dapagliflozin group regardless of the type of kidney disease (diabetic, ischemic, hypertensive, glomerulonephritis, other, or unknown) (181).

##### EMPA-KIDNEY

6609 patients with chronic kidney disease who had an eGFR > 20 but < 45 or who had an eGFR > 45 but < 90 with a urinary albumin-to-creatinine ratio of at least 200 were randomized empagliflozin 10 mg/day or placebo (182). The primary outcome was a composite of progression of kidney disease (end-stage kidney disease, a sustained decrease in eGFR to <10, a sustained decrease in eGFR of ≥40% from baseline, or death from renal causes) or death from cardiovascular causes. After a median of 2.0 years of follow-up, progression of kidney disease or death from cardiovascular causes occurred in 13.1% in the empagliflozin group and 16.9% in the placebo group (HR 0.72; 95% CI 0.64 to 0.82; P<0.001). Progression of kidney disease occurred in 11.6% in the empagliflozin group and 15.2 of the placebo group (HR 0.71; 95% CI 0.62-0.81). Similar benefits were seen in patients with or without diabetes and in patients with an eGFR < 30 and > 45\. Empagliflozin slowed the rate of progression of chronic kidney disease regardless of the level of albuminuria or the cause of chronic kidney disease (183,184).

##### Summary

Multiple trials clearly demonstrate that SGLT2 inhibitors have beneficial effects on renal function and decrease the development and progression of renal disease ([Table 16](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_sglt2/?report=objectonly)). In a meta-analysis of 8 trials with 59,747 patients there was a robust decrease in the composite end points of renal disease (HR 0.62; 95% CI, 0.56-0.70) (167). The benefits are observed in patients with and without diabetes, with and without renal disease, and also in patients with heart failure. In a smaller meta-analysis this renal disease benefit was seen in patients with and without atherosclerosis (185). These renal benefits are independent of improvement in glycemic control and occurs in patients without diabetes (186). A more recent meta-analysis of 13 studies reported that SGLT-2 inhibitors significantly reduced by 31% the occurrence of a composite primary renal outcome consisting of a doubling of serum creatinine, decline of eGFR > 50%, end-stage kidney disease, renal replacement therapy, transplantation, or renal death (HR 0.69; 95% CI 0.61-0.79) (187).

### Table 16. 

Summary of SGLT2 Inhibitors on Renal Disease

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_sglt2/?report=objectonly)

| Number| Mean Follow-up (years)| Hazard Ratio* (95% CI)  
---|---|---|---  
EMPA-REG; Empagliflozin| 7,020| 3.1| 0.54 (0.40-0.75  
CANVAS; Canagliflozin| 10,142| 3.6| 0.60 (0.47-0.77)  
DECLARE-TIMI 58; Dapagliflozin| 17,160| 4.2| 0.53 (0.43-0.66)  
VERTIS-CV; Ertugliflozin| 8,246| 3.0| 0.81 (0.63-1.04)  
CREDENCE; Canagliflozin| 4,401| 2.6| 0.66 (0.53-0.81)  
DAPA-HF; Dapagliflozin| 4,774| 1.5| 0.71 (0.44-1.16)  
EMPEROR; Empagliflozin| 3,730| 1.3| 0.52 (0.32-0.77)  
DAPA-CKD; Dapagliflozin| 4304| 2.4| 0.56 (0.45-0.68)  
  
*
    

Renal composite outcomes.

The mechanism accounting for this effect is unknown but a leading hypothesis is that an increase of sodium chloride in the macula densa due to SGLT2 inhibition triggers a cascade that reduces GFR through constriction of the afferent glomerular arterioles (tubuloglomerular feedback) (133,186). This would reduce glomerular hydrostatic pressure and initially decrease GFR, an effect that is observed with SGLT2 treatment, but in the long run this decrease in GFR protects the kidney from damage resulting in improved kidney function long-term (133).

#### METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Numerous studies have shown that treatment with SGLT-2 inhibitors decrease liver enzymes (101,188-192). Moreover, studies have shown a decrease in liver fat and liver stiffness (101,188,189,191-193). A study of 5 patients showed an improvement in liver histology after 24 weeks of therapy with canagliflozin (194). Further studies are required to determine whether SGLT-2 inhibitors will result in clinical benefits in patients with MASLD and MASH.

#### MORTALITY

A meta-analysis of 21 randomized controlled trials with 70,364 individuals reported that all-cause mortality was decreased by 14% (195). The decrease in all-cause mortality was seen with all of the SGLT2 inhibitors but was not statistically significant with ertugliflozin.

#### EFFECT OF SGLT2 INHIBITORS IN PATIENTS ON GLP1 RECEPTOR AGONIST THERAPY

A meta-analysis of 12 randomized cardiovascular or renal trials of SGLT2 inhibitors where 3065 (4*2%) of 73,238 participants with T2DM were using GLP-1RA at baseline examined the effectiveness of combination therapy (196). SGLT2 inhibitors reduced the risk of major adverse cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) in individuals both receiving and not receiving GLP-1RA (HR 0.81; 95% CI 0.63-1.03 vs 0.90; 0.86-0.94; p-heterogeneity=0.31). Similarly, the risk of hospitalization for heart failure or cardiovascular death (HR 0.76; 95%CI 0.57-1.01 vs 0.78, 0.74-0.82; p-heterogeneity=0.90), and chronic kidney disease progression (HR 0.65; 95%CI 0.46-0.94 vs 0.67; 0.62-0.72; p-heterogeneity=0.81) in individuals both receiving and not receiving GLP-1RA was reduced. Additionally, SGLT2 inhibitors decreased the rate of decline in eGFR as measured by chronic and total eGFR slope regardless of GLP-1RA use. These results are not surprising as SGLT2 inhibitors and GLP-1RA have different mechanisms of action. Thus, the beneficial effects of SGLT2 inhibitors occur even in patients on GLP1RA therapy.

### Side Effects

In a meta-analysis of 51 randomized controlled trials involving 24,371 patients it was noted that the frequency of side effects was similar with high dose and low dose SGLT-2 inhibitors (197).

#### URINARY TRACT INFECTIONS

In some but not all studies an increased risk of urinary tract infections was observed with SGLT2 inhibitors (20,132). In the large randomized cardiovascular outcome trials, an increase in urinary tract infections were not observed (137,138,150). In a meta-analysis of 10 large outcome trials with 71,553 participants the relative risk of urinary tract infection was minimal (RR 1.06, 95% CI 1.00-1.12) (198). Similarly, another meta-analysis of 213 studies with 150,140 participants found only a small increased risk of urinary tract infections (OR 1.11; 95% CI 1.06- 1.16) (199). In contrast, a meta-analysis of 86 randomized trials with 50,880 patients an increase in urinary tract infections was not observed (200). The potential increase in the occurrence and severity of urinary tract infections is due to the glycosuria as glucose is an excellent substrate for the growth of micro-organisms.

#### GENITAL MYCOTIC INFECTIONS

Genital mycotic infections (mainly balanitis and vulvovaginitis) are increased with SGLT2 inhibitor treatment (132). The risk of genital mycotic infections is greater in women than men. In a meta-analysis that included over 2000 patients treated with canagliflozin 100 mg or 300 mg vs. placebo, genital mycotic infections were seen in greater than 10% of women (100mg-10.4%, 300 mg-11.4%, placebo-3.2%) and around 4% of men (100 mg-4.2%, 300 mg-3.7%, placebo- 0.6%) (201). In a large meta-analysis of 188 studies with 121,275 participants the risk of genital mycotic infections was markedly increased (OR 3.5; 95% CI 3.1-3.9) (199). In uncircumcised men the risk of genital mycotic infections is greater than in circumcised men. Genital mycotic infections are the most common side effect seen with SGLT2 inhibitors but fortunately these infections are generally mild and relatively easy to treat (20).

The increase in genital mycotic infections is due to the glycosuria as glucose is an excellent substrate for the growth of Candida.

#### FOURNIER GANGRENE

Fournier gangrene (FG) is a necrotizing fasciitis of the perineum that is characterized by a rapidly progressive necrotizing infection of the external genitalia, perineum, and perianal region (202). Many of the patients with FG have diabetes (32-66%) (202). FG occurs most commonly in males and is a rare condition with an incidence of 3.3 in 100,000 men aged 50 to 79 years (202). In a recent case series of 59 patients over a 10-year period at a single institution, the incidence was estimated at 32 cases per 100,000 admissions (203). Risk factors included very high A1c (mean 9.6%), obesity, immunocompromised state, and illicit drug use (203). FG is a urologic emergency and requires treatment with broad-spectrum antibiotics and immediate surgical intervention (202).

A recent report described 55 FG cases in patients treated with SGLT2 inhibitors in the last 6 years since they were approved for use in the US (202). In contrast, only 19 cases of FG were reported in 35 years among patients receiving other hypoglycemic drugs. All of the SGLT2 inhibitors were associated with FG except ertugliflozin, which is likely explained by this drug only recently being approved for the treatment of diabetes. However, the authors were unable to assess the incidence of FG or whether SGLT2 inhibitors were causative. A second study compared the occurrence of FG in patients treated with SGLT2 inhibitors (15.0 per 100,000 person-years) vs DPP4 inhibitors (9.7 per 100 000 person-years) in men 65 years and older who have T2DM using large data bases (204). Other studies have not found an increased risk of FG with SGLT2 inhibitors (205,206). A major difficulty in determining if SGLT2 inhibitors actually increase the risk of FG is that FG is very rare making definitive studies difficult.

Early recognition of FG is essential to reduce morbidity and mortality. Typical presentations include systemic symptoms, such as fatigue, fever, and malaise, and local symptoms that include tenderness, erythema, and swelling (202). Pain out of proportion to the clinical findings is highly suggestive of necrotizing fasciitis (202).

#### HYPOVOLEMIA AND HYPOTENSION

SGLT2 inhibitors induce an osmotic diuresis (132). This effect can result in postural dizziness, orthostatic hypotension, falls, and dehydration, particularly in elderly individuals, patients with kidney disease, patients on either diuretics or medications that interfere with the renin-angiotensin-aldosterone system (e.g., angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers), and patients with low systolic blood pressure (132) (package insert). In a meta-analysis of 10 large outcome studies the risk of volume depletion was modestly increased (RR 1.14, 95% CI 1.06-1.23) (198). Volume status should be determined prior to initiating therapy with an SGLT2 inhibitor.

#### ACUTE KIDNEY INJURY

SGLT2 inhibitors have been reported to cause acute kidney injury (132). It is likely that volume depletion and hypotension lead to the acute kidney injury (132). In an analysis of two large health care utilization cohorts SGLT2 inhibitors were not associated with an increased risk of acute kidney injury (207). Similarly, in the cardiovascular outcome studies described earlier an increase in acute kidney injury was not observed. In fact, in a meta-analysis of 4 large studies (EMPA-REG, CANVAS, CREDENCE, and DECLARE-TIMI 58) a decrease in acute kidney injury was observed (Risk ratio 0.75; p<0.0001) (208). Similarly, a meta-analysis of 10 studies with 71,553 participants also did not observe an increase in acute kidney injury and in fact observed a decrease (RR 0.84, 95% CI 0.77-0.91) (198). Even in patients over age 75 years of age an increase in acute kidney injury was not observed with SGLT2 treatment (209).

Before initiating SGLT2 inhibitor therapy one should consider factors that may predispose patients to acute kidney injury including hypovolemia, chronic renal insufficiency, congestive heart failure, and concomitant medications (diuretics, ACE inhibitors, ARBs, NSAIDs). Consider temporarily discontinuing SGLT2 inhibitors in any setting of reduced oral intake (such as acute illness or fasting) or fluid losses (such as gastrointestinal illness or excessive heat exposure) (package insert).

#### DIABETIC KETOACIDOSIS

Diabetic ketoacidosis (DKA) has been observed in patients with T2DM treated with SGLT2 inhibitors but is a rare side effect (20,132). In some instances, the glucose levels are not very elevated despite the patient having DKA (euglycemic DKA) and this can result in a delay in diagnosing DKA (132). SGLT2 inhibitors were associated with approximately twice the risk of diabetic ketoacidosis compared to treatment with DPP-4 inhibitors (210). Additionally, in several of the large cardiovascular studies described above an increase in DKA was observed (CANVAS Trial- canagliflozin 0.6 vs. placebo 0.3 participants with an event per 1000 patient-years; CREDENCE Trial- canagliflozin 2.2 vs. placebo 0.2 per with an event per 1000 patient-years; DECLARE-TIMI 58-dapagliflozin 27 episodes vs placebo 12 episodes; VERTIS trial 0.3% 5mg ertugliflozin, 0.4% 15mg dose, and 0.1% placebo group) (138,148,150,154). In a meta-analysis of 10 studies with 71,553 participants the risk of DKA was increased (RR 2.23, 95% CI 1.36-3.63) (198).

Many of the DKA events occurred in patients with T2DM treated with insulin who had reduced or stopped insulin or experienced an intercurrent illness that could precipitate DKA (20,211). In some instances, the patients were thought to have T2DM but actually had latent autoimmune diabetes of adults (LADA), a form of Type 1 diabetes (20). The hyperglycemia in DKA associated with SGLT2 inhibitors is typically mild because the SGLT2 inhibitors reduce blood glucose levels (20). SGLT2 inhibitors should be temporarily discontinued in clinical situations known to predispose to ketoacidosis (e.g., prolonged fasting due to acute illness or surgery) (package insert). DKA developing during hospitalizations has been described emphasizing the need for vigilance when continuing SGLT-2 inhibitors in patients admitted to the hospital (212). Patients should be educated regarding this potential complication and in high-risk patients (for example patients on insulin therapy with a history of poor glycemic control or DKA) one could provide the patient with methods to measure either blood or urine ketone levels at home to facilitate the early diagnosis of DKA.

A possible mechanism for the increased risk of DKA is SGLT2 inhibitors increasing plasma glucagon levels thereby increasing ketone production (132,211). In combination with the low insulin levels this could potentiate the development of DKA.

#### OSTEOPOROSIS AND FRACTURES

In the CANVAS cardiovascular outcome study, the rate of all fractures was higher in the canagliflozin group than in the placebo group (15.4 vs. 11.9 participants with fracture per 1000 patient-years; HR 1.26; 95% CI 1.04 to 1.52) (138). A similar trend was observed for low-trauma fracture events (canagliflozin 11.6 vs. placebo 9.2 participants with fracture per 1000 patient-years; HR 1.23; 95% CI 0.99 to 1.52) (138). The incidence of fractures in the CANVAS study was increased with canagliflozin vs. placebo across subgroups based on sex, age, duration of Type 2 diabetes, baseline eGFR, and prior fracture history (213). Notably, the increase in fractures associated with canagliflozin treatment began within weeks of drug initiation indicating that the increased risk occurs rapidly (213).

In contrast, both the EMPA-REG, VERTIS, and DECLARE cardiovascular outcome studies did not demonstrate an increase in fractures with empagliflozin or dapagliflozin, respectively (137,150,154). Additionally, in the CREDENCE outcome study, canagliflozin did not increase fracture risk in patients with chronic kidney disease defined as an eGFR of 30 to <90 and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) (148). Similarly, in a pooled analysis of 8 randomized canagliflozin studies with 5867 participants (CANVAS trial excluded) an increase in fractures was not observed (213). Moreover, in a meta-analysis of 27 randomized controlled trials with an average duration of 64 weeks that compared the efficacy and safety of SGLT2 inhibitors to a placebo in 20,895 participants there was no increased risk of fractures with SGLT2 inhibitor treatment (RR 1.02; 95% CI 0.81- 1.28) (214). Similarly, a meta-analysis of 10 large outcome studies also did not observe an increase in fractures (RR 1.03; 95% CI 0.95- 1.12) (198).

Several studies have examined the effect of SGLT2 inhibitors on bone mineral density. Canagliflozin was associated with a decrease in total hip bone mineral density over 104 weeks, (placebo-subtracted changes:100mg -0.9% and 300mg -1.2%), but did not result in changes in bone mineral density in the femoral neck, lumbar spine, or distal forearm (215). In a 2-year study dapagliflozin did not significantly affect bone mineral density at the lumbar spine, femoral neck, or total hip (216). In a 26-week study ertugliflozin also had no adverse effect on bone mineral density (217).

Thus, the evidence that SGLT2 inhibitors increase the risk of osteoporosis and fractures, with the possible exception of canagliflozin, is not very strong. One should recognize though, that hypoglycemia, hypovolemia, and hypotension could increase the risk of falls and thereby increase the risk of fractures in susceptible individuals.

#### AMPUTATIONS

In the CANVAS study described above, canagliflozin was associated with an increased risk of amputations (HR 1.97; 95% CI 1.41 to 2.75), which were primarily at the level of the toe or metatarsal (138). Amputation risk was strongly associated with baseline history of prior amputation and risk factors for amputation (peripheral vascular disease and neuropathy). The risk of amputation was low with 6.3 of participants per 1000 patients-years in the canagliflozin group having an amputation vs. 3.4 in the placebo group. The basis for the increase in amputations is unknown.

