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Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective

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#  Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective 

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Sudhir Pandey

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1

Department of Pharmacology, Faculty of Pharmacy, Mahidol University, Bangkok 10400, Thailand

2

Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand

*

Author to whom correspondence should be addressed. 

_Pharmaceuticals_ **2023** , _16_(6), 836; <https://doi.org/10.3390/ph16060836>

Submission received: 10 May 2023 / Revised: 1 June 2023 / Accepted: 1 June 2023 / Published: 3 June 2023

(This article belongs to the Section [Pharmacology](/journal/pharmaceuticals/sections/pharm-pharmacology))  


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[ ](https://pub.mdpi-res.com/pharmaceuticals/pharmaceuticals-16-00836/article_deploy/html/images/pharmaceuticals-16-00836-g001.png?1685936917 "
                        <strong>Figure 1</strong><br/>
                                                    <p><b>Structural arrangement of mammalian proglucagon.</b> \(<b>A</b>\) The amino acid sequences in proglucagon have been marked as numbers. The post-translational processing produces peptides in the intestine and pancreas as shown. \(<b>B</b>\) The DPP-4 cleavage site in the amino acid chain is indicated by arrows. GRPP, glicentin-related pancreatic polypeptide; IP, intervening peptide; PC1/2/3, prohormone convertases 1/2/3; DPP-4, dipeptidyl peptidase-4.</p>
                                                ") [ ](https://pub.mdpi-res.com/pharmaceuticals/pharmaceuticals-16-00836/article_deploy/html/images/pharmaceuticals-16-00836-g002.png?1685936913 "
                        <strong>Figure 2</strong><br/>
                                                    <p>GLP-1 receptor \(GLP-1R\) gene expression \(transcripts per million; TPM\) amongst females and males in selected tissues related to the cardiovascular system and pancreas \(from GTEx Portal <a href="https://gtexportal.org/home/gene/GLP-1R" target="_blank">https://gtexportal.org/home/gene/GLP-1R</a> accessed on 21 November 2022\). Box plots are depicted as median and correspond to 25th and 75th percentiles. The pancreas expresses the higher expression \(median value, 4.5\) when compared to heart-atria \(median value, 1.7\), heart left ventricle \(median value, 0.6\), coronary artery \(median value, 0.05\), and aorta \(median value, not available\). In this cohort analysis, there are no significant sex differences in the expression pattern of GLP-1R amongst males and females.</p>
                                                ") [ ](https://pub.mdpi-res.com/pharmaceuticals/pharmaceuticals-16-00836/article_deploy/html/images/pharmaceuticals-16-00836-g003.png?1685936911 "
                        <strong>Figure 3</strong><br/>
                                                    <p><b>Systemic effects of GLP-1 and its analogs.</b> The effects on various tissues/organs illustrated in the figure are based on results obtained in several preclinical or clinical studies at physiological GLP-1 levels or after exposure to GLP-1R analogs. GLP-1R is abundantly distributed in the tissues/organs of the peripheral and central nervous system with the different expression levels leading to the distinct biological functions in each tissue/organ. In the CNS and pancreas, high expression of GLP-1R is detected, while lower expression of GLP-1R is observed in the heart, lungs, gut, muscle, kidneys, liver, PNS, and other tissues. ↑, Increase; ↓, Decrease.</p>
                                                ") [ ](https://pub.mdpi-res.com/pharmaceuticals/pharmaceuticals-16-00836/article_deploy/html/images/pharmaceuticals-16-00836-g004.png?1685936915 "
                        <strong>Figure 4</strong><br/>
                                                    <p><b>Schematic diagram representing cardioprotective molecular mechanisms of GLP-1 analogs in cardiomyocytes.</b> The GLP-1R-dependent and -independent signaling pathways have been described as contributing to healthy myocardium and heart functions under pathophysiological conditions. The binding of GLP-1 to its receptor activates adenylate cyclase, and cAMP levels are elevated, which is followed by the activation of downstream cAMP sensitive molecular effectors in a GLP-1R-dependent way. While GLP-1R-independent GLP-1\(9-36\) activates PI3K, Akt, and the downstream signaling pathway, the full mechanisms of this process are not yet known. GLP-1, glucagon-like peptide-1; cAMP, cyclic adenosine monophosphate; Akt, protein kinase B; Epac, exchange protein activated by cAMP; CREB, cAMP-response element binding protein; CaMKKβ, calcium ions/calmodulins dependent protein kinase kinases β; PINK1, PTEN-induced kinase 1; Mfn, Mitofusin; Drp, dynamin-related protein; NF-κB, nuclear factor-κB; eNOS, endothelial nitric oxide synthase; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; ERK, extracellular-signal-regulated kinase; PI3K, phosphatidylinositide 3-kinase.</p>
                                                ")

[Review Reports](/1424-8247/16/6/836/review_report) [Versions Notes](/1424-8247/16/6/836/notes)

## Abstract

**:**

Diabetes is one of the chronic metabolic disorders which poses a multitude of life-debilitating challenges, including cardiac muscle impairment, which eventually results in heart failure. The incretin hormone glucagon-like peptide-1 (GLP-1) has gained distinct recognition in reinstating glucose homeostasis in diabetes, while it is now largely accepted that it has an array of biological effects in the body. Several lines of evidence have revealed that GLP-1 and its analogs possess cardioprotective effects by various mechanisms related to cardiac contractility, myocardial glucose uptake, cardiac oxidative stress and ischemia/reperfusion injury, and mitochondrial homeostasis. Upon binding to GLP-1 receptor (GLP-1R), GLP-1 and its analogs exert their effects via adenylyl cyclase-mediated cAMP elevation and subsequent activation of cAMP-dependent protein kinase(s) which stimulates the insulin release in conjunction with enhanced Ca2+ and ATP levels. Recent findings have suggested additional downstream molecular pathways stirred by long-term exposure of GLP-1 analogs, which pave the way for the development of potential therapeutic molecules with longer lasting beneficial effects against diabetic cardiomyopathies. This review provides a comprehensive overview of the recent advances in the understanding of the GLP-1R-dependent and -independent actions of GLP-1 and its analogs in the protection against cardiomyopathies.

Keywords: 

[glucagon-like peptide-1 (GLP-1)](/search?q=glucagon-like+peptide-1+%28GLP-1%29); [GLP-1 receptor (GLP-1R)](/search?q=GLP-1+receptor+%28GLP-1R%29); [hyperglycemic cardiomyopathy](/search?q=hyperglycemic+cardiomyopathy); [cardioprotective effects](/search?q=cardioprotective+effects)




##  1\. Introduction

Metabolic diseases have been on the rise globally, and novel therapeutics with lesser or no side effects to encounter the unmet medical needs of new-age morbid situations are highly needed [1,2]. From that perspective, growth factor signaling, particularly insulin signaling, is one of the most demanding pathways for cell growth, metabolism, and homeostasis. Nevertheless, any deviation or interruption of its normal processes could lead to the development of cardiometabolic disorders and premature death or senescence of the cells [3].

Glucagon-like peptide 1 (GLP-1) is an incretin peptide hormone that aids in insulin secretion, thereby contributing to the regulation and homeostasis of bioenergetic pathway and cell survival. In the human body, GLP-1 is mainly secreted by enteroendocrine L cells in the distal intestine, pancreatic α-cells, and the central nervous system (CNS) [4]. After a meal, GLP-1 is immediately released, leading to an increase in glucose-stimulated insulin secretion (GSIS) at physiological plasma levels. Previous studies suggested that factors from the gut provoke the pancreas to aid in nutrient assimilation, which laid the foundation for the treatment of diabetic patients using extracts from porcine small intestine [5]. The first incretin hormone, gastric inhibitory polypeptide (GIP), isolated from crude extracts of the porcine small intestine, inhibited gastric acid secretion [6]. Later, it was found that GIP stimulated insulin secretion in both animals and humans; it was renamed as glucose-dependent insulinotropic polypeptide; however, the acronym was remained as the same [7].

The second incretin hormone, GLP-1, was discovered in the pancreatic islets from anglerfish. GLP-1 and GLP-2 were identified in hamsters and humans; however, GLP-1 is the main isoform that could stimulate insulin secretion upon diet ingestion [8,9]. GLP-1 is produced in two bioactive forms consisting of glycine-extended GLP-1(7-37) and amidated GLP-1(7-36) via the post-translational processing of proglucagon by proprotein convertase subtilisin-kexin type 1 (PCSK1) or type 3 (PCSK3) [10,11] (Figure 1). GLP-1 receptor (GLP-1R) is classified in class B of the G protein-coupled receptor (GPCR) family that is abundant in the CNS and pancreas, while it is also found in lower expression in the heart, lungs, gut, muscles, kidneys, liver, peripheral nervous system (PNS), and other tissues [3]. GLP-1R gene expressions (transcripts per million, TPM) amongst females and males in the cardiovascular system and pancreas (from GTEx Portal <https://gtexportal.org/home/gene/GLP1R> accessed on 21 November 2022) are shown in Figure 2. Upon binding to GLP-1R, GLP-1 and its analogs initiate a series of events, including the activation of membrane-bound adenylyl cyclase (AC) and the subsequent production of cyclic adenosine monophosphate (cAMP). Several signal transduction pathways can be initiated downstream of cAMP formation via its effectors such as protein kinase A (PKA) and exchange protein activated by cAMP (Epac) [12,13].

GLP-1(7-36) has a relatively short half-life, which is cleaved by the activity of enzyme dipeptidyl peptidase-4 (DPP-4) at its N-terminus to produce GLP-1(9-36). It was previously supposed that GLP-1(9-36) is an inactive GLP-1 metabolite due to its poor interaction with GLP-1R and lack of significant effects on stimulating insulin secretion or glucose homeostasis [14]. However, recent studies showed that GLP-1(9-36) exerts cardioprotective effects against oxidative injury in H9c2 cardiomyoblasts through the phosphoinositide 3-kinase (PI3K)/Akt/nitric oxide synthase (NOS) pathway in an GLP-1R independent mechanism [15]. Similar cardioprotective roles of GLP-1(9-36) have been observed in dog models with dilated cardiomyopathy [16] and cultured cardiac cells of Goto–Kakizaki rats [17]. It has been suggested that GLP-1(9-36) amide is an active form at physiological concentration, while other GLP-1 metabolites, such as GLP-1(28-36) and GLP-1(32-36), are metabolically inactive [18]. However, growing evidence suggested that some of these metabolites may contribute to pleiotropic effects of GLP-1, irrespective of the GLP-1R [19,20]. At pharmacological doses, these metabolites possess glucoregulatory and cytoprotective effects such as reducing oxidative stress in vascular tissues [21], protecting pancreatic β-cells [22], and suppressing oxidative stress and gluconeogenesis in liver [23].

After a meal, GLP-1 is secreted from the L-cells in a biphasic pattern that is an early immediate rise of GLP-1′s plasma concentration starting approximately 10 to 15 min after ingestion, followed by a late increase achieving the maximum level at 30–60 min, and then a gradual decline to baseline over several hours [24]. However, due to local GLP-1 degradation by DPP-4 and further degradation by DPP-4 in the liver, only 10–15% of endogenously released GLP-1 reaches the systemic circulation [25]. Due to the rapid degradation of GLP-1 by DPP-4, exogenously administered GLP-1 has a short half-life of 1–2 min. Therefore, several GLP-1 analogs (or GLP-1 mimetics) have been developed in two ways, GLP-1R agonists resistant to DPP-4-mediated degradation and DPP-4 inhibitors, both of which tend to prolong the retention time of circulating GLP-1(7-36) amide [26]. To avoid degradation by DPP-4, GLP-1 analogs have been developed by modifying the amino acid residues in the native GLP-1. Additionally, they were synthetically created through the modifications of the structure of exendin-4, a 39-amino-acid peptide initially obtained from the saliva of the lizard Heloderma suspectum, which activated GLP-1R and is inherently resistant to DPP-4 degradation [27,28].

GLP-1 analogs such as liraglutide and exendin-4 are not rapidly degraded by DPP-4, allowing them to exert long therapeutic effects that would be impossible with endogenous GLP-1 due to their extremely short half-life in systemic circulation [29,30]. GLP-1 analogs exert a plethora of additional beneficial effects beyond antidiabetic effects, including increased satiety, decreased gastric emptying, replenishment of insulin stores, cytoprotective properties, and anti-inflammatory effects [31,32,33]. Currently, there are various GLP-1 analogs approved for the treatment of type 2 diabetes (T2DM) which were developed from human GLP-1 backbone (_glutide) (e.g., albiglutide, dulaglutide, liraglutide, and semaglutide) and exendin-4 backbone (_natide) (e.g., exenatide, efpeglenatide, and lixisenatide) (Table 1). These drugs are considered more efficient than DPP-4 inhibitors that block the breakdown of GLP-1; instead, they directly activate the GLP-1R signaling [34,35].

##  2\. GLP-1 Analogs and Physiological Importance in Humans

GLP-1 and its analogs have emerged as attractive approaches to target the secondary manifestations due to hyperglycemic or diabetic conditions in the human body. Beyond their antidiabetic effects, GLP-1 analogs not only reduce diet-induced pancreatic secretions, but also diminish gastric emptying [40]. The ileal-brake activity of GLP-1 was confirmed using the GLP-1R antagonist, exendin-(9-39), which was suggested to have physiologic significance [41,42]. The inhibitory action of GLP-1 was later discovered to be mediated by a vagal pathway [43]. The systemic effects of GLP-1 and its analogs on various vital tissues and organs include reduction of insulin resistance, decrease in hyperglycemia, loss of body weight, reduction of blood pressure, decrease in reactive oxygen species (ROS) production, modulation of the inflammatory response, and improvement of reproductive function (Table 2, Figure 3) [38,44,45].

An endogenous GLP-1 is produced not only peripherally in the ileum, but also centrally in the brain, particularly in the area of nucleus of the solitary tract (NTS) of the hindbrain and the olfactory bulb, thereby controlling appetite and feeding behaviors [46]. The GLP-1 analog promotes satiety by activating GLP-1Rs in the hypothalamus and brainstem, resulting in a decline of food intake and weight loss [11,47]. Besides its metabolic functions in the brain, GLP-1 directly exhibits neuroprotective and neurotropic effects [48]. GLP-1 or exendin-4 administration into the lateral ventricles of mice reduced endogenous Aβ levels and prevented Aβ-induced cell death in rat hippocampus neurons [49]. During hypoxic injury, exendin-4 increased cell viability in cultured embryonic primary cerebral cortical and ventral mesencephalic (dopaminergic) neurons and protected against metabolic and oxidative damages. Importantly, these protective effects were not observed in neurons from GLP-1R knockout mice [50]. Exendin-4 also preserved cell viability and decreased apoptosis induced by hydrogen peroxide (H2O2)-induced oxidative stress in NSC19 neuroblastoma cells and in SOD1-G93A mutant mice models of amyotrophic lateral sclerosis [51,52].

The role of GLP-1 in the CNS, where it regulates satiety and body weight, is one of the intriguing aspects of its biology [47,53]. After activation of GLP-1Rs in the portal vein, this brain–gut axis regulates muscle glycogen synthesis and whole-body glucose clearance [54,55]. However, the relative importance of GLP-1Rs in the CNS and PNS in maintaining energy homeostasis is unknown. Previous studies have suggested that there is improved vascular function upon administration of GLP-1 in subjects with normal glucose tolerance and T2DM patients [56,57,58]. There was increased blood pressure and heart rate upon intermittent GLP-1 administration, while a modest increase in heart rate and a decrease in blood pressure was observed upon chronic activation of the GLP-1R with GLP-1 analogs [59]. This observation has raised the curiosity of many interested in the potential beneficial effects of GLP-1 on the heart. Evidently, GLP-1 and GLP-1Rs are abundantly distributed in many vital tissues, and their physiologic actions have gradually been elucidated, particularly since the advent of GLP-1 mimetics, including GLP-1R agonists and DPP-4 inhibitors.

GLP-1R expresses in various immune cells, including splenocytes, thymocytes, regulatory T cells, bone marrow-derived cells, macrophages, and invariant natural killer T cells, and thereby modulates the immune responses [60,61]. The GLP-1 analog, liraglutide, improved the psoriasis area and severity index and reduced the inflammatory cytokine secretion from natural killer T cells in patients with psoriasis [62]. In a mice model of obesity (high fat diet, HFD), liraglutide decreased cardiovascular risk factors including insulin resistance and inflammation, reduced monocyte vascular adhesion, and improved cardiac function by activating adenosine 5′-monophosphate activated protein kinase (AMPK) [63]. Moreover, liraglutide has been approved for chronic weight management in patients with obesity or weight related comorbid conditions including hyperlipidemia, hypertension, or T2DM [64,65]. Another GLP-1 analog, exndin-4, reduced mRNA levels of the proinflammatory cytokines, tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein 1 (MCP-1), and signal transducer and activator of transcription 3 (STAT-3) in HFD fed mice [66]. Additionally, the number of transforming growth factor-β (TGF- β) positive cells were increased upon GLP-1/gastrin treatment in islet transplanted nonobese diabetic animals [67].

GLP-1 analogs stimulate natriuresis at physiological levels by inhibiting sodium reabsorption via decreased activity of sodium–hydrogen exchanger 3 (NHE3) or solute carrier family 9 member 3 (SLC9A3) in the proximal tubules, resulting in decreased blood pressure in patients with diabetes [68,69]. It is yet to be confirmed whether this effect is caused by direct GLP-1R activation in the kidneys. However, the involvement of renin–angiotensin system and a neural pathway has been suggested by previous studies [68,69].

##  3\. Molecular Mechanisms Underlying Cardioprotective Effects of GLP-1 and Its Analogs

Cardiac muscle is predisposed to damage and dysfunction under several metabolic stresses, particularly under diabetic conditions and biological aging. Based on intense lines of preclinical studies both in vitro (Table 3) and in vivo (Table 4), GLP-1 analogs expressed their cardiovascular benefits via several cytoprotective molecular mechanisms.

####  3.1. GLP-1 and Its Analogs and Cardiac Functions

Clinical research has demonstrated that GLP-1R analogs improve the prognosis of cardiovascular disorders by raising the resting heart rate and decreasing arrhythmia in patients with heart failure (HF) [25,90]. Patients with HF who received GLP-1R analog for 5 weeks have shown improvements in their left ventricular ejection fraction and 6-min walking distance as well as increases in their maximal oxygen uptake [91]. Albiglutide administration for 12 weeks in patients with HF elicits an improvement in their cardiac oxygen consumption [92]. Exenatide lowered atherosclerotic levels and enhanced diastolic function in patients with T2DM [93]. Mechanistically, GLP-1 analogs improve the sympathetic nervous system, which, in turn, causes an increase in heart rate [94,95]. While the systemic effects and increased heart rate elicited by exendin-4 treatment in vivo were eliminated by blocking β-adrenergic receptor (β-AR) [96], GLP-1 treatment via peripheral or intracerebroventricular routes dose-dependently increased blood pressure and heart rate in animal models [95,97,98]. The cause of an elevated heart rate has remained intriguing; however, it might be related to the stimulation of sympathetic nervous system. GLP-1 analogs (such as exendin-4) activated c-fos expression in the adrenal medulla and medullary catecholamine neurons, indicating that central GLP-1Rs mediate neuroendocrine responses and influence sympathetic outflow [95].

Cardiovascular risk factors such as dyslipidemia and hypertension have been demonstrated to be reduced by liraglutide and exenatide. Exenatide revealed a drop in systolic blood pressure (SBP) without changes in diastolic blood pressure (DBP) in a meta-analysis of six trials including over 2000 participants, while weight loss could not entirely explain this effect [99]. However, another clinical study demonstrated that liraglutide expresses a decrease in SBP in the first two weeks of treatment independent of weight loss [100]. Exenatide has been shown to lower triglyceride levels by 12%, total cholesterol by 5%, low-density lipoprotein cholesterol by 6%, and increase high-density lipoprotein cholesterol by 24% in three-year trials, thus contributing to lowering blood pressure [101].

####  3.2. GLP-1 and Its Analogs and Myocardial Glucose Uptake

GLP-1 has been suggested to have a wide range of biological effects on several target organs, including heart, liver, brain, muscles, and adipose tissues [44,102,103]. The classic response elicited by GLP-1R activation is the improvement of cardiac function by increasing glucose uptake and coronary flow as well as the secretion of the main blood pressure and electrolyte regulator, atrial natriuretic peptide (ANP), in mice [69,104,105]. GLP-1-(7-36) amide was found to directly augment myocardial glucose uptake by increasing the translocation of glucose transporters (GLUTs), GLUT-1 and GLUT-4, in normal and ischemia/reperfusion (I/R)-induced ischemic rat hearts in a similar pattern as insulin [106]. Treatment with exendin-4 induced cardiac glucose uptake and ATP production via an increase in GLUT-1 translocation which was dependent on the expression of p38 mitogen-activated protein kinase (p38MAPK) in hypoxia/reoxygenation (H/R)-induced injury in H9c2 cardiomyoblasts [107]. However, clinical evidence suggests that baseline functions of glucose transport and insulin resistance are the main determinants of the impact of GLP-1 analog on glucose transport and glucose uptake in cardiomyocytes during hyperglycemic states in patients with T2DM [108] and during normo- or hypoglycemia in healthy subjects [109]. The occurrence of apoptosis in cardiac cells contributes to the development of diabetic cardiomyopathy, which is caused by the buildup of intracellular lipids such as saturated palmitic acids. In addition, treatment with GLP-1 analogs provoked β-catenin, signaling leading to an activation of the protein kinase B-glycogen synthase kinase-3β survival pathway and a decrease in apoptotic activation in neonatal rat cardiomyocytes exposed to palmitate [110].

####  3.3. GLP-1 Analogs and Cardiac Oxidative Stress as Well as Ischemia/Reperfusion (I/R) Injury

Previous studies have shown that GLP-1 and its analogs express cardiac-protective effects and are crucial in the regulation of heart functions. Exendin-4, for instance, reduced infarct size and enhanced mechanical function in isolated rat hearts exposed to I/R injury [111]. Likewise, exenatide infusion decreased the size of the infarct area found in a porcine model of I/R injury [112]. In addition, ejection fraction and other functional indicators were improved in patients with acute myocardial infarction (MI) after a 72-h GLP-1 infusion [113]. Moreover, treatment with GLP-1 analogs prevented the cardiomyocyte damage and apoptosis from H/R injury [114]. Liraglutide inhibited plasminogen activator inhibitor type-1 (PAI-1) and vascular adhesion molecules in vitro and in vivo and enhanced NOS activity [1]. Moreover, GLP-1R activation restored endoplasmic reticulum (ER) homoeostasis, cytoprotection, and the signaling pathways disrupted by various stress stimuli [63,115,116].

Oxidative stress ensuing from an imbalance between antioxidant defenses and the generation of ROS could result in cellular damage and apoptosis. The toxic levels of ROS are generated in patients of HF [117] and animal models of MI [118]. Recent studies have shown that GLP-1 analogs exert cardioprotective benefits through regulating the antioxidant and anti-apoptotic responses. Activation of the GLP-1R increased cAMP levels, thereby activating PKA and Epac-dependent antioxidant and anti-apoptotic cytoprotective responses against H2O2-induced oxidative damage in cardiomyocytes [71]. Although it has been reported that excessive stimulation of β-ARs results in the induction of insulin resistance in many cell types, including cardiomyocytes [119,120], adipocytes [121], and skeletal muscle [122], prolonged overstimulation of GLP-1R has not been shown to cause these detrimental effects.

GLP-1 appears to have both GLP-1R-dependent and -independent mechanisms for mediating its cardioprotective and vasodilatory effects [123]. The findings that GLP-1(9-36) maintained its vasodilatory and cardioprotective properties in hearts isolated from GLP-1R−/− mice serve as an explanation of this phenomenon [123]. In fact, GLP-1(9-36) enhanced left ventricular function and boosted myocardial glucose absorption in dogs with dilated cardiomyopathy [16]. In contrast to intact GLP-1, GLP-1(9-36) directly inhibited the generation of superoxide in human artery endothelial cells induced by high glucose or free fatty acids [124] and cytoprotective actions on mouse cardiomyocytes exposed to H2O2 [115]. This is consistent with the findings that GLP-1(9-36) leads to significant enhancement of the rate-pressure product when the GLP-1R antagonist, exendin (9-39), is administered, although the GLP-1R agonist exendin-4, which is DPP4 resistant, is no longer effective in increasing left ventricular end-diastolic pressure in isolated rat hearts [111], indicating the presence of a GLP-1R independent pathway. This is further supported by our recent findings, wherein exposure to GLP-1(9-36) inhibited H2O2-induced oxidative stress and apoptosis in H9c2 cardiomyoblasts via PI3K/Akt/NOS signaling pathway; therefore, GLP-1R analog treatment represents a potential therapeutic approach for the prevention of pathological oxidative stress and damage to the heart [15].

##  4\. Significant Roles of GLP-1 and Its Analogs in Mitochondrial Homeostasis

Mitochondria is the energy generator for the cell, oxidizing various carbon sources and producing energy in the form of ATP. Mitochondria produces intermediate substrates to be utilized in anabolic or catabolic processes and regulates crucial physiological and pathological processes such as calcium homeostasis, metabolism of biomolecules (amino acids, lipids, and glucose), oxidative stress, apoptosis, aging, and autophagy [125]. The majority of the energy for cardiac functions is derived from the oxidation of fatty acids in mitochondria. However, in T2DM, insulin resistance leads to lower glucose utilization and oxidative phosphorylation; consequently, cardiomyocytes become reliant on the oxidation of fatty acids for energy supply. This shift in substrate utilization leads to an imbalance in the uptake and oxidation of fatty acids, which ultimately causes mitochondrial dysfunction. Moreover, chronic hyperglycemia instigates mitochondrial oxidative stress and fragmentation, leading to cellular dysfunction and apoptosis [2]. In diabetic hearts, the damaged mitochondria in cardiomyocytes resulted in the generation of excessive amounts of ROS causing pathological oxidative stress, which deteriorated the myocardial functions [126].

Therefore, repair of the damaged mitochondria and replenishment of new mitochondria would be an effective strategy to maintain a healthy pool of mitochondria to ameliorate the pathological outcomes of cardiac diseases. Our recent study showed that stimulation of GLP-1R using exendin-4 exhibits antioxidant and antiapoptotic effects, as well as an improvement in mitochondrial functions via cAMP/Epac/PI3K/Akt signaling in H9c2 cardiomyoblasts exposed with methylglyoxal, an advanced glycation end product (AGE). Since intracellularly accumulation of AGEs causes mitochondrial impairment, oxidative stress, and apoptosis, attenuating methylglyoxal-induced mitochondrial abnormalities in the heart by exendin-4 may help to ameliorate and delay the progression of heart diseases [70]. Several clinical studies have also supported that GLP-1 analogs are beneficial in lowering the occurrence of adverse cardiovascular events [127,128]. GLP-1 analogs with longer half-life, such as exenatide and liraglutide, have been designed to tolerate DPP-4 degradation and are efficacious in treating T2DM [129,130]. However, long-term usage is linked to an increased risk of hypoglycemia, pancreatic cancer, thyroid cancer, and gastric ailments [131,132].

Although the precise molecular mechanisms responsible for the cardioprotective benefits of GLP-1 analogs have not been clearly identified so far, there are preclinical studies (Table 3 and Table 4) which suggest that this drug class may also be effective when administered shortly after MI through the activation of the mitophagy process and the resurrection of non-performing mitochondria. In H/R model of H9c2 cells, pretreatment with exenatide reduced mitochondrial abnormalities by diminishing oxidative stress and mitochondrial calcium overload while increasing mitochondrial ATP synthase activity or ATP synthesis and rescuing mitochondrial membrane potential (MMP) [133]. Moreover, mitochondrial uncoupling protein-3 (UCP-3) and nuclear respiratory factor-1 (NRF-1) were increased while lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), and cardiomyocyte apoptosis were decreased [133]. Liraglutide has been reported to protect cardiomyocytes from interleukin-1β (IL-1β)-induced metabolic disturbance and mitochondrial dysfunction by enhancing phosphorylated AMPK and acetyl-coA carboxylase (ACC) as well as improving peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), carnitine palmitoyltransferase-1 (CPT1), and diacylglycerol acyltransferase 1 (DGAT1) [134]. GLP-1 analog also decreased the expression of H/R-induced ER stress proteins, including glucose regulatory protein 78 (GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), and caspase-12, and exhibited cardioprotective effects by an activation of the GLP-1R/PI3K/Akt signaling pathway [114].

Hyperglycemic condition in primary cardiomyocytes has been shown to cause ER stress, mitochondrial oxidative stress, and enhanced mitochondria-associated ER membrane (MAMs)-associated proteins, including GRP75 and mitofusin-2 (MFN2). MFN2 played an important role in high glucose-induced ER stress in cardiomyocytes, while silencing of MFN2 abated mitochondrial calcium overload-mediated mitochondrial impairment, thereby decreasing ER stress-mediated cardiomyocyte apoptosis [135]. Furthermore, metabolic signaling pathways mediated by insulin-like growth factor 1 (IGF-1), mammalian target of rapamycin (mTOR), AMPK, and sirtuins are linked to the balance between nutrient anabolism and catabolism in cells, which maintain cellular homeostasis [136,137]. In both in vivo and in vitro studies, employing cardiac hypertensive model elucidated that administration of exendin-4 attenuated cardiac hypertrophy via the inhibition of mitochondrial permeability transition pore (MPTP) opening and ROS release [138].

Exendin-4 also was found to inhibit cardiac hypertrophy by upregulating GLP-1R expression and activating the AMPK signaling pathway [72]. Liraglutide could protect the heart against aortic banding-induced myocardial fibrosis and dysfunction by suppressing mTOR/p70S6K signaling and boosting autophagy [89]. Another study reported that liraglutide reduces cardiac hypertrophy via the angiotensin II/AT1R/ACE2 and AMPK/mTOR/ p70S6K pathways [76]. A recent study examined the efficacy of a newly synthesized GLP-1R agonist, compound DMB, in attenuating pathological left ventricular remodeling in a permanent coronary artery ligation mice model and suggested that increasing mitochondrial biogenesis and Parkin-associated mitophagy after MI might be a viable target for the therapeutic management of adverse cardiac remodeling [139]. In line with previous studies, liraglutide ameliorated cardiac fibrosis and cardiomyocyte death in the infarcted heart in rat, while their mechanistic findings in H9c2 cardiomyoblasts showed that SIRT1/Parkin/mitophagy pathways were involved in its cytoprotective effects [140]. Contrastingly, another study did not find any effects on adverse remodeling or cardiac function upon a similar liraglutide treatment in rats [140]. Nevertheless, excessive glucose exposure caused increased intracellular ROS, apoptosis, MMP loss, decreased autophagy, and increased phospho-mTOR (p-mTOR) and p-ULK1 levels, all of which were counteracted by GLP-1 analogs. These findings suggested that GLP-1 analogs could reverse glucose toxicity by inducing mTOR/ULK1-dependent autophagy [141].