However, the EMPA-REG OUTCOME trial with empagliflozin, the DECLARE-TIMI 58 trial with dapagliflozin, and the VERTIS CV trial with ertuglifozin did not report an increase in amputations in the patients treated with an SGLT2 inhibitor (137,150,154,218). Moreover, in the CREDENCE trial, canagliflozin also did not cause an increase in amputations in the patients treated with the SLGT2 inhibitor (148). In a meta-analysis of 7 large cardiovascular/renal outcome trials described above (excluding CANVAS) there was no increased risk of amputations in the SGLT2 inhibitor treated group vs. placebo group (RR 1.09; CI 95% 0.94-1.26) (219). Given that only one of eight large randomized trials has demonstrated an increased risk of amputations it is unlikely that SGLT2 inhibitors significantly increase the risk of amputations.

Nevertheless, before initiating SGLT2 inhibitor therapy one should consider factors in the patient history that may predispose them to the need for amputations, such as a history of prior amputation, peripheral vascular disease, severe neuropathy, and diabetic foot ulcers and weigh the risks and benefits of therapy (package insert).

#### ACUTE ILLNESS

Because of the risk of hypovolemia, hypotension, and DKA the administration of SGLT2 inhibitors should be suspended during acute illness or planned surgical procedures. SGLT2 inhibitor therapy may be resumed following recovery.

This view needs to be modified based on the results of the DARE 19 study and DEFENDER Trial (220,221). In the DARE 19 study patients hospitalized with COVID-19 and with at least one cardiometabolic risk factor (i.e., hypertension, T2DM, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease) were randomized to dapagliflozin 10 mg daily or placebo for 30 days (220). While dapagliflozin did not result in a statistically significant risk reduction in organ dysfunction or death, or improvement in clinical recovery, the drug was well tolerated indicating that SGLT2 inhibitors can be safely given to hospitalized patients if there are strong indications for their use. Additionally, The DEFENDER trial randomized intensive care unit patients to dapagliflozin (n = 248) or placebo (n = 259) hoping to improve outcomes (221). Unfortunately, the addition of dapagliflozin to critically ill patients did not improve clinical outcomes but also did not cause harm.

#### CANCER

A meta-analysis of seventy-six randomized trials with 116,375 participants followed for over 48 weeks did not find an increased risk of cancer or cancer mortality with SGLT2 inhibitors (222).

### Contraindications and Drug Interactions

#### RENAL FUNCTION

The dose of SGLT2 inhibitors needs to be adjusted based on renal function. Therefore, renal function needs to be assessed prior to initiating therapy and periodically thereafter (because changes in the recommendation occur rapidly with SGLT2 inhibitors please check the most recent package insert for the latest guidelines).

Dosage recommendations for dapagliflozin and canagliflozin are shown in [tables 17](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.dose_recommendati/?report=objectonly) and [18](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.dose_recommendati_1/?report=objectonly).

### Table 17. 

Dose Recommendations for Dapagliflozin

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.dose_recommendati/?report=objectonly)

eGFR > 45| To improve glycemic control, the recommended starting dose is 5 mg orally once daily. Dose can be increased to 10 mg orally once daily for additional glycemic control. For all other indications, the recommended starting dose is 10 mg orally once daily.  
---|---  
eGFR 25-45| 10 mg orally once daily  
eGFR < 25| Initiation is not recommended; however, patients may continue 10 mg orally once daily to reduce the risk of eGFR decline, ESKD, CV death, and heart failure.  
Dialysis| Contraindicated  
  
### Table 18. 

Dose Recommendations for Canagliflozin

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.dose_recommendati_1/?report=objectonly)

eGFR > 60| 100 mg orally once daily, taken before the first meal of the day. Dose can be increased to 300 mg once daily for additional glycemic control.  
---|---  
eGFR 30-60| 100 mg once daily.  
eGFR < 30| Initiation is not recommended, however patients with albuminuria greater than 300 mg/day may continue 100 mg once daily to reduce the risk of ESKD, doubling of serum creatinine, CV death, and hospitalization for heart failure  
Dialysis| Contraindicated  
  
Empagliflozin is not recommended for glycemic control in patients with an eGFR < 30 and is contraindicated in patients on dialysis. Data are insufficient to provide a dosing recommendation in patients who have T2DM and established cardiovascular disease with an eGFR less than 30 or who have heart failure with reduced ejection fraction with an eGFR less than 20.

Ertugliflozin is not recommended in patients with an eGFR less than 45 and is contraindicated in patients on dialysis.

Bexagliflozin is not recommended in patients with an eGFR less than 30.

### Summary

SGLT2 inhibitors are effective at lowering glucose levels and even more importantly have beneficial effects on heart failure and renal disease. They have a number of potential side effects but many are not definitively associated with SGLT2 inhibitors (fractures, urinary tract infections, amputations, Fournier's gangrene) or are rare (DKA). The major side effect is genital mycotic infections, which usually are mild and respond to treatment. In patients with pre-existing cardiovascular disease, at high risk for cardiovascular disease particularly heart failure, or with renal disease SGLT2 inhibitors are a leading therapeutic choice.

### Table 19. 

Advantages and Disadvantages of SGLT2 Inhibitors

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_1/?report=objectonly)

Advantages| Disadvantages  
---|---  
Weight loss| Urinary Tract Infections?  
No hypoglycemia| Genital Mycotic Infections  
Decrease heart failure| Increased LDL (small increase)  
Decreases renal disease| Increased risk of DKA  
Once a day administration| Postural hypotension/volume depletion  
Decrease BP| Fractures/ Osteoporosis?  
| Increased risk amputations (canagliflozin)?  
| Fournier's gangrene (rare)?  
| Expensive  
  
## COMBINATION SGLT1 AND SGLT2 INHIBITORS

### Introduction

Sotagliflozin (Zynquista, Inpefa) inhibits both SGLT1 and SGLT2 (223). Sotaglifozin's effectiveness in inhibiting SGLT-2 is similar to that of the selective SGLT-2 inhibitors discussed above but it is > 10-fold more potent in inhibiting SGLT-1 (224)**.** In the US the drug was approved in 2023 to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in patients with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors. Sotagliflozin was approved in Europe for the treatment of patients with type 1 diabetes but is no longer available. It was used in overweight patients (BMI> 27 kg/m2) when optimal insulin on its own does not achieve adequate glycemic control (package insert- https://www.ema.europa.eu/en/documents/product-information/zynquista-epar-product-information_en.pdf).

### Administration

The starting dose of sotagliflozin is 200 mg daily which may be increased to 400 mg as tolerated. In patients with decompensated heart failure, begin dosing when patients are hemodynamically stable. Renal function and volume status should be assessed prior to initiating therapy. Studies with sotagliflozin did not include patients with an eGFR less than 25 or on dialysis and in these studies, sotagliflozin was discontinued if eGFR fell below 15 or chronic dialysis was initiated.

Because of an increased risk of diabetic ketoacidosis ketone monitoring in patients with type 1 diabetes and in others at risk for ketoacidosis (patients with type 2 diabetes on insulin therapy) should be considered, particularly when precipitating conditions for diabetic ketoacidosis occur such as acute febrile illness, reduced caloric intake, ketogenic diet, surgery, insulin dose reduction, volume depletion, or alcohol abuse.

In order to avoid hypoglycemia in patients on insulin a reduction in insulin dose may be considered, particularly in patients with good glycemic control. Similarly, there is a risk of hypoglycemia in patients taking insulin secretagogues.

### Mechanism of Action

The mechanism by which inhibition of SGLT2 decreases glucose levels was discussed in the prior section on SGLT2 inhibitors. Inhibition of SGLT1 will have additional effects. In the kidney SGLT1 is responsible for approximately 10% of the transport of luminal glucose and thus inhibiting SGLT1 may facilitate SGLT2 induced loss of glucose in the urine (223,225). Moreover, SGLT1 is expressed in the small intestine and facilitates the absorption of dietary glucose (223,225,226). SGLT1 expression in the small intestine is increased in patients with diabetes (225,226). Inhibition of SGLT1 delays, and perhaps reduces, glucose absorption, and enhances circulating levels of GLP-1 reducing post-prandial glucose excursions (223,226-228). Finally, SGLT1 is expressed in human heart capillaries and whether this plays a role in cardiac protection remains to be determined (224).

### Glycemic Efficacy

#### TYPE 1 DIABETES (T1DM)

The inTandem1 trial was carried out in North American adults and randomized patients with T1DM to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) (229). Baseline A1c was 7.57% and the placebo-adjusted A1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). At 52 weeks the difference in body weight between the placebo group and 400mg sotagliflozin group was -4.32 kg (-5.00 to -3.64). Notably hypoglycemia was not increased with sotagliflozin treatment. However, DKA occurred more frequently with sotagliflozin treatment (placebo 0.4%, sotagliflozin 200mg 3.4%, sotagliflozin 400mg 4.2%).

The inTandem2 trial was carried out in European adults and randomized patients with T1DM to placebo (n = 258), oral sotagliflozin 200 mg (n = 261), or 400 mg (n = 263) (230). Baseline A1c was 7.7% and the placebo-adjusted A1c reductions were 0.37% and 0.35% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.21% and 0.37% at 52 weeks (all P < 0.001). At 52 weeks the difference in body weight between the placebo group and 400mg sotagliflozin group was −2.92 kg (-3.62 to −2.22). Hypoglycemia was not increased with sotagliflozin treatment. DKA occurred more frequently with sotagliflozin treatment (placebo 0%, sotagliflozin 200mg 2.3%, sotagliflozin 400mg 3.4%).

The inTandem3 trial was a multicenter world-wide study in patients with T1DM randomized to placebo (n=703) or sotagliflozin 400mg (n=699) for 24 weeks (231). The baseline A1c was 8.2% and sotagliflozin decreased A1 by −0.46% compared to placebo. Hypoglycemia with a blood glucose level < 55 mg/dL was significantly lower in the sotagliflozin group than in the placebo group (11.8 per person-year vs. 15.4 per person-year) but severe hypoglycemia (episode needing assistance from another person or resulting in loss of consciousness or a seizure) was similar. Notably the risk of DKA was increase with sotagliflozin treatment (sotagliflozin 3.0% and placebo 0.6%).

Thus, in patients with T1DM sotagliflozin causes a modest reduction in A1c and body weight but increases the risk of DKA.

#### TYPE 2 DIABETES

Studies of the effect of sotagliflozin on glycemic control in patients with T2DM have not been as extensive as in patients with T1DM. In a 12-week trial that compared placebo (n= 60), sotagliflozin 200mg (n= 60), or sotagliflozin 400mg (n= 60) in patients with T2DM on metformin monotherapy a decrease in A1c of -0.09%, -0.50, and -0.92% occurred in patients treated with placebo, sotagliflozin 200mg, and sotagliflozin 400mg, respectively (232). As expected, there was a decrease in body weight and an increase in urinary glucose excretion with sotagliflozin treatment. Of note a study has shown that in patients with T2DM sotagliflozin treatment is effective in lowering postprandial glucose levels even in patients with an eGFR < 45 mL/min/1.73 m2 (233).

In a small study comparing the effect of sotagliflozin and empagliflozin the decrease in A1c levels were very similar as were measurements of glycemia using continuous glucose monitoring (234).

### Other Effects

#### CARDIOVASCULAR

The SOLOIST-WHF Trial was a multicenter trial in which patients with T2DM who were recently hospitalized for worsening heart failure were randomly assigned to receive sotagliflozin 200 mg once daily (with a dose increase to 400 mg, depending on side effects) (n= 608), or placebo (n= 614) (235). The primary end point was the total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure (first and subsequent events). Because of loss of funding from the sponsor the study was stopped early and the median duration of follow-up was only 9 months. The primary end-point was reduced in the sotagliflozin group vs. placebo group (HR 0.67; 95% CI, 0.52 to 0.85; P<0.001) as was hospitalizations or urgent visits for heart failure (HR 0.64; 95% CI, 0.49 to 0.83: P <0.001). Of particular note benefit was observed in patients with reduced or preserved ejection fractions (<50% or ≥50%). This study demonstrates benefits in patients with a reduced or preserved ejection fractions and that treatment initiated during an acute heart failure episode is beneficial. DKA was uncommon in both the sotagliflozin group (0.3%) and placebo group (0.7%) but severe hypoglycemia was increased (sotagliflozin 1.5% vs placebo 0.3%).

The SCORED trial was a multicenter trial in which patients with T2DM and chronic kidney disease (eGFR- 25 to 60 ml/min/1.73 m2, albuminuria was not required), and risks for cardiovascular disease were randomized to sotagliflozin (200 mg once daily, with an increase to 400 mg once daily if unacceptable side effects did not occur) (n= 5292) or placebo (n= 5292) and followed for a median of 16 months (236). The primary end point was the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. Sotagliflozin treatment decreased the primary end point (HR 0.74; 95% CI, 0.63-0.88; P <0.001), hospitalizations or urgent visits for heart failure (HR 0.67; 95% CI, 0.55-0.82; P <0.001), and deaths from cardiovascular causes, nonfatal myocardial infarctions, and nonfatal strokes (HR 0.77; 95%CI 0.65-0.91). Sotagliflozin reduced the risk of renal disease defined as first event of sustained ≥50% decline in eGFR, eGFR <15, dialysis, or kidney transplant with 1.6% events in the sotagliflozin group and 2.6% events in the placebo group (HR 0.62; 95% CI 0.48 - 0.82; P < 0.001) (237). A1c was decreased by 0.42% compared to placebo. DKA while infrequent was increased in the sotagliflozin group (0.6% vs 0.3%; P=0.02).

#### RENAL

As noted above in the SCORED trial in patients with T2DM there was a reduction in renal disease endpoints in the participants treated with sotagliflozin.

### Side Effects

The side effects of sotagliflozin are similar to those described previously for SGLT2 inhibitors. In addition, sotagliflozin also causes diarrhea and flatulence due to the inhibition of SGLT1 mediated glucose uptake in the small intestine.

### Contraindications and Drug Interactions

Patients at high risk for DKA should not be started on sotagliflozin. Sotagliflozin is not recommended during the second and third trimesters of pregnancy or during breastfeeding.

### Summary

In patients with T1DM sotagliflozin modestly reduces A1c levels and body weight but increases the risk of DKA. In patient with T2DM sotagliflozin reduces A1c levels more effectively and decreases body weight with a relatively low risk of DKA.

While studies have shown beneficial effects of sotagliflozin on the development of heart failure and renal disease it is not clear whether this benefit is solely due to inhibition of SGLT2 or whether inhibition of SGLT1 plays a significant role.

## DOPAMINE AGONIST (CYCLOSET)

### Introduction

In 2009, a quick-release formulation of bromocriptine (Cycloset, bromocriptine-QR) was approved to improve glycemic control in patients with T2DM (238,239). Bromocriptine is a centrally-acting dopamine D2 receptor agonist that has been used for many years for the treatment of hyperprolactinemia and Parkinson's disease (238,239). It can be used to improve glycemic control in patients with T2DM either as monotherapy or in combination with other hypoglycemic drugs (238,239).

### Administration

Bromocriptine-QR should be initiated at one tablet (0.8 mg) within two hours after waking in the morning. The dose can be increased by one tablet per week until a maximum daily dose of 6 tablets (4.8 mg) or until the maximal tolerated number of tablets between 2 and 6 per day is reached. Taking bromocriptine-QR with food is recommended to decrease gastrointestinal side effects (238).

### Mechanism of Action

Bromocriptine-QR decreases insulin resistance resulting in an increase in glucose disposal and a decrease in hepatic glucose production (238). Bromocriptine-QR does not increase insulin levels (238). Thus, the effectiveness of bromocriptine-QR will be greatest in patients that are insulin resistant and produce insulin (238). Based on animal studies it is thought that bromocriptine-QR acts on the central nervous system, particularly the hypothalamus, to increase insulin sensitivity in liver, muscle, and adipose tissue (238).

### Glycemic Efficacy

In a 24 week monotherapy study the A1c level was 0.4% lower in the bromocriptine-QR group compared to placebo group (240). Both fasting and postprandial glucose levels were decreased with bromocriptine-QR treatment (240). Bromocriptine-QR treatment was associated with a decrease in triglyceride levels (32 mg/dL) but no significant change in LDL or HDL cholesterol levels or change in body weight (240). A trial adding bromocriptine-QR to sulfonylurea therapy demonstrated a 0.55% lower A1c in the bromocriptine-QR group compared to placebo (240). As in the monotherapy study fasting glucose, postprandial glucose, and triglyceride levels were decreased with no change in LDL or HDL cholesterol levels (240). Addition of bromocriptine-QR to other hypoglycemic drugs including insulin results in an approximate decrease in A1c of 0.5 to 1.0% (238,239). Hypoglycemia is a rare side effect with use of bromocriptine-QR alone, but is increased with use of insulin secretagogue therapy or insulin (239,240).

### Other Effects

#### BLOOD PRESSURE

Bromocriptine-QR modestly decreases systolic and diastolic blood pressure (239,240).

#### LIPIDS

Bromocriptine-QR treatment decreases triglyceride levels but has no significant effect on LDL or HDL cholesterol levels (239,240). The decrease in triglyceride levels is thought to be due to a decrease in hepatic triglyceride synthesis, likely due to a decrease in adipose tissue lipolysis resulting in decreased blood free fatty acid levels and decreased delivery of fatty acids to the liver for triglyceride synthesis (238).