##  5\. Co-Agonists: A Single Molecule Stimulating Multiple Peptide Receptors

There have been propositions that multiple signaling pathways would need to be targeted for an efficient clinical treatment of obesity due to the system’s redundancy in regulating food intake and body weight [142]. Using this concept, the most delicate way to treat T2DM was to combine activity of GLP-1 with that of the GIP to achieve long-lasting beneficial effects. A synthetic peptide with stimulatory activity at both the GIP receptor and GLP-1R proved to be more effective at reducing body weight and blood glucose in obese mice compared to a selective GLP-1R agonist [143]. Additionally, recent studies in mice have demonstrated that GIP receptor is expressed in hypothalamic neurons, and that activating it significantly reduced food intake and body weight, when combined with GLP-1 [144,145,146]. These initial observations, together with subsequent studies, led to the development of multi-receptor peptides affecting more than one intracellular signaling pathway, which have become the choice of treatments for T2DM and obesity.

Following the initial studies in multi-receptor peptides, a number of single-molecule GIP receptors and GLP-1R agonists were created. Tirzepatide, a dual GIP/GLP-1 receptor co-agonist for the treatment of T2DM, is a 39-amino acid linear peptide that is comparable in size to the related hormones GIP and GLP-1 [147]. In murine pancreatic islets from GIP receptor knockout mice, GLP-1R antagonist inhibited the insulin secretion stimulated by tirzepatide, while in islets lacking GLP-1Rs, GIP receptor blocker suppressed the insulin secretion upon tirzepatide stimulation. Moreover, tirzepatide decreased both food intake and body weight more prominently than selective GLP-1R agonists such as semaglutide in HFD mice [51]. Tirzepatide stimulated cAMP production in pancreatic ß-cells, similar to a combination of GLP-1 and GIP [51], while also eliciting better efficacy in controlling cardiovascular disease risk factors such as glucose levels and body weight loss in diabetic patients [148,149].

Tirzepatide ameliorated a number of cardiovascular risk factors over selective GLP-1R agonists. In blood samples analyzed from diabetic patients, triglycerides, apolipoprotein C-III, phosphatidylethanolamines/phosphatidylcholines, circulating levels of branched-chain amino acids (leucine, isoleucine, and valine), inflammatory markers (e.g., C-reactive protein), and adhesion molecules (e.g., intercellular adhesion molecule-1; ICAM-1) were reduced by tirzepatide [150,151,152]. Additionally, a preliminary proof of tirzepatide’s cardiovascular safety was elucidated by a recent meta-analysis combining all the clinical trials. The commonly specified cardiovascular end points were projected to have a risk below 1.0, and for 4-point major adverse cardiovascular events (MACE) (MI, stroke, hospitalization for angina, and all-cause death) and 3-point MACE (MI, stroke, and all-cause mortality), the hazard ratios were less than 1.3 [153].

##  6\. Conclusions and Future Directions

Inadequate exercise, high fat and highly processed diet, and excess nutrition all contribute to the rising prevalence of T2DM, which severely reduces both life expectancy and quality of life. T2DM is linked to a large worldwide mortality burden, which primarily involves cardiovascular events including HF and stroke. Therefore, new therapeutic modalities are highly required. GLP-1 analogs are relatively novel medications used for the treatment of T2DM. We summarized the recent findings pertaining to cardioprotective effects as well as molecular mechanisms of GLP-1R-dependent and -independent pathways (Figure 4). GLP-1 analogs are able to directly affect not only other important cardiovascular risk factors, including high blood pressure, dyslipidemia, or obesity, but also the hyperglycemia in diabetic patients. These characteristics were exemplified in several cardiovascular outcome trials for exendin-4, liraglutide, semaglutide, dulaglutide, albiglutide, and tirzepatide, all of which demonstrated the improvement of cardiovascular prognosis in addition to safety. Although the effects of the GLP-1R agonists were well understood, further research is necessary to fully understand their GLP-1R-dependent and -independent effects on the cardiovascular system, particularly with regard to their signaling pathways. Recently, GLP-1R-independent pathways have been identified to have direct vasodilatory and cardioprotective effects, as well as anti-inflammatory and antioxidant benefits. The protective properties of GLP-1 analogs can be thoroughly investigated using contemporary omics technologies to reveal epigenetic, metabolomics, and proteomic changes to explain the observed beneficial effects. The discovery of additional GLP-1 signaling pathways (unrelated to glucose lowering effects) is very likely to make this class of medication relevant for the treatment of several chronic diseases, including obesity, T2DM, cardiovascular diseases, cancer, neurodegenerative and neuroinflammatory diseases, and others.

## Author Contributions

Conceptualization, S.P., S.M. and W.P.; writing—original draft preparation, S.P.; writing—review and editing, S.M. and W.P.; visualization, S.P.; supervision, W.P.; funding acquisition, W.P. All authors have read and agreed to the published version of the manuscript.

## Funding

This research project was supported by grants from the National Research Council of Thailand (NRCT) and Mahidol University (Grant number: N42A650352) (to W.P.) and the Specific League Funds from Mahidol University (Grant number: SLF-2 MUPY 01/2564) (to W.P). S.P. is currently funded by an International Postdoctoral Fellowship from Mahidol University.

## Institutional Review Board Statement

Not applicable.

## Informed Consent Statement

Not applicable.

## Data Availability Statement

All data generated or analyzed during the current study are included in this published article.

## Conflicts 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.

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**Figure 1.** **Structural arrangement of mammalian proglucagon.** (**A**) The amino acid sequences in proglucagon have been marked as numbers. The post-translational processing produces peptides in the intestine and pancreas as shown. (**B**) The DPP-4 cleavage site in the amino acid chain is indicated by arrows. GRPP, glicentin-related pancreatic polypeptide; IP, intervening peptide; PC1/2/3, prohormone convertases 1/2/3; DPP-4, dipeptidyl peptidase-4. 

**Figure 1.** **Structural arrangement of mammalian proglucagon.** (**A**) The amino acid sequences in proglucagon have been marked as numbers. The post-translational processing produces peptides in the intestine and pancreas as shown. (**B**) The DPP-4 cleavage site in the amino acid chain is indicated by arrows. GRPP, glicentin-related pancreatic polypeptide; IP, intervening peptide; PC1/2/3, prohormone convertases 1/2/3; DPP-4, dipeptidyl peptidase-4.

**Figure 2.** GLP-1 receptor (GLP-1R) gene expression (transcripts per million; TPM) amongst females and males in selected tissues related to the cardiovascular system and pancreas (from GTEx Portal <https://gtexportal.org/home/gene/GLP-1R> accessed on 21 November 2022). Box plots are depicted as median and correspond to 25th and 75th percentiles. The pancreas expresses the higher expression (median value, 4.5) when compared to heart-atria (median value, 1.7), heart left ventricle (median value, 0.6), coronary artery (median value, 0.05), and aorta (median value, not available). In this cohort analysis, there are no significant sex differences in the expression pattern of GLP-1R amongst males and females. 

**Figure 2.** GLP-1 receptor (GLP-1R) gene expression (transcripts per million; TPM) amongst females and males in selected tissues related to the cardiovascular system and pancreas (from GTEx Portal <https://gtexportal.org/home/gene/GLP-1R> accessed on 21 November 2022). Box plots are depicted as median and correspond to 25th and 75th percentiles. The pancreas expresses the higher expression (median value, 4.5) when compared to heart-atria (median value, 1.7), heart left ventricle (median value, 0.6), coronary artery (median value, 0.05), and aorta (median value, not available). In this cohort analysis, there are no significant sex differences in the expression pattern of GLP-1R amongst males and females.

**Figure 3.** **Systemic effects of GLP-1 and its analogs.** The effects on various tissues/organs illustrated in the figure are based on results obtained in several preclinical or clinical studies at physiological GLP-1 levels or after exposure to GLP-1R analogs. GLP-1R is abundantly distributed in the tissues/organs of the peripheral and central nervous system with the different expression levels leading to the distinct biological functions in each tissue/organ. In the CNS and pancreas, high expression of GLP-1R is detected, while lower expression of GLP-1R is observed in the heart, lungs, gut, muscle, kidneys, liver, PNS, and other tissues. ↑, Increase; ↓, Decrease. 

**Figure 3.** **Systemic effects of GLP-1 and its analogs.** The effects on various tissues/organs illustrated in the figure are based on results obtained in several preclinical or clinical studies at physiological GLP-1 levels or after exposure to GLP-1R analogs. GLP-1R is abundantly distributed in the tissues/organs of the peripheral and central nervous system with the different expression levels leading to the distinct biological functions in each tissue/organ. In the CNS and pancreas, high expression of GLP-1R is detected, while lower expression of GLP-1R is observed in the heart, lungs, gut, muscle, kidneys, liver, PNS, and other tissues. ↑, Increase; ↓, Decrease.

**Figure 4.** **Schematic diagram representing cardioprotective molecular mechanisms of GLP-1 analogs in cardiomyocytes.** The GLP-1R-dependent and -independent signaling pathways have been described as contributing to healthy myocardium and heart functions under pathophysiological conditions. The binding of GLP-1 to its receptor activates adenylate cyclase, and cAMP levels are elevated, which is followed by the activation of downstream cAMP sensitive molecular effectors in a GLP-1R-dependent way. While GLP-1R-independent GLP-1(9-36) activates PI3K, Akt, and the downstream signaling pathway, the full mechanisms of this process are not yet known. GLP-1, glucagon-like peptide-1; cAMP, cyclic adenosine monophosphate; Akt, protein kinase B; Epac, exchange protein activated by cAMP; CREB, cAMP-response element binding protein; CaMKKβ, calcium ions/calmodulins dependent protein kinase kinases β; PINK1, PTEN-induced kinase 1; Mfn, Mitofusin; Drp, dynamin-related protein; NF-κB, nuclear factor-κB; eNOS, endothelial nitric oxide synthase; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; ERK, extracellular-signal-regulated kinase; PI3K, phosphatidylinositide 3-kinase. 

**Figure 4.** **Schematic diagram representing cardioprotective molecular mechanisms of GLP-1 analogs in cardiomyocytes.** The GLP-1R-dependent and -independent signaling pathways have been described as contributing to healthy myocardium and heart functions under pathophysiological conditions. The binding of GLP-1 to its receptor activates adenylate cyclase, and cAMP levels are elevated, which is followed by the activation of downstream cAMP sensitive molecular effectors in a GLP-1R-dependent way. While GLP-1R-independent GLP-1(9-36) activates PI3K, Akt, and the downstream signaling pathway, the full mechanisms of this process are not yet known. GLP-1, glucagon-like peptide-1; cAMP, cyclic adenosine monophosphate; Akt, protein kinase B; Epac, exchange protein activated by cAMP; CREB, cAMP-response element binding protein; CaMKKβ, calcium ions/calmodulins dependent protein kinase kinases β; PINK1, PTEN-induced kinase 1; Mfn, Mitofusin; Drp, dynamin-related protein; NF-κB, nuclear factor-κB; eNOS, endothelial nitric oxide synthase; AMPK, AMP-activated protein kinase; mTOR, mammalian target of rapamycin; ERK, extracellular-signal-regulated kinase; PI3K, phosphatidylinositide 3-kinase.

**Table 1.** List of current GLP-1 and its analogs [36,37,38,39]. 

**Table 1.** List of current GLP-1 and its analogs [36,37,38,39].

GLP-1 Analogs| Company| FDA Approval Year for T2DM| Description| Administration| Half-Life  
---|---|---|---|---|---  
**Human GLP-1 backbone (_glutide)**  
Albiglutide| GlaxoSmithKline| 2014| Extended release,  
fused to human albumin| Subcutaneous (SC), once weekly| 5–6 days  
Dulaglutide| Eli Lilly| 2014| Extended release,  
Fc region of human IgG4 | SC, once weekly| 4.7 days  
Liraglutide| Novo Nordisk| 2010| Immediate release,  
linked with free fatty acid | SC, once daily| 12–13 h  
Semaglutide| Novo Nordisk| 2017| Extended release,  
linked with free fatty acid| SC, once weekly| 5–7 days  
| Novo Nordisk| 2020| Extended release,  
linked with free fatty acid| Oral, once daily| 5–7 days  
**Exendin-4 backbone (_natide)**  
Exenatide| Eli Lilly| 2005| Immediate release| SC, twice daily| 2.4 h   
| AstraZeneca| 2012| Extended release, encapsulated in microsphere form| SC, once weekly| 3–5 days   
Efpeglenatide| Sanofi| Not available| Extended release| SC, once monthly| Not available  
Lixisenatide| Sanofi| 2016| Immediate release,  
linked with poly-lysine tail| SC, once daily| 3–4 h  
  
**Table 2.** Effects of GLP-1 and its analogs on organs/tissues [38,44,45]. 

**Table 2.** Effects of GLP-1 and its analogs on organs/tissues [38,44,45].

Organs/Tissues| Biological Effects  
---|---  
Heart| 

▪
    Protect against cardiac ischemia and myocardial damage;
▪
    Enhance heart rate and cardiac output;
▪
    Improve glucose utilization and increase fatty acid metabolism;
▪
    Vasodilation and anti-inflammatory effect;
▪
    Increase atrial natriuretic peptide (ANP) secretion.  
Brain| 

▪
    Suppress appetite and increase satiety;
▪
    Neuroprotection, improve learning and memory;
▪
    Induce proliferation of neural stem cells;
▪
    Decrease inflammation.  
Liver| 

▪
    Decrease glucose production;
▪
    Reduce liver fat and steatosis.   
Kidneys| 

▪
    Diuresis and natriuresis.  
Pancreas| 

▪
    Enhance somatostatin and insulin secretion;
▪
    Inhibit apoptosis and increase proliferation of β-cells.  
Gut| 

▪
    Delay gastric emptying time and acid secretion;
▪
    Inhibit peristalsis and lipoprotein secretion.  
Adipose tissues| 

▪
    Increase lipolysis and glucose uptake.  
Immune system| 

▪
    Reduce inflammation.  
Skeletal muscle| 

▪
    Induce glucose uptake and tissue perfusion.  
Reproductive   
system| 

▪
    Improve ovarian function; 
▪
    Increase menstrual frequency and ovulation rates; 
▪
    Decrease infertility.  
  
**Table 3.** Preclinical studies of GLP-1R agonists for cardioprotective effects (In vitro). 

**Table 3.** Preclinical studies of GLP-1R agonists for cardioprotective effects (In vitro).

GLP-1 Analogs| Study Models| Mechanistic Findings| Ref.  
---|---|---|---  
Exendin-4| Methylglyoxal-exposed  
H9c2 cardiomyoblasts| 

▪
    Inhibits intracellular and mitochondrial ROS production, apoptosis, and MMP impairment;
▪
    Upregulates genes related to mitochondrial functions and dynamics via cAMP/Epac/PI3K/Akt pathway.
| [70]  
Exendin-4| Hydrogen peroxide (H2O2) -exposed neonatal rat cardiomyocytes| 

▪
    Exhibits antioxidant effects by inducing the synthesis of catalase, GPx-1, and Mn-SOD via Epac signaling;
▪
    Elicits anti-apoptotic effects by enhancing Bcl-2 expression and inhibiting caspase-3 activity via PKA and Epac signaling.
| [71]  
Exendin-4| Phenylephrine-induced  
neonatal rat cardiomyocyte| 

▪
    Attenuates cardiac hypertrophy by upregulating GLP-1R expression and activating AMPK/mTOR signaling.
| [72]  
Exendin-4| Oxygen glucose deprivation/reoxygenation (OGD/R)  
in human ventricular cardiomyocytes| 

▪
    Restores autophagic flux induced by OGD/R through promoting nuclear translocation of TFEB;
▪
    Reduces infarct size and preserves cardiac function through anti-apoptosis and antioxidative effects.
| [73]  
Exendin-4| High-density lipoprotein (HDL)-induced human umbilical vein endothelial cells | 

▪
    Protects endothelial function by increasing HDL scavenger receptor class BI expression via AMPK/FoxO1 pathway and activating eNOS.
| [74]  
GLP-1| HL-1 cells derived from mouse atrial cardiac muscle cells| 

▪
    Regulates arrhythmogenesis through modulating calcium handling proteins.
| [75]  
Liraglutide| Angiotensin II-treated H9c2 cells | 

▪
    Decreases cardiac hypertrophy by increasing GLP-1R expression and activating AMPK;
▪
    Reduces the expression of AngII/AT1R/ACE2 and mTOR. 
| [76]  
Semaglutide| Lipopolysaccharides-treated H9c2 cells| 

▪
    Protects exercise-induced cardiomyopathy by activating AMPK pathway;
▪
    Increases autophagy, reduces ROS production and inflammatory markers (NF-κB, TNF-α, and IL-1β).
| [77]  
Semaglutide| Hypoxia/reoxygenation (H/R) injury in H9c2 cells| 

▪
    Inhibits H/R injury-induced cardiomyocyte apoptosis by activating PKG/PKCε/ERK1/2 pathway.
| [78]  
  
**Table 4.** Preclinical studies of GLP-1R agonists for cardioprotective effects (In vivo). 

**Table 4.** Preclinical studies of GLP-1R agonists for cardioprotective effects (In vivo).

GLP-1 Analogs| Study Models| Mechanistic Findings| Ref.  
---|---|---|---  
Exendin-4| Left anterior descending (LAD) coronary artery ligation-induced heart failure rats| 

▪
    Attenuates cardiac remodeling through activation of eNOS/cGMP/PKG pathway.
| [79]  
Exendin-4| LAD coronary artery ligation-induced myocardial infarction (MI) rats| 

▪
    Inhibits collagen I, collagen III, transforming growth factor-β1, phosphorylated PI3K, and Akt levels.
| [80]  
Exendin-4| High-fat diet (HFD)-induced diabetic rats| 

▪
    Inhibits cardiomyocyte pyroptosis via AMPK-TXNIP pathway.
| [81]  
Exendin-4| LAD coronary artery ligation-induced MI rats| 

▪
    Attenuates myocardial remodeling after an acute MI by activating β-arrestin-2, protein phosphatase 2A, and GSK-3, and inhibiting β-catenin.
| [82]  
Exendin-4| Streptozotocin (STZ)-induced diabetic rats| 

▪
    Downregulates NF-kB and upregulates cardiolipin, PGC1α, LC3, and beclin.
| [83]  
Exendin-4| LAD coronary artery ligation-induced MI rats| 

▪
    Reduces ventricular arrhythmias through decreasing SR calcium leak, reduced RyR2 phosphorylation, and decreased CaMK-II activity.
| [84]  
Exenatide| DPP4-deficient rats;  
Adiponectin-deficient mice| 

▪
    Prevents chronic stress induced vascular senescence.
| [85]  
Exendin-4| LAD coronary artery ligation-induced MI rats| 

▪
    Decreases susceptibility to atrial arrhythmogenesis;
▪
    Improves conduction properties and exerts antifibrotic effects via GLP-1R signaling.
| [80]  
Exendin-4| LAD coronary artery ligation-induced MI rats| 

▪
    Increases GLP-1/GLP-1R expression in ventricular tissues;
▪
    Activates eNOS/cGMP/PKG signaling and inhibits CaMKII pathway;
▪
    Inhibits pathological cardiac remodeling;
| [79]  
Liraglutide| Spontaneously hypertensive rats (SHR)| 

▪
    Delays progression of hypertension through activation of brainstem dopamine beta-hydroxylase (DBH) neurons;
▪
    Suppresses sympathetic nerve activity.
| [86]  
Liraglutide| Apolipoprotein E deficient (ApoE−/−) mice| 

▪
    Suppresses atherosclerotic lesions; 
▪
    Increases AMPK phosphorylation in aortic wall.
| [87]  
Liraglutide| HFD-feeding and STZ-induced diabetic rats | 

▪
    Reduces myocardial damage by activating the Sirt1/AMPK pathways;
▪
    Inhibits cellular pyroptosis. 
| [88]  
Liraglutide| Abdominal aortic constriction-induced cardiac fibrosis rats| 

▪
    Inhibits cardiac fibrosis and dysfunction by inhibiting mTOR/p70S6K signaling and enhancing autophagy.
| [89]  
  
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Pandey, S.; Mangmool, S.; Parichatikanond, W. Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_ **2023** , _16_ , 836. https://doi.org/10.3390/ph16060836 

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Pandey S, Mangmool S, Parichatikanond W. Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_. 2023; 16(6):836. https://doi.org/10.3390/ph16060836 

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Pandey, Sudhir, Supachoke Mangmool, and Warisara Parichatikanond. 2023\. "Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective" _Pharmaceuticals_ 16, no. 6: 836. https://doi.org/10.3390/ph16060836 

**APA Style**  


Pandey, S., Mangmool, S., & Parichatikanond, W. (2023). Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_ , _16_(6), 836. https://doi.org/10.3390/ph16060836 

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Pandey, S.; Mangmool, S.; Parichatikanond, W. Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_ **2023** , _16_ , 836. https://doi.org/10.3390/ph16060836 

**AMA Style**  


Pandey S, Mangmool S, Parichatikanond W. Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_. 2023; 16(6):836. https://doi.org/10.3390/ph16060836 

**Chicago/Turabian Style**  


Pandey, Sudhir, Supachoke Mangmool, and Warisara Parichatikanond. 2023\. "Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective" _Pharmaceuticals_ 16, no. 6: 836. https://doi.org/10.3390/ph16060836 

**APA Style**  


Pandey, S., Mangmool, S., & Parichatikanond, W. (2023). Multifaceted Roles of GLP-1 and Its Analogs: A Review on Molecular Mechanisms with a Cardiotherapeutic Perspective. _Pharmaceuticals_ , _16_(6), 836. https://doi.org/10.3390/ph16060836 

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url: https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-024-03394-z
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Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study | BMC Medicine | Full Text

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Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study 

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# Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study

  * Diaozhu Lin1 na1, 
  * Huisheng Xiao1 na1, 
  * Kexu Yang2 na1, 
  * Juan Li3 na1, 
  * Suiwen Ye4, 
  * Yanqiong Liu4, 
  * Shan Jing2, 
  * Yang Lin2, 
  * Yuanxun Yang3, 
  * Lei Huang3, 
  * Jing Yuan5, 
  * Ziyan Li5, 
  * Jinlan Yang5, 
  * Huanhuan Gao5, 
  * Ying Xie5, 
  * Mingtong Xu1 &
  * …
  * Li Yan1

Show authors

[_BMC Medicine_](/) **volume 22**, Article number: 209 (2024) Cite this article

  * 2311 Accesses

  * 15 Altmetric

  * [Metrics details](/articles/10.1186/s12916-024-03394-z/metrics)




## Abstract

### Background

TG103, a glucagon-like peptide-1 analog, is being investigated as an option for weight management. We aimed to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese without diabetes.

### Methods

In this randomized, double-blind, placebo-controlled, multiple-dose phase 1b study, participants aged 18–75 years with a body-mass index (BMI) ≥ 26.0 kg/m2 and body weight ≥ 60 kg were enrolled from three centers in China. The study included three cohorts, and in each cohort, eligible participants were randomly assigned (3:1) to one of three once-weekly subcutaneous TG103 groups (15.0, 22.5 and 30.0 mg) or matched placebo, without lifestyle interventions. In each cohort, the doses of TG103 were escalated in 1-week intervals to the desired dose over 1 to 4 weeks. Then participants were treated at the target dose until week 12 and then followed up for 2 weeks. The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Secondary endpoints included pharmacokinetic and pharmacodynamic profiles of TG103 and the occurrence of anti-drug antibodies to TG103.

### Results

A total of 147 participants were screened, and 48 participants were randomly assigned to TG103 (15.0, 22.5 and 30.0 mg groups, _n_ = 12 per group) or placebo (_n_ = 12). The mean (standard deviation, SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, and the mean BMI was 29.8 (2.5) kg/m2. A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Most AEs were grade 1 or 2 in severity, and there were no serious adverse events (SAEs), AEs leading to death, or AEs leading to discontinuation of treatment. The steady-state exposure of TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The mean values of Cmax,ss ranged from 951 to 1690 ng/mL, AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. TG103 had a half-life of 110–116 h, with a median Tmax of 36–48 h. After treatment for 12 weeks, the mean (SD) values of weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and that in the placebo group was 1.37 (2.13) kg. The least square mean percent weight loss from baseline to D85 in all the TG103 groups was more than 5% with _p_ < 0.05 for all comparisons with placebo.

### Conclusions

In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. TG103 demonstrated preliminary 12-week body weight loss without lifestyle interventions, thus showing great potential for the treatment of overweight and obesity.

### Trial registration

ClinicalTrials.gov, NCT04855292. Registered on April 22, 2021.

[Peer Review reports](/articles/10.1186/s12916-024-03394-z/peer-review)

## Background

Overweight and obesity are defined by the World Health Organization (WHO) as abnormal or excessive fat accumulation that may present a health risk, which is an increasing global public health issue [[1](/articles/10.1186/s12916-024-03394-z#ref-CR1 "World Health Organization. Overweight and obesity. 
                  https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
                  
                . Accessed 10 May, 2023.")]. The WHO has identified obesity as the most prevalent chronic disease worldwide and estimated that globally, there are more than 650 million people with obesity [[2](/articles/10.1186/s12916-024-03394-z#ref-CR2 "Kivimäki M, Strandberg T, Pentti J, Nyberg ST, Frank P, Jokela M, et al. Body-mass index and risk of obesity-related complex multimorbidity: an observational multicohort study. Lancet Diabetes Endocrinol. 2022;10:253–63.")]. China is one of the countries with the fastest rate of increasing obesity prevalence in the world [[3](/articles/10.1186/s12916-024-03394-z#ref-CR3 "Mu L, Liu JM, Zhou GH, Wu CQ, Chen BW, Lu Y, et al. Obesity prevalence and risks among chinese adults: findings from the China PEACE million persons project, 2014–2018. Circ Cardiovasc Qual Outcomes. 2021;14: e007292.")]. Therefore, obesity and its associated health problems may also have a significant economic impact on the health care system [[4](/articles/10.1186/s12916-024-03394-z#ref-CR4 "Specchia ML, Veneziano MA, Cadeddu C, Ferriero AM, Mancuso A, Ianuale C, et al. Economic impact of adult obesity on health systems: a systematic review. Eur J Public Health. 2015;25:255–62.")].

Overweight and obese populations are at major risk for a range of comorbidities, including cardiovascular disease, gastrointestinal disease, type-2 diabetes, joint and muscle diseases, respiratory problems, and psychological problems that can significantly impact their daily lives and increase the risk of death [[5](/articles/10.1186/s12916-024-03394-z#ref-CR5 "Fruh SM. Obesity: Risk factors, complications, and strategies for sustainable long-term weight management. J Am Assoc Nurse Pract. 2017;29:S3-14."), [6](/articles/10.1186/s12916-024-03394-z#ref-CR6 "GBD 2015 Obesity Collaborators, Afshin A, Forouzanfar MH, Reitsma MB, Sur P, Estep K, et al. Health effects of overweight and obesity in 195 countries over 25 years. N Engl J Med. 2017;377:13–27.")]. The chance of developing diabetes, heart disease, and other weight-related health risks increases with increasing body mass index (BMI) [[7](/articles/10.1186/s12916-024-03394-z#ref-CR7 "Powell-Wiley TM, Poirier P, Burke LE, Després J-P, Gordon-Larsen P, Lavie CJ, et al. Obesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2021;143:e984-1010.")]. There is also strong evidence that at any given BMI, these health risks are markedly higher in some ethnic groups than in others. It appears that Asians experience higher risks of hypertension and cardiovascular disease at lower levels of BMI compared to other racial groups [[8](/articles/10.1186/s12916-024-03394-z#ref-CR8 "Stommel M, Schoenborn CAJO. Variations in BMI and prevalence of health risks in diverse racial and ethnic populations. Obesity. 2010;18:1821–6.")].

The development of obesity is mainly caused by complex interactions between genetic, metabolic, neuroendocrine, behavioral, and environmental factors involved in the regulation of energy balance and fat storage [[9](/articles/10.1186/s12916-024-03394-z#ref-CR9 "Theilade S, Christensen MB, Vilsbøll T, Knop FK. Obesity, Metabolism: An overview of obesity mechanisms in humans: Endocrine regulation of food intake, eating behaviour and common determinants of body weight. Diabetes Obes Metab. 2021;23:17–35.")]. Lifestyle modification is the recommended foundation of treatment for individuals with overweight or obesity [[10](/articles/10.1186/s12916-024-03394-z#ref-CR10 "Wadden TA, Tronieri JS, Butryn ML. Lifestyle modification approaches for the treatment of obesity in adults. Am Psychol. 2020;75:235–51.")]. As lifestyle and behavioral interventions result in moderate weight loss, which is often regained, obesity treatment strategies should be escalated by the addition of pharmacological and/or surgical interventions if necessary [[11](/articles/10.1186/s12916-024-03394-z#ref-CR11 "Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21:201–23.")]. Surgical treatments include liposuction, lipectomy and various procedures to reduce food absorption, but they may cause complications such as malnutrition, anemia and narrowing of the digestive tract and thus require strict indications [[12](/articles/10.1186/s12916-024-03394-z#ref-CR12 "Albaugh VL, Abumrad NN. Surgical treatment of obesity. F1000Res. 2018;7:617.")]. Meanwhile, surgical interventions have high requirements for indications and are incapable of satisfying the treatment needs of all overweight and obese populations. Thus, pharmacological interventions may be used in the management of obesity as an adjunct to lifestyle modification as the second-line treatment for obesity [[13](/articles/10.1186/s12916-024-03394-z#ref-CR13 "Singh AK, Singh R. Pharmacotherapy in obesity: a systematic review and meta-analysis of randomized controlled trials of anti-obesity drugs. Expert Rev Clin Pharmacol. 2020;13:53–64.")]. Pharmacological development for obesity has been hampered by concerns over safety and a paucity of substantial efficacy. Historically, there has been a collection of anti-obesity medication failures that have occurred after regulatory approval, due to adverse cardiovascular effects, increased suicidal risk or enhanced likelihood of drug dependence and abuse [[11](/articles/10.1186/s12916-024-03394-z#ref-CR11 "Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov. 2022;21:201–23.")]. However, the use of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) is promoting the belief that drug-based management of obesity may be possible for long-term treatment with suitable tolerability and safety. GLP-1, an enteric-derived hormone secreted by the human intestine, has shown great potential in both diabetes and obesity treatment. GLP-1 can reduce body weight in various ways, including inhibiting gastrointestinal motility and gastric juice secretion, suppressing appetite, delaying gastric emptying and acting on the central nervous system (especially the hypothalamus) to produce a feeling of satiety in humans [[14](/articles/10.1186/s12916-024-03394-z#ref-CR14 "Trapp S, Brierley D. Brain GLP-1 and the regulation of food intake: GLP-1 action in the brain and its implications for GLP-1 receptor agonists in obesity treatment. Br J Pharmacol. 2022;179:557–70.")]. Several GLP-1 RAs have been approved for the treatment of obesity. Liraglutide was initially used to treat type 2 diabetes and was later approved by the U.S. Food and Drug Administration (FDA) in 2014 for the treatment of obesity due to its demonstrated effects on weight loss [[15](/articles/10.1186/s12916-024-03394-z#ref-CR15 "Gao X, Hua XL, Wang X, Xu WB, Zhang Y, Shi C, et al. Efficacy and safety of semaglutide on weight loss in obese or overweight patients without diabetes: a systematic review and meta-analysis of randomized controlled trials. Front Pharmacol. 2022;13: 935823.")]. Semaglutide is a longer-acting GLP-1 RA that was also approved by the FDA for weight management in the United States on 4 June 2021 [[16](/articles/10.1186/s12916-024-03394-z#ref-CR16 "Kluger AY, McCullough PA. Semaglutide and GLP-1 analogues as weight-loss agents. Lancet. 2018;392:615–6."), [17](/articles/10.1186/s12916-024-03394-z#ref-CR17 "Singh G, Krauthamer M, Bjalme-Evans M. Wegovy \(semaglutide\): a new weight loss drug for chronic weight management. J Investig Med. 2022;70:5–13.")]. However, in China, orlistat is the only approved agent for this setting. No GLP-1 RAs are currently approved for the treatment of overweight or obesity in China. Therefore, there are unmet medical needs for this population in China.

TG103 is a recombinant protein that uses Fc-fusion protein technology to link human GLP-1 and Fc fragments via IgD, which could avoid lysosomal degradation and reduce renal clearance. Preclinical pharmacological tests have shown an affinity for the GLP-1 receptor and a long half-life, making it possible to provide patients with weekly injections of the GLP-1 analog in clinical treatment. The results of a previous single ascending dose (SAD) study of TG103 injection in a healthy population showed good tolerability and safety of TG103 [[18](/articles/10.1186/s12916-024-03394-z#ref-CR18 "Jin JL, Cui G, Mi N, Wu W, Zhang X, Xiao CY, et al. Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects. Eur J Pharm Sci. 2023;185: 106448.")]. Nonclinical rodent studies have shown that TG103 reduces body weight and food intake, consistent with other GLP-1 RAs that reduce body weight primarily through appetite suppression (data not shown).

This study aimed to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of once-weekly subcutaneous TG103 injection (target doses 15.0, 22.5, and 30.0 mg) versus placebo in nondiabetic participants with overweight or obesity.

## Methods

### Study design

This was a randomized, double-blind, placebo-controlled, multiple-dose clinical trial to evaluate the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of TG103 in participants who are overweight or obese without diabetes. The trial included 3 periods: an approximately 4-week screening period, a 12-week dosing period and a 2-week follow-up period. Eligible participants were enrolled into three paralleled dose cohorts (15.0, 22.5 and 30.0 mg) with 16 participants in each cohort. Within each cohort, participants were randomized in a 3:1 ratio to receive TG103 injection or placebo subcutaneously (SC) once a week (QW) for 12 weeks. Each cohort was started at a low dose of 7.5 mg and gradually uptitrated at weekly intervals until the target dose of each cohort was reached.

The trial was conducted at three centers in China and was sponsored by CSPC Baike (Shandong) Biopharmaceutical Co., Ltd. The trial was reviewed and approved by the institutional review board or ethics committee of each participating center and was conducted in accordance with the principles of the Declaration of Helsinki. All the participants provided written informed consent before study initiation. The trial was registered at clinicaltrials.gov (NCT04855292).

### Participants

Eligible participants were aged between 18 and 75 years (inclusive) with a BMI ≥ 26.0 kg/m2. Participants should weigh 60 kg or more and remain stable in weight (self-reported weight change of less than 5% within 3 months). The criteria for inclusion also included fasting blood glucose of 3.9–7.0 mmol/L (exclusive) and HbA1c < 6.5%. Key exclusion criteria included a confirmed diagnosis of type-1 or type-2 diabetes mellitus, and the presence of secondary obesity induced by metabolic disorders (e.g., Cushing’s syndrome, hypothyroidism, etc.) or drug treatment (e.g., glucocorticoids, tricyclic antidepressants, atypical antipsychotics, etc.). Participants who had a history of allergy to any GLP-1 analogs, or who have had previous severe allergic reactions to food or drugs, etc., were also excluded from the trial.

### Randomization and blinding

Eligible participants were randomized within each cohort in a 3:1 ratio using a block scheme via an interactive web-response system. The randomization schedule was prepared by the sponsor. All the study medications were in sealed packages with similar appearances. Participants, investigators, study site staff and sponsor representatives were blinded to the assigned study treatment.

### Procedures

Eligible participants were randomized to receive either TG103 injection or placebo in three paralleled dose cohorts: cohort A, 15.0 mg dose group (TG103: placebo = 12:4); cohort B, 22.5 mg dose group (TG103: placebo = 12:4); and cohort C, 30.0 mg dose group (TG103: placebo = 12:4). Participants in each cohort were started at a low dose of 7.5 mg and gradually increased over 1 to 4 weeks to the target dose, which was administered once a week for 12 weeks.

Blood samples for PK were collected after the first target dose and after the last target dose (12th dose) to measure TG103 concentrations. Blood samples of 3.5 mL for PK analysis were collected from participants at prespecified time points (Additional file 1: Table S1) to assess the serum concentrations of TG103. Predose blood samples of 3.5 mL for immunogenicity tests were collected on Days 1, 15, 29, and 57, and Day 99 (21 ± 2 days after the last dose). Samples were tested for anti-drug antibodies (ADA).

### Outcomes and assessments

The primary endpoint was safety and tolerability assessed by the incidence and severity of adverse events (AEs) from baseline to the end of the follow-up period. Safety assessments included physical examination, vital signs, laboratory examination, electrocardiogram (ECG) and AEs. Secondary endpoints included PK and PD profiles of TG103 and occurrence of TG103 ADA. PD endpoints were comprised the proportion of participants with a baseline weight loss of more than 5%, and change from baseline to end of treatment (defined as 1 week after the last dose) in weight, waistline, waist-hip ratio, blood pressure (systolic blood pressure and diastolic blood pressure) and blood lipase levels.

Serum concentrations of TG103 was detected using a double-antibody sandwich assay. The method was established and validated by central lab. The PK parameters of TG103 were derived using noncompartmental methods and comprised steady-state maximum concentration (Cmax,ss), time to maximum concentration (Tmax), area under the concentration–time curve from time zero to time of the last measurable concentration (AUC0-t), area under the concentration–time curve from time zero to infinity (AUC0-inf), area under the concentration–time curve during a dosing interval at steady state (AUCss), average steady-state concentration during a dosing interval (Cavg,ss), steady-state minimum concentration (Cmin,ss), steady-state apparent total body clearance (CLss/F), apparent total volume of distribution (Vz/F), and terminal half-life (t1/2). The immunogenicity and presence of ADA were determined by a validated immunoassay on an electrochemiluminescence (ECL) platform to detect ADA against TG103.

### Statistical analysis

The sample size was not based on a formal statistical power calculation. The sample size of 16 participants per group was empirically determined to provide preliminary safety, tolerability, PK and PD data. No formal hypothesis testing was planned. The dose selection for this study was based on completed animal trials and the results of the first SAD trials in healthy participants conducted in Germany and China [[18](/articles/10.1186/s12916-024-03394-z#ref-CR18 "Jin JL, Cui G, Mi N, Wu W, Zhang X, Xiao CY, et al. Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects. Eur J Pharm Sci. 2023;185: 106448.")].

Baseline characteristics were summarized by descriptive statistics, using number and proportion for categorical data and mean (standard deviation, SD), mean (standard error, SE) or median (range) for continuous data (full analysis set, FAS). Safety endpoints were analyzed in all participants who were exposed to at least one dose of the trial product (safety analysis set, SS) and summarized by descriptive statistics. PK endpoints were analyzed in all participants randomly assigned to treatment who received TG103 with at least one measurable concentration (pharmacokinetic concentration analysis set, PKCS) or with at least one valid PK parameter (pharmacokinetic parameter analysis set, PKPS). PD endpoints were analyzed in all participants who randomly received a trial product with at least one efficacy result (pharmacodynamics analysis set, PDS). Immunogenicity analyses were performed in the safety population (SS).

For analyses of the primary endpoint of safety and the secondary endpoints of pharmacodynamics, participants who were given placebo were pooled across groups. Safety analyses were performed using descriptive statistics using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03. All analyses were performed with SAS 9.4 software. Non-compartmental analysis for PK parameters was performed with Phoenix WinNonlin v8.2. The power function model was used to evaluate the linear relationship between the exposure (Cmax,ss, AUCss, AUC0-t and AUC0-inf) and dose: PK parameter: ln (y) = β0 \+ β1* ln (Dose), where 90% CI of slope β1 point estimate including 1 indicates dose-proportional increase.

Based on the PDS, an analysis of covariance (ANCOVA) was conducted to evaluate the effect of each dose group of TG103 on body weight after 12 weeks of treatment, using the dose group as a fixed effect and the baseline body weight as a covariate. Logistic regression analysis based on PDS, with dose group as a fixed effect and baseline body weight as a covariate, was performed to evaluate the difference between the effect of each dose group of TG103 on body weight and that of placebo, using the proportion of participants with a ≥ 5% reduction in body weight from baseline after 12 weeks of treatment.

## Results

### Participants

Between July 25, 2018, and Dec 17, 2019, a total of 147 participants were screened for eligibility, of whom 48 were enrolled. In each group, 16 participants were randomized, with 12 assigned to TG103 and 4 assigned to placebo (Fig. [1](/articles/10.1186/s12916-024-03394-z#Fig1)). Five participants withdrew from the study early, of whom 3 withdrew consent voluntarily, 1 was lost to follow-up, and 1 quit for other reasons. The remaining 43 participants (89.6%) completed the trial. All randomized participants (_n_ = 48) were exposed to treatment and were included in the FAS, SS and PDS. Except for 2 participants in the 22.5 mg group who reported major deviation, which may affect the PK analysis, all the other participants receiving TG103 (_n_ = 34) were included in the PKCS and PKPS. Thirty (62.5%) of 48 participants were males. The mean (SD) age of the participants was 33.9 (10.0) years; the mean bodyweight was 81.65 (10.50) kg, the mean BMI was 29.8 (2.5) kg/m2, and the mean waist circumference was 97.98 (7.52) cm. Baseline characteristics were generally similar across treatment groups (Table [1](/articles/10.1186/s12916-024-03394-z#Tab1)).

**Fig. 1**

[![figure 1](//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12916-024-03394-z/MediaObjects/12916_2024_3394_Fig1_HTML.png)](/articles/10.1186/s12916-024-03394-z/figures/1)

Study design and overall participant distribution

[Full size image](/articles/10.1186/s12916-024-03394-z/figures/1)

**Table 1 Baseline demographics characteristics**

[ Full size table](/articles/10.1186/s12916-024-03394-z/tables/1)

### Safety

A total of 466 AEs occurred in 45 of the 48 participants, with 35 (97.2%) in the TG103 group and 10 (83.3%) in the pooled placebo group. Except for 2 participants in the TG103 22.5 mg dose group and 1 participant in the placebo group who had grade 3 AEs deemed to be related to treatment by the investigator, all other participants had grade 1 or 2 AEs. There were no SAEs, no AEs leading to death, and no AEs leading to discontinuation of treatment.

The AEs occurring in at least 20% of participants in the TG103 group were decreased appetite (58.3%), nausea (55.6%), diarrhea (52.8%), injection-site reaction (47.2%), hypertriglyceridemia (33.3%), vomiting (33.3%) and hyperuricemia (22.2%). The AEs occurring in at least 20% of participants in the pooled placebo group were hypertriglyceridemia (41.7%), decreased appetite (25.0%), and hyperuricemia (25.0%).

The most commonly reported AEs were gastrointestinal disorders, with 58.3% in the 15.0 mg group, 91.7% in the 22.5 mg group, 83.3% in the 30.0 mg group and 16.7% in the placebo group. Among the gastrointestinal disorders, the incidence of vomiting (25.0% in the 15.0 mg group, 33.3% in the 22.5 mg group, 41.7% in the 30.0 mg group, 0 in the placebo group), diarrhea (33.3% in the 15.0 mg group, 50.0% in the 22.5 mg group, 75.0% in the 30.0 mg group, 8.3% in the placebo group), and abdominal distension (0 in the 15.0 mg group, 25.0% in the 22.5 mg group, 33.3% in the 30.0 mg group, 8.3% in the placebo group), increased with the increasing dose to some extent. The injection-site reaction also showed a dose-dependent increase of 33.3% in the 15.0 mg group, 50.0% in the 22.5 mg group, 58.3% in the 30.0 mg group and 8.3% in the placebo group.

Decreased appetite was reported as an AE more frequently with higher doses of TG103 with 50.0% in the 15.0 mg group, 50.0% in the 22.5 mg group, 75.0% in the 30.0 mg group and 25.0% in the placebo group. A summary of treatment-emergent AEs is presented in Table [2](/articles/10.1186/s12916-024-03394-z#Tab2). 

**Table 2 Treatment-emergent adverse events**

[ Full size table](/articles/10.1186/s12916-024-03394-z/tables/2)

### Pharmacokinetics

Following subcutaneous administration, TG103 demonstrated slow absorption with Cmax ranging from 5.85 to 96.00 h, and the median Tmax was 36.02, 35.82 and 48.03 h for doses of 15.0, 22.5 and 30.0 mg after the last target dose, respectively. After the last target dose, the mean values of Cmax,ss were 951, 1410 and 1690 ng/mL, respectively; AUC0-t ranged from 150 to 321 μg*h/mL, and AUC0-inf ranged from 159 to 340 μg*h/mL. The serum concentration–time curves of TG103 after the last target dose of each group are shown in Fig. [2](/articles/10.1186/s12916-024-03394-z#Fig2)A&B. A summary of the PK parameters of TG103 after the last target dose is shown in Table [3](/articles/10.1186/s12916-024-03394-z#Tab3). The steady-state exposure to TG103 increased with increasing dose and was proportional to Cmax,ss, AUCss, AUC0-t and AUC0-inf. The β1 point estimates (90% confidence interval, [CI]) of Cmax,ss, AUCss, AUC0-t and AUC0-inf were 0.972 (0.329, 1.616), 1.085 (0.604, 1.566), 1.133 (0.683, 1.583) and 1.129 (0.683, 1.574), respectively. The blood concentration of TG103 stabilized before the 10th, 11th and 12th doses in each dose group, which demonstrated that TG103 had reached a steady state by the 10th dose (Fig. [2](/articles/10.1186/s12916-024-03394-z#Fig2)C&D). A summary of the PK parameters of TG103 after the first target dose is shown in Additional file 1: Table S2 and the serum concentration–time curves of TG103 after the first target dose are shown in Additional file 1: Fig. S1.

**Fig. 2**

[![figure 2](//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12916-024-03394-z/MediaObjects/12916_2024_3394_Fig2_HTML.png)](/articles/10.1186/s12916-024-03394-z/figures/2)

Pharmacokinetic profile of TG103. Serum concentration–time curves of TG103 after the last target dose: (**A**) Linear plots and (**B**) Semilogarithmic plots. The blood concentration of TG103 before the 10th, 11th and 12th doses in each dose group: (**C**) Linear plots and (**D**) Semilogarithmic plots. Error bars represent standard deviation

[Full size image](/articles/10.1186/s12916-024-03394-z/figures/2)

**Table 3 Summary of pharmacokinetic parameters of TG103 after the last target dose**

[ Full size table](/articles/10.1186/s12916-024-03394-z/tables/3)

### Immunogenicity

The incidence of antibodies to TG103 was 22.2% (8/36), with 5 participants (41.7%) in the TG103 15.0 mg group, 1 participant (8.3%) in the 22.5 mg group and 2 participants (16.7%) in the 30.0 mg group testing positive for immunogenicity. All participants in the placebo group tested negative for immunogenicity during the test.

The results of the exploratory analysis of the effect of immunogenicity on PK showed that exposure levels were lower in immunogenic-positive participants in the 15.0 mg group (Cmax,ss of 669 ng/mL and AUC0-t of 134 μg*h/mL) than in negative participants (Cmax,ss of 1190 ng/mL and AUC0-t of 163 μg*h/mL). Similar results were also observed for AUCss and AUC0-inf in immunogenic-positive participants in the 15.0 mg group. Due to the low number of immunogenic-positive participants in the 22.5 mg and 30.0 mg groups, no further analysis was performed.

### Pharmacodynamics

Based on the PDS, the mean weight change from baseline by day and the mean percent weight loss from baseline by day for each dose group are shown in Fig. [3](/articles/10.1186/s12916-024-03394-z#Fig3)A&C. The results of the change in efficacy outcomes from baseline to week 12 are presented in Table [4](/articles/10.1186/s12916-024-03394-z#Tab4). The mean (SD) values of D85 weight loss from baseline in the TG103 15.0 mg, 22.5 mg and 30.0 mg groups were 5.65 (3.30) kg, 5.35 (3.39) kg and 5.13 (2.56) kg, respectively, and the mean (SD) values of D85 weight loss from baseline in the placebo group were 1.37 (2.13) kg (Fig. [3](/articles/10.1186/s12916-024-03394-z#Fig3)B).

**Fig. 3**

[![figure 3](//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs12916-024-03394-z/MediaObjects/12916_2024_3394_Fig3_HTML.png)](/articles/10.1186/s12916-024-03394-z/figures/3)

Change from baseline in body weight and waist circumference. **A** Change from baseline in body weight over time. **B** Change from baseline in body weight at week 12. **C** Percentage change from baseline in body weight over time. **D** Change from baseline in waist circumference over time. Data are plotted as the mean (SD)

[Full size image](/articles/10.1186/s12916-024-03394-z/figures/3)

**Table 4 Change in efficacy outcomes from baseline to week 12**

[ Full size table](/articles/10.1186/s12916-024-03394-z/tables/4)

The least square mean (SE) percent weight loss from baseline to D85 in the TG103 15.0 mg, 22.5 mg, and 30.0 mg groups were -7.24 (0.97)%, -5.79 (1.05)%, and -6.47 (1.02)%, respectively, and that of the placebo group was -1.76 (0.93)%. There was also a significant difference in each dose group compared to the placebo group (_p_ < 0.05 for all comparisons). The least square mean differences between each dose group and placebo (TG103 group—placebo group) were -5.48% (95% CI, -8.77, -2.19), -4.03% (95% CI, -7.51, -0.55), and -4.71% (95% CI, -8.08, -1.33), respectively. The upper 95% CIs for the least square mean differences were less than 0, and the p values were all less than 0.05. Therefore, the weight reduction in each TG103 dose group after 12 weeks of treatment was better than that in the placebo group.

The odds ratios (95% CI) of the proportion of participants in the TG103 15.0, 22.5 and 30.0 mg groups who showed a ≥ 5% reduction in body weight from baseline over that in the placebo group were 33.73 (95% CI, 2.78, 408.63), 8.93 (95% CI, 0.78, 102.43), and 19.14 (95% CI, 1.62, 226.56), respectively. Except for the TG103 22.5 mg group, the 95% CIs of the odds ratio in both the TG103 15.0 and 30.0 mg groups did not contain 1, and the p values were less than 0.05; therefore, the proportion of participants with a ≥ 5% reduction in body weight from baseline was significantly higher in the TG103 15.0 mg and 30.0 mg groups than in the placebo group.

After 12 weeks of treatment, waist circumference (Fig. [3](/articles/10.1186/s12916-024-03394-z#Fig3)D) and waist-to-hip ratio decreased in each group compared to baseline, but there was no significant difference between each group and the placebo group. The systolic blood pressure decreased the most in the 30.0 mg group, followed by 22.5 mg, and decreased less in the 15.0 mg and placebo groups. The diastolic blood pressure in all TG103 treatment groups showed some reduction from the baseline from the placebo group.

## Discussion

This was a randomized, double-blind, placebo-controlled, multiple-dose clinical trial to evaluate the safety, tolerability, PK and PD characteristics of different doses of once-weekly TG103 in overweight or obese participants without diabetes mellitus. Overall, in this phase 1b trial, treatment with TG103 15.0–30.0 mg for 12 weeks was generally well tolerated in participants with overweight or obesity, showing preliminary efficacy in weight loss.

In our previous SAD study, a single ascending dose of TG103 (3.0–22.5 mg) was evaluated in healthy Chinese participants. Here, we added a higher dose of 30.0 mg in this study. That decision was based on a PopPK analysis that was performed on concentration data of TG103 in healthy Chinese subjects. Body weight and sex as covariates were the main factors affecting the clearance and volume of distribution of TG103 in vivo, and body weight had a greater effect on the volume of distribution and clearance. It was shown that the higher the body weight, the higher the clearance, and therefore the in vivo exposure was relatively low in the obese population when given the same dose (data not shown). Meanwhile, the additional 30.0 mg dose group in this trial is also within the safe range, considering the maximum recommended starting dose (MRSD) of 58 mg based on the preclinical crab monkey study.

The overall safety and tolerability of the trial was good. No participants withdrew because of AEs, while four withdrew for personal reasons and one was lost to follow-up. In this trial, most AEs were CTCAE grade 1 or 2 in severity. Three participants experienced grade 3 AE, with 2 participants in the 22.5 mg group (hypertriglyceridemia and blood creatine phosphokinase increased) and 1 in the placebo group (blood creatine phosphokinase increased). The occurrence of gastrointestinal disorders was expected because of the known effect of GLP-1 analogs on gastrointestinal motility and was in line with previous studies [[19](/articles/10.1186/s12916-024-03394-z#ref-CR19 "Sun F, Chai SB, Yu K, Quan XC, Yang ZR, Wu SS, et al. Gastrointestinal adverse events of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Technol Ther. 2015;17:35–42."), [20](/articles/10.1186/s12916-024-03394-z#ref-CR20 "Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–48.")]. The incidence of gastrointestinal-related AEs, such as decreased appetite, vomiting, diarrhea, and abdominal distension, showed a dose-dependent increase to some extent. Similar to other previous studies, more gastrointestinal-related AEs were observed in the higher-dose TG103 group, while all AEs were mild to moderate and resolved without any intervention. In this study, the use of dose titration has been observed in clinical practice to mitigate adverse gastrointestinal reactions and improve patient clinical tolerance of GLP-1 agonists. Decreased appetite is classified as a nutritional and metabolic disease according to the system organ class of AEs; however, it is commonly considered to be associated with delayed gastric emptying and centrally mediated effects. Since GLP-1 has a role in suppressing appetite, the participants receiving GLP-1 agonists usually experience decreased appetite, and we also observed a high incidence of decreased appetite (58.3%) in the TG103 group. The injection-site reaction also showed a dose-dependent increase. Increased heart rate has been reported after some GLP-1 RAs administration in several studies. Our preclinical evaluation in cynomolgus monkeys showed that TG103 had no effect on heart rate, and this finding has also been confirmed in previous Phase I clinical trials conducted in both German and Chinese healthy subjects. In this study, there was one case of increased heart rate reported in the TG103 30 mg group. The AE was graded as 1 according to CTCAE 5.0 and judged by the investigator to be unrelated to the drug.

Based on the results of a SAD study of a single dose of TG103, in which the mean half-life of different doses of TG103 (3.0, 7.5, 15.0 and 22.5 mg) was 147.16 to 184.72 h, a once-weekly dose interval was used in this study. This dosing interval was also similar to other weight reduction studies of GLP-1 receptor agonists, such as semaglutide [[20](/articles/10.1186/s12916-024-03394-z#ref-CR20 "Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–48.")]. In this study, we reported the PK profile of TG103 after multiple doses. Before the 10th dose, TG103 reached a steady state. The mean serum concentration of TG103 after subcutaneous administration of 15.0 to 30.0 mg showed a dose-dependent increase, with a similar course of change in TG103 concentrations over time in all dose groups. The Tmax values at different doses were similar to those reported in the SAD study. The t1/2 of TG103 in this study was between the values reported in the single-dose study of healthy Chinese and German populations [[18](/articles/10.1186/s12916-024-03394-z#ref-CR18 "Jin JL, Cui G, Mi N, Wu W, Zhang X, Xiao CY, et al. Safety, pharmacokinetics, and pharmacodynamics of TG103, a novel long-acting GLP-1/Fc fusion protein after a single ascending dose in Chinese healthy subjects. Eur J Pharm Sci. 2023;185: 106448.")]. The exposure of the TG103 15.0 mg and 22.5 mg groups after the last target dose was higher than that after the first target dose. To a certain extent, this demonstrated that there was some accumulation of TG103 after multiple doses. However, since the first target dose was not the first dose administered to the participants, the accumulation ratio of TG103 was not calculated in this study.

This study initially explored the effect of immunogenicity on the PK profile, and the preliminary results showed that participants with positive immunogenicity had lower levels of drug exposure than those with negative immunogenicity in the 15.0 mg group. However, due to the limited number of immunogenic-positive participants in each group of this study, there is insufficient evidence to characterize the effect of ADA on the PK of TG103. Further studies with larger sample sizes are needed to evaluate the impact of ADA on clearance of TG103.

According to the preclinical animal pharmacodynamic model, TG103 at doses of 2.5, 7.5, and 22.5 mg/kg all significantly reduced body weight and body weight growth rate in obese mice, with a dose correlation between 2.5 mg/kg and 7.5 mg/kg, which converted to approximately 12.0 mg and 36.0 mg in humans. Meanwhile, based on the safety results of our previous phase I study, therefore, three dose levels between 12.0 to 36.0 mg (15.0, 22.5 and 30.0 mg) were selected for the weight loss study in this trial. In this study, we preliminarily assessed the weight loss efficacy of TG103 at three dose levels in participants with overweight and obesity without diabetes. Mean weight reductions were seen in all the dose groups of TG103 without lifestyle interventions, showing obvious differences compared to the placebo group. Weight loss of at least 5% has been associated with improvements in cardiovascular risk factors, prevention of type-2 diabetes, and improvements in obesity-associated complications [[20](/articles/10.1186/s12916-024-03394-z#ref-CR20 "Enebo LB, Berthelsen KK, Kankam M, Lund MT, Rubino DM, Satylganova A, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2·4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–48.")]. In this study, there were several participants in each dose group achieved a weight loss of > 5%. There was also a reduction in other secondary endpoints of efficacy, such as waist circumference, waist-to-hip ratio, blood pressure, etc., to some extent. However, there was no significant difference between the TG103 treatment group and the placebo group. The treatment period of this study was 12 weeks, which also included the incremental process of different dose groups; therefore, the treatment period of different dose groups at the target dose was different. Meanwhile, the overall treatment period was also shorter compared to the other phase II or phase III studies in which weight loss was chosen as the primary endpoint [21,22,[23](/articles/10.1186/s12916-024-03394-z#ref-CR23 "O’Neil PM, Birkenfeld AL, McGowan B, Mosenzon O, Pedersen SD, Wharton S, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018;392:637–49.")]. Therefore, only preliminary efficacy was observed in this trial. Furthermore, TG103 was observed to have a similar effect on weight loss in the three dose groups in this trial, which may be related to factors such as the short treatment time, small sample size, and differences in diet and exercise among participants in different dose groups in this study. It’s necessary to be further verified in studies with a larger sample size and long-term treatment to more adequately assess the efficacy and dose–effect relationship of TG103.

There were some limitations in this trial. This trial had a relatively short duration and a small sample size. The short duration of the trial and the short time that participants were treated at the final target dose might have restricted treatment efficacy and safety assessments. The sample size might limit further analysis of the effect of immunogenicity on the PK profile in different dose groups. The trial was designed to primarily assess the safety and tolerability of TG103 in participants with overweight and obesity without diabetes; and weight loss, waist circumference, etc., were assessed as secondary endpoints. The multiple comparison of each dose level of TG103 and placebo was not conducted, so the p-values should be interpreted with consideration. Therefore, the efficacy data were preliminary results. Trials with longer treatment periods are needed to fully assess the efficacy and safety of TG103 and to assess whether its efficacy is sustained. The efficacy of TG103 in participants who are overweight and obese with diabetes also needs to be further investigated.

Given the good safety and potential efficacy of TG103 in participants with overweight and obesity, two phase II trials to further evaluate the efficacy and safety of TG103 in Chinese adults who are overweight or obese without diabetes (NCT05299697) and with type-2 diabetes (NCT05063253) are ongoing.

## Conclusions

In this trial, all three doses of once-weekly TG103 were well tolerated with an acceptable safety profile. Pharmacokinetic parameters support once-weekly dosing of TG103, and this dosing regimen was associated with preliminary 12-week weight loss without lifestyle interventions. TG103 preliminarily showed great potential for the treatment of participants with overweight and obesity without diabetes. Future trials with larger sample sizes and longer treatment periods are needed to fully assess the efficacy and safety of TG103 in participants who are overweight or obese.

## Availability of data and materials

Data used in the present study can be accessed upon request from the corresponding authors.

## Abbreviations

ADA:
    

Anti-drug antibodies

AE:
    

Adverse event

BMI:
    

Body-mass index

CI:
    

Confidence interval

CTCAE:
    

Common Terminology Criteria for Adverse Events

ECG:
    

Electrocardiogram

ECL:
    

Electrochemiluminescence

FAS:
    

Full analysis set

FDA:
    

Food and Drug Administration

GLP-1:
    

Glucagon-like peptide-1

NCI:
    

National Cancer Institute

PD:
    

Pharmacodynamic

PDS:
    

Pharmacodynamics analysis set

PK:
    

Pharmacokinetic

PKCS:
    

Pharmacokinetic concentration analysis set

PKPS:
    

Pharmacokinetic parameter analysis set

QW:
    

Once a week

SAD:
    

Single ascending dose

SAE:
    

Serious adverse event

SC:
    

Subcutaneously

SD:
    

Standard deviation

SE:
    

Standard error

SS:
    

Safety analysis set

RA:
    

Receptor agonist

WHO:
    

World Health Organization

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## Acknowledgements

The authors would like to thank the participants who participated in this trial and their families and the investigators, study coordinators, study teams, and nurses who assisted. We also thank Tingyuan Yang for her assistance with manuscript writing and editing which greatly improved the manuscript.

## Funding

The trial was sponsored by CSPC Baike (Shandong) Biopharmaceutical Co., Ltd.