#### CARDIOVASCULAR DISEASE

A 52-week, randomized, double-blind, multicenter trial evaluated cardiovascular safety in 3,095 patients with T2DM treated with bromocriptine-QR or placebo (241). The composite end point of first myocardial infarction, stroke, coronary revascularization, or hospitalization for angina or congestive heart failure occurred in 1.8% of the bromocriptine-QR treated vs. 3.2% of the placebo-treated patients resulting in a 40% decrease in cardiovascular events (HR 0.60; CI 0.37- 0.96). Clearly further studies to confirm this finding and to elucidate the mechanism of this beneficial effect are required.

### Side Effects

The most common side effect of bromocriptine-QR therapy is nausea which is usually transient and improves with time (239,240). This side effect can be minimized by reducing the dose (239,240). In the pooled phase 3 trials adverse events leading to discontinuation occurred in 539 (24%) of the bromocriptine-QR treated patients and 118 (9%) of the placebo-treated patients. This between-group difference was driven mostly by gastrointestinal adverse events, particularly nausea (package insert). Similarly, in the bromocriptine-QR safety trial adverse events leading to discontinuation of drug occurred in 24% of the bromocriptine-QR treated patients and 15% of the placebo-treated patients, a difference again driven mostly by gastrointestinal adverse events, particularly nausea (package insert).

Hypotension resulting in syncope can occur particularly in patients on anti-hypertensive medications (package insert). Other side effects include somnolence, fatigue, vomiting, headache, and dizziness (package insert).

### Contraindications and Drug Interactions

Bromocriptine-QR is metabolized by the Cyp3A4 system and therefore the drug should not be used with strong CYP3A4 inhibitors (e.g., azole antimycotics, HIV protease inhibitors) and the dose should not exceed 1.6 mg during concomitant use of a moderate CYP3A4 inhibitor (e.g., erythromycin) (package insert).

Bromocriptine-QR is contraindicated in patients with syncopal migraine because it increases the likelihood of a hypotensive episode (package insert). The use of bromocriptine-QR in patients with severe psychotic disorders in not recommended as it may exacerbate the disorder or diminish the effectiveness of drugs used to treat the disorder (for example clozapine, olanzapine, ziprasidone) (package insert).

### Summary

Bromocriptine-QR has modest effects on A1c levels by decreasing insulin resistance. In clinical trials the drug was often discontinued due to nausea. Because of the modest effects on A1c and the prominent side effects this drug is not widely used in the treatment of patients with T2DM. If further studies confirmed the decrease in cardiovascular events in patients treated with bromocriptine-QR the use of this drug would increase.

### Table 20. 

Advantages and Disadvantages of Bromocriptine-QR

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_2/?report=objectonly)

Advantages| Disadvantage  
---|---  
Decreases triglycerides| Need to titrate dose  
Once a day dosing| Modest effect on A1c  
Cardiovascular benefits?| Frequent discontinuation due to GI side effects  
Decrease BP| Expensive  
Neutral weight effect|   
Hypoglycemia uncommon|   
  
## OVERVIEW OF THE INCRETIN SYSTEM

The incretin effect refers to a greater insulin stimulatory effect after an oral glucose load than from an intravenous (IV) glucose infusion when plasma glucose concentrations are matched (242). Thus, glucose and other nutrients delivered via the gastrointestinal tract potentiates the ability of the beta cells in the pancreas to produce insulin resulting in greater insulin secretion than with IV glucose (243). The increase in insulin levels with IV glucose is only approximately one‐third of that elicited by oral glucose. The majority of the incretin effect is due to two GI hormones, glucose-dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1) with GIP having a dominant role ([Figure 6](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F6/?report=objectonly)) (242). The basal plasma levels of the incretin hormones are low but after eating the levels increase reaching concentrations that augment the insulin secretory responses if glucose levels are high but are ineffective at low glucose concentrations (i.e. glucose dependent effect) (242).

Patients with T2DM have a significant reduction of the incretin effect but GLP-1 and GIP levels in the blood after meals are not reduced in patients with T2DM (242). Rather decreased functional beta cell mass and resistance to the effects of GLP-1 and GIP in patients with T2DM accounts for the decreased incretin effect (242). Infusion of GIP or GLP-1 has a decreased effect on insulin secretion in patients with T2DM (resistance to effect of GIP and GLP-1) compared to normal individuals likely secondary to decreased functional beta cell mass (242). Achieving near-normoglycemia by intensified insulin regimens improved beta cell responsiveness to exogenous GIP and GLP-1, although the increase in insulin secretion was still much lower than in individuals without diabetes (242). The reduced incretin effect in patients with T2DM occurs after the diagnosis of diabetes is established, suggesting this abnormality is secondary to the diabetic state rather than the cause of diabetes (243).

### Glucagon Like Peptide-1 (GLP-1)

GLP-1 is cleaved from the pro-glucagon molecule by pro-hormone convertase enzymes in the intestine (243). GLP-1 is stored in the L-cells of the intestine, predominantly in the ileum and colon, and is released at mealtime in response to neurohormonal signals and the presence of food in the gut (242,243). GLP-1 affects postprandial glucose levels through several mechanisms, including enhancing insulin secretion by the beta cells and inhibiting postprandial glucagon secretion by the alpha cells in a glucose-dependent manner (i.e. GLP-1 does not stimulate insulin secretion or inhibit glucagon secretion unless glucose levels are elevated) (243). This glucose dependent effect accounts for why incretin-based drugs do not cause serious hypoglycemia. Activation of GLP-1 receptors on beta cells increases cAMP levels, which potentiates insulin release in the presence of elevated glucose concentrations. In addition, GLP-1 slows the rate of gastric emptying, which is often paradoxically accelerated in patients with diabetes (243). GLP-1 also acts as a postprandial satiety signal through neurohormonal networks that signal the brain to suppress appetite and food intake, which can lead to weight loss (243). Animal studies suggest that exogenous GLP-1 has the ability to increase islet size, enhance beta-cell proliferation, inhibit beta-cell apoptosis, and regulate islet growth (244). The administration of GLP-1 intravenously increases insulin secretion, reduces glucagon secretion, and decreases glucose levels during fasting and in the post-prandial state (242). GLP-1 is rapidly degraded by dipeptidyl peptidase 4 (DPP-4) into inactive peptides (half-life is minutes) ([Figure 6](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F6/?report=objectonly)).

![Figure 6. . Incretin Hormone Secretion and Effect on Pancreas.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image006.jpg)

### Figure 6. 

Incretin Hormone Secretion and Effect on Pancreas.

### Glucose-Dependent Insulinotropic Peptide (GIP)

Within minutes after ingestion of food, GIP is secreted from the K-cells located in the proximal region of the jejunum (242,243). GIP helps maintain normal glucose homeostasis by stimulating an increase in insulin secretion by the beta cells ([Figure 6](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F6/?report=objectonly)). Studies have suggested that the increase in insulin with food intake (Incretin effect) is primarily mediated by GIP (242). In contrast to GLP-1, GIP does not inhibit glucagon secretion, and in fact may stimulate glucagon secretion during euglycemic states. Additionally, GIP has no effect on gastric emptying. GIP concentrations in patients with T2DM are either normal or slightly increased following a meal indicating that the failure to secrete is not the explanation for the decreased incretin effect. Rather, beta cells in patients with T2DM are resistant to GIP. GIP is rapidly degraded by DPP-4 into inactive peptides (half-life is minutes) ([Figure 6](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F6/?report=objectonly)). The characteristics of GLP-1 and GIP are shown in [table 21](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.characteristics_o/?report=objectonly).

### Table 21. 

Characteristics of GLP-1 and GIP

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.characteristics_o/?report=objectonly)

| GLP-1| GIP  
---|---|---  
Post meal levels in patients with diabetes| Normal| Normal  
Effect on insulin secretion| Stimulates| Stimulates  
Effect on glucagon secretion| Inhibits| No effect or stimulates  
Gastric emptying| Delays| No effect  
Satiety| Induces| Induces  
Degradation by DPP-4| Yes| Yes  
  
## DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS

### Introduction

The currently available DPP-4 inhibitors in the US are sitagliptin (Januvia), saxagliptin (Onglyza), linagliptin (Tradjenta), and alogliptin (Nesina). Vidigliptin (Galvus) is available in Europe (245). DPP-4 inhibitors can be used as monotherapy, dual therapy, triple drug therapy, or in combination with insulin (245). These drugs are very similar and the minor differences will be discussed below.

### Administration

The recommended dose of sitagliptin is 100 mg once daily with or without food. In patients with moderate renal impairment (eGFR >30 mL/min/1.73 m2 but < 45, the dose of sitagliptin is 50 mg once daily. In patients with severe renal impairment (eGFR <30) the dose of sitagliptin is 25 mg once daily.

The recommended dosage of saxagliptin is 2.5 mg or 5 mg once daily with or without food. In patients with a creatinine clearance CrCl ≤50 mL/min the dose of saxagliptin is 2.5 mg.

The recommended dose of linagliptin is 5 mg once daily with or without food. No dose adjustment is required for decreased renal function.

The recommended dose of alogliptin is 25 mg once daily with or without food. The dose of alogliptin is 12.5 mg once daily for patients with moderate renal impairment (CrCl ≥30 to <60 mL/min) and 6.25 mg with severe renal impairment (CrCl <30 mL/min).

Renal function should be checked prior to initiating treatment and periodically because dose adjustments are required for all DPP-4 inhibitors except linagliptin.

### Mechanism of Action

DPP-4 inhibitors increase the concentration and activity of the endogenous incretins, GLP-1 and GIP, by inhibiting the proteolytic cleavage of these hormones by DPP-4, into inactive molecules (245). As discussed above, GLP-1 is secreted by L-cells in the intestines and stimulates insulin secretion and suppresses glucagon secretion in a glucose dependent manner. GIP is secreted by the K cells in the proximal intestine and stimulates insulin secretion in a glucose dependent manner.

An increase in active GLP-1 and GIP potentiates glucose induced insulin secretion and an increase in GLP-1 inhibits glucagon secretion (245). Together an increase in insulin and a decrease in glucagon will result in a decrease in blood glucose levels. Of note, DPP-4 inhibition results in a 2-3-fold increase in postprandial active GLP-1 levels, which is not at a level that delays gastric emptying or increases satiety and induces weight loss. This is in contrast to GLP-1 receptor agonist administration that results in marked elevations in active GLP1 activity that is equivalent to a >10-fold increase in GLP-1, which can delay gastric emptying and increase satiety.

### Glycemic Efficacy

DPP-4 inhibitors typically reduce A1c levels by 0.5-1.0% and are less effective in lowering A1c compared to metformin, TZDs, SGLT2 inhibitors, and GLP-1 receptor agonists ([Table 6](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly)) (13,20,245). With regards to sulfonylureas, studies have shown a greater decrease in A1c with sulfonylureas compared to DPP-4 inhibitors in short term studies but in studies greater than one year the effect of sulfonylureas and DPP-4 inhibitors on A1c were similar (20,245). The ability of DPP-4 inhibitors to lower A1c is similar in monotherapy and when DPP-4 inhibitors are used in combination with other drugs (20,245). The decrease in A1c is similar for the different DPP-4 inhibitors (13,20). DPP-4 inhibitors are effective in lowering postprandial glucose levels. Because of their mechanism of action, DPP-4 inhibitors do not cause hypoglycemia but can potentiate the hypoglycemia induced by insulin or sulfonylureas (20,245). An adjustment in the dose of sulfonylureas or insulin may be required to reduce the risk of hypoglycemia.

The results of the GRADE study, which compared glargine insulin, glimepiride, liraglutide, and sitagliptin added to metformin, are discussed in the section entitled "OVERVIEW OF DRUGS". The GLP1 receptor agonist was better than the sulfonylurea which was better than DPP-4 inhibitor in glycemic control (15).

### Other Effects

#### WEIGHT

DPP-4 inhibitors are weight neutral (20,245).

#### BLOOD PRESSURE

A meta-analysis of 15 trials involving 5,636 participants found that DPP-4 inhibitors compared to placebo reduced systolic BP (mean difference, -3.04  mmHg: P < 0.00001) and diastolic BP (mean difference, -1.47 mmHg; P < 0.00001) (246).

#### LIPIDS

DPP-4 inhibitors decrease postprandial triglycerides by reducing circulating chylomicrons by decreasing intestinal lipoprotein production while having minimal effects on fasting lipid levels (247).

#### CARDIOVASCULAR DISEASE

The effect of the DPP-4 inhibitors saxagliptin, alogliptin, sitagliptin, and linagliptin on cardiovascular endpoints has been reported. In the saxagliptin study (SAVOR‐TIMI 53 trial), 16,492 patients with T2DM who had a history of cardiovascular events or who were at high risk were randomized to saxagliptin or placebo for 2.1 years (248). Saxagliptin did not increase or decrease cardiovascular death, myocardial infarction, or ischemic stroke. Interestingly more patients treated with saxagliptin were admitted to the hospital for heart failure. The risk of heart failure with saxagliptin was greatest in patients at a high overall risk of heart failure (i.e., history of heart failure, impaired renal function, or elevated baseline levels of NT-proBNP) (249). Additionally, in the patients treated with saxagliptin the increase in heart failure was an early event with a 6-month rate of 1.1% vs. 0.6% in the placebo group (HR 1.80, p=0*001) and a 12-month rate of 1*9% vs. 1*3% (1.46; p=0.002) (249). In contrast, after 12 months no difference in the rate of heart failure was observed in the saxagliptin and placebo groups indicating that the development of heart failure is an early event (249)

In the alogliptin trial (EXAMINE), 5,380 patients with either an acute myocardial infarction or unstable angina within the previous 15-90 days were randomized to alogliptin or placebo and followed for a median of 18 months (250). As seen in the saxagliptin study the rates of cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke) were similar in the alogliptin and placebo groups. The risk of hospitalization for heart failure was not statistically increased in the entire subset of patients treated with alogliptin (251). However, the hazard ratio for the subgroup of patients without heart failure at baseline was 1.76, p=0.026) (251).

In the sitagliptin trial (TECOS), 14,671 patients with established cardiovascular disease were randomized to sitagliptin or placebo for 3 years (252). Sitagliptin did not decrease the risk of major adverse cardiovascular events or increase hospitalization for heart failure. Finally, in the linagliptin trial (CARMELINA), 6,979 patients at high risk for cardiovascular disease were randomized to linagliptin or placebo for a median follow-up of 2.2 years (253). As in the other DPP-4 inhibitor studies, linagliptin did not have a beneficial effect on cardiovascular events. Additionally, linagliptin did not increase the risk of hospitalization for heart failure (254).

Thus, these results indicate that DPP-4 inhibitors do not reduce cardiovascular disease. Whether specific DPP-4 inhibitors (saxagliptin, alogliptin) increase the risk of heart failure remains to be resolved. Of note, a meta-analysis of 30 randomized controlled trials involving 29,938 patients comparing the effects of saxagliptin vs. placebo or sulfonylureas did not observe an increase in heart failure (RR 0.99, 95% CI 0.89 to 1.10; p = 0.85) (255).

#### RENAL DISEASE

Changes in renal function were examined in the large cardiovascular outcome trials described above. In the SAVOR-TIMI 53 trial treatment with saxagliptin decreased albuminuria but had no effect on eGFR (256). Saxagliptin reduced the development of macroalbuminuria independent of changes in A1c levels (248,256). Doubling of serum creatinine, initiation of chronic dialysis, renal transplantation, or serum creatinine >6.0 mg/dL, were similar in the saxagliptin and placebo groups (256). In the TECOS trial treatment sitagliptin also reduced the urinary albumin to creatinine ratio with no effect on eGFR (257). In the CARMELINA trial many of the patents had pre-existing renal disease (74% of patients had prevalent diabetic kidney disease, 43% had an eGFR below 45 mL/min/1.73 m2, 15.2% had an eGFR below 30 mL/min/1.73 m2 and 80% had a urinary albumin creatinine ratio >30 mg/g) (253). Treatment with linagliptin reduced the progression of albuminuria but had no effect on death due to renal failure, ESRD, or sustained 40% or higher decrease in eGFR from baseline (253).

Taken together these studies indicate that DPP-4 inhibitors decrease proteinuria but do not provide data suggesting an improvement or delay in worsening of renal function. However, using large data bases studies have suggested that DPP-4 inhibitors have favorable effects on renal function and decrease the development of end stage renal disease (258-260). Randomized trials of DPP4 specifically examining the effect of renal parameters would be helpful.

### Side Effects

DPP-4 inhibitors have been safe drugs with minimal side effects and are well tolerated by patients. Very rarely hypersensitivity reactions including urticaria, facial edema, anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome have occurred (261). Bullous pemphigoid has also rarely been associated with DPP-4 inhibitor treatment (261).

#### ACUTE PANCREATITIS

The package insert of DPP-4 inhibitors indicates that acute pancreatitis is a complication of DPP-4 inhibitor treatment. The individual results of the SAVOR-TIMI, EXAMINE, and TECOS trials discussed above did not show an increased risk of pancreatitis or pancreatic cancer. However, two meta-analyses of these studies demonstrated an 80% increased risk of acute pancreatitis in patients using DPP-4 inhibitors compared with those receiving standard care (262,263). It should be noted that the absolute risk was small (0.13%), which would result in one to two additional cases of acute pancreatitis for every 1,000 patients treated for 2 years (263). Thus, pancreatitis appears to be a rare side effect of DPP-4 inhibitors. In patients on DPP-4 inhibitors who have GI symptoms suggestive of pancreatitis further evaluation is indicated. The diagnosis of acute pancreatitis requires the presence of two of the following three criteria: acute onset of persistent, severe, epigastric pain often radiating to the back, elevation in serum lipase or amylase to three times or greater than the upper limit of normal, and characteristic findings of acute pancreatitis on imaging (264).