## Author information

Author notes

  1. Diaozhu Lin, Huisheng Xiao, Kexu Yang and Juan Li contributed equally to this work.




### Authors and Affiliations

  1. Department of Endocrinology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

Diaozhu Lin, Huisheng Xiao, Mingtong Xu & Li Yan

  2. Clinical Pharmacology Centre, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

Kexu Yang, Shan Jing & Yang Lin

  3. Phase I Clinical Trials Unit, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China

Juan Li, Yuanxun Yang & Lei Huang

  4. Phase I Clinical Trial Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China

Suiwen Ye & Yanqiong Liu

  5. CSPC Pharmaceutical Group Co., Ltd, Shijiazhuang, China

Jing Yuan, Ziyan Li, Jinlan Yang, Huanhuan Gao & Ying Xie




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### Contributions

MTX ang LY conceived and designed the study. DZL, HSX, KXY, JL, SWY, YQL, SJ, YL, YXY, LH, MTX and LY contributed to the acquisition, analysis, and interpretation of the data. JY drafted the analysis plan, performed the statistical analysis, and interpreted the data. ZYL, JLY, HHG and YX contributed to the analysis plan and data interpretation. DZL, HSX, KXY and JL wrote the first draft of the manuscript. All authors read and approved the final manuscript.

### Corresponding authors

Correspondence to [Mingtong Xu](mailto:xuming@21cn.com) or [Li Yan](mailto:yanli@mail.sysu.edu.cn).

## Ethics declarations

### Ethics approval and consent to participate

The trial was reviewed and approved by the institutional review board or ethics committee of each participating center and was conducted in accordance with the principles of the Declaration of Helsinki. All the participants provided written informed consent before study initiation. Sun Yat-sen Memorial Hospital: 2021-YW-036. Beijing Anzhen Hospital: (2021) Pharmaco ethics approval No.16. Nanjing Drum Tower Hospital: 2021-130-02.

### Consent for publication

Not applicable.

### Competing interests

Jing Yuan, Ziyan Li, Jinlan Yang, Huanhuan Gao, and Ying Xie are employees of CSPC Pharmaceutical Group Co., Ltd. All other authors declare no conflicts of interest.

## Additional information

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## Supplementary Information

### [12916_2024_3394_MOESM1_ESM.docx](https://static-content.springer.com/esm/art%3A10.1186%2Fs12916-024-03394-z/MediaObjects/12916_2024_3394_MOESM1_ESM.docx)

Additional file 1: Table S1. Blood sampling schedule for pharmacokinetic assessments. Table S2. Summary of pharmacokinetic parameters of TG103 after first target dose. Fig. S1. Serum concentration–time curves of TG103 after the first target dose: (A) Linear plots and (B) Semi-logarithmic plots. Error bars represent standard deviation.

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### Cite this article

Lin, D., Xiao, H., Yang, K. _et al._ Safety, tolerability, pharmacokinetics, and pharmacodynamics of TG103 injection in participants who are overweight or obese: a randomized, double-blind, placebo-controlled, multiple-dose phase 1b study. _BMC Med_ **22** , 209 (2024). https://doi.org/10.1186/s12916-024-03394-z

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  * Received: 02 August 2023

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  * Published: 29 May 2024

  * DOI: https://doi.org/10.1186/s12916-024-03394-z




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title: GLP-1 drugs for weight loss: Should you worry about muscle mass loss?
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# How to preserve muscle on weight-loss drugs like Wegovy

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Written by Deep Shukla — Fact checked by Jill Seladi-Schulman, Ph.D. —  Updated on January 7, 2025

![person's hands reaching for green-colored weight on gym floor](https://media.post.rvohealth.io/wp-content/uploads/sites/3/2024/11/muscle-loss-Stocksy_txp0ea61167Lg2400_Medium_4473836-Header-1024x575.jpg)[Share on Pinterest](https://www.pinterest.com/pin/create/button/?url=https%3A%2F%2Fwww.medicalnewstoday.com%2Farticles%2Fhow-to-preserve-muscle-mass-on-weight-loss-drugs-like-wegovy&media=https%3A%2F%2Fmedia.post.rvohealth.io%2Fwp-content%2Fuploads%2Fsites%2F3%2F2024%2F11%2Fmuscle-loss-Stocksy_txp0ea61167Lg2400_Medium_4473836-Header-1024x575.jpg&description=GLP-1%20drugs%20for%20weight%20loss%3A%20Should%20you%20worry%20about%20muscle%20mass%20loss%3F "Share on Pinterest")How can you preserve muscle mass if you are using GLP-1 drugs for weight loss? Top experts weigh in. Image credit: Santi Nuñez/Stocksy.

The development of GLP-1 drugs, such as Wegovy and Zepbound, has ushered in a new era in weight management. While these drugs can lead to significant weight loss, there are concerns about the accompanying loss of muscle tissue. This Special Feature discusses the challenges associated with assessing changes in muscle mass that accompany GLP-1 drug-induced weight loss, the potential impact of muscle mass loss, and how to preserve muscle mass.

Lifestyle changes can lead to successful weight loss, but many find it [challenging](https://www.cambridge.org/core/services/aop-cambridge-core/content/view/8FB832F4BE4630FC24AC977B0D8D9104/S2048679018000113a.pdf/successful_and_unsuccessful_weightloss_maintainers_strategies_to_counteract_metabolic_compensation_following_weight_loss.pdf) to achieve and maintain a healthy weight in the long term.

[Bariatric surgery](https://www.medicalnewstoday.com/articles/269487) can cause substantial and sustained weight loss but is generally recommended in cases of severe obesity. In contrast, drugs such as [Wegovy](https://www.medicalnewstoday.com/articles/drugs-wegovy) and [Zepbound](https://www.medicalnewstoday.com/articles/drugs-zepbound) have shown an ability to produce weight loss almost to a similar extent as bariatric surgery.

Drugs such as Wegovy mimic the actions of glucagon-like peptide-1 (GLP-1), a hormone secreted by the gastrointestinal tract, and are referred to as [GLP-1 agonists](https://www.ncbi.nlm.nih.gov/books/NBK551568/).

## 

How do GLP-1 drugs lead to weight loss?

GLP-1 agonists facilitate weight loss by stimulating insulin secretion, delaying the emptying of the stomach contents, and reducing hunger.

The glucose-dependent insulinotropic polypeptide (GIP), another gastrointestinal hormone, plays a similar role to the GLP-1 hormone, and GIP receptors are another target for weight-loss drugs.

For instance, tirzepatide, sold under the brand name Zepbound, binds to both GLP-1 and GIP receptors.

While these drugs are effective in inducing weight loss, whether this approach to weight management is healthy remains controversial. Specifically, there are concerns that GLP-1 agonists may cause a loss of muscle mass and function.

Such a loss of muscle mass and function is common in old age and is termed [sarcopenia](https://www.medicalnewstoday.com/articles/318501). The loss of muscle mass and function in sarcopenia is associated with impaired physical function, reduced quality of life, and an increased risk of falls, illness, and death.

[Christopher McGowan, MD](https://trueyouweightloss.com/about/meet-the-team/dr-christopher-mcgowan/), a gastroenterologist and obesity medicine specialist, told _Medical News Today_ that:

> “Losing weight at the expense of lean muscle can lead to future problems, including reduced basal metabolic rate, decreased strength, fitness, and tone, reduced bone density, and an increased risk of weight recurrence. For these reasons, it is essential to prioritize muscle preservation.”

## 

Why is weight loss associated with muscle loss?

Muscle loss as a result of weight reduction in individuals with overweight or obesity is a normal phenomenon. Individuals with obesity and overweight tend to have [more muscle mass](https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15728) than those with a healthy weight.

In individuals with obesity, the muscle tissue shows an accumulation of fat and changes in muscle fiber composition, resulting in reduced mobility and performance.

Notably, higher levels of infiltration of fat into muscles are [associated](https://academic.oup.com/biomedgerontology/article/70/8/1030/2947703) with decreased muscle strength and deficits in function.

**Weight loss induced by lower calorie intake is generally[accompanied by muscle loss](https://pmc.ncbi.nlm.nih.gov/articles/PMC5421125/) and lower fat levels in the muscle tissue. In other words, weight loss results in an improvement in muscle composition but a decline in muscle volume.**

Besides facilitating movement, muscles help absorb glucose (sugar) in response to insulin secreted after a meal. Obesity is characterized by impaired glucose uptake by the muscles and the liver.

This reduced sensitivity of muscles to insulin in obesity results in an increased breakdown of muscle protein and, subsequently, muscle loss. In contrast, weight loss improves muscle insulin sensitivity, which, in turn, helps prevent muscle protein breakdown. 

Since weight loss is typically associated with muscle loss, the concern with GLP-1 drugs is whether these medications induce excessive muscle loss than expected for the achieved decline in weight.

## 

How do we know if muscle loss on GLP-1 drugs is unhealthy?

One of the obstacles in determining the impact of GLP-1 agonists on muscle health has been the dearth of direct measurements of muscle volume and composition.

Studies examining the efficacy of GLP-1 drugs used for weight loss have generally quantified changes in fat and lean mass, with changes in lean mass serving as a surrogate for muscle mass. 

Lean mass consists of fat-free tissue, which includes muscles, organs, bones, water, and fluids. Even [15% of adipose (fat) tissue](https://academic.oup.com/jes/article/8/11/bvae164/7775409) is estimated to be made up of lean mass. Consequently, a considerable loss of adipose tissue is expected to be accompanied by a significant loss of fat-free mass.

**Lean mass is thus unlikely to reflect changes in muscle mass accurately. Moreover, studies examining the impact of GLP-1 drugs on weight loss have reported considerable[variation](https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.15728) in the proportion of lean mass lost due to the same GLP-1 drug. **

[Magnetic resonance imaging (MRI)](https://www.medicalnewstoday.com/articles/146309) can directly assess changes in muscle mass and composition, including fat infiltration. However, the Food and Drug Administration (FDA) [guidelines](https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=58) do not require the assessment of muscle quality or volume in clinical trials assessing the efficacy of GLP-1 drugs for weight loss. 

Additionally, the threshold to define unhealthy muscle mass has been debated. For instance, muscle mass is influenced by an individual’s biological sex, body weight, height, and body mass index (BMI). 

To address this issue, researchers have devised a method to assess healthy muscle volume by quantifying the magnitude by which an individual’s muscle mass differs from that of a standard group belonging to the same sex and with a similar body type.

## 

Who should worry about unhealthy muscle loss on GLP-1 drugs?

Studies using MRI showed that [liraglutide](https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13445) (Victoza), a GLP-1 agonist used for diabetes, and [tirzepatide](https://www.easd.org/media-centre/home.html?j=118422&sfmc_sub=77326945&l=327_HTML&u=1738265&mid=110007893&jb=1#!resources/tirzepatide-achieves-significant-weight-loss-without-adverse-effects-on-muscle-composition-surpass-3-mri-d33f2a13-d83e-4112-8763-621e82d3e128) (Zepbound) led to muscle loss that was expected with the observed magnitude of weight loss after accounting for age and the presence of other conditions. 

**Both liraglutide and tirzepatide effectively reduced muscle fat levels, thus improving muscle composition. In other words, evidence from a few studies suggests that GLP-1-agonist-induced weight loss may lead to expected levels of muscle loss while improving muscle quality, but further research is needed.**

Muscles also play other [vital roles](https://www.thelancet.com/journals/landia/article/PIIS2213-8587\(24\)00272-9/fulltext), including secreting signaling molecules called myokines that modulate metabolism and inflammation and supporting protein synthesis in a starved state or during illness. Whether these functions of muscle tissue are affected by GLP-1-induced weight loss is unknown.

Individuals with a sedentary lifestyle, poor nutrition, co-occurring conditions, or at an advanced age are more likely to be at risk of experiencing the adverse effects of muscle loss associated with GLP-1-induced weight loss. 

According to McGowan:

> “Anyone with baseline reduced muscle mass should be cautious when starting a GLP-1 medication. For example, older adults with sarcopenia may be at the highest risk, as a further reduction in lean mass could jeopardize overall health and mobility. The use of GLP-1 medications in older adults has yet to be thoroughly studied in prospective clinical trials.”

“Likewise, anyone with baseline osteopenia or osteoporosis may be at risk of a further decrease in bone density and an increased risk of falls and fractures,” he added. ”Other at-risk populations include individuals on chronic steroids, which cause muscle wasting, patients unable to engage in strength and resistance training, or patients with muscle-wasting conditions like [chronic kidney disease](https://www.medicalnewstoday.com/articles/172179).”

McGowan also noted that even healthy individuals should expect some muscle loss. Although the muscle loss observed after GLP-1 treatments seem to be in line with the levels of expected weight loss, maintaining or increasing muscle mass can also prevent or retard weight regain in all individuals using these medications.

**Individuals who rapidly lose a large amount of weight commonly[regain](https://pmc.ncbi.nlm.nih.gov/articles/PMC5764193/) most of the weight in the subsequent 5 years.**

Since muscles contribute to energy expenditure at more than twice the rate of fat tissue, the reduction in muscle and other lean mass accompanying fat loss results in lower energy expenditure after weight reduction. Thus, preventing muscle loss during weight reduction can help maintain higher levels of energy expenditure and avoid weight regain.

## 

How can you preserve muscle mass on GLP-1 drugs?

Researchers have yet to examine strategies to preserve or increase muscle mass during weight loss induced by GLP-1 drugs. However, considerable evidence exists on approaches to prevent muscle loss due to aging or weight loss induced by calorie restriction or bariatric surgery.

**Muscle loss associated with the use of GLP-1 drugs can be mitigated by consuming a protein-rich diet and regular exercise. A moderate increase in protein consumption can help preserve muscle mass during weight loss.**

[Meghan Garcia-Webb, MD](https://weightmedicinemd.com/), a board-certified physician in internal medicine, lifestyle medicine, and obesity medicine, told _MNT_ that: “A good goal is to aim for 1.0-1.2 grams of protein per kilogram, which is the ideal protein intake per body weight daily. So for someone who wanted to weigh 150 lbs [pounds], getting around 70-80 grams of protein daily would be a good goal.”

McGowan further advised that “working closely with a registered dietitian can provide valuable insight and a customized nutrition plan while tracking intake can ensure one meets these recommended goals.“

“GLP-1 medications can make you feel sick,“ he cautioned. “If you are nauseous, bloated, or uncomfortable, you are more likely to choose less nutritious, easier-to-digest foods, often low in protein. If medication side effects prevent you from reaching your nutrition goals, the dosage may need to be adjusted.”

Supplementation with whey protein and essential amino acids can also help meet the desired daily protein intake and facilitate muscle protein synthesis. 

**Endurance and resistance or weight training are effective in slowing down muscle loss accompanying weight loss. Moreover, resistance training can also increase muscle strength and improve physical function. Resistance training results in increased protein synthesis in the muscles and their composition and function.**

Meghan Garcia-Webb said that:

> “Strength training is very important to anyone starting a GLP-1 agonist medication. I advise training at least twice per week for 30 minutes. If a patient is brand new to resistance training, I always recommend meeting with a trainer once or twice to make sure they know how heavy they should lift and that they are maintaining proper form.“

## 

‘Staying consistent’ most important aspect of weight-loss treatment

[Beverly Tchang, MD](https://ro.co/weight-loss/dr-beverly-tchang/), an assistant professor of Clinical Medicine at Weill Cornell Medicine, and obesity medicine advisor for Ro, also noted to _MNT_ that “people who are at risk of frailty or sarcopenia (e.g., elderly) and taking a GLP-1 [drug] should be more mindful of incorporating resistance training to mitigate lean mass loss.”

Data from the United States suggest that some patients discontinue GLP-1 drugs within [the first year](https://pmc.ncbi.nlm.nih.gov/articles/PMC11127113/), with one of the reasons being the cost of drugs. Weight regain is common after the discontinuation of these medications.

**McGowan emphasized that: “The key to healthy, sustainable weight loss is maintaining protein intake and nutrition, performing regular resistance exercise, and staying consistent. Starting and stopping a medication can be detrimental and will all but guarantee weight regain and future difficulty losing weight.”**

“Monitoring body composition during treatment can provide critical information. Options include bioelectrical impedance scales, DEXA scans, or a simple tape measure to assess nonscale changes. This knowledge can help guide treatment and provide essential reassurance during times of minimal weight loss,” he added.

Besides lifestyle changes, drugs that help prevent muscle loss may also be used in combination with GLP-1. Growth hormone and drugs that stimulate the release of growth hormone are used to slow down muscle loss after bariatric surgery and could be potentially used in combination with GLP-1 drugs.

However, growth hormone treatment is expensive and associated with adverse effects, including muscle and joint pain and risk of diabetes.

Currently, preclinical and clinical studies are also assessing drugs that prevent muscle loss by blocking the action of hormones, such as activin and myostatin, that inhibit muscle growth. One such treatment being investigated in clinical trials is the monoclonal antibody [Bimagrumab](https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774903), which blocks the receptor for the hormone activin II.

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[Can we use food and diet as medicine? If so, to what extent? What are the pros and cons of this approach to healthcare? We investigate.](https://www.medicalnewstoday.com/articles/can-food-be-medicine-pros-and-cons?utm_source=ReadNext)

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[What to know about Ozempic microdosing](https://www.medicalnewstoday.com/articles/drugs-microdosing-ozempic?utm_source=ReadNext)

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##  Weight Loss Peptides and Supplement Use 

We know many of you are curious about these compounds and how they can help you reach your weight loss goals. Our staff also understands that these resources have changed our industry forever, so as a company, we want to make sure both our employees and customers are knowledgeable about these peptides and understand how they can aid both sides of the spectrum. 

## Disclaimer

 _**READ BEFORE CONTINUING**_

At Active Nutrition, we do not sell or provide any weight loss peptides. We acknowledge their presence in the market and aim to ensure that any supplements you take are safe and free of adverse interactions with peptides.

This page is not intended as an endorsement of peptides or any weight loss treatments. Always consult with a healthcare professional before starting any new supplement or treatment.

## Common Weight Loss Peptides

Two common weight loss peptides are semaglutide and tirzepatide.

  * Semaglutide, commonly sold as Ozempic and Wegovy, is a glucagon-like peptide analog (GLP-1) that is shown to reduce appetite, improve eating control, and suppress cravings. It is also shown to improve glycemic control. 
  * Tirzepatide, commonly sold as Mounjaro and Zepbound,is also a glucagon-like peptide analog (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). It is shown to reduce appetite, improve eating control, and suppress cravings. It is shown to have increased effectiveness compared to Semaglutide.



## The Role of the InBody Machine

**Personalized assessment:** "Offered at all 5 Active Nutrition stores, our inBody machine is a valuable tool for tracking your progress and making informed decisions about your weight loss journey. It provides detailed insights into your body composition, including muscle mass, fat mass, and water retention. By regularly using the inBody machine, you can monitor how your body is responding to peptide therapy and make adjustments as needed. This personalized approach can help optimize your results and minimize potential risks."

## Supplement Recommendations

  * **Potential supplements:** One key thing with taking any sort of weight loss peptide is that there is better given results when paired with good nutrition and exercise. Here are a couple of supplements that may complement your weight loss goals.
  * **Protein powder:** A high-quality protein powder can help support muscle mass and keep you satisfied longer.
  * **Creatine:** Creatine is a natural substance that can improve muscle performance and mass. 
  * **Greens and Reds:** Greens supplements offer a concentrated source of nutrients from leafy vegetables, while reds supplements provide antioxidants and potential benefits for heart health
  * **Omega-3 fatty acids:** These essential nutrients can help reduce inflammation and improve overall health."



## Potential Side Effects

  * **Importance of informed use:** It's crucial to understand that peptides, like any supplement, can have potential side effects. While these are generally mild, it's essential to consult with a healthcare professional before starting any new regimen.
  * **Common side effects:** Some common side effects associated with these weight loss peptides may include nausea, headaches, dizziness, and changes in mood. It's important to listen to your body and discontinue use if you experience any adverse reactions.



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url: https://researchrepository.ucd.ie/entities/publication/6795d333-f435-4739-82e9-d9cf7acb592c
title: The impact intentional weight loss can have on patients living with sleep apnea
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# The impact intentional weight loss can have on patients living with sleep apnea

Author(s)

[ Alruwaily, Ayyad  __](/items/3e81670a-27b3-41a5-aa8f-03e6526e29ef)

Uri

<http://hdl.handle.net/10197/26394>

Date Issued

2024 

Date Available

2024-07-15T08:58:37Z 

Abstract

Background: As the global prevalence of obesity continues to rise, the health and economic burden of a variety of obesity-related complications is becoming more substantial. A body mass index (BMI) over 25 kg/m2 is considered overweight, and over 30 kg/m2 is used to define obesity. Obesity is a recognized risk factor for many illnesses, such as type 2 diabetes mellitus (T2DM), non-alcoholic fatty liver disease (NAFLD), hypertension, myocardial infarction, and vascular disease, osteoarthritis, multiple cancers, and obstructive sleep apnea (OSA). the development of Obstructive Sleep Apnea (OSA), a widely underdiagnosed condition which impacts significantly patient health and quality of life. In recent years, devices that enable diagnosis and monitoring of OSA in the community have become more popular, given the extensive resource requirements of formal full polysomnography (PSG) testing for OSA. Objective: The first study aimed to determine changes in detailed polysomnography parameters after weight loss surgery in patients with obstructive sleep apnea. The second study aimed to investigated whether liraglutide 3.0 mg would reduce the severity of OSA and other obesity-related complications compared with usual care. The third study aimed to assess the result of bariatric surgery on OSA and other obesity-related complications. Methods: The first study, recruited 5 patients in the Sleep Disorders Unit in St Vincent’s Healthcare Group, Dublin Ireland, between 2019 and 2021. The second study recruited 40 patients from the STRIVE study at St. Vincent’s University Hospital (SVUH), Dublin, between 2019 and 2020 and the third study recruited 24 patients from the bariatric surgery unit at St. Vincent's University Hospital (SVUH), Dublin, from 2018 to 2020 with a BMI of 38.4 to 58.2 kg/m2, before and after laparoscopic sleeve gastrectomy (LSG) or Roux- en-Y gastric bypass (RYGB). In the first study, the 5 patients completed a questionnaire concerning possible daily or nocturnal symptoms, medication, intoxications, and medical history. The Epworth Sleepiness Scale (ESS) was included in the questionnaire. Patients used a scale of 0–3 for each of the questions on the ESS. The scale measured the level of falling asleep in eight different situations, giving an overall score between 0 and 24: the higher the score, the sleepier the individual. We performed overnight polysomnography (PSG) on all 5 patients. PSGs were conducted preoperatively and postoperatively within one year. Embla Sandman, Version 10.1.1, was used to conduct PSGs. For the second and third study the King's Obesity Staging Criteria (KOSC) was used. The KOSC comprise nine health domains: Airways, Body mass index, Cardiovascular disease, Diabetes, Economic complications, Functional limitations, Gonadal axis, Health status (perceived), and Body Image. These domains were used to assess the effectiveness of Liraglutide 3.0mg for weight-loss (in the second study) and bariatric surgery for weight loss (in the third study). Results: In the first study on 5 patients, the following parameters were tested 1) apnea, 2) oxygenation, 3) symptoms of sleepiness, 4) sleep and 5) surrogate markers of cardiovascular risk after one-year bariatric surgery. We observed a significant improvement in the majority of polysomnography parameters. The severity classifications Apnea Hypopnea Index (AHI) used were mild (AHI = 5-14), moderate (AHI = 15- 30), and severe (AHI > 30). We found that participants' total AHI had improved significantly in Hypopnea (p < 0.03) and Apnea Hypopnea Index (p < 0.03). In the second study on 40 patients and the third study on 24 patients, the King's Obesity Staging Criteria (KOSC) comprise nine health domains: each domain, a person's health is assigned a score of 0 ('normal health'), 1 ('at risk'), 2('established disease'), or 3 ('advanced disease'). The two groups were analyzed using multivariate logistic regression to evaluate the null hypothesis that there is no change in participants' 9 domains between the two groups when measured at baseline and 52 weeks after commencement as part of the STRIVE RCT. Multivariate logistic regression showed a trend towards those without OSA benefiting more in cardiovascular health (p = 0.06). Those with OSA benefited more regarding improved in body image after 52 weeks (p =0.03). Conclusion: The three most important findings and the meaning of our study were improvements in the patient's OSA as measured by AHI. The study also demonstrates statistically significant correlations between AHI and anthropometric variables of weight, BMI, waist circumference, and neck circumference while suggesting baseline AHI may have been used as a predictor for AHI improvement with weight-loss 7 interventions. All oxygen parameters improved significantly after bariatric surgery and decreased the risk of coronary artery disease, heart attacks, heart failure, and strokes.

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Type of Material

Master Thesis

Publisher

University College Dublin. School of Medicine

Qualification Name

M.Sc.

Copyright (Published Version)

2024 the Author

Subjects

[Obstructive sleep apn...](javascript:void\(0\);)

[Weight loss](javascript:void\(0\);)

[Polysomnography](javascript:void\(0\);)

[Liraglutide](javascript:void\(0\);)

[Bariatric surgery](javascript:void\(0\);)

Language

English 

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Peer reviewed

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title: Use of novel glucose-lowering therapies in novel populations with type 2 diabetes
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# Use of novel glucose-lowering therapies in novel populations with type 2 diabetes

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thesis

posted on 2024-09-17, 08:32 authored by Ehtasham Ahmad

The phenotype of T2D is rapidly evolving due to increasingly sedentary lifestyles and unhealthy eating behaviours. Many individuals are diagnosed with T2D at a younger age. This presents unique challenges including early onset of complications and impaired physical function. Experts agree that the overall aim of T2D management should be to maintain optimal glycaemic control and avoid complications while achieving good quality of life and functional independence with due consideration of social determinants of health. Consequently, there is an emerging need to encourage use of “newer” glucose-lowering therapies (GLTs), which confer both glycaemic and metabolic benefits, in diverse populations.

The focus of my thesis is to explore the use of “newer” or novel agents; namely sodium–glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs), in diverse T2D populations which have not been focus of much research. These include;

• young-onset T2D

• people with impaired physical function

• people who fast during Ramadan

• people who had COVID-19 infection

The use of novel GLTs is expected to improve metabolic and functional outcomes for these populations.

The initial plan of my PhD was to focus on the impact of dapagliflozin, an SGLT2i, on physical function in people with T2D, through a randomised-controlled trial (RCT). However, this was adversely impacted by the COVID-19 pandemic. Recruitment was delayed by ~12 months and when it began, targets were difficult to achieve due to staffing issues and social distancing restrictions. Thus, it was agreed to undertake additional projects focusing on use of novel therapies in novel populations. Undertaking this additional work meant acquiring new skills, expanding knowledge and networking with external peers. As a result, this thesis represents large body of diverse but interconnected work which has been either published or presented at conferences.

I have highlighted my contributions in individual chapters.

## History

## Supervisor(s)

Melanie Davies; David Webb

## Date of award

2024-07-03

## Author affiliation

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## Awarding institution

University of Leicester

## Qualification level

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## Qualification name

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SciELO  Brasil - Pharmacologic Treatment of Obesity in adults and its impact on comorbidities: 2024 Update and Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM) Pharmacologic Treatment of Obesity in adults and its impact on comorbidities: 2024 Update and Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM) 

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CONSENSUS • Arch. Endocrinol. Metab. 68  • 2024 • <https://doi.org/10.20945/2359-4292-2024-0422> [linkcopy](javascript:;)

#  ![Open-access](https://ds.scielo.org/img/logo-open-access.svg) Pharmacologic Treatment of Obesity in adults and its impact on comorbidities: 2024 Update and Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM)

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### ABSTRACT

Pharmacological treatment of obesity is passing through many changes in the last decades; different agents have been approved, and newer options are leaning towards higher efficacy and a more favourable safety profile; however, medications approved for a longer time are still available and useful for many patients. This document is an 2024 Update Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM), with the aim of reviewing all the approved medications for the management of obesity in Brazil (sibutramine, orlistat, liraglutide, semaglutide and bupropion/naltrexone fixed dose), with the addition of tirzepatide, that is approved in other countries and likely approved soon in Brazil. The review is focused on efficacy, safety profile and the impact of drugs (based on existing studies) on different comorbidities.

Obesity; antiobesity drugs; weight loss

### INTRODUCTION

Obesity is a chronic and recurrent disease that causes or aggravates more than two hundred other diseases and is associated with increased morbidity, disability, and mortality. Following international epidemiological trends, data from the Brazilian Institute of Geography and Statistics (IBGE) show that obesity already affects a quarter of the adult population in Brazil; with its galloping rates, projections indicate that by 2035 up to 40% of the Brazilian population could be in the obesity range (1). In this scenario, it is unquestionable that every health professional must understand obesity, as even if they do not treat it directly, they will evaluate and treat people living with this disease. Welcoming the patient appropriately and discussing the consequences and therapeutic options for obesity and its related comorbidities in each consultation is essential.

The pharmacologic treatment of obesity is undergoing a transitioning period but remains extremely stigmatized. Several reasons contributing to this stigmatization have been addressed in an editorial (2); among them, the stigma of obesity itself stands out, as it is still viewed as solely dependent on “lifestyle.” Data shows that only 1% of individuals for whom medications for obesity are clinically recommended actually receive them, and many who do not have such recommendations end up using them for aesthetic purposes (3,4).

Recently, the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM) produced a joint document emphasizing the importance of language in reducing stigma (5). Using the term “antiobesity medications” is always recommended, while the term “weight loss drugs” should be avoided. Treating obesity is much more than “losing weight,” as it includes maintaining the lost weight and the benefits beyond weight loss. Additionally, “losing weight” can be desired by anyone, not just those with a chronic disease.

In this context, an important point that emerges is how pharmacologic treatments developed following the standards of evidence-based medicine, with approval from regulatory agencies and well-conducted clinical studies, are often confused and interchanged with treatments that have no scientific support and are potentially dangerous – from manipulated formulas to herbs sold on the internet, serums, and injections produced with no regard for sanitary or health concerns. Much of the stigma surrounding treatment has also been caused by older medications known for their poor risk-benefit ratio and various medications that have been discontinued in recent decades due to unacceptable side effects. An additional reason is the low efficacy of some drugs that had outcomes falling short of those desired by both physicians and patients.

Thankfully, advancements in pharmacologic treatments have overcome previously described barriers (6). New medications, some already available on the market and others still under investigation, have the potential to achieve clinically relevant weight losses. Outcome studies show that their therapeutic targets extend far beyond weight loss, with clear objectives of improving health indicators and quality of life. The present document aims to compile the existing evidence on antiobesity medications already approved by the National Health Surveillance Agency (Anvisa), along with their main efficacy and safety data.

Despite many advances, we are still far from ensuring proper access to medications for all individuals with obesity. The high cost of some medications is still a major barrier. The development of study protocols showing clear benefits and optimal pharmacoeconomic profiles may facilitate the future inclusion of some of these medications in the Unified Health System (SUS).

Considering all the above, it becomes quite clear that Abeso and SBEM have the duty of producing a document explaining the therapeutic options approved by Anvisa for the treatment of obesity, to guide specialists and nonspecialists toward serious and ethical treatment and distance patients from dangerous, ineffective, and expensive treatments, which remain so common in our country.

It is important to emphasize that obesity treatment goes far beyond medications, with lifestyle changes (LSCs) remaining the cornerstone. However, this document focuses on pharmacologic treatment, aiming to familiarize the reader with therapeutic options along with their effects on body weight, metabolic effects, and side effects. The treatment of obesity is complex, and many of its nuances and clinical questions will not be answered here. In the future, the two societies will collaborate on a broader and more comprehensive document to address, based on existing literature, practical questions aiming to facilitate treatment management. However, for the transformative time we are currently in, this data compilation – written by experts in the field who conducted an in-depth review of the literature for the most complete and current evidence – will serve as a guide to improve the care of people living with obesity.

### 1\. SIBUTRAMINE

#### 1.1 Mechanism of action

Sibutramine works by inhibiting the reuptake of norepinephrine and serotonin in the synaptic cleft and, to a lesser extent, by inhibiting the reuptake of dopamine. Its main effect is on regulating food intake, prolonging satiety rather than reducing hunger. Considering this pharmacologic characteristic, sibutramine should be classified as a satiety-inducing agent and not as an anorectic agent (7).

#### 1.2 Dosage/usage instructions

Sibutramine is commercially available in 10 mg and 15 mg tablets for daily use in patients aged ≥ 18 years. The prescription must be written on a controlled B2 prescription form, accompanied by a consent form completed by the physician and the patient in triplicate, in accordance with Anvisa standards (8).

#### 1.3 Tolerability/side effects

The main side effects of sibutramine are associated with its noradrenergic stimulation and sympathomimetic properties, the most common being xerostomia (29.2%), tachycardia (20.9%), constipation (18.9%), hypertension (17.5%), insomnia (17.2%), and headache (11.3%) (9).

#### 1.4 Absolute contraindications

Based on the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT; described in item 1.5.6, “Effects of sibutramine on lipid metabolism”), sibutramine is contraindicated in patients with type 2 diabetes mellitus (T2DM) with at least one additional risk factor (_e.g._ , hypertension controlled by medication, dyslipidemia, active smoking, or diabetic kidney disease with evidence of microalbuminuria), coronary artery disease (CAD), stroke, arrhythmia, heart failure (HF), and inadequately controlled hypertension (levels above 145 x 90 mmHg) (10).

#### 1.5 Efficacy

##### 1.5.1 Effects of sibutramine on body weight

In a systematic review of 29 clinical studies, sibutramine led to a weight loss of 2.8 kg in 12 weeks, 6 kg in 24 weeks, and 4.5 kg in 54 weeks of treatment. In studies with a duration of 44-54 weeks, the difference in the proportions of participants achieving 5% weight loss was 34% for sibutramine _versus_ 19% for placebo, and for those achieving 10% weight loss, it was 31% for sibutramine _versus_ 12% for placebo (11).

Sibutramine led to improvement in anthropometric measurements. A Cochrane database systematic review of studies on weight loss medications with 12-18 months of follow-up assessed the effect of sibutramine on reducing weight, waist circumference, and body mass index (BMI). Patients using sibutramine lost 4.3% more weight than those using placebo in 10 of the evaluated studies. Five studies showed a BMI reduction of 1.5 kg/m2, and eight studies showed a waist circumference reduction of 4.0 cm (12).

##### 1.5.2 Effects of sibutramine on weight loss maintenance

Sibutramine has also proven effective in preventing weight regain when added after dietary interventions. The double-blind, randomized controlled trial (RCT) Sibutramine Trial on Obesity Reduction and Maintenance (STORM) showed the benefits of sibutramine on weight loss and maintenance over 2 years of treatment. In the study, 605 patients with obesity received sibutramine (10 mg/day) associated with a low-calorie diet for 6 months. Patients who achieved > 5% weight loss after 6 months were allocated to continue sibutramine or switch to placebo for 18 months. The sibutramine group had greater weight loss than the placebo group at 2 years (-4.0 kg [-2.4 to -5.6 kg]), reinforcing the importance of maintaining the medication for longer after the initial weight loss (13).

Another systematic review including three studies evaluated weight loss maintenance with sibutramine. The analysis showed that after an initial dietary weight loss intervention lasting 1-6 months, individuals who achieved a body weight loss of at least 5% were randomized to treatment with placebo or sibutramine. The results demonstrated that 10%-30% more individuals treated with sibutramine compared with placebo were successful in maintaining the initial loss (defined as the maintenance of 80%-100% of the weight lost after 12-18 months of treatment) (14).

##### 1.5.3 Effects of sibutramine on body composition

The effects of sibutramine on body composition have been evaluated in very specific studies. The first RCT evaluated the effects of sibutramine 10 mg for 12 weeks in 24 adolescents. No difference in body composition was found in the sibutramine group compared with the placebo group (15). The second RCT, with the same duration as the first (12 weeks), evaluated sibutramine at doses of 10 mg and 15 mg in 181 individuals with obesity. The sibutramine group showed a trend toward a greater reduction in body fat percentage than the placebo group (p = 0.05). No difference in lean mass was observed between the groups (16).

In the STORM study, a subgroup analysis showed a preferential reduction of visceral adipose tissue compared with subcutaneous tissue in body composition assessed by computed tomography (17).

##### 1.5.4 Effects of sibutramine in patients with prediabetes/glucose intolerance

We found no studies evaluating sibutramine in this population.

##### 1.5.5 Effects of sibutramine in patients with type 2 diabetes mellitus

A meta-analysis evaluating long-duration, high-quality studies on glycemic control in patients with T2DM showed that treatment with sibutramine is associated with a slight improvement in glycemic control (18). Specifically, an RCT with a 1-year duration evaluating 195 individuals with T2DM and daily sibutramine doses of 15 mg and 20 mg showed that patients using this medication experienced improved glycemic control in parallel with weight loss. Individuals with a 10% weight loss showed an average 1.2% reduction in glycated hemoglobin (HbA1c) level (19).

##### 1.5.6 Effects of sibutramine on lipid metabolism

A meta-analysis of 29 studies showed that treatment with sibutramine is associated with a slight improvement in low-density lipoprotein cholesterol (LDL-c) and triglyceride levels (18). Sibutramine was associated with a reduction in triglyceride levels, in addition to a slight increase in high-density lipoprotein cholesterol (HDL-c) levels compared with placebo, with better results observed in patients with greater weight loss (18). Another meta-analysis showed improvement in triglyceride levels compared with placebo (-7.7 mmol/L) and an increase in HDL-c (1.5 mg/L), while LDL-c levels did not differ between groups (14).

##### 1.5.7 Effects of sibutramine on blood pressure and heart rate

In a meta-analysis conducted by Rucker and cols., seven of the included studies showed that the use of sibutramine was associated with an increase in systolic (mean 1.7 mmHg, from 0.1 to 3.3 mmHg) and diastolic (mean 2.4 mmHg, from 1.5 to 3.3 mmHg) blood pressure (BP) and heart rate (mean 4.5 bpm, from 3.5 to 5.6 bpm) (14). Despite the observed increase in BP levels, BP control in individuals with previously controlled hypertension was not compromised when their antihypertensive medication was adjusted (20).

Therefore, sibutramine must be used with regular heart rate and BP monitoring. Patients who present a significant increase in these parameters should have their treatment discontinued. Of note, the treatment can be carried out as long as the absolute contraindications are respected (item 1.4, “Absolute contraindications”).

##### 1.5.8 Effects of sibutramine on obstructive sleep apnea syndrome

An uncontrolled study of 87 patients with obesity using sibutramine 10 mg/day for 6 months showed that this treatment associated with LSCs resulted in a weight loss of 8.3 ± 4.7 kg, which was accompanied by reductions in neck circumference, obstructive sleep apnea syndrome (OSAS) severity (decrease in apnea-hypopnea index [AHI] of 16.3+/-19.4 events/h), and Epworth sleepiness scale score (decrease of 4.5+/-4.6) (21).

A study compared the efficacy of weight loss induced by sibutramine _versus_ continuous positive airway pressure (CPAP) treatment over a 1-year period in 40 patients with obesity, specifically evaluating their effects on sleep respiratory parameters. The sibutramine group had a body weight decrease of 5.4 ± 1.4 kg compared with the CPAP group, which had no weight loss. Treatment with CPAP improved all respiratory and sleep parameters, while sibutramine-induced weight loss improved only the nocturnal profile of arterial oxygen saturation (22).

##### 1.5.9 Effects of sibutramine in patients with polycystic ovary syndrome

An RCT including 40 women with obesity and polycystic ovary syndrome (PCOS) evaluated the efficacy of sibutramine therapy alone or combined with ethinylestradiol-cyproterone (EE-CPA) on clinical and metabolic parameters in women with obesity and PCOS. At the end of the study, there were significant decreases in BMI value, Ferriman-Gallwey hirsutism score, and serum total testosterone, free testosterone, and dehydroepiandrosterone sulfate (DHEAS) levels and a significant increase in sex hormone-binding globulin (SHBG) level in both groups. The sibutramine group had a greater reduction in body weight, waist/hip ratio, diastolic BP (DBP), and triglyceride levels, along with improvement in insulin sensitivity, which are important pathophysiological factors in PCOS (23).

A small, open-label, randomized study included 59 women with overweight or obesity and PCOS treated with sibutramine 10 mg for 6 months. The women were divided into a group on a low-calorie diet plus sibutramine and another group on a low-calorie diet alone. Body weight decreased in both groups, but the decrease was greater with sibutramine. In both groups, all women with an abnormal oral glucose tolerance test (OGTT) at baseline had normal glucose tolerance at 6 months. The free androgen index, glucose area under the curve, and fasting triglyceride level decreased at 6 months only in the group using sibutramine (24).

##### 1.5.10 Effects of sibutramine in patients with male hypogonadism

In a case report of a patient with a mutation in the melanocortin 4 receptor (MC4R) who had obesity and hypogonadotropic hypogonadism and was experiencing increasing body weight, sibutramine led to the maintenance of body weight and improved body composition and metabolic abnormalities related to obesity (25).

##### 1.5.11 Effects of sibutramine on metabolic dysfunction-associated steatotic liver disease

Only one small study has evaluated the effects of sibutramine on metabolic dysfunction-associated steatotic liver disease (MASLD). Thirteen individuals with obesity and nonalcoholic steatohepatitis (NASH) were evaluated over a 6-month period. There was a 10.2% decrease in body weight, along with a reduction of 47% in insulin resistance and declines of 41% in AST, 59% in ALT, and 27% in gamma-glutamyl transferase levels. Ultrasonographic regression of steatosis was observed in 11 of 13 patients using sibutramine. The study concluded that sibutramine-induced weight loss reduced insulin resistance and improved biochemical markers and ultrasonographic findings in patients with NASH (26).

##### 1.5.12 Effects of sibutramine on quality of life

A pooled analysis of four RCTs evaluated 555 patients with obesity regarding the impact of sibutramine treatment on quality of life assessed by the Impact of Weight on Quality of Life (IWQOL) and Short Form Health Survey (SF-36) scales. The SF-36 scale is a questionnaire with 36 questions that cover several dimensions of physical and mental health, including physical function, pain, vitality, and mental health, among other aspects. The IWQOL questionnaire assesses health-related quality of life specifically in patients with obesity. It comprises 31 questions evaluating patients’ perceptions of their weight, self-esteem, social life, physical activity, physical comfort, and other quality-of-life aspects. The study found that weight loss in the sibutramine group led to a significant improvement in quality of life, with the improvement being proportional to the weight loss (27).

##### 1.5.13 Effects of sibutramine on osteoarticular diseases

We found no studies evaluating sibutramine in this population.

##### 1.5.14 Effects of sibutramine in patients with chronic kidney disease

We found no studies evaluating sibutramine in this population.

##### 1.5.15 Effects of sibutramine on cardiovascular diseases

The SCOUT study assessed cardiovascular outcomes in individuals with cardiovascular disease (CVD; coronary artery disease, stroke, or peripheral arterial occlusive disease), T2DM with one or more cardiovascular risk factors, or both. In patients treated with sibutramine, the risk rate of cardiovascular events increased by 16%, with the risk of nonfatal acute myocardial infarction (AMI) increasing by 28% and the risk of nonfatal stroke increasing by 36%. Thus, sibutramine was associated with an increased risk of nonfatal cardiovascular events in this group of patients. The risks of death from cardiovascular causes and cardiorespiratory arrest were not different between the two groups (28).

### 2\. ORLISTAT

#### 2.1 Mechanism of action

Orlistat acts in the gastrointestinal tract by decreasing the absorption of dietary fats. Its mechanism of action involves irreversibly inhibiting gastric and pancreatic lipases, which reduces the hydrolysis of triglycerides into fatty acids and monoglycerides and decreases the absorption of ingested fat by 30% (29,30).

#### 2.2 Dosage/usage instructions

The recommended daily dose of orlistat is 120 mg to be taken during or up to 1 hour after each of the three main meals (29).

#### 2.3 Tolerability/side effects

The main side effects associated with orlistat therapy are related to the gastrointestinal system. A meta-analysis including 16 studies found that over 80% of patients treated with orlistat had at least one gastrointestinal side effect (12). The most frequent gastrointestinal side effects were steatorrhea, urgency to defecate, and flatulence with fat elimination, each with frequency rates of 15%-30% in most studies (14). Notably, the effects of diarrhea and abdominal pain are commonly observed in individuals with low adherence to diet (31).

Due to its effect on reducing the absorption of intestinal fat, chronic use of orlistat results in decreased absorption of fat-soluble vitamins (A, D, E, and K) (30). Additionally, dietary fat can bind to calcium in the intestinal lumen, leading to increased intestinal absorption of oxalate and preventing oxalate from naturally binding with intraluminal oxalate. The increase in circulating oxalate can lead to hyperoxaluria, a condition associated with the formation of kidney stones (32,33).

#### 2.4 Absolute contraindications

Orlistat is contraindicated in pregnant and breastfeeding women. Patients with chronic malabsorption syndrome or cholestasis should also not use this medication (34).

#### 2.5 Efficacy

##### 2.5.1 Effects of orlistat on body weight

A meta-analysis including RCTs with a duration of at least 1 year and the use of orlistat 120 mg three times daily found greater weight reductions in the orlistat group compared with the placebo group. Patients treated with orlistat lost 2.9 kg (2.5-3.2 kg) more weight than those treated with placebo. A greater number of participants in the orlistat group achieved clinically significant weight loss, with 21% and 12% achieving 5% and 10% of body weight loss, respectively. The same study showed a greater reduction in waist circumference with orlistat therapy (2.06 cm) compared with placebo (12).

##### 2.5.2 Effects of orlistat on body weight maintenance

The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study was designed to evaluate the prevention of diabetes in individuals with prediabetes using orlistat. This 4-year RCT included 3,305 patients with obesity and without a T2DM diagnosis who had normal glucose tolerance or were intolerant to oral glucose. Intensive LSCs were recommended, associated with treatment with orlistat or placebo. Weight loss was significantly greater with orlistat than with placebo at 1 year (10.6 _versus_ 6.2 kg, respectively) and remained significantly greater at the end of the fourth year of the study (5.8 _versus_ 3.0 kg, respectively) (35).

##### 2.5.3 Effects of orlistat on body composition

Two small studies evaluated the effects of orlistat on body composition. The first, an RCT, compared the effects of 1 year of treatment with orlistat or placebo on body composition assessed by dual-energy X-ray absorptiometry (DXA). Interestingly, weight loss was significant in both the orlistat and placebo groups, but there was no significant difference between the two groups (11.2 ± 7.5 kg _versus_ 8.1 ± 7.5 kg). There was also no significant difference between groups in relation to body composition parameters (fat-free mass [FFM], fat mass [FM], or percentage fat mass [FM%]), although both groups showed reductions in these three parameters (36). The second study included 72 patients who completed a 2-year RCT comparing orlistat _versus_ placebo. Body composition (FM and FFM) was assessed using bioimpedance, and the FM/FFM ratio was calculated. After a 12-month period, the groups had a significant reduction in FFM, but the difference between the two groups was not significant. In contrast, patients in the orlistat group had a greater reduction in FM (38.0 ± 7.6 kg to 29.1 ± 11.2 kg) than those in the placebo group (37.5 ± 8.5 kg to 32.3 ± 11.2 kg) (37).

##### 2.5.4 Effects of orlistat in patients with prediabetes/glucose intolerance

The effects of orlistat in individuals with prediabetes were evaluated in the XENDOS study (described previously). After 4 years of treatment, the cumulative risk of developing diabetes was 9.0% in the placebo group and 6.2% in the orlistat treatment group, corresponding to a risk reduction of 37.3%. Among 21% of the individuals with impaired glucose tolerance at baseline, the incidence of T2DM decreased by 45.0% over 4 years of orlistat therapy (35).

##### 2.5.5 Effects of orlistat on glycemic control in patients with type 2 diabetes mellitus

A meta-analysis included 2,550 patients with obesity and T2DM who used orlistat 120 mg three times daily or placebo. Weight loss was 2.4 kg greater in the orlistat group than in the placebo group. Patients treated with orlistat had significantly greater reductions in mean fasting plasma glucose and HbA1c levels than those treated with placebo (1.39 mmol/L _versus_ 0.47 mmol/L and 0.74% _versus_ 0.31%, respectively) (38).

A systematic review analyzed 12 RCTs of orlistat associated with LSCs in individuals with T2DM. Orlistat, compared with lifestyle interventions alone, led to a greater mean weight loss (2.10 kg) (39).

A subgroup analysis of patients with T2DM from five studies included in a meta-analysis of orlistat for weight loss showed a 2.3% weight reduction, along with decreases in fasting blood glucose by 1.0 mmol/L (95% CI = 0.6-1.5 mmol/L) and HbA1c levels by 0.4% (95% CI = 0.2%-0.6%) (12).

##### 2.5.6 Effects of orlistat on lipid metabolism

A systematic review and meta-analysis evaluated the effects of orlistat on different lipid profile parameters. It included 13 studies assessing the effects of orlistat on total cholesterol (n = 5,206), 13 studies with effects on LDL-c (n = 5,206), 11 studies with effects on HDL-c (n = 4,152), and 11 studies with effects on triglycerides (n = 4,456). The results showed that orlistat promoted average reductions of 12.4 mg/dL in total cholesterol (10.8-14.3 mg/dL), 10.05 mg/dL in LDL-c (8.5-11.6 mg/dL), and 1.1 mg/dL in HDL-c (0.77-1.5 mg/dL). No significant effects were observed on triglyceride levels (12).

A 24-week RCT evaluated the effects of orlistat 120 mg three times daily _versus_ placebo on weight loss and serum lipids in patients with obesity and dyslipidemia. The mean percentage of weight loss was 6.8% in the orlistat group compared with 3.8% in the placebo group (p < 0.001). The orlistat group, compared with the placebo group, experienced a significant reduction in total cholesterol (11.9% _versus_ 4.0%, respectively) and LDL-c (17.6% _versus_ 7.6%, respectively; p < 0.001). For different weight reductions, the change in LDL-c level was more pronounced in the orlistat group, indicating a possible direct effect of orlistat on cholesterol reduction independent of weight reduction (40).

##### 2.5.7 Effects of orlistat on blood pressure and heart rate

A meta-analysis of 16 studies found a 1.5 mmHg (0.9-2.2 mmHg) reduction in placebo-subtracted systolic BP (SBP) in 13 studies and a 1.4 mmHg (0.7-2.0 mmHg) reduction in DBP in 12 studies (12).

##### 2.5.8 Effects of orlistat on obstructive sleep apnea syndrome

One RCT compared orlistat _versus_ placebo over a 2-year period in patients with obesity. Orlistat improved the quality of life among patients with OSAS, but its effect on AHI was not measured (41). Another randomized study compared orlistat 120 mg three times daily _versus_ placebo for 2 years in 743 patients with obesity. The use of orlistat to promote weight loss resulted in improved vitality among patients with OSAS, as measured by the SF-36, but the trial did not measure AHI or other sleep parameters (42).

##### 2.5.9 Effects of orlistat in patients with polycystic ovary syndrome

A meta-analysis of eight studies evaluated the use of oral contraceptives (OCP) plus orlistat compared with OCP alone in patients with PCOS with overweight or obesity. The combined OCP plus orlistat treatment was more effective than OCP alone in reducing weight and hormonal, lipid, and insulin metabolism parameters, as well as improving ovulation and pregnancy rates compared with OCP alone (43). A systemic review of six RCTs assessed the efficacy of orlistat _versus_ metformin in women with obesity and PCOS and found significant reductions in weight loss along with total cholesterol and triglyceride levels in the orlistat group compared with the metformin group (44).

##### 2.5.10 Effects of orlistat in patients with male hypogonadism

There are no studies on the effects of orlistat in patients with male hypogonadism.

##### 2.5.11 Effects of orlistat on metabolic dysfunction-associated steatotic liver disease

A meta-analysis of seven studies, of which only three were RCTs, evaluated the effects of orlistat in patients with MASLD and overweight or obesity. In all, 330 patients with hepatic steatosis or steatohepatitis were evaluated. Despite the improvement in laboratory parameters (transaminases), no improvement in steatosis, steatohepatitis, or fibrosis was observed (45). A systematic review of studies assessing weight loss medications evaluated the effect of orlistat 120 mg twice daily associated with LSCs in six studies lasting at least 24 weeks and including patients with MASLD and overweight or obesity. All studies found reduced hepatic fat content and/or reduced liver enzymes (ALT and AST) concomitant with a 5%-10% reduction in body weight loss. Additionally, three studies reported improvement in histopathological findings. The results suggest that the reduction in hepatic fat content was primarily due to weight loss, with no evidence of independent effects of orlistat on MASLD (46).

##### 2.5.12 Effects of orlistat on quality of life

One RCT compared orlistat _versus_ placebo over a 2-year period in patients with obesity. Patients treated with orlistat reported significantly greater satisfaction with their antiobesity medication than those receiving placebo at 1 and 2 years (p < 0.001 in the orlistat 120 mg group; p < 0.05 in the orlistat 60 mg group). Patients who used orlistat 120 mg experienced improved quality of life (47).

##### 2.5.13 Effects of orlistat on osteoarticular diseases

A 6-month RCT including 50 women aged 45-60 years with obesity and Kellgren-Lawrence stage II-III knee osteoarthritis found that weight reduction was significantly greater in patients treated with orlistat (9.05%; average 9.5 kg) than in those who only followed a hypocaloric diet (2.54%; average 2.66 kg). Body weight reduction in patients with orlistat reduced joint pain by 52% and joint stiffness by 51%, and improved joint functional insufficiency by 51% and quality of life by 52% (48).

A retrospective, non-placebo-controlled study analyzed the medical records of 10 women with overweight and knee osteoarthritis treated for 6 months with orlistat 120 mg three times daily, aerobic exercise, and exercise for muscle mass gain. Osteoarthritis symptoms were assessed before treatment, at the end of treatment, and 6 months posttreatment. Significant improvement in scores reflecting knee pain, stiffness, and function was seen at the end of treatment with orlistat compared with placebo (37 _versus_ 21, 44.5 _versus_ 28.3, and 45.5 _versus_ 27.1, respectively), along with a reduction in BMI (32.9 kg/m2 _versus_ 29.5 kg/m2, respectively). Although the mean BMI returned to the baseline value (31.1 kg/m2) after 6 months, the improvement in the other parameters persisted (23.9, p = 0.028; 27.1, p = 0.028; and 32.9, p = 0.037, respectively) (49).

##### 2.5.14 Effects of orlistat in patients with chronic kidney disease

We found no studies evaluating orlistat in chronic kidney disease (CKD).

##### 2.5.15 Effects of orlistat in patients with cardiovascular outcomes

We found no RCTs evaluating the cardiovascular safety of orlistat.

### 3\. LIRAGLUTIDE

#### 3.1 Mechanism of action

Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue (GLP-1a) that shares 97% homology with the native GLP-1. Structural modifications to the protein increased its circulation half-life from 1-2 minutes to 13 hours (50). Liraglutide acts on hypothalamic neurons involved in energy balance and centers linked to pleasure and reward, stimulates pancreatic glucose-dependent insulin production, inhibits glucagon and somatostatin, and slows gastric emptying (51).

#### 3.2 Dosage/usage instructions

Liraglutide 3.0 mg was approved by the US Food and Drug Administration (FDA) in 2014 for treating obesity; this dose was higher than the one previously approved for treating T2DM (1.8 mg). The medication should be introduced gradually to minimize side effects, which are commonly gastrointestinal in nature. Liraglutide comes with a delivery system containing 3 mL, capable of dispensing doses of 0.6 mg, 1.2 mg, 1.8 mg, 2.4 mg, or 3.0 mg. The treatment should begin with 0.6 mg/day subcutaneously and increase by 0.6 mg each week until reaching the maximum dose of 3.0 mg/day.

#### 3.3 Tolerability/side effects

The most common adverse events are mainly related to the gastrointestinal system and affect more than 5% of patients. These side effects include nausea, vomiting, diarrhea, constipation, abdominal pain, and dyspepsia. In 94% of cases, these events are mild or moderate, usually related to the medication dose (hence the recommendation for gradual increase), transient, and rarely lead to treatment interruption (52).

Serious adverse events affect more than 0.2% of patients and include a higher incidence of cholelithiasis and acute cholecystitis, attributed to both weight loss and reduced gallbladder contractility. The risk of pancreatitis was slightly higher in the liraglutide group (0.4%) than the placebo group (0.1%), but this difference was not significant (52). The medication has an overall excellent safety profile, including in neuropsychiatric aspects, with no interaction with centrally acting medications, and demonstrates good efficacy.

#### 3.4 Absolute contraindications

The few contraindications to liraglutide include pregnancy, breastfeeding, and hypersensitivity to the drug or its excipients. Caution is recommended when liraglutide is used by patients with a previous history of acute pancreatitis. Its use should be avoided by patients with a personal or family history of multiple endocrine neoplasia or medullary thyroid cancer, as the drug has been shown to induce thyroid C-cell hyperplasia in rodents (53).

#### 3.5 Efficacy

##### 3.5.1 Effects of liraglutide on body weight

Preliminary studies have shown significantly greater weight loss with liraglutide than placebo or orlistat (54,55). Subsequently, a series of studies named Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) analyzed the use of liraglutide in the treatment of obesity and its complications. In the SCALE Obesity and Prediabetes study, 63.2% and 33.1% of the patients lost, respectively, more than 5% and 10% of their initial weight after 56 weeks (52). The study continued for another 2 years, to a total of 3 years, in patients with prediabetes. The 5%, 10%, and 15% weight loss in patients randomized to liraglutide were 49.6%, 24.8%, and 11%, respectively (56). In the SCALE Maintenance study, patients with obesity who lost 6% of weight with diet and physical activity were randomized to liraglutide 3.0 mg or placebo for 1 year. Those who used liraglutide had an additional loss of 6.1% compared with those who used placebo, reinforcing the importance of chronic and multidisciplinary treatment of obesity (57). A recent study evaluated patients who lost an average of 13.1 kg over 8 weeks on a low-calorie diet. Those who were subsequently randomized to a combination of liraglutide 3.0 mg and physical exercise achieved an additional weight loss of 3.4 kg, and at 1 year, 33% were able to maintain a weight loss of over 20% of their initial weight (58).

##### 3.5.2 Effects of liraglutide on body weight maintenance

The effects of liraglutide on weight loss maintenance were evaluated in the SCALE Maintenance study described previously (57).

##### 3.5.3 Effects of liraglutide on body composition

The study cited previously also analyzed body composition using DXA and reported a 3.9% reduction in absolute body fat percentage, which was double the decrease observed in the exercise group (1.7%) (58). Another study published in the same year assessed the use of liraglutide 3.0 mg in decreasing visceral fat, evaluated using magnetic resonance imaging. At 36 weeks, there was an average 12.5% reduction with liraglutide compared with 1.6% with placebo (59).

##### 3.5.4 Effects of liraglutide in patients with prediabetes/glucose intolerance

The effects of liraglutide in preventing the progression of prediabetes to T2DM and improving insulin resistance with weight loss are well established (59). However, studies with animal models suggest other complex direct actions of liraglutide in inhibiting the progression of prediabetes (60,61). Some clinical studies have evaluated the effects of liraglutide in individuals with prediabetes.

Kim and cols. compared the effects of liraglutide doses up to 1.8 mg _versus_ placebo in a group of patients aged 40-70 years with overweight or obesity and prediabetes. Weight loss associated with liraglutide was accompanied by a 29% reduction in peripheral insulin resistance, as assessed by the insulin suppression test. Additionally, 75% of the individuals on liraglutide achieved normal fasting plasma glucose compared with 19% of those on placebo (62).

The most important RCT was the SCALE Obesity and Prediabetes trial, in which 2,254 patients with overweight or obesity and prediabetes were randomized, in a 2:1 ratio, to liraglutide 3.0 mg or placebo, combined with a standardized diet and exercise. The study showed significant and sustained results of improved glycemic control with reduced insulin resistance in the context of 6.1% weight loss over 3 years in patients using liraglutide. Only 2% of the participants in the liraglutide group developed diabetes, compared with 6% in the placebo group. Liraglutide led to an approximately 80% reduction in T2DM risk, and the estimated time to onset of T2DM over 160 weeks was 2.7 times longer in the liraglutide group compared with the placebo group. Furthermore, at 160 weeks, 66% of patients on liraglutide achieved normoglycemia, compared with 36% of those on placebo. An additional _post hoc_ analysis was conducted at week 172 to address the lack of follow-up data for withdrawn participants, assuming that diabetes was undiagnosed in 1% of the participants withdrawn from the liraglutide group and in 0% of those withdrawn from the placebo group. The results showed that the risk of T2DM remained 66% lower in the participants who received liraglutide (52,56).

##### 3.5.5 Effects of liraglutide on glycemic control in patients with type 2 diabetes mellitus

Considering that controlling excess weight is one of the priorities in T2DM management, liraglutide has become one of the first-choice treatments for patients with T2DM and obesity due to its mechanism of action of direct hypoglycemic effects and body weight reduction (63).

The safety, tolerability, and efficacy of liraglutide were initially assessed in the treatment of T2DM through the Liraglutide Effect and Actions in Diabetes (LEAD) program. This program consisted of six RCTs that assessed liraglutide as a standalone treatment and in combination with oral antidiabetic drugs (OADs) at different stages of the disease. Levels of HbA1c decreased by 0.8%-1.6% from baseline with liraglutide at doses up to 1.8 mg (64). Rapid and sustained reductions in fasting plasma glucose level (up to 43.2 mg/dL) were observed from baseline to the end of each LEAD study. Liraglutide also effectively reduced postprandial glucose levels, with a mean reduction over three meals of up to 48.6 mg/dL across the six LEAD studies. These RCTs also confirmed a low risk of hypoglycemia with liraglutide, which is consistent with its glucose-dependent insulin secretion stimulating action (65).