#### ARTHRALGIA

Severe and disabling arthralgia in patients taking DPP-4 inhibitors has been reported (265). The time to onset of symptoms following initiation of drug therapy varied from one day to years. Patients experienced relief of symptoms upon discontinuation of the medication and a subset of patients experienced a recurrence of symptoms when restarting the same drug or a different DPP-4 inhibitor. If a patient develops severe joint pain discontinue the DPP-4 inhibitor.

### Contraindications and Drug Interactions

It is unknown whether patients with a history of pancreatitis or who are at increased risk for the development of pancreatitis should be started on DPP-4 inhibitors. Given the availability of other hypoglycemic drugs many clinicians avoid the use of DPP-4 inhibitors in these patients.

The dosage of saxagliptin is 2.5 mg once daily when co-administered with a strong cytochrome P450 3A4/5 inhibitor (e.g., ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin) (package insert).

### Summary

DPP-4 inhibitors, while not the most potent drugs at lowering A1c, nevertheless are very attractive to use in the treatment of patients with T2DM as they are safe drugs that do not have many side effects. They do not cause hypoglycemia, weight gain, or cardiovascular disease. Unfortunately, they do not reduce the risk of cardiovascular disease or prevent loss of renal function.

### Table 22. 

Advantages and Disadvantages of DPP-4 Inhibitors

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_3/?report=objectonly)

Advantages| Disadvantages  
---|---  
No hypoglycemia| Pancreatic disease  
Weight neutral| Heart failure (saxagliptin/alogliptin)?  
Decreases postprandial glucose| Arthritis  
Once a day| Bullous pemphigoid  
Well tolerated| Relatively expensive  
Decreases BP| Modest glycemic lowering  
  
## INJECTABLE GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

### Introduction

There are currently six GLP-1 RAs available in the US, three drugs administered daily and three drugs administered weekly ([Figure 6](/sites/books/NBK279141/figure/pharmaco-agent-diab2.F6/?report=objectonly)). Albiglutide (Tanzeum) was withdrawn from the market for commercial reasons and is no longer available. GLP-1 RAs can be used in combination with multiple oral anti‐diabetic drugs or in combination with insulin (266). The circulating concentrations of GLP-1 RA activity are much higher than physiological levels of GLP-1 activity (20). The GLP-1 RAs that are similar to exendin-4 (Exenatide and Lixisenatide) are eliminated by the kidneys and therefore in patients with severe renal disease these drugs are contraindicated (20). In contrast, the drugs that are analogues of GLP-1 are degraded by peptidases (20).

![Figure 6. . Structure of GLP-1 Receptor Agonists.](/sites/books/NBK279141/bin/pharmaco-agent-diab2-Image007.jpg)

### Figure 6. 

Structure of GLP-1 Receptor Agonists.

#### SHORT ACTING GLP-1 RECEPTOR AGONISTS

Exenatide (Byetta) is a synthetic exendin-4 that is a peptide originally isolated from the saliva of the Gila monster that has a 53% homology with human GLP-1 and is resistant to degradation by DPP-4 (20,266). Lixisenatide (Adylyxin) is an exendin-4 analogue with six Lys residues added at the C terminus to confer resistance to DPP-4 (20,266).

#### LONG ACTING GLP-1 RECPTOR AGONISTS

Even though liraglutide (Victoza) is administered daily it is considered a long acting GLP-1 RA because its effects on fasting glucose levels are similar to weekly GLP-1 RAs and its effects on gastric emptying wane as seen with weekly GLP-1 RAs. Liraglutide is an analogue of GLP-1 with the addition of a 16-carbon fatty acid chain that masks the DPP-4 cleavage site preventing degradation (8,179). Once weekly exenatide (Bydureon and Bydueron BCise) is a sustained-release formulation that consists of exenatide embedded within biodegradable polymeric microspheres of poly (DL-lactic-co-glycolic acid) (20). Dulaglutide (Trulicity) has two copies of a GLP-1 analogue covalently linked to an Fc fragment of human IgG4 (20,266). Semaglutide (Ozempic) is an analogue of human GLP‐1 RA and is linked via a hydrophilic spacer and a fatty acid side chain to albumin (266).

For information on the use of GLP-1 RAs for the treatment of weight loss see the Endotext chapter entitled "Pharmacologic Treatment of Overweight and Obesity in Adults" (267).

### Administration

#### SHORT ACTING GLP-1 RECEPTOR AGONISTS

Initiate exenatide at 5 ug twice daily; increase to 10 ug twice daily after 1 month based on clinical response. Inject subcutaneously within 60 minutes prior to morning and evening meals (or before the two main meals of the day).

The starting dose of lixisenatide is 10 ug subcutaneously once daily within one hour before the first meal of the day for 14 days and then increase the dose to the maintenance dose of 20 ug once daily.

#### LONG ACTING GLP-1 RECPTOR AGONISTS

Initiate liraglutide with a dose of 0.6 mg per day for one week. After one week at 0.6 mg per day, the dose should be increased to 1.2 mg. If the 1.2 mg dose does not result in acceptable glycemic control, the dose can be increased to 1.8 mg. Inject subcutaneously once-daily at any time of day, independently of meals.

The recommended dose of long acting exenatide is 2 mg subcutaneously once every 7 days (weekly). The dose can be administered at any time of day, with or without meals.

The recommended initiating dose of dulaglutide is 0.75 mg subcutaneously with or without food once weekly. The dose may be increased to 1.5 mg once weekly to achieve glycemic control. If after 4 weeks glycemic control is not achieved the dose can be increased to 3.0 mg once weekly and then after another 4 weeks to 4.5 mg once weekly for additional glycemic control.

The recommended initiating dose of semaglutide is 0.25 mg subcutaneous injection with or without food once weekly for 4 weeks. The 0.25 mg dose is intended for treatment initiation and is not effective for glycemic control. After 4 weeks on the 0.25 mg dose, increase the dosage to 0.5 mg once weekly. If additional glycemic control is needed after at least 4 weeks on the 0.5 mg dose, the dosage may be increased to 2 mg once weekly (note the maximum dose for the treatment of obesity is 2.4mg).

Note that exenatide and lixisenatide are contraindicated in patients with renal dysfunction (for details see Contraindications section).

Information on the pen delivery systems for the GLP-1 RAs is shown in [table 23](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.characteristics_o_1/?report=objectonly).

### Table 23. 

Characteristics of GLP-1 Receptor Agonist Pen Devices

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.characteristics_o_1/?report=objectonly)

Generic| Exenatide| Exenatide| Exenatide| Lixisenatide| Liraglutide| Dulaglutide| Semaglutide  
---|---|---|---|---|---|---|---  
Brand| Byetta| Bydureon| Bydureon  
BCise| Lyxumia| Victoza| Trulicity| Ozempic  
Single or multiple use| Multiple| Single| Single| Multiple| Multiple| Single| Multiple  
Dose*| 5 or 10ug| 2mg| 2mg| 10 or 20ug| 0.6, 1.2, or 1.8mg| 0.75 or 1.5mg| 0.25, 0.5, 1.0 or 2mg  
Preparation| None| Resuspend| Mix| None| None| None| None  
  
*
    

Only the liraglutide pen can deliver different doses.

### Mechanism of Action

GLP-1 RAs potentiate glucose dependent insulin secretion increasing insulin levels and lowering glucose levels (20). In addition, GLP-1 RAs potentiate the glucose dependent inhibition of glucagon secretion, which will also lower glucose levels (20). Finally, because of the supraphysiological levels of GLP-1 activity, GLP-1 RAs may delay gastric emptying resulting in a decrease in postprandial glucose levels and induce satiety, which will decrease food intake (20).

### Glycemic Efficacy

GLP-1 RAs typically lower A1c by 1-2% (20). The efficacy of GLP-1 RAs vary with semaglutide being the most potent and lixisenatide being the least potent (see [table 6](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly)) (13). Note [table 6](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.estimated_efficac/?report=objectonly) does not include the 3.0mg and 4.5mg of dulaglutide, which lower A1c by 1.6% and 1.8% respectively (268). In general, long acting GLP-1 RAs are better at lowering A1c levels compared to short acting agents (13,266). The efficacy in lowering A1c is similar in monotherapy and during combination therapy (20). The reduction in A1c is sustained over several years (164). Long acting GLP-1 RAs lower fasting glucose levels more effectively than short acting drugs (266). Conversely, short acting GLP-1 RAs lower postprandial glucose excursions to a greater extent than long acting agents (266). Short acting GLP-1 RAs induce a substantial retardation in gastric emptying, which likely contributes significantly to the lowering of postprandial glucose excursions after meals when they are administered (266). Notably, the ability of short acting GLP-1 RAs to prevent postprandial glucose excursions is greatly diminished for meals when they are not administered (266). In patients with diminished beta cell function the glycemic response to GLP-1 RAs therapy is reduced (269).

The GRADE trial compared treatment with liraglutide to treatment with a sulfonylurea or DPP4 inhibitor (15). As one would expect liraglutide was more effective in lowering A1c levels and more patients achieved an A1c level less than 7% than with either sulfonylurea or DPP4 inhibitor therapy.

Studies have compared adding a GLP-1 RA to basal insulin vs. adding rapid acting insulin to basal insulin (270). In a meta-analysis there were no differences in lowering A1c levels but treatment with basal insulin plus GLP-1 RA led to a significant reduction in body weight, whereas basal insulin plus rapid acting insulin treatment was associated with weight gain (difference -2.95 kg; p = 0.0001) (270). Additionally, patients treated with basal insulin plus GLP-1 RA were less likely to experience symptomatic hypoglycemia (OR: 0.52; p < 0.0001) and severe hypoglycemia (OR: 0.27; p = 0.07) than those treated with basal insulin plus rapid acting insulin. Thus, adding a GLP-1 RA to basal insulin instead of bolus insulin will result in similar improvements in glycemic control with fewer side effects.

Studies have also compared adding insulin therapy vs. adding a GLP-1 RA. In a meta-analysis of 19 studies GLP-1 RAs reduced A1c levels slightly more than insulin therapy (difference -0.12%, P < .0001) (271). As expected, hypoglycemia was less frequent in the patients treated with the GLP-1 RAs.

Because the effect of GLP‐1 RAs on insulin and glucagon secretion are glucose dependent they have a low potential to cause hypoglycemia (20,266). The risk of hypoglycemia increases when GLP-1 RAs are used in combination with insulin or insulin secretagogues (266).

Both GLP-1 RAs and SGLT-2 inhibitors have been shown to decrease cardiovascular disease (GLP-1 RAs primarily decrease atherosclerotic complications while SGLT-2 inhibitors primarily decrease heart failure). Therefore, the use of these drugs in combination to prevent cardiovascular disease has been proposed. In an analysis of four randomized trials adding a GLP-1 RA to a SGLT-2 inhibitor it was reported that the addition of a GLP-1 receptor agonist resulted in a greater reduction in HbA1c (-0.74%), body weight (-1.61 kg), and systolic blood pressure (-3.32 mmHg) demonstrating the benefits of using these drugs in combination (272).

### Other Effects

#### WEIGHT LOSS

GLP-1 RAs induce weight loss (20,266). A comparison of the ability of the maximum dose of different GLP-1 RAs to induce weight loss are shown in [table 24](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glprece/?report=objectonly). It should be recognized that the weight loss shown in [Table 24](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glprece/?report=objectonly) represents averages. In clinical practice some patients lose a large amount of weight with GLP-1 RAs while other patients can actually gain weight. The author has personally seen patients' loss more than 50 lbs. Higher doses of liraglutide and semaglutide are approved for the treatment of obesity, which is discussed in the Endotext chapter "Pharmacologic Treatment of Overweight and Obesity in Adults" (273). Studies have compared the effect of high doses of GLP-1 RAs used for weight loss and lower doses used for treating diabetes ([table 25](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.comparison_of_low/?report=objectonly)). In general, higher doses of GLP-1 RAs result in a modest further lowering of A1c and a more robust decrease in body weight.

### Table 24. 

Effect of GLP-Receptor Agonists on Mean Weight Loss (13)

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glprece/?report=objectonly)

GLP-1 Receptor Agonist| Mean Weight Loss  
---|---  
Dulaglutide 1.5mg weekly| 1.1Kg  
Exenatide 10ug bid| 1.2Kg  
Exenatide 2mg weekly| 1.1Kg  
Liraglutide 1.8mg qd| 1.5Kg  
Lixisenatide 20ug qd| 0.7Kg  
Semaglutide 1mg weekly| 3.8Kg  
  
    

Based on a baseline weight of 90 kg after 26 weeks of treatment.

### Table 25. 

Comparison of Low and High Dose GLP-1 RAs on A1c and Body Weight

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.comparison_of_low/?report=objectonly)

| Change in A1c (%)| Change in Body Weight (% or kg)  
---|---|---  
**SCALE Diabetes (** **274** **)**  
Placebo| -0.3%| -2.0%  
Liraglutide 1.8mg qd| -1.1%| -4.7%  
Liraglutide 3.0mg qd| -1.3%| -6.0%  
**STEP-2 (** **275** **)**  
Placebo| -0.4%| -3.4%  
Semaglutide 1mg weekly| -1.5%| -7.0%  
Semaglutide 2.4mg weekly| -1.6%| -9.6%  
**SUSTAIN FORTE (** **276** **)**  
Semaglutide 1mg weekly| -1.9%| -6.2%  
Semaglutide 2.0mg weekly| -2.2%| -7.2%  
**AWARD-11 (** **268** **)**  
Dulaglutide 1.5mg weekly| -1.5%| -3.1kg  
Dulaglutide 3.0mg weekly| -1.7%| -4.0kg  
Dulaglutide 4.5mg weekly| -1.9%| -4.7kg  
  
The exact mechanisms responsible for the decrease in weight are not yet fully understood but both central and peripheral mechanisms are thought to play a part in activating receptors in the central nervous system associated with weight loss (266). GLP‐1 RAs are thought to reduce body weight through decreased gastrointestinal motility and the promotion of satiety via the activation of GLP‐1 receptors in various regions of the brain (266).

#### BLOOD PRESSURE

GLP-1 RAs result in modest but significant reductions in systolic blood pressure (2-5 mmHg) (20).

#### HEART RATE

The effects of GLP-1 RAs on heart rate differ between drugs. Short-acting GLP-1 RAs result in a modest increase (1-3 beats per minute) while long-acting GLP-1 RAs are associated with a more pronounced and sustained increase (3-10 beats per minute) during the day and night (277).

#### LIPIDS

GLP-1 RAs can favorably affect the lipid profile by inducing weight loss (decreasing triglycerides and very modestly decreasing LDL-C levels) (82). In a review by Nauck and colleagues it was noted that GLP-1 RAs lowered TG levels by 18 to 62 mg/dl depending upon the specific GLP-1 RA while decreasing LDL-C by 3-8 mg/dl and increasing HDL-C by less than 1 mg/dl (247). Additionally, GLP-1 RAs reduce postprandial triglycerides by reducing circulating chylomicrons by decreasing intestinal lipoprotein production (82,247).

#### ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

The effect of six GLP-1 RAs on cardiovascular disease has been reported.

##### ELIXA

In the Elixa trial 6,068 patients with T2DM and who recently had a myocardial infarction or been hospitalized for unstable angina were randomized to placebo or lixisenatide, and followed for a median of 25 months (278). The primary end point of cardiovascular death, myocardial infarction, stroke, or hospitalization for unstable angina was similar in the placebo or lixisenatide groups.

##### LEADER Trial

In contrast, the LEADER trial has shown that liraglutide decreased cardiovascular events (279). In this trial 9,340 patients with T2DM at high cardiovascular risk (~ 81% with established cardiovascular disease) were randomly assigned to receive liraglutide or placebo. After a median time of 3.5 years, the primary outcome of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke occurred in significantly fewer patients in the liraglutide group (13.0%) than in the placebo group (14.9%) (HR 0.87, P=0.01). Additionally, deaths from cardiovascular causes (HR 0.78, P=0.007) or any cause was lower in the liraglutide group than in the placebo group (HR 0.85; P=0.02). Interestingly patients with established cardiovascular disease or decreased renal function (eGFR < 60) appeared to derive the greatest benefit of liraglutide treatment (280,281). The decrease in cardiovascular events were similar in patients with and without a history of heart failure (282). Finally, a significant reduction in amputations with liraglutide vs. placebo was observed (HR 0.65; P = 0.03]) (283).

##### SUSTAIN 6 Trial

In support of the beneficial effects of some GLP1 receptor agonists to reduce cardiovascular events, semaglutide has also been shown to reduce cardiovascular events (284). In this trial, 3,297 patients with T2DM with established cardiovascular disease (83%), chronic heart failure, chronic kidney disease, or age >60 with at least one cardiovascular risk factor were randomized to receive once-weekly semaglutide (0.5 mg or 1.0 mg) or placebo for 104 weeks. The primary outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke occurred in 6.6% of the semaglutide group and 8.9% of the placebo group (HR 0.74; P = 0.02).