The SCALE Diabetes study included 846 adults with overweight or obesity and with T2DM, randomized to receive liraglutide 3.0 mg, liraglutide 1.8 mg, or placebo for 56 weeks. Reductions in HbA1c level from baseline were 1.3%, 1.1%, and 0.3% in each group, respectively, and the percentages of individuals achieving HbA1c level of 6.5% or lower at the end of the study were 56.5%, 45.6%, and 15%, respectively. Liraglutide 3.0 mg was significantly superior to liraglutide 1.8 mg regarding glucose-related measures, including HbA1c values, fasting plasma glucose, fasting proinsulin, proinsulin-to-insulin ratio, and change in OAD association. However, the study authors advised caution in interpreting the comparison between the two doses, as the analyses were not controlled for multiplicity (66).

A systematic review published in 2016 included 43 studies conducted in Europe (n = 24), the United States (n = 5), and Asia-Pacific (n = 14), evaluating a total of 7,413 patients with T2DM treated with liraglutide as monotherapy or combined with hypoglycemic agents. The studies ranged in duration from 3 to 24 months (46.5%; n = 20 with ≥ 12 months) and assessed liraglutide doses between 0.9 and 1.8 mg. Liraglutide treatment resulted in HbA1c changes from -0.6% to -2.26% and reduced plasma glucose values, regardless of baseline HbA1c levels and follow-up duration. Overall, 29.3%-64.5% and 22%-41% of patients with T2DM treated with liraglutide achieved target HbA1c levels of 7% and 6.5%, respectively. Over time, treatment with liraglutide resulted in a mean change of -1.3 to -8.7 kg in absolute weight from baseline. Hypoglycemia with liraglutide monotherapy occurred at a ≤ 0.8% rate and was more frequent in patients using liraglutide combined with hypoglycemic agents (0-15.2%) (67).

A subsequent multicenter study conducted across 45 diabetes clinics in Italy included 1,723 patients who received liraglutide doses of up to 1.8 mg and were followed for up to 24 months. In all, 43.5% of the patients achieved a reduction in HbA1c of ≥ 1% in 12 months, and 40.9% reached the HbA1c target of ≤ 7% at 24 months with liraglutide monotherapy or combined with other hypoglycemic agents (68). Other studies in a “real-world” context have confirmed the glycemic control results observed in RCT conditions (69).

##### 3.5.6 Effects of liraglutide on lipid metabolism

Studies in animals and humans suggest that liraglutide may have some effects on lipid metabolism, independent of weight loss. In rats, the effects of liraglutide have been shown to impact pathways involved in increased cholesterol efflux (70) and in the expression of genes involved in the breakdown of lipoproteins containing apolipoprotein (apo) B-100, which is the main component of very-low-density lipoprotein cholesterol (VLDL-c), intermediate-density lipoprotein cholesterol (IDL-c), LDL-c, and lipoprotein (a) particles (71). In the same study, treatment of patients with T2DM with liraglutide 1.2 mg for 6 months significantly reduced plasma apo B-100 and fasting triglyceride levels and induced breakdown of triglyceride-rich lipoproteins (VLDL-c and IDL-c) and LDL-c (71).

Taskinen and cols. observed specific effects of liraglutide 1.8 mg on postprandial chylomicron metabolism in a small group of individuals with T2DM. Liraglutide led to a marked decrease in apo B-48 production in the intestine, increased the size of postprandial chylomicrons in circulation, dramatically reduced the direct clearance of chylomicrons, and decreased the hepatic secretion of VLDL-triglycerides (72). In another study, liraglutide reduced postprandial hyperlipidemia by increasing apo B-48 catabolism and reducing apo B-48 production in patients with T2DM (73).

In a Finnish study center, 22 patients with T2DM using metformin and statin were randomized to receive liraglutide 1.8 mg or placebo for 16 weeks. At the end of the study, serum concentrations of triglycerides, chylomicrons, and large VLDL-c particles after a high-fat mixed meal were significantly lower in the liraglutide group but not in the placebo group, despite similar weight losses in both two groups. Concentrations of apo C-III, a critical regulator of postprandial triglyceride metabolism, decreased markedly in the fasting and postprandial periods in the liraglutide group but not in the placebo group (74).

A meta-analysis of the results of the LEAD trials revealed significant reductions from baseline in total cholesterol (5.0 mg/dL), LDL-c (7.7 mg/dL), and triglycerides (17.7 mg/dL; p < 0.01 for all) among patients treated with liraglutide 1.8 mg, although these reductions were not significant compared with placebo or active comparators (61). In contrast, the SCALE Diabetes study showed that liraglutide 3.0 mg, but not liraglutide 1.8 mg, significantly improved total cholesterol, VLDL-c, HDL-c, and triglyceride levels compared with placebo; no effects were observed on levels of LDL-c or free fatty acids (66).

##### 3.5.7 Effects of liraglutide on blood pressure and heart rate

Studies have confirmed the effect of liraglutide on reducing BP values. This effect was attributed not only to the associated weight loss but also to a combination of other mechanisms, such as the promotion of natriuresis (75) and vasodilation (76).

Notably, GLP-1as are generally associated with a slight increase in heart rate. Current data indicate that this effect does not result in increased cardiovascular risk, although a pronounced increase in heart rate may be associated with adverse clinical outcomes in patients with advanced HF (77).

A pooled analysis of the six LEAD RCTs, including data from almost 2,800 individuals with T2DM, showed that participants receiving liraglutide experienced significantly greater mean reductions in SBP values than those receiving placebo at 26 weeks relative to baseline. These reductions were noticeable after 2 weeks of treatment. Although the trials were not statistically powered to evaluate BP reduction, consistent reductions were observed in SBP values with liraglutide (1.8 mg or 1.2 mg once daily), with reductions of 2.1-6.7 mmHg from baseline to the end of the treatment period (26-52 weeks). Small and nonsignificant reductions from baseline in DBP values were observed with liraglutide in most of these trials. The SBP reductions observed in patients treated with liraglutide correlated weakly with weight loss. Liraglutide 1.2 mg and 1.8 mg were associated with a significant mean increase of 3 beats per minute (bpm) in pulse rate, compared with a mean increase of 1 bpm with placebo (78). A similar heart rate increase with liraglutide (3 bpm) has also been found in the LEADER study, which will be detailed later (79).

Kumarathurai and cols. observed a significant increase in heart rate and reduction in heart rate variability (HRV) in patients with newly diagnosed T2DM and stable CAD who received liraglutide 1.8 mg for 12 weeks compared with placebo. This HRV reduction was not mediated by the increased heart rate observed after liraglutide therapy, suggesting a direct influence of liraglutide on sympathovagal balance (80).

In an RCT, liraglutide was associated with a significant SBP reduction compared with placebo when added to patients with T2DM already treated with multiple daily insulin injections. Although significant correlations were found between reductions in SBP and reductions in body weight and BMI, one in three liraglutide-treated patients who experienced a marked reduction in SBP did not have a substantial decrease in body weight. A greater SBP reduction was predicted by higher baseline DBP values and by lower baseline mean values of glucose regulation parameters. One explanation for this latter finding is that patients with higher mean values of glucose regulation parameters are more likely to experience blood glucose improvement with liraglutide, which decreases glycosuria and, thus, attenuates weight loss. Therefore, from a BP perspective, some patients may benefit from the use of liraglutide despite not having improvements in other traditional metabolic risk factors (81).

Zhao and cols. evaluated the effect of liraglutide on BP in a meta-analysis of 18 RCTs. The authors observed that, compared with placebo, liraglutide reduced SBP by 3.18 mmHg but had no significant effect on DBP. Only three RCTs evaluated the effect of liraglutide at the doses of 2.4 mg and 3.0 mg. Although no RCTs have been published on liraglutide 3.0 mg specifically among patients with obesity and hypertension, a subgroup analysis defined by liraglutide dose, compared with placebo, showed significant SBP reductions with the doses of 2.4 mg/day (-5.01 mmHg) and 3.0 mg/day (-3.67 mmHg) and DBP reduction (-1.46 mmHg) with the dose of 3.0 mg/day (82).

##### 3.5.8 Effects of liraglutide on obstructive sleep apnea syndrome

Although the association of OSAS with both obesity and T2DM is well established (83), only a few studies have directly measured with polysomnography the effects of liraglutide in patients with OSAS.

The classic RCT SCALE Sleep Apnea evaluated the effects of liraglutide 3.0 mg in individuals with obesity and moderate or severe OSAS who were reluctant or unable to use CPAP therapy. After 32 weeks of treatment, a significantly greater reduction in mean AHI was observed in the treated group compared with the placebo group, both of which were also addressed with monthly counseling on diet and exercise (-12.2 ± 1.8 events/h _versus_ -6.1 ± 2.0 events/h, respectively). The improvement in OSAS outcomes was associated with the degree of weight loss at the end of the study (84).

A recently published study included individuals with T2DM and moderate or severe OSAS randomized to a control group or a liraglutide group. Both groups used CPAP and received drug treatment for T2DM, except for the first group, which received liraglutide at a dose of up to 1.8 mg. After 3 months of follow-up, the mean BMI, AHI, and SBP values in the liraglutide group were lower than those in the control group, while minimum oxygen saturation was higher in the liraglutide group (85).

##### 3.5.9 Effects of liraglutide in patients with polycystic ovary syndrome

The effects of liraglutide in women with PCOS were assessed in a series of studies, both as a standalone and in combination with metformin, demonstrating significant weight loss and reduction in testosterone levels. The results were heterogeneous regarding insulin resistance and menstrual patterns. Most studies used liraglutide doses between 1.2 mg and 1.8 mg. Although few studies have evaluated fertility and gestational outcomes with GLP-1as, weight loss is known to be the most significant factor affecting the improvement of these parameters in PCOS (86). It is important to note that the liraglutide package insert recommends discontinuing the medication if the patient desires to become pregnant.

The effects of GLP-1as in women with PCOS have been evaluated in a meta-analysis of six studies with liraglutide (1.2-1.8 mg) and one with exenatide. A significant weight loss and reduction in total testosterone levels was observed, but no effects were found in abdominal circumference, fasting insulinemia, homeostasis model assessment of insulin resistance (HOMA-IR) values, or SHBG level. Only one study evaluated hirsutism and menstrual cycles, and this study found no significant changes after liraglutide treatment (87).

A recent meta-analysis compared the effects of liraglutide (1.2-1.8 mg), metformin, and the combination of metformin + liraglutide in women with overweight or obesity and PCOS. Compared with the group treated with metformin alone, the metformin + liraglutide group showed greater weight loss and reduction in waist circumference, fasting blood glucose, and insulin levels, but no difference in HOMA-IR values. When the standalone treatments with metformin _versus_ liraglutide were compared, liraglutide was only superior to metformin in terms of weight loss. There was no significant difference between metformin, liraglutide, and combined metformin plus liraglutide in improving total testosterone, free testosterone, or SHBG levels. Although two studies reported improvements in menstrual cycles with the combined therapy compared with metformin alone, they used different indicators, hindering a meta-analysis of these data (88).

The effects of liraglutide 1.8 mg on ovarian morphology, hormonal levels, and menstrual bleeding patterns were evaluated in a double-blind RCT including 72 women with overweight or obesity and PCOS. The group treated with liraglutide experienced a reduction in ovarian volume, along with an increase in SHBG level, reduction in free testosterone level, and improvement in bleeding rate (89). While most studies evaluated lower doses of liraglutide, a double-blind RCT assessed the effects of liraglutide 3.0 mg for 32 weeks in 82 women with obesity and PCOS, reporting significant weight loss, improvement in hyperandrogenism, and restoration of menstrual cycles (90).

The pregnancy rates after _in vitro_ fertilization were investigated in an open-label RCT including 28 women with obesity and PCOS, comparing the effects of metformin plus liraglutide 1.2 mg _versus_ metformin alone for 12 weeks. The pregnancy rate per embryo transfer was significantly greater in the combined treatment group (85.7%) compared with the metformin alone group (28.6%), and the cumulative pregnancy rates over a 12-month period were 69.2% and 35.7%, respectively (91).

##### 3.5.10 Effects of liraglutide in patients with male hypogonadism

Studies evaluating the effects of liraglutide in patients with male hypogonadism do not allow for definitive conclusions but suggest an improvement in testosterone levels and sexual function accompanying weight loss and improvement in metabolic parameters. It is unclear whether the effects of liraglutide in patients with male hypogonadism are mediated exclusively by the reduction in adiposity. In animal models, there is evidence of direct effects of central GLP-1 signaling on the gonadal axis. Intracerebroventricular GLP-1 injection induces an immediate luteinizing hormone (LH) surge in male rats (92).

A retrospective observational study has evaluated the effects of liraglutide added to testosterone replacement therapy (TRT), metformin, and LSCs on erectile function in men with obesity, T2DM, and hypogonadism. In the first year, all 43 patients (aged 45-59 years) received TRT, metformin, and LSC recommendations. In the second year, those who did not reach the target HbA1c value received additional liraglutide 1.2 mg daily. The group that received liraglutide showed additional weight loss and improvement in erectile function compared with the group that did not receive it (93).

A prospective, randomized, open-label study evaluated the effects of liraglutide 3.0 mg daily compared with testosterone 50 mg (1% transdermal gel) for 16 weeks in 30 men with a mean age of 46 years, obesity, and functional hypogonadism. The weight loss was only significant in the group that received liraglutide. Both groups experienced improvements in total testosterone levels, libido, and sexual function. Follicle-stimulating hormone (FSH) and LH levels increased in the liraglutide group and decreased in the testosterone group (94).

In a prospective study, 110 young (aged 18-35 years) men with obesity and functional hypogonadism were divided according to their desire for fertility into three groups to receive gonadotropins, liraglutide 3.0 mg, or transdermal testosterone 60 mg for 4 months. The group that received liraglutide showed significant weight loss and higher levels of testosterone and gonadotropins, as well as improved erectile function and conventional sperm parameters relative to baseline levels and compared with the other groups (95).

##### 3.5.11 Effects of liraglutide on metabolic dysfunction-associated steatotic liver disease

Liraglutide has demonstrated benefits in patients with MASLD, reducing liver fat content and improving steatohepatitis. In addition to its weight loss effect in reducing lipotoxicity, other mechanisms have been proposed, such as modification of portal and peripheral insulin and glucagon concentrations, and improvements in hepatocyte mitochondrial function and hepatic insulin sensitivity (96).

Four RCTs showed a reduction in liver fat content assessed by magnetic resonance imaging-based techniques after treatment with liraglutide 1.8 mg for 6 months. The study evaluated adults with overweight or obesity and T2DM (97-99) and women with overweight and PCOS (100). Other studies have reported similar results.

The LEAN study, a double-blind RCT, examined the effects of liraglutide on steatohepatitis and fibrosis. Armstrong and cols. randomized 52 overweight patients with biopsy-proven steatohepatitis to receive liraglutide 1.8 mg or placebo for 48 weeks. The primary outcome of resolution of steatohepatitis occurred in 39% of patients in the liraglutide group _versus_ 9% of those in the placebo group (p = 0.019), and progression of fibrosis occurred in 9% of patients receiving liraglutide and in 36% of those receiving placebo (101).

##### 3.5.12 Effects of liraglutide on quality of life

Treatment with liraglutide resulted in improved quality-of-life parameters compared with placebo in an RCT. The benefits appeared to be associated with weight loss, as they were greater in individuals with greater weight loss, regardless of treatment arm.

One of the secondary outcomes of the SCALE Obesity and Prediabetes study was health-related quality of life, assessed using the SF-36, IWQOL-Lite, and Treatment Related Impact Measure – Weight after 56 weeks of treatment with liraglutide 3.0 mg. Compared with the placebo group, the liraglutide group had higher SF-36 scores in the general physical and mental health domains, higher IWQOL-Lite total scores, and more favorable individual domain scores on both instruments. In the assessment with the Treatment Related Impact Measure – Weight, the total score was also higher in the liraglutide group, despite a lower score for the experience of side effects (102). The greatest benefits were observed in the physical aspects of the IWQOL-Lite and in self-esteem (103). Quality of life was also assessed in the continuation of the SCALE Obesity and Prediabetes study for 160 weeks, which showed that the improvement demonstrated after 1 year of treatment with liraglutide 3.0 mg was generally maintained after 3 years (104).

##### 3.5.13 Effects of liraglutide on osteoarticular diseases

While preclinical studies have suggested positive effects of GLP-1 receptor agonists in osteoarthritis (105), including direct effects on various joint cell types (106), an RCT found no significant benefits of liraglutide 3.0 mg for pain associated with knee osteoarthritis, despite a relatively small weight difference between the groups (107). Gudbergsen and cols. randomized 156 patients with overweight or obesity and knee osteoarthritis who had lost more than 5% of weight with dietary intervention for 8 weeks to receive liraglutide 3.0 mg or placebo for 52 weeks. At the end of the study, the difference in weight between the groups was 3.9 kg, and there was no significant difference in knee pain, as measured by a subscale of the Knee Injury and Osteoarthritis Outcome Score (KOOS). However, it is important to highlight that the average weight loss with the pre-randomization dietary intervention was 12.5 kg and there was a significant improvement in symptoms during this period. Consequently, at the time of randomization, the patients had mild-to-moderate pain, which may have limited the potential of pharmacologic intervention to promote further improvement (107).

##### 3.5.14 Effects of liraglutide in patients with chronic kidney disease

Kidney disease is one of the most important complications of T2DM and the most common cause of CKD and end-stage renal disease (ESRD). A recent review looked at medications with established evidence for treating diabetic kidney disease. Among them are incretin-based therapeutic agents, including liraglutide, which have demonstrated vasotropic actions, suggesting a potential to reduce the risk of diabetic kidney disease (108).

In the Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes (LEADER) study, liraglutide showed cardiovascular and renal benefits, particularly in participants with CKD. The results suggested that reductions in HbA1c and SBP values may moderately mediate the renal benefits of liraglutide. Potential benefits may be driven by other mediators or direct mechanisms (109). A _post hoc_ analysis evaluated the safety of liraglutide treatment in patients with CKD. A total of 9,340 patients with T2DM were randomized to receive either liraglutide or placebo, both in addition to standard treatment. Of these, 2,158 had CKD and 7,182 had no CKD (defined as an estimated glomerular filtration rate [eGFR] < 60 and ≥ 60 mL/min, respectively); 966 patients had macroalbuminuria, and 2,456 had microalbuminuria (urine albumin-to-creatinine ratio > 300 mg/g and ≥ 30 to ≤ 300 mg/g, respectively). At the beginning of the study, the mean eGFR was 46 ± 11 mL/min in patients with CKD and 91 ± 22 mL/min in those without CKD. The risk of severe hypoglycemia was significantly lower with liraglutide compared with placebo in patients with CKD or with micro- or macroalbuminuria (hazard ratio [HR] = 0.63 and 0.57, respectively). The study concluded that the use of liraglutide in patients with CKD was safe, with no difference between patients with and without CKD (110). No dosage adjustment is necessary for patients with mild or moderate renal impairment.

Experience is limited in patients with severe renal insufficiency. A study evaluated the safety and efficacy of liraglutide in patients with T2DM and ESRD dependent on dialysis. Twenty-four patients with T2DM and ESRD and 23 control individuals with T2DM and normal renal function were randomized to receive 12 weeks of liraglutide (titrated to a maximum dose of 1.8 mg) or placebo as an add-on to ongoing antidiabetic treatment. Glycemic control improved in both groups treated with liraglutide, and the basal insulin dose decreased accordingly. Body weight also decreased in both groups treated with liraglutide. The plasma concentration of liraglutide was 49% higher in the ESRD group compared with the control group. Nausea and vomiting occurred more frequently among liraglutide-treated patients with ESRD compared with control individuals. The study concluded that reduced treatment doses and a prolonged titration period may be advisable (111), although liraglutide is currently not recommended in this population.

##### 3.5.15 Effects of liraglutide on cardiovascular outcomes

Studies in animal models have shown liraglutide effects in reducing oxidative stress and inflammation and preventing apoptosis of endothelial cells; these effects were independent of glycemic control or weight loss and may contribute to the cardiovascular protective action of this drug (112,113). Beneficial effects in reducing inflammatory markers and neutralizing oxidative stress and endothelial dysfunction in individuals treated with liraglutide have also been described (112).

Cardiovascular outcomes of liraglutide were investigated in the LEADER study, in which 9,340 individuals with T2DM and high cardiovascular risk were randomized and followed for a median of 3.8 years. The group treated with liraglutide at a dose of up to 1.8 mg had a 13% reduction in primary outcomes (cardiovascular death, nonfatal AMI, or nonfatal stroke) compared with the placebo group. Mortality from cardiovascular causes was lower in the liraglutide group (4.7% _versus_ 6.0% in the placebo group). Nonfatal myocardial infarction, nonfatal stroke, and hospitalizations due to HF were less frequent in the liraglutide group, but the differences compared with placebo were not significant (79).

A _post hoc_ analysis of the LEADER study was performed to evaluate the treatment effect of liraglutide _versus_ placebo on cardiovascular outcomes by LDL-c level < 50 mg/dL, 50-70 mg/dL, and > 70 mg/dL and statin use at the beginning of the study. The results suggest that the benefits of liraglutide on mortality and cardiovascular outcomes appear consistent in patients with T2DM at high cardiovascular risk, independent of LDL-c level, and persist even in the setting of very low baseline LDL-c levels and concomitant statin use. These data suggest that the potential antiatherosclerotic effects of the medication are complementary to its effect in reducing lipids (113).

No RCTs have been conducted to assess the cardiovascular benefits of the 3.0 mg dose in patients with obesity without T2DM. However, a _post hoc_ analysis was performed using pooled data from 5,908 participants from the five RCTs of the SCALE program (liraglutide _versus_ placebo or orlistat). In that study, liraglutide 3.0 mg was not associated with increased cardiovascular risk. Since wide confidence intervals were found, and two retrospective studies were included in the analysis, it is not possible to claim cardiovascular protection with the medication, only noninferiority compared with placebo regarding this outcome (114).

### 4\. SEMAGLUTIDE

#### 4.1 Mechanism of action

Semaglutide is a long-acting GLP-1a that mimics the effects of native GLP-1. Like other GLP-1as, semaglutide has effects in various locations and multiple actions, including reduced caloric intake, increased satiety, and decreased hunger, leading to weight loss (115). In animal models, GLP-1as act both on the hypothalamus, stimulating anorexigenic pathways, and on the mesolimbic system, influencing the reward system (116).

In a study including 72 adults with overweight or obesity and comparing semaglutide 2.4 mg _versus_ placebo, _ad libitum_ energy intake was 35% lower with semaglutide than placebo (1,736 _versus_ 2,676 kJ, respectively; estimated treatment difference -940 kJ). Semaglutide reduced hunger and potential food intake, and increased fullness and satiety compared with placebo. The CoEQ scores indicated better dietary control and reduced food cravings with semaglutide compared with placebo (p < 0.05). These effects resulted in a 9.9% reduction in body weight with semaglutide and 0.4% with placebo (117).

Semaglutide is 89% bioavailable after subcutaneous injection. Peak concentrations occur 3 days after injection, and a steady state is reached by week 5 when injected once weekly. Similar exposure was achieved in three subcutaneous administration sites: abdomen, thigh, and upper arm. More than 99% of semaglutide binds to plasma albumin, providing protection against degradation and renal clearance. Semaglutide is modified through the substitution of alanine at position 8 to protect it from natural degradation by dipeptidyl peptidase 4 (DPP-4). The elimination half-life of semaglutide is approximately 1 week; therefore, it remains in circulation for approximately 5-7 weeks after the last dose. Semaglutide is eliminated in urine and feces. No dosage adjustments are required based on hepatic or renal function (115,118).

#### 4.2 Dosage/usage instructions

Weight loss with semaglutide is dose-dependent, with higher doses resulting in greater weight loss. The package insert recommends an initial subcutaneous dose of 0.25 mg once weekly, with no relation to meal times. The dose should be titrated every 4 weeks, increasing to 0.5 mg, 1.0 mg, 1.7 mg, and 2.4 mg, which is the maximum effective dose for weight loss. In patients with poor tolerance to dose titration, it is recommended to consider a 4-week “delay” in dose titration, _i.e._ , to maintain the maximum tolerated dose for 4 weeks longer before attempting a new dose increase. The goal should be toward the maximum tolerated dose, although some patients in clinical practice are “hyper-responders” and experience significant weight loss with lower doses (118).

#### 4.3 Tolerability/side effects

The most common side effects of semaglutide occur in the gastrointestinal tract, as with other GLP-1as.

The Semaglutide Treatment Effect in People with Obesity (STEP) studies were a pivotal phase 3 clinical trial series evaluating subcutaneous semaglutide 2.4 mg weekly for weight loss. Data from these studies served for discussions regarding the weight loss efficacy, safety profile, tolerability, and effects of semaglutide on cardiometabolic parameters. In STEP 1, nausea, diarrhea, vomiting, and constipation occurred in 74.2% of participants in the semaglutide group and 47.9% of those in the placebo group. As a rule, events were mild to moderate in severity and transient, resolving permanently after treatment discontinuation. Gallbladder-related disorders (mainly cholelithiasis) were reported in 2.6% and 1.2% of participants in the semaglutide and placebo groups, respectively. Three participants in the semaglutide group had mild acute pancreatitis (two had gallstones); all participants made a full recovery. Serious adverse events were reported in 9.8% of patients in the semaglutide group and 6.4% of those in the placebo group and included mainly severe gastrointestinal and hepatobiliary events. One death was reported in each group, and neither was considered related to the receipt of semaglutide or placebo, as assessed by an independent external event adjudication committee. There was no difference between groups regarding the incidence of benign or malignant neoplasms, cardiovascular events, acute renal failure, or hypoglycemia (119).

The other STEP studies had a similar pattern of side effects. In a meta-analysis of four studies, including three studies from the STEP series and with a total of 3,613 patients, Tan and cols. found that the risk of gastrointestinal adverse events was 1.59 times higher with semaglutide (RR = 1.59, 95% CI = 1.34-1.88). The risk of discontinuation due to adverse events was twice as high in the semaglutide group (RR = 2.19), and the risk of severe adverse events (SAEs), particularly biliary tract diseases (cholelithiasis and cholecystitis) and acute pancreatitis, was 1.6 times higher in the semaglutide group (120).

In a large database analysis conducted in the United States (PharMetrics Plus) with approximately 16 million patients, Sodhi and cols. compared users of the GLP-1as liraglutide and semaglutide with those using the combination of naltrexone and bupropion (N/B). They found that GLP-1a use was associated with an increased risk of pancreatitis (HR = 9.09), intestinal obstruction (HR = 4.22), and gastroparesis (HR = 3.67), but not of biliary disease (HR = 1.50, nonsignificant), differing from findings in the STEP studies. Two aspects of the study must be highlighted: first, the confidence interval was very wide, suggesting that the sample was not adequate; second, the indiscriminate use of GLP-1as may have increased the risk of side effects, among other consequences (121).

#### 4.4 Absolute contraindications

The use of semaglutide is contraindicated during pregnancy and in cases of hypersensitivity to semaglutide or any of its excipients (122).

#### 4.5 Efficacy

##### 4.5.1 Effects of semaglutide on body weight

The efficacy of semaglutide for weight loss was initially demonstrated in a phase 2 study, in which patients with overweight or obesity and without T2DM were divided into seven groups: five using daily subcutaneous semaglutide at different doses (0.05 mg, 0.1 mg, 0.2 mg, 0.3 mg, and 0.4 mg), one using liraglutide 3.0 mg, and one using placebo. At the end of the study, the mean weight loss in patients using semaglutide was 6.0% (0.05 mg), 8.6% (0.1 mg), 11.6% (0.2 mg), 11.2% (0.3 mg), and 13.8% (0.4 mg), showing a clear superiority of semaglutide over placebo (2.3%). Starting at a daily dose of 0.2 mg, which is equivalent to 1.4 mg per week, weight loss with semaglutide was greater than that with liraglutide (7.8%) (123).

In STEP 1, a total of 1,961 patients with overweight or obesity and without T2DM were evaluated and followed up for 68 weeks. All participants were instructed to follow a hypocaloric diet with a 500 kcal/day deficit and practice 150 minutes of physical activity per week. At the end of the study, participants in the semaglutide 2.4 mg group lost on average 16.9% of weight, while those in the placebo group lost 2.4%. The nadir was reached at week 60 (119).

The STEP 2 study evaluated 1,210 patients with T2DM with a BMI > 27 kg/m2 and HbA1c levels between 7.0% and 10%. The patients were divided into three groups: semaglutide 2.4 mg, semaglutide 1.0 mg, and placebo. At 68 weeks, semaglutide 2.4 mg led to greater weight loss than semaglutide 1.0 mg. Patients in the semaglutide 2.4 mg group lost an average of 9.6% of their body weight, compared with 7.0% in the semaglutide 1.0 mg group and 3.4% in the placebo group (124). A comparison of the results of the STEP 1 and STEP 2 studies showed that the participants with T2DM lost less weight than those without T2DM, replicating the finding by studies conducted with other medications.

The STEP 3 study evaluated 611 patients and had a design virtually identical to that of STEP 1, differing only in the degree of LSCs, which were more intensive. At the end of the 68-week period, the intervention group lost an average of 16% of body weight, while the placebo group lost 5.7% (125).

The STEP 4 study was designed to assess the effects of continuing _versus_ interrupting semaglutide treatment in individuals with overweight or obesity. A total of 902 patients received semaglutide in escalating doses of up to 2.4 mg/week, with an average weight loss of 10%. At week 20, half of the group was randomized to continue on semaglutide while the other half was switched to placebo. At the end of the study, at week 68, the semaglutide group had an additional weight loss of approximately 7.9%, with an average weight loss of 17.4%, while the group that interrupted treatment had an average weight regain of 6.9%, with an average weight loss of 5.0%. The results of this study highlighted the importance of maintaining pharmacologic treatment in patients with obesity (126).

The STEP 5 study was designed to evaluate the long-term effects of subcutaneous semaglutide 2.4 mg once weekly compared with placebo, as an add-on to behavioral intervention, on body weight and cardiometabolic risk factors in adults with overweight or obesity. At follow-up week 104, the mean decrease in body weight was 15.2% in the semaglutide group and 2.6% in the placebo group, demonstrating the long-term efficacy of the treatment (127).

A widely used way of assessing weight loss is by evaluating weight loss categories, _i.e._ , classifying weight loss into different categories, generally based on the percentage of weight loss. [Table 1]() highlights the categorical weight loss observed in the STEP series studies.

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****Table 1****  
Categorical weight loss with weekly semaglutide 2.4 mg in the STEP series studies, divided according to the percentage of weight lost   


##### 4.5.2 Effects of semaglutide on weight maintenance

See the description of the STEP 4 study above.

##### 4.5.3 Effects of semaglutide on body composition

Modification of body composition is an increasingly valued parameter in studies with antiobesity drugs. The therapeutic target is quality weight loss, _i.e._ , weight loss at the expense of fat mass with preservation or minimal loss of lean mass. The effects of semaglutide on body composition were investigated in the STEP 1 study, where a subgroup of 140 participants underwent body composition analysis using DXA. Despite a decrease in lean mass in absolute terms (-5.26 kg in the semaglutide group _versus_ 1.83 kg in the placebo group; difference -3.43 kg), there was a predominant reduction in fat mass (-8.36 kg in the semaglutide group _versus_ -1.37 kg in the placebo group; difference -6.99 kg), which resulted in patients having decreased percentage of body fat at the end of the study (119).