##### EXSCEL Trial

The effect of once weekly exenatide vs. placebo on cardiovascular outcomes was tested in 14,752 patients with T2DM, 73% who had cardiovascular disease (285). The primary outcome was the occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. After a median follow-up of 3.2 years (duration of drug exposure 2.4 years) the primary outcome was reduced in the exenatide treated group but this difference just missed achieving statistical significance (HR 0.91; 95% CI 0.83-1.00; p=0.06). While not statistically significant these results are consistent with the results observed with other GLP-1 receptor agonists. It should be recognized that a high percentage of patients discontinued exenatide therapy in this trial (>40%) and this could have adversely affected the ability of exenatide treatment to favorably effect cardiovascular outcomes.

##### HARMONY Outcomes Trial

The effect of once weekly albiglutide vs. placebo was tested in 9,463 patients with T2DM and cardiovascular disease (286). The primary outcome was first occurrence of cardiovascular death, myocardial infarction, or stroke. After a median follow-up of 1.6 years a 22% decrease in the primary endpoint was observed in the albiglutide group (HR 0.78, p<0*0001). It should be noted that albiglutide is no longer available as it was removed from the market due to commercial considerations by the manufacturer.

##### REWIND Trial

This was a randomized study of weekly dulaglutide (1.5 mg) or placebo in 9,901 patients with T2DM who had either a previous cardiovascular event or cardiovascular risk factors (approximately 70% of patients did not have prior cardiovascular disease) (287). During a median follow-up of 5.4 years the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes was decreased by 12% in the dulaglutide treated group (HR 0.88, p=0.026). The decrease in events was similar in participants with and without previous cardiovascular disease. In an analysis that focused on stroke it was noted that dulaglutide reduced ischemic stroke by 25% compared to placebo but had no effect on hemorrhagic stroke (288).

##### GRADE Trial

This trial compared the effect of adding 4 different hypoglycemic agents to metformin therapy in 5,047 patients with a relatively short duration of diabetes (mean 4.2 years) (16). The vast majority of participants had no history of cardiovascular disease (6% had positive history). The duration of this trial was approximately 5 years. The results are shown in [table 26](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.cardiovascular_ou/?report=objectonly) and suggest that in this population treatment with liraglutide has beneficial effects on cardiovascular disease. One should note that this was predominantly a primary prevention trial. This trial supports the observations in the REWIND trial that patients without cardiovascular disease may benefit from GLP-1 agonist therapy. However, because of the complexity of this trial the authors note "These results should not be viewed as definitive proof that GLP-1 RAs reduce the incidence of cardiovascular disease in low-risk populations". Clearly additional trials are required in low-risk populations.

### Table 26. 

Cardiovascular Outcomes in the GRADE Trial

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.cardiovascular_ou/?report=objectonly)

Outcome  
Rate* (95% CI)| Glargine  
(N=1263)| Glimepiride  
(N=1254)| Liraglutide (N=1262)| Sitagliptin (N=1268)  
---|---|---|---|---  
Any cardiovascular disease| 1.87  
(1.54-2.25)| 1.92  
(1.59-2.31)| 1.36  
(1.08-1.69)| 2.00  
(1.66-2.39)  
MACE**| 1.05  
(0.81-1.34)| 0.96  
(0.73-1.24)| 0.78  
(0.57-1.03)| 1.12  
(0.87-1.41)  
Hospitalization for heart failure| 0.42  
(0.27-0.61)| 0.48  
(0.33-0.69)| 0.22  
(0.12-0.38)| 0.48  
(0.32-0.68)  
Death from cardiovascular causes| 0.33  
(0.21-0.51)| 0.26  
(0.15-0.42)| 0.14  
(0.07-0.27)| 0.33  
(0.21-0.51)  
  
*
    

Rate is events per 100 participant years.

**
    

MACE- death from cardiovascular disease or nonfatal myocardial infarction or stroke.

##### Summary

Thus, most studies have clearly demonstrated that treatment with GLP-1 RAs reduces cardiovascular events. Why there are differences in results between these studies is unknown but could be due to differential effects of the GLP-1 RAs, differences in the patient populations studied, or other unrecognized variables. A meta-analysis of 7 cardiovascular outcome studies using GLP-1 RAs (ELIXA (lixisenatide), LEADER (liraglutide), SUSTAIN-6 (semaglutide), EXSCEL (exenatide), Harmony Outcomes (albiglutide), REWIND (dulaglutide), and PIONEER 6 (oral semaglutide) reported a 12% decrease in cardiovascular death, stroke, or myocardial infarction (p<0.0001), 12% decrease in cardiovascular deaths (p<0.003), 16% decrease in fatal or non-fatal strokes (p<0*0001), and 9% decrease in fatal or non-fatal myocardial infarctions (p=0.043) (289) ([Table 27](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_glp1_r/?report=objectonly)). It should be noted that in a large randomized trial (n= 17,604) in patients with obesity without diabetes semaglutide decreased a composite of endpoint consisting of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke by 20% compared to placebo (HR 0.80; 95%CI 0.72 to 0.90; P<0.001) (290). Thus, GLP-1 RAs reduce cardiovascular disease in patients with and without diabetes.

### Table 27. 

Summary of GLP-1 Receptor Agonist Cardiovascular Outcome Trials

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.summary_of_glp1_r/?report=objectonly)

| Number| Prior CVD| HbA1c| Mean Follow-up (years)| Hazard Ratio* (95% CI)| P value  
---|---|---|---|---|---|---  
ELIXA  
Lixisenatide| 6068| 100%| 7.7%| 2.1| 1.02  
(0.89-1.17)| 0.78  
LEADER  
Liraglutide| 9340| 81%| 8.7%| 3.8| 0.87  
(0.78-0.97)| 0.015  
SUSTAIN 6  
Semaglutide| 3297| 83%| 8.7%| 2.1| 0.74  
(0.58-0.95)| 0.016  
EXSCEL  
Exenatide| 14,752| 73%| 8.0%| 3.2| 0.91  
(0.83-1.00)| 0.061  
HARMONY  
Albiglutide| 9463| 100%| 8.7%| 1.6| 0.78  
(0.68-0.90)| <0.001  
REWIND  
Dulaglutide| 9901| 31%| 7.3%| 5.4| 0>88  
(0.79-0.99)| 0.026  
PIONEER 6**  
Semaglutide oral| 3183| 85%| 8.2%| 1.3| 0.79  
(0.57-1.11)| 0.17  
**Overall (** **289** **)** | | | | |  **0.88**   
**(0.82-0.94)** |  **< 0.001**  
  
*
    

CVD death, MI, Stroke. ** The Pioneer study is included in this table to provide information on all the studies examining the effect of GLP-1raon cardiovascular disease.

The mechanism accounting for this decrease in cardiovascular disease is uncertain but could be related to reductions in glycated hemoglobin, body weight, systolic blood pressure, postprandial triglyceride levels, inflammation, or the direct effect of activation of GLP-1 receptors on the atherosclerotic process such as improving endothelial function (291).

The effect of a GLP-1 receptor agonist (efpeglenatide- not available) in patients on an SGLT-2 inhibitor was determined in the AMPLITUDE-O trial (292). The effect of efpeglenatide vs. placebo on cardiovascular and renal outcomes (macroalbuminuria) was similar in the absence and presence of baseline SGLT-2 inhibitors. (see section below on combination therapy).

#### HEART FAILURE

Several of the large cardiovascular outcome trials described above have analyzed the effect of administration of GLP-1 RAs in the subgroup of patients with a history of heart failure. In the EXSCEL trial patients with heart failure at baseline had no decrease in all-cause mortality whereas mortality was reduced in the subgroup without HF (HR 0.79; CI 0.68-0.92) (293). Similarly, in the combined data from the SUSTAIN-6 and PIONEER-6, patients with prior heart failure were the only subgroup that did not have a decrease in cardiovascular events (294). In contrast, in the LEADER trial the decrease in cardiovascular events were similar in patients with and without a history of heart failure (282).

The large cardiovascular outcome studies have determined the effect of GLP-1 RAs on the occurrence of heart failure events. In a meta-analysis of the seven large cardiovascular outcome trials with a combined total of 56,004 participants, hospital admission for heart failure was decreased by 9% (HR 0.91, 0.83-0.99; p=0.028) (289) ([Table 28](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glp1_ra/?report=objectonly)). In the SELECT trial that determined the effect of semaglutide 2.4mg weekly in patients with obesity who were not diabetic a decrease in heart failure events was also observed (HR 0.82; 95%CI 0.71- 0.96) (290).

### Table 28. 

Effect of GLP-1 RAs on Heart Failure

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_glp1_ra/?report=objectonly)

Cardiovascular Outcome Trial| Heart Failure Hospitalization Heart Failure (HR (CI))  
---|---  
ELIXA (lixisenatide)| 0.96 (0.75-1.23)  
LEADER (liraglutide)| 0.87 (0.73-1.05)  
SUSTAIN-6 (semaglutide)| 1.11 (0.77-1.61)  
EXSCEL (exenatide)| 0.94 (0.78-1.13)  
HARMONY (albiglutide)| 0.71 (0.53-0.94)  
PIONEER-6 (oral semaglutide)| 0.86 (0.48-1.55)  
REWIND (dulaglutide)| 0.93 (0.77-1.12)  
Meta-analysis (289)| 0.91 (0.83-0.99)  
  
    

HR= hazard ratio; CI= 95% confidence interval.

In patients with heart failure with preserved ejection fraction, a BMI> 30, and type 2 diabetes the effect of weekly semaglutide (2.4 mg) (n= 310) vs placebo (n= 306) for 52 weeks was determined (295). The Kansas City Cardiomyopathy Questionnaire clinical summary score, a measure of symptoms and physical limitations, was greatly improved in the semaglutide group and the 6-minute walk distance increased by 12.7 meters in the semaglutide group and decreased by 1.6 meters in the placebo group. Additionally, the NT-proBNP level decreased by 23% in the semaglutide vs. 4.6% the placebo group. Finally, hospitalization or urgent visit for heart failure was decreased in the semaglutide group (2.3% vs 5.9%). Similar beneficial effects of semaglutide on heart failure with preserved ejection fraction have been observed in patients without diabetes (296). The mechanisms accounting for this improvement is uncertain but could be related to reductions in glycated hemoglobin, body weight, systolic blood pressure, postprandial triglyceride levels, inflammation, or the direct effect of activation of GLP-1 receptors on the myocardium.

The results of these studies provide evidence that GLP-1 RAs have favorable effects on heart failure and additional studies are in progress to confirm and extend these findings.

#### RENAL DISEASE

The cardiovascular outcome studies described above also examined the effect of GLP-1 RAs on kidney disease.

##### ELIXA Trial

Lixisenatide treatment decreased urinary albumin-to-creatinine ratio in patients with pre-existing micro or macroalbuminuria (297). Additionally, lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo (297). However, no significant differences in eGFR decline or the number of patients doubling their serum creatinine levels were seen between the lixisenatide treated group vs. placebo group (297).

##### LEADER Trial

The renal outcome in this trial was a composite of new-onset persistent macroalbuminuria, persistent doubling of the serum creatinine level, end-stage renal disease, or death due to renal disease. The renal outcome occurred in fewer patients in the liraglutide group than in the placebo group (HR 0.78; P=0.003) (298). This favorable outcome was driven primarily by a decrease in the development of macroalbuminuria. The renal benefits did not appear to be driven by changes in A1c, body weight, or decreases in systolic BP.

##### SUSTAIN 6 Trial

In this trial, new or worsening nephropathy, defined as persistent macroalbuminuria, persistent doubling of the serum creatinine, or a creatinine clearance < 45ml/min/1.73m2, occurred in 3.8% of the patients in the semaglutide group and 6.1% of the patients in the placebo group (HR 0.64; P=0.005) (284). As seen in the LEADER trial this favorable outcome was driven primarily by a decrease in the development of macroalbuminuria.

##### EXSCEL Trial

Exenatide treatment resulted in a reduction in new‐onset macroalbuminuria compared with placebo (2.2% vs 2.8%, P = 0.031), with no significant changes in either microalbuminuria (7.2% vs 7.5%) or ESKD requiring renal replacement therapy (0.7% vs 0.9%) (285).

##### REWIND Trial

The renal outcome included the occurrence of new macroalbuminuria (UACR >33*9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy (299). During a median follow-up of 5.4 years the renal outcome developed in 17.1% of patients in the dulaglutide group and in 19.6% of patients in the placebo group (HR 0.85, p=0*0004). This beneficial effect was driven by a reduction in the development of macroalbuminuria (HR 0.77; p<0.0001)

##### AWARD 7 Trial

While the large studies described above demonstrated that GLP-1 RAs primarily decrease albuminuria the AWARD 7 trial provides data on eGFR. The Award 7 was a multicenter randomized trial of dulaglutide 0.75mg weekly (n= 190), 1.5mg weekly (n= 193), or daily insulin glargine (n= 194) in patients with T2DM and Stage 3 and 4 chronic kidney disease (300). At 52 weeks, eGFR was higher with dulaglutide 1.5 mg (eGFR 34.0; p=0.005 vs insulin glargine) and dulaglutide 0.75 mg (eGFR 33.8; p=0*009 vs insulin glargine) than with insulin glargine (31.3mL/min per 1*73 m2). In contrast to the cardiovascular studies described above at 52 weeks dulaglutide 1.5 mg and 0.75 mg did not affect albuminuria.

##### FLOW Trial

In this trial patients with T2DM and chronic kidney disease (defined by an eGFR of 50 to 75 and a urinary albumin-to-creatinine ratio of >300 and <5000 or an eGFR of 25 to <50 and a urinary albumin-to-creatinine ratio of >100 and <5000) were randomized to receive semaglutide 1.0 mg weekly (n= 1767) or placebo (n= 1766) and followed for a median of 3.4 years (301). The primary outcome was a composite of the onset of kidney failure (dialysis, transplantation, or an eGFR of <15 ml), at least a 50% reduction in the eGFR from baseline, or death from kidney-related or cardiovascular causes and was decreased by 24% in the semaglutide group (HR 0.76; 95% CI 0.66 to 0.88; P = 0.0003). Notably, the composite of the kidney-specific components of the primary outcome was reduced by 21% (HR 0.79; 95% CI, 0.66 to 0.94) while cardiovascular death was reduced by 29% (HR 0.71; 95% CI, 0.56 to 0.89). Additionally, the decrease in eGFR was slower in the semaglutide group. These beneficial effects were seen regardless of glycemic control, eGFR, or albumin‐to‐creatinine ratio. Interestingly, in patients taking an SGLT2 inhibitor no benefit was observed but the number of events in this subgroup was very small and therefore larger studies are required to address this important issue.

##### Summary

The Flow trial in combination with the other trials demonstrates that GLP-1 RAs have beneficial effects on kidney function decreasing albuminuria and slowing the decrease in eGFR. A pooled analysis of the LEADER (liraglutide) and SUSTAIN 6 trials found a preservation in eGFR with GLP-1 RAs, particularly in patients with a reduced baseline eGFR (302). Moreover, the FLOW trial demonstrated a decrease in clinically important kidney outcomes including kidney failure (dialysis, transplantation, or an eGFR of <15 ml), a 50% reduction in the eGFR, or death from kidney-related causes. Similar beneficial effects on renal function have been observed in patients with obesity treated with semaglutide (303). Specifically, there was a 22% decrease in the development of the composite kidney endpoint (death from kidney disease, initiation of chronic kidney replacement therapy, onset of persistent eGFR) < 15, persistent ≥50% reduction in eGFR or onset of persistent macroalbuminuria), primarily due to a reduction in persistent macroalbuminuria, in the semaglutide group compared to placebo.

#### METABOLIC DYSFUNCTION ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) AND METABOLIC DYSFUNCTION ASSOCIATED STEATOHEPATITIS (MASH)

Studies have suggested that GLP-1 RAs have beneficial effects on MASLD and MASH (101). A meta-analysis of liraglutide studies and a separate meta-analysis of lixisenatide studies have reported that these drugs decrease liver enzymes (304,305). A 12-week randomized trial in 60 patients with MASLD of exenatide + basal insulin vs. rapid acting insulin + basal insulin demonstrated lower liver enzymes in the exenatide treated group (306). Moreover, the reversal rate of fatty liver was greater in the group treated with exenatide (93.3%) than the intensive insulin group (66.7%) (p < 0.01). Similarly, liraglutide and dulaglutide has also been shown to decrease intrahepatic fat (307-309).

In the LEAN Trial 52 patients with MASH were randomized to liraglutide 1.8 mg daily or placebo and followed for 48 weeks (310). Resolution of MASH occurred in 39% of patients treated with liraglutide and only 9% of patients in the placebo group (RR 4.3; p=0.019). Progression of fibrosis occurred in 9% of patients in the liraglutide group versus 36% of patients in the placebo group (p=0.04).

A recent trial of semaglutide subcutaneously given daily (0.1, 0.2, and 0.4 mg) demonstrated an improvement in MASH without a beneficial effect on fibrosis (311). Whether weekly semaglutide or daily oral semaglutide would have similar effects is unknown.

While these data are suggestive larger and longer studies on the effect of GLP-1 RAs on MASLD and MASH are required.

#### EFFECT OF GLP1 RECEPTOR AGONISTS IN PATIENTS ON SGLT2 INHIBITOR THERAPY

As discussed earlier, the effect of a GLP-1 RA (efpeglenatide- not available) in patients on an SGLT-2 inhibitor was determined in the AMPLITUDE-O trial (292). The effect of efpeglenatide vs. placebo on cardiovascular and renal outcomes (macroalbuminuria) was similar in the absence and presence of baseline SGLT-2 inhibitors. In the HARMONY trial the effect of albiglutide in patients on an SGLT-2 inhibitor on cardiovascular death, myocardial infarction, or stroke was similar.

In patients with T2DM and chronic kidney disease treated with semaglutide (FLOW trial), a small number of patients were taking a SGLT2 inhibitor at baseline (N = 550) (312). The primary outcome was a composite of kidney failure, ≥50% estimated glomerular filtration rate reduction, kidney death, or cardiovascular death. In patients not taking an SGLT2 inhibitor (N = 2,983) the primary endpoint was reduced by 27% (HR 0.73; 95% CI 0.63-0.85; P < 0.001) and the kidney specific endpoint by 25% (HR 0.75; 95%CI 0.61-0.90; P = 0.003). In patients on a SGLT2 inhibitor at baseline the primary endpoint and kidney specific endpoint were not decreased (Primary endpoint- HR 1.07; 95% CI 0.69-1.67; P = 0.755; Kidney endpoints- HR 1.18; 95%CI 0.71-1.98; P = 0.532). In contrast, cardiovascular death, all cause death, and non-fatal MI were decreased in the sitagliptin group to a similar degree with or without SGLT2 inhibitor use at baseline. Thus, the results of this analysis do not provide strong evidence that adding a GLP1 RA to a SGLT2 inhibitor will provide additional benefits on renal outcomes.

Thus, treatment with a GLP-1 RA reduces cardiovascular events to a similar degree in patients regardless of whether they are taking an SGLT2 inhibitor at baseline. The effect of a GLP-1 RA on renal outcomes in patients on a SGLT2 inhibitor is not clear. It should be recognized that there were only a small number of patients on combination therapy in the studies described above, which limits the ability to make firm conclusions and larger studies of combination therapy are required.

### Side Effects

#### GASTROINTESTINAL

The most common adverse effects are GI and include nausea, vomiting, constipation, and diarrhea (266). These symptoms are usually transient, resolving overtime (20). The GI side effects can be reduced by slowly increasing the dose (20). GI side effects tend to be more pronounced with short acting GLP-1 RAs (266). Dehydration can occur secondary to GI side effects and can result in acute kidney failure (package insert).

#### GALL BLADDER DISEASE

Observational studies have shown an association of treatment with GLP-1 RAs and bile duct and gallbladder disease (313). Additionally, a meta-analysis of randomized trials using GLP-1 RAs reported an association with an increased risk of cholelithiasis (314). Higher doses and a longer duration of treatment increased the risk of gallbladder disease (315). Finally, large cardiovascular trials with liraglutide (LEADER Trial), exenatide (EXSCEL Trial), and lixisenatide (ELIXA Trial) also reported an increased risk of gall bladder or biliary tract disease (278,285,316), however the large cardiovascular trial with semaglutide (SUSTAIN 6) did not observe an increase (284). It has been hypothesized that weight loss and/or decreased gallbladder motility induced by GLP-1 RAs could contribute to this increase in gall bladder disease.

#### INJECTION-SITE REACTIONS

Injection-site reactions (rash, erythema) are also common with GLP-1 RAs (20). Subcutaneous injection-site nodules may occur with the use of weekly exenatide (package insert), an abnormality that is due to the formulation.

#### MEDULLARY THYROID CANCER

Thyroid C-cell hyperplasia and medullary cell carcinoma has also been raised as possible concerns based on preclinical studies in rodents, but clinical studies in humans have not shown any indication of thyroid disorders (20). A meta-analysis of the four large cardiovascular outcome studies described above did not demonstrate an increased risk of medullary thyroid cancer with GLP-1 RA treatment (317)

#### PANCREATITIS

Subclinical increases in pancreatic enzyme levels are commonly observed with all GLP‐1 RAs and pancreatitis has been reported (266). Importantly increases in lipase and amylase were not predictive of subsequent pancreatitis (318). A meta-analysis of four large cardiovascular outcome studies described above did not demonstrate an increased risk of pancreatitis or pancreatic cancer with GLP-1 RA treatment (317,319). A meta-analysis of all seven cardiovascular outcome studies also did not demonstrate an increase in pancreatitis with GLP-1 RA treatment (320).

#### RETINOPATHY

In the SUSTAIN 6 trial described above the rates of retinopathy complications (vitreous hemorrhage, blindness, or conditions requiring treatment with an intravitreal agent or photocoagulation) were significantly higher in the semaglutide group compared to the placebo group (hazard ratio, 1.76; P=0.02) (284). This increased risk of retinopathy complications has been attributed to the magnitude and rapidity of A1c reduction during the first 16 weeks of treatment in patients who had pre-existing retinopathy and poor glycemic control at baseline ("early worsening") (321). A meta-analysis of GLP-1 RA cardiovascular trials found an association between retinopathy and the magnitude of A1c reduction supporting the hypothesis that the increase in retinopathy in SUSTAIN 6 was due to lowering of A1c (322).

Of note, other trials using semaglutide did not observe an increased risk of retinopathy (321). Additionally, an increase in diabetic retinopathy was not observed in the other cardiovascular outcome trials (278,279,285,286). In a meta-analysis of 60 studies with 60,077 patients, treatment with GLP-1RAs did not increase the incidence of diabetic retinopathy, macular edema, retinal detachment, or retinal hemorrhage (323). However, the incidence of vitreous hemorrhage was higher in subjects treated with GLP-1 RAs compared with placebo (odds ratios 1.93; 95% CI 1.09 to 3.42). Thus, it is possible that GLP-1 RA treatment results in an increase in diabetic eye disease. A 5 years eye safety study for semaglutide, the FOCUS trial ([NCT03811561](https://clinicaltrials.gov/show/NCT03811561 "Study NCT03811561")), is currently underway and should provide a definitive answer.

#### RISKS RELATED TO ANESTHESIA

As discussed above GLP-1 RAs slow gastric emptying and the retention of gastric contents could increase the risk of aspiration during surgical procedures. The American Society of Anesthesiologists recommended "For patients on daily dosing consider holding GLP-1 agonists on the day of the procedure/surgery. For patients on weekly dosing consider holding GLP-1 agonists a week prior to the procedure/surgery. This suggestion is irrespective of the indication (type 2 diabetes mellitus or weight loss), dose, or the type of procedure/surgery. If the patient has no GI symptoms, but the GLP-1 agonists were not held as advised, proceed with 'full stomach' precautions…" (324). A clinical practice update by the American Gastroenterological Association (AGA) pointed out the lack of meaningful data and that well-designed studies investigating patients on GLP-1 RAs are needed (324). In the absence of definitive data they advised that patients on GLP-1 RAs who have followed standard perioperative procedures and who do not have symptoms of nausea, vomiting, dyspepsia, or abdominal distention, to proceed with upper and/or lower endoscopy. In patients with symptoms suggesting possible retained gastric contents, transabdominal ultrasonography can be used to assess the presence of stomach contents but evidence to support this is lacking. Rapid-sequence intubation can be considered if there is uncertainty. "Lastly, when possible, placing patients on a liquid diet the day before sedated procedures may be a more acceptable strategy, in lieu of stopping GLP-1 RAs, and more consistent with the holistic preprocedural management of other similar conditions." Clearly this is an area that requires additional studies and health care providers will need to use their judgement in deciding how to manage anesthesia in patients taking GLP-1 RAs.

#### SUICIDE

Concerns have been raised that GLP-1 RAs increase the risk of suicide and self-harm. A large cohort study compared 124,517 patients started on a GLP-1 RA and 174,036 patients started on an SGLT2 inhibitor and did not find an association between use of GLP-1 RAs and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders (325). Other studies have reported similar results (326-328).

### Contraindications and Drug Interactions

#### RENAL

Care needs to be exercised in patients with severe renal disease as they are more susceptible to the side effects of GLP-1 RAs and more likely to have serious side effects (package inserts). There is limited data in patients with end stage renal disease.

Exenatide should not be used in patients with severe renal impairment (creatinine clearance < 30 mL/min) or end-stage renal disease (package insert). Caution should be applied when initiating or escalating doses of exenatide from 5 mcg to 10 mcg in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min) (package insert).

Weekly exenatide is not recommended for use in patients with eGFR below 45 mL/min/1.73m2 or end stage renal disease (package insert).

Lixisenatide is not recommended in patients with end stage renal disease (eGFR <15 mL/min/1.73 m2) (package insert).

No dose adjustments for liraglutide, semaglutide, or dulaglutide are recommended for patients with renal impairment (package insert).

#### OTHER

Exenatide is not recommended in patients with gastroparesis or severe gastrointestinal disease (package insert).

In patients with a history of pancreatitis or at high risk for pancreatitis many clinicians avoid GLP-1 RAs.

GLP-1 RAs are contraindicated in patients with a personal or family history of Medullary Thyroid Cancer and in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) (package insert).

### Summary

The ability of GLP-1 RAs to effectively decrease A1c levels, reduce atherosclerotic cardiovascular disease, renal disease, and induce significant weight loss make these drugs very attractive in the treatment of patients with T2DM. Additionally, once weekly administration for certain drugs in this class can improve compliance.

### Table 29. 

Advantages and Disadvantages of GLP- 1 Receptor Agonists

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_4/?report=objectonly)

Advantages| Disadvantages  
---|---  
Weight Loss| GI side effects  
No Hypoglycemia| Requires Injection  
Reduce CVD (liraglutide, semaglutide, dulaglutide)| Pancreatitis?  
Improve NAFLD| Thyroid cancer?  
Once a week therapy possible| Gall bladder disease  
Decrease renal disease| Expensive  
Decrease postprandial glucose|   
Improve heart failure|   
  
## ORAL GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS

### Introduction

**I** n 2019 an oral form of semaglutide (Rybelsus) became available. To facilitate absorption of semaglutide, which is a 31 amino acid peptide, the tablet contains a permeation enhancer N-(8-[2-hydroxybenzoyl]amino)caprylic acid (SNAC, Eligen® Technology, Emisphere Technologies), which is a small fatty acid derivative that accelerates the absorption of semaglutide across the gastric epithelium avoiding the activation of proteolytic enzymes and pH-induced degradation in the stomach (329). This allows for the absorption of an intact peptide. One should note that the bioavailability of oral semaglutide is very low as the dose of oral semaglutide is 7-14 mg per day vs 0.5-2.0 mg once a week with the injectable dose.

### Administration

The oral form of semaglutide must be taken at least 30 minutes before the first food, beverage, or other oral medications of the day with no more than 4 ounces of plain water (package insert). Waiting less than 30 minutes, or taking with food, beverages (other than plain water), or other oral medications will adversely affect the absorption of semaglutide. Waiting more than 30 minutes to eat may increase the absorption. The starting dose is 3 mg once daily for 30 days. After 30 days on the 3 mg dose, increase the dose to 7 mg once daily. The dose may be increased to 14 mg once daily if additional glycemic control is needed after at least 30 days on the 7 mg dose (package insert). Patients treated with once weekly semaglutide 0.5 mg injections can be transitioned to oral semaglutide 7 mg or 14 mg a day. No dose adjustment is recommended for patients with renal or hepatic impairment (package insert).

### Mechanism of Action

The mechanism of action is identical to injected GLP-1 RAs described above.

### Glycemic Efficacy

In a meta-analysis of five trials of oral semaglutide vs. placebo, treatment with oral semaglutide reduced HbA1c by 0.89% (330). In the Pioneer 1 study 703 patients were randomized (mean baseline HbA1c 8.0%) to placebo vs. various doses of oral semaglutide (331). After 26 weeks of treatment A1c decreased by -0.6% in the 3 mg group, -0.9% in the 7 mg group, and -1.1% in the 14 mg group compared to placebo (P < 0.001 for all results). If the decrease in A1c was adjusted for premature drug discontinuation or initiation of rescue medication the estimated decreases in A1c were -0.7% in the 3 mg group, -1.2% in the 7 mg group, and -1.4% in the 14 mg group (P < 0.001 for all).

Studies have also examined the ability of oral semaglutide to lower A1c vs. other drugs. Compared to sitagliptin, oral semaglutide 7mg per day reduced A1c by -0.3% while 14mg per day reduced A1c by 0.5% (P < .001 for both) (332). In a similar trial with flexible dose adjustment of semaglutide, treatment with semaglutide (60% on 14mg per day) resulted in a 1.4% decrease in A1c while 100mg sitagliptin decreased A1c by 0.7% (333). In a randomized trial comparing switching to oral semaglutide vs. DPP-4 inhibitor continuation A1c was decreased by 0.7% in the semaglutide group compared to continuing the DPP4 inhibitor (334). In a trial comparing empagliflozin vs. oral semaglutide, treatment with semaglutide resulted in a greater decrease in A1c compared to empagliflozin (-1.3% vs. -0.9%; P < 0.0001) (335). In a comparison of liraglutide 1.8mg per day vs. oral semaglutide 14mg per day the change from baseline in A1c was -1.2% (SE 0*1) with oral semaglutide and -1.1% with subcutaneous liraglutide (336). If the decrease in A1c was adjusted for premature drug discontinuation or initiation of rescue medication then oral semaglutide treatment resulted in a slightly greater decreases in A1c than subcutaneous liraglutide (estimated treatment difference -0*2%). Finally, early in the development of oral semaglutide various doses of oral semaglutide were compared to weekly injected semaglutide (337). Compared to placebo 10mg per day of oral semaglutide reduced A1c by -1.2%, 20mg by -1.4%, while 1mg per week of injected semaglutide decreased A1c by 1.9% (not significantly different than the 20mg oral dose). Thus, oral semaglutide is more effective in lowering A1c levels than DPP-4 inhibitors or SGLT2 inhibitors and similar to liraglutide and perhaps slightly less potent than injected semaglutide.

While not approved studies have shown that higher doses of oral semaglutide are more effective in lowering A1c levels (14mg- 1.5% decrease, 25mg- 1.8% decrease, 50mg- 2.0% decrease) (338).

### Other Effects

#### WEIGHT LOSS

In a meta-analysis of weight loss, treatment with oral semaglutide reduced body weight by 2.99 kg compared to placebo (330). In a 26-week study comparing sitagliptin vs. oral semaglutide the 7mg dose resulted in a 1.6kg decrease and the 14mg dose a 2.5kg decrease in weight compared to sitagliptin (332). In contrast, oral semaglutide 14mg and empagliflozin 25mg resulted in a similar decrease in body weight at 26-weeks (-3.8 vs. -3.7kg) and 52-weeks (-3.8 vs. -3.6kg) (335). Finally, in a 26-week trial oral semaglutide resulted in greater weight loss (-4.4 kg than liraglutide (-3*1 kg) (336).

While not approved higher doses of oral semaglutide are more effective in decreasing body weight ((14mg- 4.7% decrease, 25mg- 7.3% decrease, and 50mg- 8.5% decrease) (338).

#### BLOOD PRESSURE AND PULSE RATE

In a meta-analysis of blood pressure, treatment with oral semaglutide reduced systolic blood pressure by 3.16 mmHg and increased pulse rate by 1.90 beats per minute compared with placebo (330).

#### CARDIOVASCULAR DISEASE

In the PIONEER 6 study 3,183 patients with T2DM at high cardiovascular risk (age of ≥50 years with established cardiovascular or chronic kidney disease, or age of ≥60 years with cardiovascular risk factors) were randomly assigned to receive oral semaglutide or placebo (339). After a median time of 15.9 months, major adverse cardiovascular events, the primary outcome, occurred in 3.8% of the subjects treated with oral semaglutide and 4.8% of the placebo group (HR 0.79; 95% CI 0.57 to 1.11). Deaths from cardiovascular causes were 0.9% in the oral semaglutide group and 1.9% in the placebo group (HR 0.49; 95% CI, 0.27 to 0.92) while death from any cause occurred in 1.4% in the oral semaglutide group and 2.8% in the placebo group (HR 0.51; 95% CI, 0.31 to 0.84). It should be noted that the primary outcome was not statistically decreased in this study, which may be due to the relatively small number of subjects studied and the short duration of the study that together resulted in a small number of events. Additionally, more patients in the placebo group received treatment with an SGLT2 inhibitor than in the oral semaglutide group and SGLT2 inhibitors are well recognized to reduce cardiovascular disease events (see section on SGLT2 inhibitors), which could also have diminished the ability to observe a decrease in events in the oral semaglutide group. Because the glucose lowering, weight loss, and many other effects of oral semaglutide are very similar to injected semaglutide many experts consider the effects on cardiovascular and renal disease to also be similar.

### Side Effects

The most common adverse effects are GI and include nausea, vomiting, constipation, and diarrhea (329). Transient mild or moderate nausea was the most common adverse event occurring in 5-21% of subjects treated with oral semaglutide (329).