##### 4.5.4 Effects of semaglutide in patients with prediabetes/glucose intolerance

In a _post hoc_ analysis of the STEP 1, 3, and 4 studies, including approximately 3,375 patients with overweight or obesity and prediabetes, the intervention group (semaglutide 2.4 mg) experienced improvement in all glycemic parameters after 68 weeks of treatment, with reductions in the risk of progression from prediabetes to T2DM between 84% and 89%, demonstrating the therapeutic potential of the drug (128).

The STEP 10 study evaluated the effects of semaglutide 2.4 mg on reversing prediabetes to normoglycemia in patients with obesity. A total of 207 patients were randomized, including 138 to the semaglutide group and 69 to the placebo group. At 52 weeks, 81.1% of patients treated with semaglutide showed blood glucose normalization compared with 14.1% of those treated with placebo (OR = 19.8; p < 0.0001). Regarding HbA1c, the average level at baseline was 5.9% and at week 52, the level was 0.5% lower in the semaglutide group compared with the placebo group (129).

##### 4.5.5 Effects of semaglutide in patients with type 2 diabetes mellitus

The efficacy of semaglutide for glycemic control was well demonstrated in the SUSTAIN series of studies, where semaglutide was administered subcutaneously at a dose of 1.0 mg/week, and in the PIONNER series of studies, where it was administered orally at a dose of up to 14 mg/day (130). These two development programs included only patients with T2DM and will not be discussed in this document.

In the STEP 2 study, the 2.4 mg dose was tested in overweight patients with T2DM. At the end of the 68-week follow-up period, the HbA1c level decreased by 1.6%, which was not significantly different from the 1.5% decrease with the 1.0 mg dose (124). In a meta-analysis assessing changes in cardiometabolic parameters, semaglutide treatment of patients with overweight or obesity without T2DM resulted in a 7.5% reduction in fasting blood glucose.

##### 4.5.6 Effects of semaglutide on lipid profile

A meta-analysis evaluating changes in cardiometabolic parameters in patients with overweight or obesity and without T2DM found that semaglutide reduced serum levels of LDL-c by 6%, triglycerides by 18%, and non-HDL-c by 8%, but did not change significantly the HDL-c level (131).

##### 4.5.7 Effects of semaglutide on blood pressure and heart rate

In a meta-analysis including 4,744 patients, semaglutide resulted in mean decreases of 4.83 mmHg in SBP and 2.45 mmHg in DBP among patients with obesity without T2DM. All GLP-1as increase heart rate, and this applies to semaglutide as well. Semaglutide leads to an average heart rate increase of 2-5 bpm. However, this effect appears to be caused by direct stimulation of the sinus node rather than reflex tachycardia due to stimulation of the autonomic nervous system and is not associated with an increased risk of adverse cardiac events (132).

##### 4.5.8 Effects of semaglutide on polycystic ovary syndrome

Jensterle and cols. randomized 25 women with obesity and PCOS (33.7 ± 5.3 years, BMI 36.1 ± 3.9 kg/m2) to receive semaglutide 1.0 mg or placebo for 16 weeks. The authors assessed the participants’ tongues in regard to volume, fat tissue, and fat proportion using magnetic resonance imaging. Tongue fat tissue and fat proportion reduced significantly after semaglutide _versus_ placebo (-1.94 ± 5.51 cm3 _versus_ 3.12 ± 4.87 cm3 and 0.02 ± 0.07 cm3 _versus_ 0.04 ± 0.06 cm3, respectively). Correlation analysis revealed that these reductions were associated with those in body weight, BMI, and waist circumference (133). This was the first study confirming the beneficial effect of semaglutide among women with obesity and PCOS.

Recommendations on PCOS were recently published by a global task force (Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome). In the absence of adequate evidence, the consensus recommendations were prepared by the committee in collaboration with consumer organizations. Recommendation 4.5.1 states that “antiobesity medications, including liraglutide, semaglutide, both glucagon-like peptide-1 (GLP-1) receptor agonists and orlistat, could be considered, in addition to active lifestyle intervention, for the management of higher weight in adults with PCOS as per general population guidelines” (134).

##### 4.5.9 Effects of semaglutide on obstructive sleep apnea syndrome

No studies specifically on semaglutide and OSAS are currently available.

##### 4.5.10 Effects of semaglutide in patients with male hypogonadism

No studies specifically on semaglutide and male hypogonadism are currently available.

##### 4.5.11 Effects of semaglutide on metabolic dysfunction-associated steatotic liver disease

A phase 2 RCT included 320 patients with biopsy-confirmed NASH and liver fibrosis who were randomized to receive subcutaneous semaglutide at daily doses of 0.1 mg, 0.2 mg, or 0.4 mg or placebo for 72 weeks. The primary endpoint of NASH resolution without worsening fibrosis was achieved by 40%, 36%, and 59% of participants in the semaglutide 0.1 mg, 0.2 mg, and 0.4 mg groups, respectively, compared with 17% of those in the placebo group (p < 0.001). However, no difference between the groups was observed regarding improvement in fibrosis stage. In conclusion, semaglutide treatment of patients with NASH and fibrosis led to a significantly higher number of patients experiencing resolution of NASH compared with placebo treatment, with no difference in improvement in fibrosis stage (135).

Another phase 2, double-blind, placebo-controlled study included 71 patients with biopsy-confirmed NASH-related cirrhosis and BMI ≥ 27 kg/m2. In all, 49 (69%) patients were of the female sex. The patients had a mean age of 59.5 years and a mean BMI of 34.9 kg/m2; 53 (75%) patients had T2DM. In total, 47 patients were randomized to the semaglutide group and 24 patients to the placebo group. After 48 weeks, there was no significant difference between the two groups regarding the proportion of patients with improvement in liver fibrosis of one stage or more without worsening of MASLD (5 [11%] of 47 patients in the semaglutide group _versus_ 7 [29%] of 24 patients in the placebo group; HR = 0.28; p = 0.087). There was also no significant difference between groups in the proportion of patients achieving NASH resolution (p = 0.29). Similar proportions of patients in each group reported adverse events (42 [89%] patients in the semaglutide group _versus_ 19 [79%] patients in the placebo group) and SAEs (6 [13%] patients _versus_ 2 [8%] patients, respectively). The most frequent adverse events were nausea (21 [45%] _versus_ 4 [17%]), diarrhea (9 [19%] _versus_ 2 [8%]), and vomiting (8 [17%] _versus_ none). Liver and kidney functions remained stable. There were no events of hepatic decompensation or deaths. In conclusion, semaglutide did not significantly improve fibrosis or lead to NASH resolution compared with placebo among patients with NASH and compensated cirrhosis (136). An ongoing phase 3 study of semaglutide in individuals with MASLD/metabolic dysfunction-associated steatohepatitis (MASH) is scheduled to be completed in 2028.

##### 4.5.12 Effects of semaglutide on quality of life

The quality of life of patients participating in clinical studies can be assessed using quality of life scores. In studies with semaglutide, the questionnaires used for this purpose were the SF-36 and IWQOL-Lite-CT. In the STEP studies, a significant improvement in quality of life was observed among patients using semaglutide when compared with placebo (123-127).

##### 4.5.13 Effects of semaglutide on osteoarticular diseases

The STEP 9 RCT included individuals with obesity and a clinical diagnosis of knee osteoarthritis with radiological findings and pain (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC] pain subscale score ≥ 40). The individuals were randomized to semaglutide 2.4 mg (n = 271) or placebo (n = 136) and were followed for 68 weeks. In addition to weight loss, patients randomized to semaglutide experienced significantly greater reduction in the pain scale (-41.7 points) compared with those randomized to placebo (-25.5 points; difference -14.1 points; p < 0.001), along with improvement in the subscale assessing physical function and reduced use of analgesics (137).

##### 4.5.14 Effects of semaglutide in patients with chronic kidney disease

In a real-world study of 122 patients with obesity and T2DM, treatment with semaglutide resulted in weight loss, reduced blood glucose levels, and a 50% decrease in albuminuria, with no impact on eGFR. The treatment withdrawal rate due to side effects was 5.9%, which is similar to that observed in studies carried out with patients without CKD (138). In a _post hoc_ analysis of the STEP 1, 3, and 4 studies, the use of semaglutide also decreased albuminuria in patients with overweight or obesity and without diabetes, with no effects on eGFR (139).

A prespecified analysis of the SELECT study (described in item 4.5.15, “Effects of semaglutide on cardiovascular risk protection”) evaluated the effects of semaglutide on renal outcomes. The outcomes assessed included death from renal causes, initiation of dialysis therapy or renal transplantation, development of eGFR < 15 mL/min/1.73 m2, persistent reduction of over 50% in eGFR compared with baseline, and development of persistent macroalbuminuria. Patients randomized to semaglutide had a 22% reduction in this composite outcome (HR = 0.78; p = 0.02), with the endpoints determined primarily by persistent ≥ 50% reduction of eGFR and the onset of macroalbuminuria. Treatment with semaglutide also led to a smaller absolute reduction in eGFR compared with placebo (-0.86 mL/min/1.73 m2 _versus_ -1.61 mL/min/1.73 m2, respectively) after 104 weeks and had an effect on reducing albuminuria (140).

Finally, the results of the FLOW study, which evaluated the effects of semaglutide 1.0 mg in patients with T2DM and CKD, have been published. The outcomes were similar to those previously described in the SELECT study, with cardiovascular death also included as a primary outcome. The study was interrupted prematurely due to efficacy, with the semaglutide 1.0 mg group demonstrating a 24% reduction in the primary outcome (141).

##### 4.5.15 Effects of semaglutide on cardiovascular risk protection

The cardiovascular safety of semaglutide was investigated in patients with T2DM and high cardiovascular risk in the SUSTAIN-6 study, with 3,297 patients randomized to weekly subcutaneous semaglutide 0.5 mg or 1.0 mg or placebo, for 104 weeks. The primary composite outcome of cardiovascular death, nonfatal AMI, or nonfatal stroke occurred in 108 of 1,648 patients (6.6%) in the semaglutide group and in 146 of 1,649 patients (8.9%) in the placebo group (odds ratio [OR] = 0.74; 95% CI, 0.58-0.95; p < 0.001 for noninferiority) (142).

The results of the SELECT study, the first study to demonstrate the cardiovascular benefit of a medication in individuals with obesity without diabetes, were published in 2023. In this multicenter, double-blind RCT designed to assess superiority, more than 17,000 patients with BMI ≥ 27 kg/m2 and CVD were randomized to receive weekly 2.4 mg of subcutaneous semaglutide or placebo. During a median follow-up of 39.8 months, a primary event (cardiovascular death, nonfatal AMI, or nonfatal stroke) occurred in 569 of 8,803 patients (6.5%) in the semaglutide group and in 701 of 8,801 patients (8.0%) in the placebo group (OR = 0.80; 95% CI, 0.72-0.90; p < 0.001). The study concluded that semaglutide 2.4 mg was superior to placebo, leading to a 20% reduction in the incidence of cardiovascular events in patients with overweight or obesity and established CVD (143).

Another landmark study was the STEP-HFpEF, the first study evaluating the effects of a GLP-1a in patients with HF with preserved ejection fraction (HFpEF). The RCT evaluated the impact of 52 weeks of treatment with semaglutide 2.4 mg in 529 patients with HFpEF and obesity. The primary outcomes were symptom improvement (assessed using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score [KCCQ-CSS]) and body weight reduction. Secondary outcomes included changes in the 6-minute walk distance and reductions in high-sensitivity C-reactive protein (CRP), among others. Patients randomized to semaglutide had a significant reduction in KCCQ-CSS scores relative to placebo (-16.6 points _versus_ -8.7 points, respectively), significant body weight loss (-13.3% _versus_ -2.6%, respectively), and reduction in secondary outcomes (including a reduction in high-sensitivity CRP). In patients with obesity and HFpEF, treatment with semaglutide led to improvement in symptoms, physical limitations, and exercise capacity (144).

### 5\. NALTREXONE AND BUPROPION

#### 5.1 Mechanism of action

Bupropion is a dopamine and norepinephrine reuptake inhibitor recommended for the treatment of depression and smoking cessation. It has an anorectic effect, related to the stimulation of pro-opiomelanocortin (POMC) neurons located in the arcuate nucleus (ARC) of the hypothalamus. These neurons release alpha-melanocyte-stimulating hormone (α-MSH), which acts on MC4R, decreasing food intake and increasing energy expenditure. Despite the demonstration of this effect in animal models, clinical studies have shown a modest weight-reducing effect of bupropion monotherapy, causing it not to meet the criteria for approval as a monotherapy for obesity (145).

Naltrexone is an opioid receptor antagonist used primarily in the treatment of alcohol and opioid dependence. It is metabolized by the hepatic enzyme dihydrodiol dehydrogenase into its active metabolite 6β-naltrexol. Both naltrexone and 6β-naltrexol are competitive antagonists at μ- and κ-opioid receptors in the central nervous system (CNS). In POMC neurons, β-endorphin release exerts negative feedback by binding to μ-opioid receptors on the POMC neuron itself, decreasing α-MSH release activity. Although studies with naloxone (another opioid antagonist) have shown reduced food intake in rats, studies with naltrexone have been disappointing, as it led to minimal or no weight loss as a monotherapy (145).

The idea of associating an opioid receptor antagonist to block the autoinhibitory feedback in POMC neurons of the ARC emerged as a good strategy to enhance the anorectic effect of bupropion. This led to the development of the fixed-dose combination of naltrexone and bupropion. The fixed-dose combination of naltrexone 8 mg and bupropion 90 mg (Contrave®) has a synergistic effect (145).

#### 5.2 Dosage/usage instructions

The dosage of the N/B combination should be titrated weekly. The starting dose is one tablet in the morning for 7 days, followed by a progressive increase to one tablet every 12 hours in the second week, two tablets in the morning and one tablet at night in the third week, and two tablets every 12 hours from the fourth week onward. Tablets should not be broken, chewed, or crushed, and total daily doses exceeding 32 mg/360 mg per day are not recommended. The tablet can be administered with meals but should not be taken with high-fat meals due to a significant increase in systemic exposure to bupropion and naltrexone (146).

#### 5.3 Tolerability and side effects

The most common adverse events, affecting over 4% of the individuals who used this medication, were nausea (32.5%), constipation (19.2%), vomiting (17.6%), and headache (10.7%), as well as dizziness, insomnia, xerostomia, diarrhea, anxiety, hot flushes, fatigue, and tremor (146).

A meta-analysis evaluating study discontinuation due to adverse effects of antiobesity agents included four studies assessing the N/B combination. Out of 2,044 participants in the N/B group, 501 had adverse events compared with 175 of 1,319 in the placebo group (OR = 2.6) (147). [Table 2]() describes the SAEs and discontinuation rates observed in the phase 3 studies. The most frequent adverse reactions leading to discontinuation were nausea (6.3%), headache (1.7%), and vomiting (1.1%).

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****Table 2****  
Description of severe adverse events and discontinuation rates in phase 3 studies of the naltrexone/bupropion combination   


#### 5.4 Absolute contraindications

The combination of N/B is contraindicated in the following clinical conditions: uncontrolled hypertension, epilepsy or history of seizures, severe hepatic impairment, grade 5 CKD, presence of CNS tumor, history of bipolar disorder, bulimia or anorexia nervosa (increased risk of seizures), chronic use of opioid or opiate agonists or partial agonists or acute withdrawal of opiates, abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs, concomitant administration of monoamine oxidase inhibitors (MAOIs; a gap of at least 14 days must be given between discontinuation of MAOI and treatment initiation), and known allergy to bupropion or naltrexone (146).

The N/B combination should be suspended 24-72 hours before small- and medium-size surgeries and 72 hours before major surgeries or procedures requiring intensive pain management with opioids to eliminate the antagonistic effect of the medication on opioid analgesia, while bupropion should be continued. It is recommended to reintroduce N/B 7 days after cessation of opioids in the postoperative period.

#### 5.5 Efficacy

##### 5.5.1 Efficacy of bupropion/naltrexone on body weight

The weight loss and categorical weight loss percentages of 5% and 10% found in the main studies are summarized in [Table 3](). The clinical development program for the N/B combination was named Contrave Obesity Research (COR) and involved two phase 2 studies and four phase 3 studies: COR-I (148), COR-II (149), COR-BMOD (Behavior Modification) (150), and COR-Diabetes (151).

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****Table 3****  
Main studies evaluating the naltrexone/bupropion combination in obesity treatment   


##### 5.5.2 Effects on body composition

In a 24-week phase 2 study comparing placebo, naltrexone monotherapy, bupropion monotherapy, and one of three N/B dose combinations for efficacy and safety, a subgroup underwent body composition analysis using DXA and computed tomography. Eighty participants completed this subgroup analysis. The N/B combination resulted in weight loss and greater reduction in body fat (-14.0 ± 1.3%) than placebo (-4.0 ± 2.0%), naltrexone monotherapy (-3.2 ± 2.5%), and bupropion monotherapy (-4.1 ± 2.9%; all p < 0.01). The reduction in visceral adipose tissue mass was also greater with N/B (-15.0 ± 1.8%) than with placebo (-4.6 ± 2.7%), naltrexone monotherapy (-0.1 ± 3.5%), and bupropion monotherapy (-2.3 ± 4.2%; all p < 0.01). The reductions in body fat and visceral adipose tissue mass with N/B were proportional to weight loss, and weight loss with N/B was not associated with a greater relative reduction in lean mass than placebo or monotherapies (154).

##### 5.5.3 Effects on glycemic control in patients with type 2 diabetes mellitus

The COR-Diabetes study evaluated patients with T2DM who did not achieve the glycemic goal of HbA1c level < 7% with oral antidiabetic agents or with diet and exercise alone. In the entire population of these four studies, 24% of participants had hypertension and 54% had dyslipidemia at baseline (151). [Table 4]() presents the main results of the COR-Diabetes study.

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****Table 4****  
Variation in glycemic parameters in patients with type 2 diabetes mellitus treated with the naltrexone/bupropion combination in the COR-Diabetes study   


##### 5.5.4 Effects of bupropion/naltrexone in patients with prediabetes/glucose intolerance

The effects of the N/B combination in patients with prediabetes/glucose intolerance have not been evaluated.

##### 5.5.5 Effects of bupropion/naltrexone on lipid metabolism

In the COR-Diabetes (151) study, which evaluated patients with T2DM outside the HbA1c target, 54% had dyslipidemia at baseline. Compared with placebo, participants treated with N/B had a mean reduction of 11.2% in triglycerides (_versus a_ reduction of 0.8% in the placebo group) and an increase of 3.0 ± 0.5 mg/dL in HDL-c (_versus a_ reduction of 0.3 ± 0.6 mg/dL in the placebo group), with no significant effect on LDL-c. The magnitude of these variations in the COR-I (148) and COR-BMOD (150) studies was similar.

##### 5.5.6 Effects of bupropion/naltrexone on blood pressure and heart rate

The N/B combination may elevate SBP and/or DBP values and increase resting heart rate. Both BP and pulse should be measured prior to therapy initiation with the N/B combination and monitored at regular intervals consistent with usual clinical practice, particularly in patients with controlled hypertension prior to treatment. The N/B combination should not be administered to patients with uncontrolled hypertension. Among patients treated with the N/B combination in placebo-controlled clinical studies, mean SBP and DBP values were approximately 1 mmHg above those at baseline at weeks 4 and 8, similar to those at baseline at week 12, and approximately 1 mmHg below those at baseline between weeks 24 and 56. In contrast, among patients treated with placebo, the mean BP value was approximately 2-3 mmHg below the baseline value across the same time points, yielding statistically significant differences between groups at all assessments during this period. The largest mean differences between the groups were observed in the first 12 weeks (treatment difference +1.8 to +2.4 mmHg for SBP; +1.7 to +2.1 mmHg for DBP) (148-153).

##### 5.5.7 Effects on obstructive sleep apnea syndrome

The effects of the N/B combination in patients with OSAS have not been evaluated.

##### 5.5.8 Effects of bupropion/naltrexone in patients with polycystic ovary syndrome

The effects of the N/B combination in women with PCOS have not been evaluated.

##### 5.5.9 Effects of bupropion/naltrexone in patients with male hypogonadism

The effects of the N/B combination in men with hypogonadism have not been evaluated.

##### 5.5.10 Effects of bupropion/naltrexone on metabolic dysfunction-associated steatotic liver disease

There are limited data on the effects of the N/B combination in patients with MASLD. In a _post hoc_ analysis of four RCTs, the N/B combination for 1 year resulted in an improvement in fibrosis-4 index (FIB-4; a noninvasive index of liver fibrosis) independent of potential confounders, including weight change. The effect of N/B intervention was independently associated with a decrease in ALT (155).

##### 5.5.11 Effects of bupropion/naltrexone on quality of life

The N/B combination was evaluated in a multicenter, randomized, controlled, open-label study examining weight-related quality of life, control over eating behavior, and sexual function after 26 weeks of treatment plus a comprehensive LSC program (N/B + LSC, n = 153) or usual care (UC, n = 89), which included minimal lifestyle intervention.

Participants in the N/B + LSC group and UC group lost, respectively, 9.46% and 0.94% of their initial body weight at week 26 (p < 0.0001). The participants in the N/B + LSC group had greater improvement in the total IWQOL score compared with those in the UC group (p < 0.0001). Among participants with moderate/severe scores on the binge eating scale, 91% of N/B + LSC participants _versus_ 18% of UC participants experienced improvement. In participants with sexual dysfunction defined by the Arizona Sexual Experiences Scale, 58% of N/B + LSC participants and 19% of UC participants no longer met the criteria for dysfunction at week 26 (156).

##### 5.5.12 Effects of bupropion/naltrexone on osteoarticular diseases

The effects of the N/B combination in patients with osteoarthritis or other osteoarticular diseases have not been evaluated.

##### 5.5.13 Effects of bupropion/naltrexone in patients with renal disease

The effects of the N/B combination in patients with renal disease have not been evaluated.

##### 5.5.14 Effects of bupropion/naltrexone on cardiovascular diseases

The LIGHT study was designed to determine the cardiovascular safety of N/B compared with placebo in patients with overweight or obesity. The trial enrolled 8,910 patients with overweight or obesity who had increased cardiovascular risk, but after public disclosure by the sponsor of confidential interim data during the trial, the study’s academic leadership recommended termination of the trial, which was agreed by the sponsor. Male participants were older than 45 years and female participants were older than 50 years, and the mean age was 61.0 ± 7.3 years. For the 25% interim analysis, cardiovascular outcomes occurred in 59 patients treated with placebo (1.3%) and in 35 patients treated with N/B (0.8%; HR = 0.59). After 50% of planned events, cardiovascular outcomes occurred in 102 patients (2.3%) in the placebo group and in 90 patients (2.0%) in the N/B group (157).

### 6\. TIRZEPATIDE

At the time this document was prepared, tirzepatide was only approved in Brazil for the treatment of patients with T2DM (September 2023). However, it has already been approved in Europe (April 2024) and in the United States (November 2023) for the treatment of obesity. The application for approval has already been submitted to Anvisa, and the authors of the present document believe that approval in Brazil should be obtained in the near future. Until approval is granted, the use of tirzepatide for the treatment of obesity in Brazil will be considered off-label.

#### 6.1 Mechanism of action

Tirzepatide, the first medication in the incretin class with a dual mechanism of action, is a synthetic peptide with dual agonism action on GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors. Notably, GIP is a peptide secreted by K cells in the duodenum and jejunum in response to nutrient intake. It regulates energy balance through cell surface receptor signaling in CNS cells and adipose tissue (158).

Engineered from the native GIP sequence, preclinical data show a proportionally higher affinity of tirzepatide for GIP receptors compared with GLP-1 receptors (1:5). The GIP receptor activation appears to act synergistically with GLP-1 receptor activation to yield a greater weight reduction in mice than that achieved with GLP-1 receptor monoagonism (158).

The exact molecular mechanisms involved in the therapeutic effects of tirzepatide on glycemic control and body weight are not yet fully understood. One hypothesis is that GLP-1 activity reduces glucose levels, facilitating the effects of GIP on resensitized beta cells. Tirzepatide also appears to act as a more potent coagonist compared with GLP-1, with little β-arrestin recruitment and receptor internalization, which could explain its superior activity in target cells (159).

#### 6.2 Dosage/usage instructions

The initial dose of tirzepatide to begin titration is 2.5 mg applied subcutaneously once weekly. After 4 weeks, the dose should be increased to 5 mg. Increases of 2.5 mg can be made every minimum period of 4 weeks, reaching a maximum once-weekly dose of 15 mg. Based on the pharmacokinetics of tirzepatide, no dose adjustment is recommended based on age, gender, or body weight or in patients with hepatic or renal impairment (including those with ESRD) (160).

#### 6.3 Tolerability/side effects

In the SURMOUNT-1 study, the most common adverse events were gastrointestinal in nature. Nausea was the most frequent side effect, observed in 24.6%-31% of patients, mainly during the dose titration period. Other reported effects were diarrhea and constipation (23% and 11.7%, respectively), all with mild-to-moderate severity, causing treatment discontinuation in a maximum of 7.1% of patients (161).

Tirzepatide, at doses of 5 to 15 mg, was well tolerated during the SURPASS program: SAEs were reported in 1%-8% of participants with diabetes (SURPASS 1-3) (162-164) and in 6%-17% of participants with more advanced diabetes (SURPASS 4-5) (165,166) – these SAE rates are similar to those reported in placebo and active comparator groups.

The incidence of gastrointestinal adverse events was similar between tirzepatide, semaglutide, and dulaglutide. Most adverse events were mild to moderate, dose-dependent, and occurred during dose escalation and subsequent reduction.

#### 6.4 Absolute contraindications

The use of tirzepatide is contraindicated during pregnancy and in patients with a personal history of chronic pancreatitis or a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B.

#### 6.5 Efficacy

##### 6.5.1 Efficacy of tirzepatide on body weight

The phase 3 SURMOUNT-1 RCT compared the response to weekly tirzepatide at doses of 5 mg, 10 mg, or 15 mg _versus_ placebo in 2,539 adults with obesity or BMI > 27 kg/m2associated with at least one weight-related complication, excluding diabetes. The follow-up duration was 72 weeks, including the 20-week dose-escalation period (161). In this study, the average initial weight was 104.8 kg, and BMI was 38 kg/m2. The mean reduction in body weight observed at week 72 with tirzepatide was 16.0% (16.8%-15.2%) with the 5 mg dose, 21.4% (22.2%-20.6%; which was equivalent to 22.2 kg body weight reduction) with the 10 mg dose, and 20.9% (21.9%-19.9% or 23.6 kg) with the 15 mg dose.

The SURMOUNT-2 RCT evaluated treatment with subcutaneous tirzepatide (10 mg or 15 mg) once weekly or placebo for 72 weeks in 1,514 adults with obesity and T2DM. The primary outcomes were the percent change in body weight from baseline and body weight reduction of 5% or more. At baseline, the mean body weight was 100.7 kg (standard deviation ± 21.1 kg), BMI was 36.1 kg/m2 (±6.6 kg/m2), and HbA1c level was 8.02% (±0.89%). The mean changes in body weight at week 72 with tirzepatide 10 mg and 15 mg were -12.8% (±0.6%) and -14.7% (±0.5%), respectively, and -3.2% (±0.5%) with placebo, resulting in estimated treatment differences _versus_ placebo of -9.6% (95% CI = -11.1 to -8.1%) with tirzepatide 10 mg and -11.6% (95% CI = -13.0 to -10.1%) with tirzepatide 15 mg (all p < 0.0001) (167).

The SURMOUNT-3 RCT evaluated the impact of tirzepatide in individuals with obesity who had an adequate response to treatment with intensive LSCs. It included 579 individuals with BMI > 30 kg/m2 or 27 kg/m2 (with at least one comorbidity associated with obesity) who achieved a minimum weight loss of 5% after 12 weeks of intensive LSCs. After randomization, patients receiving tirzepatide for 72 weeks had a mean weight change of -18.5% compared with -2.5% in the placebo group (168).

[Table 5]() highlights the categorical weight loss observed in the SURMOUNT series studies.

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****Table 5****  
Categorical weight loss with weekly tirzepatide 10 mg or 15 mg in the SURMOUNT series of studies, according to the percentage of weight lost   


##### 6.5.2 Effects of tirzepatide on weight maintenance

The effects of tirzepatide on weight maintenance were evaluated in the SURMOUNT-4 RCT. This study enrolled 783 participants in an initial 36-week open-label period who received tirzepatide 10 mg or 15 mg. At week 36, a total of 670 participants were randomized to continue treatment with tirzepatide (n = 335) or switch to placebo (n = 335) for an additional 52 weeks. In the initial 36-week period, participants (mean initial weight 107.3 kg) lost an average of 20.9% of their body weight. From weeks 36 to 88, participants who remained on tirzepatide had an average additional weight loss of 5.5%, while the group randomized to placebo gained an average of 14.0%. In conclusion, withdrawal of tirzepatide led to a substantial regain of lost weight, while the continuation of the medication not only maintained the weight lost but also led to an additional weight loss (169).

##### 6.5.3 Effects of tirzepatide on body composition

In the SURMOUNT-1 study, a subgroup of 160 participants underwent body composition analysis using DXA. The results showed greater fat mass reduction in the tirzepatide group compared with the placebo group (33.9% _versus_ 8.2%, respectively, difference -25.7%). Similarly, the ratio between total fat mass and lean mass reduced more in the tirzepatide group (from 0.93 to 0.70) than in the placebo group (from 0.95 to 0.88), from baseline to week 72 (161).

A plethysmography analysis was conducted to compare body composition changes in 45 individuals with T2DM treated with tirzepatide 15 mg/week, 44 treated with semaglutide 1 mg/week, and 28 treated with placebo. At week 28, the tirzepatide-treated group experienced greater fat mass reduction than the placebo group (9.6 kg [12.4 to 6.9 kg]; p < 0.001) and semaglutide group (3.8 kg; p < 0.002). Similarly, the reduction in FFM was greater in the tirzepatide group compared with the placebo group (1.5 kg; p < 0.001) and semaglutide group (0.8 kg; p < 0.018) (170).

##### 6.5.4 Effects of tirzepatide in patients with prediabetes/glucose intolerance

In the SURMOUNT-1 study, 95.3% of individuals with prediabetes at baseline reverted to normoglycemia with tirzepatide, compared with 61.9% in the placebo group (161). Treatment with tirzepatide significantly reduced the 10-year predicted risk of T2DM development compared with placebo in participants with obesity or overweight, independent from baseline glycemic status. This was the finding of a _post hoc_ analysis of the SURMOUNT-1 study, which used a cardiometabolic disease staging risk score to calculate the predicted 10-year risk of T2DM at baseline and at study weeks 24 and 72. At week 72, the mean absolute predicted risk score reductions for T2DM were significantly greater in the tirzepatide groups (5 mg, 12.4%; 10 mg, 14.4%; 15 mg, 14.7%) compared with the placebo group (0.7%). Participants with prediabetes had greater mean reductions in risk score from baseline (16.0%-20.3%) compared with those without prediabetes (10.1%-11.3%) (171).