Severe hypoglycemia is uncommon in patients treated with oral semaglutide (329). The risk of hypoglycemia is increased when oral semaglutide is used in combination with insulin secretagogues (e.g., sulfonylureas) or insulin. Patients may require a lower dose of the secretagogue or insulin to reduce the risk of hypoglycemia when used in combination with oral semaglutide.

The safety profile of oral semaglutide is similar to other GLP-1 RAs (see side effect section for GLP1 receptor agonists).

### Contraindications and Drug Interactions

Similar to other GLP1 RAs oral semaglutide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with Multiple Endocrine Neoplasia syndrome type 2.

No notable drug interactions have been described (package insert).

### Summary

The delivery of a GLP1 RA via the oral route is advantageous and make oral semaglutide an attractive choice in the treatment of patients with T2DM who do want to inject medications given its ability to decrease A1c, body weight, and blood pressure with few serious side effects. Some patients may have difficulty following the relatively complex instructions for taking this medication. It should be noted that weight loss is less with oral semaglutide and studies using higher doses for weight loss are underway. It is likely that the other beneficial effects of GLP1 receptor agonists (e.g., reducing cardiovascular disease and renal disease) will also occur with the oral formulation.

## DUEL GLP-1 RECEPTOR AND GIP RECEPTOR AGONIST

### Introduction

Tirzepatide (Mounjaro) is a 39 amino acid peptide that was engineered from the native GIP sequence and has agonist activity at both the GIP and GLP-1 receptors (340,341). A C20 fatty diacid moiety is conjugated at the position 20 lysine residue, which facilitates binding to albumin thereby resulting in a half-life after administration of approximately 5 days allowing for weekly administration (340,341).

For information on the use of tirzepatide for the treatment of weight loss see the Endotext chapter entitled "Pharmacologic Treatment of Overweight and Obesity in Adults" (267).

### Administration

Tirzepatide is administered weekly at any time of day, with or without meals. The starting dose is 2.5mg subcutaneously and after 4 weeks the dose is increased to 5 mg (341). Depending upon the response one may increase the dosage in 2.5 mg increments every 4 weeks to a maximum dose of 15 mg per week (341). No dosage adjustment is recommended for renal or hepatic disease (package insert).

### Mechanism of Action

Both GLP-1 and GIP stimulate insulin secretion in a glucose dependent fashion (342). The higher the glucose the greater the effect with no effect when glucose levels are in the normal to low range (342). As one would expect tirzepatide stimulates both first- and second-phase insulin secretion (341,343). GLP-1 inhibits glucagon secretion when glucose levels are increased while GIP will stimulate glucagon secretion, particularly when glucose levels are in the normal to low range (342). Tirzepatide reduces fasting and postprandial glucagon concentrations (343). These effects on insulin and glucagon secretion lead to decreases in glucose levels with a low risk of hypoglycemia as the increase in insulin secretion and decrease in glucagon secretion are dependent on elevated glucose levels. In addition, tirzepatide improves insulin sensitivity (343,344). While this increase in insulin sensitivity may be due to weight loss studies suggest that there may be additional factors contributing to the improved insulin sensitivity (344). GIP may have peripheral effects that could enhance insulin sensitivity.

Pharmacologic levels of GLP-1 slow gastric emptying and induce satiety by activating receptors in the hypothalamus thereby leading to decreased food intake and weight loss (342). GIP also appears to have central effects leading to decreased food intake in rodents but the effect in humans is not well defined (342).

### Glycemic Efficacy

A number of different studies (SURPASS trials) have examined the effect of 5mg, 10mg, and 15mg of tirzepatide on glycemic control under a variety of clinical situations ([Table 30](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.decrease_in_hba1c/?report=objectonly)). SURPASS 1 compared tirzepatide vs. placebo in patients on no medications (345), SURPASS 2 compared tirzepatide vs. semaglutide at a dose of 1 mg in patients on metformin (346), SURPASS 3 compared tirzepatide vs. degludec insulin in patients on metformin alone or in combination with an SGLT2 inhibitor (347). SURPASS 4 compared tirzepatide vs glargine insulin in patients treated with any combination of metformin, sulfonylurea, or SGLT-2 inhibitor (348), and SURPASS 5 compared tirzepatide vs. placebo in patients treated with glargine insulin with or without metformin (349). The treatment duration was 40 weeks in SURPASS 1, 2, and 5 and 52 weeks in SURPASS 3 and 4. Baseline A1c levels were between 7.9% and 8.5% in the SURPASS studies.

### Table 30. 

Decrease in HbA1c with Tirzepatide Treatment

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.decrease_in_hba1c/?report=objectonly)

| SURPASS 1| SURPASS 2| SURPASS 3| SURPASS 4| SURPASS 5  
---|---|---|---|---|---  
| Tirzepatide vs. Placebo| Tirzepatide vs. Semaglutide| Tirzepatide vs. Degludec| Tirzepatide vs.  
Glargine| Tirzepatide vs. Placebo  
Baseline A1c| 7.9%| 8.3%| 8.2%| 8.5%| 8.3%  
Tirzepatide 5mg| -1.8| -2.0| -1.9| -2.1| -2.1  
Tirzepatide 10mg| -1.7| -2.2| -2.0| -2.3| -2.4  
Tirzepatide 15mg| -1.7| -2.3| -2.1| -2.4| -2.3  
Comparator| -0.1| -1.9| -1.3| -1.4| -0.9  
  
It should be noted that the reduction in A1c induced by tirzepatide is quite impressive and results in an A1c level in an "intensive" control range. For example, in the SURPASS 2 trial 80% of patients had an A1c < 6.5% and 46% < 5.7% on 15mg tirzepatide. Additionally, comparison with semaglutide (SURPASS 2) demonstrated a modestly greater lowering of A1c with tirzepatide. A greater difference in the ability to decrease A1c was seen in an earlier study comparing tirzepatide vs. dulaglutide (tirzepatide 5mg- 1.6%, 10mg- 2.0%,15 mg- 2.4%; duluglutide 1.5mg- 1.1%) (350). Note the comparisons with semaglutide and dulaglutide used doses in these studies that were not the maximal dose. Comparisons with insulin therapy (SURPASS 3 and 4) show better glycemic control with tirzepatide, which is likely due to an increased risk of hypoglycemia with insulin therapy that limits treatment. In SURPASS 3, 48% of patients on insulin therapy had a blood glucose < 70mg/dL while on tirzepatide treatment 8-14% of patients had a blood glucose < 70mg/dL. The SURPASS 6 trial compared the addition of tirzepatide vs. insulin lispro three times per day (351). Tirzepatide decreased A1c by -2.1% vs -1.1% with insulin lispro with less severe hypoglycemia and greater weight loss. Severe hypoglycemia is not frequently observed with tirzepatide in the absence of concomitant insulin or sulfonylurea therapy. Finally, it is worth noting that the additional A1c reduction with an increased dose of tirzepatide is very modest. This is important to recognize that in patients that have side effects with higher doses of tirzepatide treatment it is not necessary to achieve maximal doses of tirzepatide to robustly improve glycemic control.

### Other Effects

#### WEIGHT LOSS

Significant weight loss has been observed with tirzepatide administration. [Table 31](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.decrease_in_weigh/?report=objectonly) shows the weight loss observed in the SURPASS trials. In contrast to the modest effects of increased doses of tirzepatide on A1c levels increased doses of tirzepatide have a greater effect on weight loss. At the 15mg dose over a 10% loss in weight is observed. It should be noted that in SURPASS 2 tirzepatide is compared to semaglutide 1.0mg, which is not the dose that is recommended for weight loss (the recommended dose is 2.4mg) and therefore one cannot be certain that tirzepatide is more efficacious than higher doses of semaglutide. In a comparison of tirzepatide vs. dulaglutide, tirzepatide resulted in greater weight loss (tirzepatide 5mg- 4.8kg, 10mg- 8.7kg, 15mg-11.3kg; dulaglutide 1.5mg- 2.7kg) (350). In a large 72-week trial focused on weight loss (SURMONT-2) in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg (n=312) and 15 mg (n=311) resulted in a 9.6% and 11.6% loss in weight compared to the placebo group (n=315) (352).

### Table 31. 

Decrease in Weight with Tirzepatide Treatment

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.decrease_in_weigh/?report=objectonly)

| SURPASS 1| SURPASS 2| SURPASS 3| SURPASS 4| SURPASS 5  
---|---|---|---|---|---  
| Tirzepatide vs. Placebo| Tirzepatide vs. Semaglutide| Tirzepatide vs. Degludec| Tirzepatide vs.  
Glargine| Tirzepatide vs. Placebo  
Tirzepatide 5mg| -6.3kg/ -7.9%| -7.6kg/ -8.5%| -7.0kg/ -8.1%| -6.4kg/ -8.1%| -5.4kg/ -6.6%  
Tirzepatide 10mg| -7.0kg/ -9.3%| -9.3kg/ -11.0%| -9.6kg/ -11.4%| -8.9kg/ -10.7%| -7.5kg/ -8.9%  
Tirzepatide 15mg| -7.8kg/ -11.0%| -11.2kg/ -13.1%| -11.3kg/ -13.9%| -10.6kg/ -13.0%| -8.8kg/ -11.6%  
Comparator| -1.0kg/ -0.9%| -5.7kg/ -6.7%| +1.9kg/ +2.7%| +1.7kg/ +2.2%| +1.6kg/ +1.7%  
  
#### BLOOD PRESSURE AND PULSE

In the SURPASS studies described above tirzepatide treatment decreased systolic BP by 2.8 to 12.6 mm Hg and diastolic BP by 0.8 to 4.5 mm Hg (340). Tirzepatide treatment increased heart rate by approximately 2 to 4 beats per minute.

#### LIPIDS

In the SURPASS studies described above plasma triglyceride levels were consistently decreased by 13-25% ([table 32](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_tirzape/?report=objectonly)). In most studies with the exception of SURPASS 5, HDL cholesterol levels increased by 3-11%. Total cholesterol and LDL cholesterol levels are modestly decreased in most studies. Not unexpectedly given the decrease in triglyceride levels small LDL particles were decreased (353). The decrease in triglycerides could be related to weight loss, which is well known to affect triglycerides (354). Additionally, GIP and tirzepatide increase lipoprotein lipase activity, which could increase the clearance of triglyceride rich lipoproteins (342,353). Finally, tirzepatide lowered Apo-CIII levels, which could also play a role in the decrease in triglyceride levels (353).

### Table 32. 

Effect of Tirzapetide 15mg on Lipid Levels

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_tirzape/?report=objectonly)

| SURPASS 1| SURPASS 2| SURPASS 3| SURPASS 4| SURPASS 5  
---|---|---|---|---|---  
| Tirzepatide vs. Placebo| Tirzepatide vs. Semaglutide| Tirzepatide vs. Degludec| Tirzepatide vs.  
Glargine| Tirzepatide vs. Placebo  
Total Cholesterol| -7.6%| -1.5%| -3.0%| -5.6%| -12.6%  
Triglycerides| -25.7%| -13.3%| -13.0%| -16.1%| -19.4%  
LDLc| -10.8%| +1.2%| -3.8%| -9.3%| -17.3%  
HDLc| +11.3%| +2.7%| +9.2%| +7.9%| -0.8%  
  
    

Results are percent change in tirzepatide group minus percent change in comparator group.

#### CARDIOVASCULAR DISEASE

A meta-analysis of seven randomized controlled trials with 4,887 participants treated with tirzepatide and 2,328 control participants found that MACE 4 (cardiovascular death, myocardial infarction, stroke, and hospitalized unstable angina) was decreased but not statistically significant (HR 0.80; 95% CI, 0.57-1.11) (355). One should note that the number of events in this meta-analysis was small because the duration of these studies was relatively short (approximately 1 year) and the population of patients included in these studies were not at high risk for cardiovascular events (only 1/3 with pre-existing cardiovascular disease). A long-term trial dedicated to determining the effect of tirzepatide on cardiovascular disease is ongoing (SURPASS-CVOT trial [NCT04255433](https://clinicaltrials.gov/show/NCT04255433 "Study NCT04255433")) (356).

#### RENAL DISEASE

A post-hoc analysis of the SURPASS-4 compared the effect of tirzepatide and glargine insulin on kidney function with a median treatment duration of treatment 85 weeks (357). The mean rate of eGFR decline was -1.4 per year in the combined tirzepatide groups and -3.6 per year in the insulin group (between-group difference 2.2 [95% CI 1.6 to 2.8]) with a greater benefit in participants with eGFR < 60 (i.e., patients with pre-existing kidney disease). It should be noted that tirzepatide treatment resulted in an early decrease in eGFR, however, after 12 weeks eGFR values were higher in the tirzepatide group than in the glargine insulin group. Additionally, urine albumin to creatinine ratio in the glargine insulin group increased but in the tirzepatide treated group there was very little change. The UACR stabilizing effect of tirzepatide was similar in SGLT2 inhibitor users vs. non-users suggesting that these drugs will have additive beneficial effects on kidney function. The SURPASS 1, 3, and 5 trials similarly showed beneficial effects on urine albumin to creatinine ratio. The SURPASS 2 trial compared tirzepatide and semaglutide and there was no difference in the urine albumin to creatinine ratio. The effect of tirzepatide on urine albumin to creatinine ratio and eGFR did not appear to be mediated by changes in HbA1c or bodyweight. Most importantly, tirzepatide reduced the risk of the composite kidney endpoint of new-onset macroalbuminuria, eGFR decline of at least 40%, end-stage kidney disease, or death due to kidney failure by 42% (HR 0.58; 95% CI 0.43-0.80), mainly due to a reduction in new-onset macroalbuminuria (357).

These results strongly suggest that tirzepatide has beneficial on kidney function but further studies dedicated to determining the benefits of tirzepatide on renal function are indicated.

#### LIVER DISEASE

Liver fat content was decreased to a greater degree with tirzepatide treatment compared to treatment with insulin degludec (358). Additionally, tirzepatide decreased alanine aminotransferase and aspartate aminotransferase levels (359).

A recent randomized trial compared the response to tirzepatide 5, 10, or 15mg vs. placebo in patients with metabolic dysfunction-associated steatohepatitis (MASH) with moderate or severe fibrosis after 52 weeks of treatment (360). Resolution of MASH without worsening of fibrosis was seen in 10% of the patients in the placebo group, 44% of the patients in the 5-mg tirzepatide group, 56% of the patients in the 10-mg tirzepatide group, and 62% of the patients in the 15-mg tirzepatide group (P<0.001 for all three comparisons with placebo group). Improvement of at least one fibrosis stage without worsening of MASH occurred in 30% of the placebo group, 55% of the 5-mg tirzepatide group, 51% of the 10-mg tirzepatide group, and 51% of the 15-mg tirzepatide group. As seen in other studies alanine aminotransferase and aspartate aminotransferase decreased by approximately 50% and liver fat by 40-50% in patients treated with tirzepatide compared to placebo.

These studies suggest that tirzepatide will have beneficial effects in patients with metabolic dysfunction associated steatotic liver disease (MASLD) and MASH.

#### OBSTRUCTIVE SLEEP APNEA

In individuals who were not diabetic but were obese with moderate-to-severe obstructive sleep apnea, treatment with tirzepatide resulted in "a clinically meaningful change in sleep-disordered breathing and alleviation of perceived sleep disturbance and sleep-related impairment, as well as reductions in common obstructive sleep apnea-related cardiovascular risk factors" (361). Hopefully future studies will determine if similar beneficial effects with tirzepatide treatment occur in patients with diabetes and obstructive sleep apnea.

### Side Effects

The side effects described in the section on GLP-1 RAs also are of concern with tirzepatide.

Patients treated with tirzepatide in combination with a sulfonylurea or insulin may have an increased risk of hypoglycemia. The risk of hypoglycemia may be decreased by a reduction in sulfonylurea or insulin dose.

The incidence of pancreatitis was increased in patients treated with tirzepatide compared to comparator treatment ((0.23 patients per 100 years of exposure vs. 0.11 patients per 100 years of exposure) (package insert). Additionally, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was increased with tirzepatide treatment (0.6% of tirzepatide-treated patients and 0% of placebo-treated patients) (package insert).

As with other GLP-1 RAs nausea, diarrhea, vomiting, dyspepsia, constipation, and decreased appetite are common side effects.

### Contraindications and Drug Interactions

Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with MEN2. Tirzepatide has not been studied in patients with a prior history of pancreatitis and it is unknown if patients with a history of pancreatitis are at higher risk for developing pancreatitis.

Tirzepatide delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. The delay is largest after the first dose and diminishes over time.

### SUMMARY

The major advantage of tirzepatide compared to GLP-1 RAs is the greater decrease in weight and A1c levels.

## INSULIN-GLP-1 RECEPTOR AGONIST COMBINATIONS

### Introduction

There are currently two insulin-GLP-1 RA combinations available for use; glargine insulin/lixisenatide (iGlarLixi) (Soliqua) and degludec insulin/liraglutide (iDegLira) (Xultophy). Both combine a basal insulin with a once-a-day GLP-1 RA. iGlarLixi contains 100U glargine and 33 ug lixisenatide per ml. iDegLira contains 100U degludec insulin and 3.6 mg liraglutide per ml.

### Administration

In patients naive to basal insulin or to a GLP-1 RA, currently on a GLP-1 RA, or currently on less than 30 units of basal insulin daily the recommended starting dosage of iGlarLixi 100/33 is 15 units (15 units insulin glargine/5 ug lixisenatide) given subcutaneously once daily. In patients currently on 30 to 60 units of basal insulin daily, with or without a GLP-1 RA the recommended starting dosage of iGalLixi 100/33 is 30 units (30 units insulin glargine/10 ug lixisenatide) given subcutaneously once daily. After starting with the recommended dose, titrate the dosage upwards or downwards by two to four units weekly based on the patient's glycemic control until the desired fasting plasma glucose is achieved. Administer iGlarLixi 100/33 subcutaneously once a day within an hour prior to the first meal of the day. The maximum dose of iGlarLixi 100/33 is 60 units daily (60 units insulin glargine/20 ug lixisenatide).

The recommended starting dose of iDegLira 100/3.6 is 16 units (16 units of insulin degludec and 0.58 mg of liraglutide) given subcutaneously once-daily. After starting the recommended starting dose, titrate the dosage upwards or downwards by two units every three to four days based on the patient's blood glucose monitoring results and glycemic control goal until the desired fasting plasma glucose is achieved. Administer iDegLira 100/3.6 by subcutaneous injection once-daily at the same time each day with or without food. The maximum dose of iDegLira 100/3.6 is 50 units daily (50 units of insulin degludec and 1.8 mg of liraglutide).

### Mechanism of Action

Basal insulin regulates fasting blood glucose levels between meals and overnight while a GLP-1 RA lowers postprandial glucose levels (362). Together this drug combination results in 24-hour glycemic control.

### Glycemic Efficacy

A number of studies have compared the ability of the combination of insulin-GLP RA to lower A1c levels compared to either insulin alone or GLP-1 RA alone (362). [Table 33](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_combina/?report=objectonly) shows the results of two large studies. As shown in [Table 33](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_combina/?report=objectonly) combination therapy was better at lowering A1c levels compared to the individual components (362). Additionally, the risk of hypoglycemia was similar with combination therapy compared to basal insulin alone. In a study of patients poorly controlled on glargine insulin adding rapid acting insulin (basal/bolus therapy) vs. switching to iDegLira was found to result in a similar reduction in A1c levels but the risk of hypoglycemia was greater with basal/bolus insulin (363). Not unexpectedly basal/bolus insulin resulted in greater weight gain (difference 3.6 kg) (363). Indirect comparisons suggest that iDegLira reduces A1C slightly more (< 0.5%) than iGlarLixi but this could be due to different study design, different patient populations, or other differences between the trials (362). A meta-analysis of 8 studies concluded that iDegLira and iGlarLixi demonstrated no significant differences in absolute HbA1c changes, fasting plasma glucose levels, or body weight changes relative to baseline (364). Moreover, a small head-to-head comparison of iDegLira and iGlarLixi did not demonstrate differences in glycemic control (365).

### Table 33. 

Effect of Combination Therapy vs Individual Components on Key Outcomes

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_combina/?report=objectonly)

Study| Treatment| A1c Reduction| % Subjects with Hypoglycemia| Change in Body Weight (Kg)  
---|---|---|---|---  
Rosenstock et al (366)| iGlarLixi| 1.6%| 26| -0.3  
| Glar| 1.3%| 24| +1.1  
| Lixi| 0.9%| 6| -2.3  
Gough et al (367)| iDegLira| 1.9%| 32| -0.5  
| Deg| 1.4%| 39| +1.6  
| Lira| 1.3%| 7| -3.0  
  
### Other Effects

As shown in [Table 33](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.effect_of_combina/?report=objectonly) the typical weight gain seen with insulin therapy alone is blunted with combination therapy.

### Side Effects

Studies have noted that the typical GI side effects seen with GLP-1 RA therapy is blunted with combination therapy (148). The likely explanation is that the titration of the GLP-1 RA is slower with combination therapy (148).

### Contraindications

The maximum daily insulin dose of 60 units for iGlarLixi and 50 units for iDegLira, may not be sufficient in patients requiring higher daily basal insulin doses (e.g., patients with severe insulin resistance). The maximum dose is determined by the GLP-1 RA (the max dose of iDegLira delivers 1.8 mg of liraglutide while the max dose of iGlarLixa delivers 20 ug of lixisenatide). Conversely, there may be some patients who require only a low dose of basal insulin and thus because of the fixed ratio of basal insulin to GLP-1 RA the dose of the GLP-1 RA may be too low. These examples are a limitation of fixed ratio delivery systems. In these patients one can use basal insulin and a GLP-1 RA independently. It should be noted that for the majority of patients the fixed ratio will be acceptable.

### Summary

The effects of combination therapy are predictable based on studies of basal insulin and GLP-1 RAs but providing them in a single injection provides convenience and makes it easier for patients to comply. Additionally, these combination drugs are titrated based on fasting glucose values and therefore frequent home blood glucose monitoring is not required, which also makes compliance easier. In patients who do not have adequate control on basal insulin alone or a GLP-1 RA alone combination therapy can be a useful therapeutic option.

## BILE ACID SEQUESTRANTS

### Introduction

Colesevelam (Welchol) is a non-absorbed, polymeric, LDL cholesterol lowering and glucose lowering agent that is a high-capacity bile acid-binding molecule (368). This drug was developed primarily to lower LDL cholesterol levels and was later noted to have favorable effects on blood glucose levels and was approved for improving glycemic control in patients with T2DM (20,368). It should be noted that other bile acid sequestrants (cholestyramine) also have favorable effects on glycemic control (369).

### Administration

The recommended dose of colesevelam is 6 tablets once daily or 3 tablets twice daily with meals (tabs 625 mg). Alternatively, one can take one 3.75-gram packet once daily mixed with water, fruit juice, or diet soft drinks and taken with meals or one flavored chewable bar (80 calories per bar) with meals. For patients with difficulty swallowing tablets the use of packets or chewable bars is recommended.

### Mechanism of Action

The mechanism by which bile acid sequestrants improve glucose metabolism is not well understood and the literature on this topic is often contradictory (370,371). Colesevelam does not alter hepatic or peripheral insulin sensitivity or decrease glucose GI absorption (371,372). Neither acute nor chronic treatment affect post oral glucose tolerance test blood glucose levels (372). Additionally, colesevelam treatment did not alter endogenous glucose production, gluconeogenesis, or glycogenolysis (371,372). Thus, the mechanisms accounting for the decrease in glucose effect of bile acid sequestrants remain unclear.

A leading hypothesis is that bile acid sequestrants improve glucose metabolism by stimulating the incretin pathway. Colesevelam increases GLP-1 and GIP concentrations suggesting that an increase in incretins contributes to the improvement in glycemic control (372-374). There are two pathways by which colesevelam increases GLP-1 secretion; (1) TGR5-mediated GLP-1 secretion in L cells and (2) intestinal proglucagon expression.

TGR5 is a G protein-coupled receptor expressed in many organs and tissues including the intestine (372,374). Bile acids activate TGR5 on the surface of intestinal L cells promoting GLP-1 secretion (372,374,375). Bile acid sequestrants appear to augment TGR5 activation and GLP-1 release, which occurs primarily in the distal intestine and colon (372,375,376).

FXR is a nuclear hormone receptor that complexes with RXR to alter the expression of a large number of genes (374). Bile acids are a ligand for FXR and activate FXR thereby regulating gene expression (374). FXR activation in intestinal L cells decreases proglucagon expression resulting in a decrease in GLP-1 production (377). Conversely, a decrease in bile acids due to binding to colesevelam increases GLP-1 gene expression and secretion in response to glucose improving glucose metabolism (377).

It is likely that there are both incretin dependent and independent mechanisms that account for the improvement in glycemic control with colesevelam treatment. The exact mechanisms by which bile acid sequestrants lower A1c levels remain to be elucidated.

### Glycemic Efficacy

Colesevelam has modest effects on glycemic control, lowering A1c levels by approximately 0.5% when added to metformin, sulfonylureas, pioglitazone, or insulin (20,368,378). Colesevelam does not lead to an increase in weight (368). In combination with metformin hypoglycemia is not a problem but when used in combination with insulin or sulfonylureas hypoglycemia may occur (368).

### Other Effects

#### LIPIDS

Colesevelam lowers LDL cholesterol levels by 15-20% and has only a modest effect on HDL cholesterol levels (368,379). The effect of bile acid sequestrants on triglyceride levels varies (379). In patients with normal triglyceride levels, bile acid sequestrants increase triglyceride levels by a small amount. However, as baseline triglyceride levels increase, the effect of bile acid sequestrants on plasma triglyceride levels becomes greater, and can result in substantial increases in triglyceride levels (379). In patients with triglycerides > 500mg/dl the use of bile acid sequestrants is contraindicated (379).

#### CARDIOVASCULAR DISEASE

There have been no randomized studies that have examined the effect of bile acid sequestrants on cardiovascular end points in subjects with diabetes. In non-diabetic-subjects bile acid sequestrants have reduced cardiovascular events (380,381). Since bile acid sequestrants have a similar beneficial impact on serum lipid levels in diabetic and non-diabetic subjects one would anticipate that these drugs would also result in a reduction in events in the diabetic population.

### Side Effects

Colesevelam does not have major systemic side effects as it is not absorbed and remains in the intestinal tract (379). However, it does cause gastrointestinal (GI) side effects (379). Constipation is a common side effect and can be severe. In addition, patients will often complain of bloating, dyspepsia, abdominal discomfort, and aggravation of hemorrhoids. Because of GI distress, a small number of patients will discontinue therapy with colesevelam. One can reduce or ameliorate these GI side effects by increasing hydration, adding fiber to the diet (psyllium), and using stool softeners.

### Contraindications and Drug Interactions

Colesevelam treatment is contraindicated in patients with a history of bowel obstruction and is cautioned in those with a history of gastrointestinal motility disorders (i.e., gastroparesis) or gastrointestinal surgery (368,379). Colesevelam is contraindicated in patients with plasma triglyceride levels > 500 mg/dL or a history of hypertriglyceridemia-induced pancreatitis (package insert).

In the intestine bile acid sequestrants can impede the absorption of many other drugs (379). Colesevelam, which requires a much lower quantity of drug because of its high affinity and binding capacity for bile salts, has less of an effect on the absorption of other drugs than other bile acid sequestrants but can still adversely affect the absorption of certain drugs ([Table 34](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.drugs_affected_by/?report=objectonly)) (379). Administration of these drugs, as well as vitamin supplements, 4 hours prior to administration of colesevelam minimizes pharmacokinetic interactions (379). This is particularly important with drugs that have a narrow toxic/therapeutic window, such as thyroid hormone, digoxin, or warfarin. It can be difficult for some patients, particularly those on multiple medications, to take colesevelam given the need to separate pill ingestion.

### Table 34. 

Drugs Affected by Colesevelam

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.drugs_affected_by/?report=objectonly)

L-thyroxine| Cyclosporine| Glimepiride| Glipizide  
---|---|---|---  
Glyburide| Phenytoin| Olmesartan| Warfarin  
Oral contraceptives| Repaglinide| Fenofibrate| Vitamin Supplements  
  
Colesevelam may also decrease the absorption of fat-soluble vitamins A, D, E, and K (package insert).

### Summary

Colesevelam has the advantage of lowering both A1c and LDL cholesterol levels. However, the efficacy of lowering A1c and LDL cholesterol levels is modest compared to other drugs. Additionally, in our patients with diabetes who are often on multiple medications it can be difficult to coordinate taking colesevelam with these other medications.

### Table 35. 

Advantages and Disadvantages of Colesevelam

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_5/?report=objectonly)

Advantages| Disadvantages  
---|---  
Lowers LDL cholesterol| Increases triglyceride levels particularly if already high  
Minimal systemic effects| GI side effects  
Once a day administration possible| Inhibits the absorption of other drugs  
No hypoglycemia| Modest effect on A1c  
Weight neutral| Relatively Expensive  
  
## PRAMLINTIDE (SYMLIN)

### Introduction

Pramlintide is a soluble synthetic analog of human amylin (382). Amylin is co-sequestered and co-secreted with insulin by the pancreatic beta cells in response to nutrient stimuli (382). Amylin secretion in response to nutrients is absent in type 1 diabetes and in patients with T2DM there is impaired beta-cell secretion of amylin in response to nutrients (382). Amylin suppresses post-prandial arginine-stimulated glucagon secretion, suppresses appetite, and slows gastric emptying time through effects on the brain (382).

### Administration

In patients with T2DM initiate pramlintide at 60 ug subcutaneously immediately prior to each major meal. Increase the dose from 60 to 120 ug prior to each major meal when no clinically significant nausea has occurred for at least 3 days. Note the dose used to treat patients with Type 1 diabetes differs from the dose used in patients with T2DM.

### Mechanism of Action

Pramlintide attenuates post-prandial glucagon secretion, enhances satiety, and reduces food intake, which together improve glycemic control (382). These effects are mediated centrally (382)

### Glycemic Efficacy

In a review of three randomized trials in patients with T2DM comparing pramlintide vs. placebo the A1c level was decreased by approximately 0.3-0.6% in the pramlintide group (383). Postprandial glucose excursions are significantly blunted with the addition of pramlintide (382). Pramlintide has only minimal effects on fasting glucose levels (383).

In a study comparing rapid acting insulin vs. pramlintide with meals a similar reduction in A1c was observed (384). In contrast to rapid acting insulin, patients treated with pramlintide did not gain weight (384). Additionally, the frequency of hypoglycemia was less with pramlintide compared with rapid acting insulin (384).

### Other Effects

Pramlintide treatment decreases weight (approximately 1-3 kg), which is likely due to decreased food intake (382,383). In a comparison of food intake during an ad libitum buffet meal, treatment with pramlintide resulted in an approximately 200 calorie decrease in food intake compared to placebo administration (385). Pramlintide also decreases gastric emptying (382).

### Side Effects

A major side effect of pramlintide is nausea which can lead to patients discontinuing this drug (383).

Although pramlintide alone does not cause hypoglycemia, in combination with rapid acting meal time insulin the two drugs synergistically increase the risk of severe hypoglycemia (382). Therefore, rapid acting meal time insulin needs to be reduced upon initiation of pramlintide treatment to decrease the risk of hypoglycemia (382). Reducing rapid acting meal time insulin by 30-50% is recommended during the initial dose titration period (382).

### Contraindications and Drug Interactions

Pramlintide is contraindicated in patients with hypoglycemia unawareness and confirmed gastroparesis (package insert).

### Summary

Pramlintide is currently seldom used. Its modest effect on A1c levels coupled with the difficulties of administration (extra injections) and side effects has led to minimal use of this agent. Additionally, its major advantage of weight loss is now superseded by the use of GLP-1 RAs.

### Table 36. 

Advantages and Disadvantages of Pramlintide

[View in own window](/sites/books/NBK279141/table/pharmaco-agent-diab2.T.advantages_and_di_6/?report=objectonly)

Advantages| Disadvantages  
---|---  
Weight loss| Hypoglycemia  
Decrease postprandial glucose| Frequent dosing  
| GI side effects  
| Expensive  
| Modest reduction in A1c  
  
## SUMMARY

A large number of drugs are now available for lowering glucose levels. For information on the management of T2DM and selecting amongst the available pharmacological agents see the chapter by Schroeder (5). For information on the use of these drugs to treat diabetes during pregnancy, in children and adolescents, and for the prevention of diabetes see other Endotext chapters (2-4).

## ACKNOWLEDGEMENTS

This work was supported by grants from the Northern California Institute for Research and Education.

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Feingold KR. Oral and Injectable (Non-Insulin) Pharmacological Agents for the Treatment of Type 2 Diabetes. [Updated 2024 Sep 11]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. 




### In this Page

  * ABSTRACT
  * INTRODUCTION
  * OVERVIEW OF DRUGS
  * SULFONYLUREAS
  * MEGLINATIDES
  * METFORMIN
  * THIAZOLIDINEDIONES (TZDS)
  * ALPHA-GLUCOSIDASE INHIBITORS
  * SODIUM-GLUCOSE TRANSPORT PROTEIN 2 (SGLT2) INHIBITORS
  * COMBINATION SGLT1 AND SGLT2 INHIBITORS
  * DOPAMINE AGONIST (CYCLOSET)
  * OVERVIEW OF THE INCRETIN SYSTEM
  * DIPEPTIDYL PEPTIDASE-4 (DPP-4) INHIBITORS
  * INJECTABLE GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS
  * ORAL GLUCAGON LIKE PROTEIN-1 (GLP-1) RECEPTOR AGONISTS
  * DUEL GLP-1 RECEPTOR AND GIP RECEPTOR AGONIST
  * INSULIN-GLP-1 RECEPTOR AGONIST COMBINATIONS
  * BILE ACID SEQUESTRANTS
  * PRAMLINTIDE (SYMLIN)
  * SUMMARY
  * ACKNOWLEDGEMENTS
  * REFERENCES



### LINKS TO WWW.ENDOTEXT.ORG

  * [View this chapter in Endotext.org](https://www.endotext.org/chapter/modalities-for-treatment-of-diabetes/oral-and-injectable-non-insulin-pharmacological-agents-for-the-treatment-of-type-2-diabetes/)



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