##### 6.5.5 Effects of tirzepatide in patients with type 2 diabetes mellitus

A recent meta-analysis evaluated 6,609 individuals with T2DM included in seven RCTs lasting at least 12 weeks to analyze the efficacy of different tirzepatide doses (5 mg, 10 mg, and 15 mg) in reducing HbA1c levels compared with other antidiabetic agents or placebo. Tirzepatide was superior in reducing HbA1c levels in a dose-dependent manner, with mean differences ranging from -1.62% to -2.06% _versus_ placebo, -0.29% to -0.92% _versus_ GLP-1as, and -0.70% to -1.09% _versus_ basal insulin regimens (172).

The SURPASS-2 study included 1,876 patients with T2DM and compared tirzepatide 5 mg, 10 mg, and 15 mg _versus_ semaglutide 1 mg in a 1:1:1:1 design for 40 weeks, with the primary outcome of reduction in HbA1c level. The mean reductions in HbA1c levels were 2.01%, 2.24%, and 2.30% with tirzepatide 5 mg, 10 mg, and 15 mg, respectively, and 1.86% with semaglutide 1.0 mg. The baseline mean HbA1c level was 8.28%. After 40 weeks, almost half of the patients who received tirzepatide 10 mg and 15 mg (40% and 46%, respectively) had HbA1c levels ≤ 5.7%. This was observed in 27% of the patients who received tirzepatide 5 mg and in 19% of those who received semaglutide 1 mg (163).

##### 6.5.6 Effects of tirzepatide on lipid metabolism

In the SURPASS 1 to 5 study programs, treatment with tirzepatide at doses of 5 mg, 10 mg, and 15 mg resulted in reductions in serum triglyceride and LDL-c levels (162-166,173).

##### 6.5.7 Effects of tirzepatide on blood pressure and heart rate

In the SURPASS 1 to 5 program studies, tirzepatide treatment of patients with T2DM resulted in mean reductions in SBP and DBP values of 6-9 mmHg and 3-4 mmHg, respectively. There was a mean reduction in SBP and DBP of 2 mmHg each in patients treated with placebo. In placebo-controlled phase 3 studies, treatment with tirzepatide resulted in a mean heart rate increase of 2-4 bpm compared with a mean heart rate increase of 1 bpm with placebo (162-166). In the SURMOUNT-1 study, individuals with obesity/overweight without diabetes had mean reductions of 7.2 mmHg in SBP and 4.8 mmHg in DBP with tirzepatide compared with mean reductions of 1 mmHg and 0.8 mmHg, respectively, with placebo (161).

##### 6.5.8 Effects of tirzepatide on obstructive sleep apnea syndrome

A 52-week RCT (SURMOUNT-OSA) was conducted to evaluate the efficacy and safety of tirzepatide at the maximum tolerated dose (10 mg or 15 mg) _versus_ placebo as an adjunct to diet and exercise in participants with moderate-to-severe OSAS (AHI ≥ 15). Patients treated with tirzepatide (10 mg or 15 mg weekly) experienced an AHI reduction of 27.4 events/hour compared with 4.8 events/hour in those treated with placebo. As a secondary outcome, tirzepatide led to a mean AHI reduction of 55% compared with 5.0% with placebo. Finally, the mean weight loss was 18.1% in the tirzepatide group compared with 1.3% in the placebo group (174).

##### 6.5.9 Effects of tirzepatide in patients with polycystic ovary syndrome

Tirzepatide has not been evaluated for effects in women with PCOS.

##### 6.5.10 Effects of tirzepatide in patients with male hypogonadism

Tirzepatide has not been evaluated for effects in patients with male hypogonadism.

##### 6.5.11 Effects of tirzepatide on nonalcoholic fatty liver disease

A study used magnetic resonance imaging to evaluate the liver fat content, volume of visceral adipose tissue, and abdominal subcutaneous adipose tissue in 296 individuals with T2DM treated with tirzepatide or insulin degludec participating in the SURPASS-3 study. At week 52, the participants using tirzepatide (pooled tirzepatide 10 mg and 15 mg groups) experienced significantly greater mean reductions in liver fat content compared with those using insulin degludec (-8.1% _versus_ -3.4%), respectively, from a baseline liver fat content of 15.7% and 16.6%, respectively (175).

At 52 weeks, participants treated with tirzepatide 5 mg, 10 mg, and 15 mg had significantly greater reductions in volume of visceral adipose tissue (-1.10 L, -1.53 L, and -1.65 L, respectively) and abdominal subcutaneous adipose tissue (-1.40 L, -2.25 L, and -2.05 L, respectively) compared with their respective baseline values of 6.6 L and 10.4 L. These reductions contrasted with the increases observed in the insulin degludec-treated group (0.38 L and 0.63 L) (175). Overall, 67%-81% of tirzepatide-treated participants achieved at least a 30% reduction in liver fat content.

Another _post hoc_ analysis evaluated the effects of tirzepatide on MASLD and fibrosis biomarkers in patients with T2DM compared with dulaglutide and placebo for 26 weeks and showed that the higher dose of tirzepatide significantly decreased MASLD-related biomarkers and increased adiponectin in these patients (176).

A phase 2 RCT was conducted to evaluate the effects of tirzepatide treatment in individuals with biopsy-confirmed MASH and stage F2 or F3 fibrosis. The patients were randomized to placebo or tirzepatide 5 mg, 10 mg, or 15 mg (n = 190) and treated for 52 weeks, when the biopsy was then repeated. The percentage of patients who achieved the MASH improvement endpoint without fibrosis progression was 10% in the placebo group, 44% in the tirzepatide 5 mg group, 56% in the tirzepatide 10 mg group, and 62% in the tirzepatide 15 mg group. The percentage of patients who had improvement in at least one fibrosis stage (without worsening of MASH) was 30% in the placebo group, 55% in the tirzepatide 5 mg group, 51% in the tirzepatide 10 mg group, and 61% in the tirzepatide 15 mg group (177).

##### 6.5.12 Effects of tirzepatide on quality of life

An exploratory analysis of the phase 3 SURPASS J-mono study assessed treatment satisfaction using the Japanese translation of the Diabetes Treatment Satisfaction Questionnaire (DTSQs) and the DTSQc version. After 52 weeks of treatment, there was a trend toward greater satisfaction among patients who received any dose of tirzepatide compared with those who received dulaglutide. The overall mean DTSQc scores at week 52 were significantly higher with tirzepatide 5 mg, 10 mg, and 15 mg _versus_ dulaglutide 0.75 mg (11.5, 12.1, and 12.3, respectively, _versus_ 8.9; p < 0.001). _Post hoc_ subgroup analyses demonstrated greater treatment satisfaction with tirzepatide compared with dulaglutide in the subgroup with ages below 65 years (p < 0.001) and baseline BMI ≥ 25 kg/m2 (p < 0.01), along with similar treatment satisfaction across treatment arms in the subgroup with ages 65 years or above and with BMI < 25 kg/m2 (178).

##### 6.5.13 Effects of tirzepatide on osteoarticular diseases

Tirzepatide has not been evaluated for effects in osteoarticular diseases.

##### 6.5.14 Effects of tirzepatide in patients with chronic kidney disease

An exploratory _post hoc_ analysis of SURPASS-4 showed that tirzepatide reduced the decline in eGFR and decreased the urine albumin-to-creatinine ratio (UACR) compared with insulin glargine in individuals with T2DM and high cardiovascular risk. At baseline, participants had a mean eGFR of 81 mL/min/1.73 m2 and median UACR of 15 mg/g (17% of participants had eGFR < 60 mL/min/1.73 m2, 28% had microalbuminuria, and 8% had macroalbuminuria). The mean rate of eGFR decline was -1.4 mL/min/1.73 m2 per year for the combined tirzepatide treatment groups _versus_ -3.6 mL/min/1.73 m2 per year in the insulin group. The UACR increased from baseline with insulin glargine (36.9%) but not with tirzepatide (-6.8%), with a between-group frequency difference of -31.9%. Participants receiving tirzepatide had fewer occurrences of the composite renal outcome (time to first occurrence of eGFR decline of at least 40% from baseline, ESRD, death due to renal failure, or new-onset macroalbuminuria) compared with those receiving insulin glargine (HR = 0.58; 95% CI = 0.43-0.8). These findings were primarily driven by a reduced number of individuals developing new-onset macroalbuminuria (179).

##### 6.5.15 Effects of tirzepatide on cardiovascular diseases

A meta-analysis of cardiovascular outcomes included seven RCTs with at least 26 weeks of follow-up comparing the time to occurrence to the first prespecified major adverse cardiac event (MACE; including cardiovascular death, AMI, stroke, and hospitalization for unstable angina) between participants using combined doses of tirzepatide (n = 4,887) and controls (n = 2,328). One-third of the participants had established CVD. In all, 142 participants experienced at least one MACE event after treatment for just over 1 year. The HRs comparing tirzepatide _versus_ control were 0.80 (95% CI = 0.57-1.11) for MACE-4 (_i.e._ , the four major adverse cardiac events considered in the trial), 0.90 (95% CI = 0.50-1.61) for cardiovascular death, and 0.80 (95% CI = 0.51-1.25) for all-cause death (180). These results suggest that tirzepatide does not increase cardiovascular risk. However, the exact impact of tirzepatide on cardiovascular outcomes in individuals with T2DM and established CVD will be addressed in the SURPASS-CVOT trial, an ongoing study evaluating the noninferiority and superiority of tirzepatide _versus_ dulaglutide 1.5 mg for cardiovascular safety in individuals with T2DM and atherosclerosis confirmed by prior CVD (ClinicalTrials.gov Identifier: NCT04255433).

[Table 6]() presents the effects of the different medications approved for treating obesity in Brazil after an average treatment period of 1 year. Differences in methodology and statistical analysis among the studies hinder a direct comparison between the medications.

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****Table 6****  
Efficacy of 1-year treatment of individuals with obesity using medications approved for treating obesity in Brazil   


In conclusion, historically, pharmacological treatments for obesity have been underutilized, with very few drug options available for a long time. Fortunately, this landscape is changing rapidly. In recent years, several new drugs with varying mechanisms of action, efficacy, and safety profiles (see [Table 7]() for summary) have emerged in Brazil. This document aims to provide a comprehensive literature review of the available pharmacological options with out establishing a definitive guideline, which is expected to be published in the near future. The goal is to familiarize healthcare providers with these options, whether they prescribe them as medical doctors or simply receive patients in use (who could need guidance) or refer them to treatment. We hope this document can serve as an useful guide and also a tool to reduce stigma surrounding obesity pharmacology.

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****Table 7****  
Most common and specific side effects of the anti obesity pharmacologic agents   


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### Acknowledgements

none.

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  * Funding:

expenses with English translation were covered by both societies equally.




### Publication Dates

  * **Publication in this collection**  
16 Dec 2024
  * **Date of issue**  
2024



### History

  * **Received**  
21 Oct 2024
  * **Accepted**  
28 Oct 2024



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##### Authorship

**Rodrigo O. Moreira**  


Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, BrasilInstituto Estadual de Diabetes e Endocrinologia Luis CapriglioneBrasilRio de Janeiro, RJ, Brasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil[]()

Centro Universitário Presidente Antonio Carlos – Campus Juiz de Fora, Juiz de Fora, MG, BrasilCentro Universitário Presidente Antonio CarlosBrasilJuiz de Fora, MG, Brasil Centro Universitário Presidente Antonio Carlos – Campus Juiz de Fora, Juiz de Fora, MG, Brasil[]()

Centro Universitário de Valença, Valença, RJ, BrasilCentro Universitário de ValençaBrasilValença, RJ, Brasil Centro Universitário de Valença, Valença, RJ, Brasil[]()

  * <https://orcid.org/0000-0003-1561-2926>



**Cynthia M. Valerio**  


Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, BrasilInstituto Estadual de Diabetes e Endocrinologia Luis CapriglioneBrasilRio de Janeiro, RJ, Brasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil[]()

  * <https://orcid.org/0000-0003-2292-1735>



**Alexandre Hohl**  


Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, BrasilUniversidade Federal de Santa CatarinaBrasilFlorianópolis, SC, Brasil Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil[]()

  * <https://orcid.org/0000-0002-8073-5837>



**Cristiane Moulin**  


Centro Especializado em Diabetes, Obesidade e Hipertensão, Secretaria de Saúde do Distrito Federal, Brasília, DF, BrasilSecretaria de Saúde do Distrito FederalBrasilBrasília, DF, Brasil Centro Especializado em Diabetes, Obesidade e Hipertensão, Secretaria de Saúde do Distrito Federal, Brasília, DF, Brasil[]()

  * <https://orcid.org/0009-0006-7213-2418>



**Fábio Moura**  


Universidade de Pernambuco, Recife, PE, BrasilUniversidade de PernambucoBrasilRecife, PE, Brasil Universidade de Pernambuco, Recife, PE, Brasil[]()

Instituto de Medicina Integrada de Pernambuco, Recife, PE, BrasilInstituto de Medicina Integrada de PernambucoBrasilRecife, PE, Brasil Instituto de Medicina Integrada de Pernambuco, Recife, PE, Brasil[]()

  * <https://orcid.org/0000-0001-6721-6437>



**Fábio R. Trujilho**  


Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, BrasilCentro de Diabetes e Endocrinologia da BahiaBrasilSalvador, BA, Brasil Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, Brasil[]()

  * <https://orcid.org/0009-0000-1987-8348>



**Fernando Gerchman**  


Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrasilUniversidade Federal do Rio Grande do SulBrasilPorto Alegre, RS, Brasil Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil[]()

Serviço de Endocrinologia e Metabolismo, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, BrasilHospital de Clínicas de Porto AlegreBrasilPorto Alegre, RS, Brasil Serviço de Endocrinologia e Metabolismo, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil[]()

  * <https://orcid.org/0000-0001-5873-9498>



**Livia L. Correa**  


Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, BrasilInstituto Estadual de Diabetes e Endocrinologia Luis CapriglioneBrasilRio de Janeiro, RJ, Brasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil[]()

  * <https://orcid.org/0000-0003-4656-4381>



**Marcio C. Mancini**  


Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrasilUniversidade de São PauloBrasilSão Paulo, SP, Brasil Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil[]()

  * <https://orcid.org/0000-0003-1278-0406>



**Maria Edna Melo**  


Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrasilUniversidade de São PauloBrasilSão Paulo, SP, Brasil Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil[]()

  * <https://orcid.org/0000-0002-1216-7532>



**Rodrigo N. Lamounier**  


Departamento de Clínica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrasilUniversidade Federal de Minas GeraisBrasilBelo Horizonte, MG, Brasil Departamento de Clínica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil[]()

Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, BrasilHospital Mater DeiBrasilBelo Horizonte, MG, Brasil Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, Brasil[]()

  * <https://orcid.org/0000-0001-7432-9085>



**Simone van de Sande-Lee**  


Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, BrasilUniversidade Federal de Santa CatarinaBrasilFlorianópolis, SC, Brasil Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil[]()

  * <https://orcid.org/0000-0002-5592-1603>



**Thaísa D. G. Trujilho**  


Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, BrasilCentro de Diabetes e Endocrinologia da BahiaBrasilSalvador, BA, Brasil Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, Brasil[]()

  * <https://orcid.org/0000-0001-5162-1905>



**Paulo A. C. Miranda**  


Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, BrasilHospital Mater DeiBrasilBelo Horizonte, MG, Brasil Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, Brasil[]()

Serviço de Endocrinologia e Metabolismo, Santa Casa da Misericórdia de Belo Horizonte, Belo Horizonte, MG, BrasilSanta Casa da Misericórdia de Belo HorizonteBrasilBelo Horizonte, MG, Brasil Serviço de Endocrinologia e Metabolismo, Santa Casa da Misericórdia de Belo Horizonte, Belo Horizonte, MG, Brasil[]()

  * <https://orcid.org/0000-0001-5433-3386>



**Bruno Halpern**  


Centro de Obesidade, Hospital Nove de Julho, São Paulo, SP, BrasilHospital Nove de JulhoBrasilSão Paulo, SP, Brasil Centro de Obesidade, Hospital Nove de Julho, São Paulo, SP, Brasil[]()

  * <https://orcid.org/0000-0003-0973-5065>



**Correspondence to:** Bruno Halpern [brunohalpern@hotmail.com](mailto:brunohalpern@hotmail.com)

**Disclosures:**

ROM – Bayer, AstraZeneca, Servier, Sanofi-Aventis, Merck, Novo Nordisk, PTC Therapeutics, Eurofarma. CMV: Novo Nordisk, PTC Therapeutics, AMRYT Pharma, Libbs, Merck, AstraZeneca. CMV – Boehringer-Ingelheim, Ely Lilly, Novo Nordisk, Merck, Chiesi, PTC. AH – Bayer, BracePharma, Boehringer-Ingelheim, SEM, Eurofarma, Eli Lilly, Mantecorp, Merck, Novo Nordisk, PTC, Servier Supera, Takeda. CM – Merck, Novo Nordisk. FM – AstraZeneca, Boehringer-Ingelheim, Eli Lilly, Libbs, Novo Nordisk. FRT – Aché, Astra Zeneca, Boehringer Ingelheim, BracePharma, Eli Lilly, SEM, Eurofarma, Johson & Johnson, Merck, Myralis, Novo Nordisk, ScitechMedical, Servier, Takeda. FG – Merck, Novo Nordisk, Eli Lilly, Amryt, Abbott, PTC Therapeutics, Capes, CNPq, FIPE-HCPA. LLC – Novo Nordisk, Eli Lilly, Merck, Nestlé Health Sciences. MCM – Merck, Novo Nordisk, EMS, BracePharma, Eli Lilly. MEM – Novo Nordisk, Merck, BracePharma. RNL – Abbott, Astra Zeneca, Eli Lilly, EMS, Merck, Medtronic, Novo Nordisk. SSL – Abbott, Merck, Novo Nordisk, Eli Lilly. TDGT – Merck, Novo Nordisk, Eli Lilly, Eurofarma, Nestlé Health Sciences. PACM – IPSEN, Eli Lillym Aché, Novo Nordisk, Merck. BH – Abbott Nutrition, Astra Zeneca, Boehringer Ingelheim, Currax, Eli Lilly, Eurofarma, Johnson e Johnson, Merck, Novo Nordisk.

#####  SCIMAGO INSTITUTIONS RANKINGS 

Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, BrasilInstituto Estadual de Diabetes e Endocrinologia Luis CapriglioneBrasilRio de Janeiro, RJ, Brasil Instituto Estadual de Diabetes e Endocrinologia Luis Capriglione, Rio de Janeiro, RJ, Brasil[]()  


Centro Universitário Presidente Antonio Carlos – Campus Juiz de Fora, Juiz de Fora, MG, BrasilCentro Universitário Presidente Antonio CarlosBrasilJuiz de Fora, MG, Brasil Centro Universitário Presidente Antonio Carlos – Campus Juiz de Fora, Juiz de Fora, MG, Brasil[]()  


Centro Universitário de Valença, Valença, RJ, BrasilCentro Universitário de ValençaBrasilValença, RJ, Brasil Centro Universitário de Valença, Valença, RJ, Brasil[]()  


Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, BrasilUniversidade Federal de Santa CatarinaBrasilFlorianópolis, SC, Brasil Departamento de Clínica Médica, Universidade Federal de Santa Catarina, Florianópolis, SC, Brasil[]()  


Centro Especializado em Diabetes, Obesidade e Hipertensão, Secretaria de Saúde do Distrito Federal, Brasília, DF, BrasilSecretaria de Saúde do Distrito FederalBrasilBrasília, DF, Brasil Centro Especializado em Diabetes, Obesidade e Hipertensão, Secretaria de Saúde do Distrito Federal, Brasília, DF, Brasil[]()  


Universidade de Pernambuco, Recife, PE, BrasilUniversidade de PernambucoBrasilRecife, PE, Brasil Universidade de Pernambuco, Recife, PE, Brasil[]()  


Instituto de Medicina Integrada de Pernambuco, Recife, PE, BrasilInstituto de Medicina Integrada de PernambucoBrasilRecife, PE, Brasil Instituto de Medicina Integrada de Pernambuco, Recife, PE, Brasil[]()  


Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, BrasilCentro de Diabetes e Endocrinologia da BahiaBrasilSalvador, BA, Brasil Serviço de Obesidade e Lipodistrofia, Centro de Diabetes e Endocrinologia da Bahia, Salvador, BA, Brasil[]()  


Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, BrasilUniversidade Federal do Rio Grande do SulBrasilPorto Alegre, RS, Brasil Departamento de Clínica Médica, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brasil[]()  


Serviço de Endocrinologia e Metabolismo, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, BrasilHospital de Clínicas de Porto AlegreBrasilPorto Alegre, RS, Brasil Serviço de Endocrinologia e Metabolismo, Hospital de Clínicas de Porto Alegre, Porto Alegre, RS, Brasil[]()  


Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, BrasilUniversidade de São PauloBrasilSão Paulo, SP, Brasil Grupo de Obesidade, Disciplina de Endocrinologia e Metabolismo, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil[]()  


Departamento de Clínica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, BrasilUniversidade Federal de Minas GeraisBrasilBelo Horizonte, MG, Brasil Departamento de Clínica Médica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil[]()  


Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, BrasilHospital Mater DeiBrasilBelo Horizonte, MG, Brasil Serviço de Endocrinologia, Hospital Mater Dei, Belo Horizonte, MG, Brasil[]()  


Serviço de Endocrinologia e Metabolismo, Santa Casa da Misericórdia de Belo Horizonte, Belo Horizonte, MG, BrasilSanta Casa da Misericórdia de Belo HorizonteBrasilBelo Horizonte, MG, Brasil Serviço de Endocrinologia e Metabolismo, Santa Casa da Misericórdia de Belo Horizonte, Belo Horizonte, MG, Brasil[]()  


Centro de Obesidade, Hospital Nove de Julho, São Paulo, SP, BrasilHospital Nove de JulhoBrasilSão Paulo, SP, Brasil Centro de Obesidade, Hospital Nove de Julho, São Paulo, SP, Brasil[]()  


##### Tables

  * Tables (7) 



Thumbnail 

****Table 1****  
Categorical weight loss with weekly semaglutide 2.4 mg in the STEP series studies, divided according to the percentage of weight lost 

Thumbnail 

****Table 2****  
Description of severe adverse events and discontinuation rates in phase 3 studies of the naltrexone/bupropion combination 

Thumbnail 

****Table 3****  
Main studies evaluating the naltrexone/bupropion combination in obesity treatment 

Thumbnail 

****Table 4****  
Variation in glycemic parameters in patients with type 2 diabetes mellitus treated with the naltrexone/bupropion combination in the COR-Diabetes study 

Thumbnail 

****Table 5****  
Categorical weight loss with weekly tirzepatide 10 mg or 15 mg in the SURMOUNT series of studies, according to the percentage of weight lost 

Thumbnail 

****Table 6****  
Efficacy of 1-year treatment of individuals with obesity using medications approved for treating obesity in Brazil 

Thumbnail 

****Table 7****  
Most common and specific side effects of the anti obesity pharmacologic agents 

#####  table_chart****Table 1**** Categorical weight loss with weekly semaglutide 2.4 mg in the STEP series studies, divided according to the percentage of weight lost   


Study/duration | Population | Loss > 5% | Loss > 10% | Loss > 15% | Loss > 20%  
---|---|---|---|---|---  
STEP 1 (68 weeks) | Individuals with overweight or obesity and without T2DM | 86.4% | 69.1% | 50.5% | 34.8%  
STEP 2 (68 weeks) | Individuals with T2DM, with BMI > 27 kg/m2 and HbA1c between 7.0% and 10% | 73.2% | 49.9% | 28.2% | 14.2%  
STEP 3 (68 weeks) | Same as STEP 1, with more intense lifestyle changes | 86.6% | 75.3% | 55.8% | 35.7%  
STEP 4 (68 weeks) | Same as STEP 1, but evaluated the effects of interrupting __versus__ continuing medication (weight maintenance) | 88.7% | 79.0% | 63.7% | 39.6%  
STEP 5 (104 weeks) | Same as STEP 1, but longer study duration | 77.1% | 61.8% | 52.1% | 36.1%  
  
  * Prepared by the authors.




#####  table_chart****Table 2**** Description of severe adverse events and discontinuation rates in phase 3 studies of the naltrexone/bupropion combination   


Study | Incidence of SAE | Discontinuation rates  
---|---|---  
Intervention | Control | Intervention n/N | Control n/N  
COR-I (148) | SAE 1.6%: 1 fatal myocardial infarction and 1 heart failure (both considered not DR) | 1 pericardial effusion | 287/583 | 291/581  
COR-II (149) | SAE 2%: 1 myocardial infarction, 1 seizure | SAE 1.4% | 461/1,001 241 AE | 226/495 68 AE  
COR-BMOD (150) | Two cholecystitis (possibly DR), 0 suicidal ideations | 2 suicidal ideations, 0 cholecystitis | 249/591 | 84/202  
COR-DM (151) | NS 3.9% | NS 4.7% | 160/335 | 70/170  
  
  * AE: adverse event; SAE: severe adverse event; n/N: number of discontinuations/total number of study participants; NS: not specified; DR: drug-related.




#####  table_chart****Table 3**** Main studies evaluating the naltrexone/bupropion combination in obesity treatment   


Publication | Participant characteristics and publication | Weight loss subtracted from placebo | Weight loss ≥ 5% | Weight loss ≥ 10% | Weight loss ≥ 15%  
---|---|---|---|---|---  
Greenway and cols. (N = 238) (152) | BMI 30-40 kg/m2, 16 weeks | -3% | - | - | -  
Greenway and cols. (N = 419) (153) | BMI 30-40 kg/m2, 24 weeks (N/B 32/400 mg) | -4.65% | - | - | -  
COR-I (N = 1,742) (148) | BMI 30-40 kg/m2 without comorbidities or BMI 27-29.9 kg/m2 with dyslipidemia or hypertension, 56 weeks | -4.8% | 62% | 34% | 17%  
COR-BMOD (N = 793) (150) | BMI 30-40 kg/m2 without comorbidities or BMI 27-29.9 kg/m2 with dyslipidemia or hypertension, 56 weeks | -4.2% | 80.4% | 55.2% | 39.5%  
COR-II (N = 1,496) (149) | BMI 30-40 kg/m2 without comorbidities or BMI 27-29.9 kg/m2 with dyslipidemia or hypertension, 28 weeks | -4.6% | 64.9% | 39.4% | 18.9%  
COR-DM (N = 505) (151) | BMI 27-40 kg/m2 with T2DM, 56 weeks | -2.8% | 53.1% | 26.3% | NA  
  
  * * All studies used naltrexone/bupropion (N/B) 32/360 mg unless otherwise noted.

  * BMOD: Behavior Modification; COR: Contrave Obesity Research; BMI: body mass index; NA: not available in the publication.




#####  table_chart****Table 4**** Variation in glycemic parameters in patients with type 2 diabetes mellitus treated with the naltrexone/bupropion combination in the COR-Diabetes study   


| N/B combination (n = 265) | Placebo (n = 159) | N/B minus placebo (mean)  
---|---|---|---  
Baseline | Change from baseline (mean) | Baseline | Change from baseline (mean)  
HbA1c (%) | 8.0 | -0.6 | 8.0 | -0.1 | -0.5*  
Fasting blood glucose (mg/dL) | 160.0 | -11.9 | 163.9 | -4.0 | -7.9  
  
  * Based on the last observation carried forward (LOCF) during the COR-DM study.

  * * Statistically significant _versus_ placebo (p < 0.001).




#####  table_chart****Table 5**** Categorical weight loss with weekly tirzepatide 10 mg or 15 mg in the SURMOUNT series of studies, according to the percentage of weight lost   


Study/duration | Population | Loss > 5% | Loss > 10% | Loss > 15% | Loss > 20%  
---|---|---|---|---|---  
SURMOUNT-1 (72 weeks) (161) | Individuals with overweight or obesity and without T2DM | 90.9%* | 83.5%* | 70.6%* | 56.7%*  
SURMOUNT-2 (72 weeks) (167) | Individuals with T2DM, with BMI > 27 kg/m2 and HbA1c between 7.0% and 10% | 79/83%** | 61/65%** | 40/48%** | 22/31%**  
SURMOUNT-3 (72 weeks) (168) | Same as SURMOUNT-1; after 12 weeks, patients who achieved > 5% weight reduction with intensive lifestyle change were randomized to placebo or tirzepatide | 87.5% | 76.7% | 65.4% | 44.7%  
SURMOUNT-4 (36 weeks open-label + 52 weeks) (169) | Same as SURMOUNT-1; after 36 weeks, patients on tirzepatide 10 mg or 15 mg were randomized to placebo or tirzepatide | 97.3% | 92.1% | 84.1% | 69.5%  
  
  * * Tirzepatide 15 mg/week.

  * ** Tirzepatide 10 mg/15 mg.




#####  table_chart****Table 6**** Efficacy of 1-year treatment of individuals with obesity using medications approved for treating obesity in Brazil   


| Percentage achieving weight loss goals in 1 year with medication  
---|---  
Medication | Starting weight (kg) | 1 year* | >5% | >10% | >15% | >20% | >25%  
Sibutramine 10 mg (181) | - | -4.4 kg (SIB)/-1.6 kg (PLB)/NA | 39 | 7 | NA | NA | NA  
Sibutramine 15 mg (181) | - | -6.4 kg (SIB)/-1.6 kg (PLB)/NA | 57 | 34 | NA | NA | NA  
Orlistat 120 mg (42) | 99.1 (61.0-148.6) | -3.9 kg/NA% | 68.5 | 29.5 (loss between 10.1 and 20.0%) | 9.3 | NA  
Liraglutide 3.0 mg (52) | 106.2 ± 21.2 | -5.6 kg/-5.4% | 63.2 | 33.1 | 14.4 | NA | NA  
Semaglutide 2.4 mg (119) | 105.4 ± 22.1 | -12.7 kg/-12.4% | 86.4 | 69.1 | 50.5 | 32 | NA  
*Tirzepatide 10 mg (161) | 105.6 ± 22.92 | NA kg/-16.4% | 88.9 | 78.1 | 66.6 | 50.1 | 32.3  
*Tirzepatide 15 mg (161) | 105.6 ± 22.92 | NA kg/-17.8% | 90.9 | 83.5 | 70.6 | 56.7 | 36.2  
Naltrexone/bupropion (N/B) 32/360 mg (148) | 99.7 ± 15.9 | -8.1% (N/B)/-1.8% (PLB)** -8.0 kg (N/B)/-1.9 kg (PLB)*** | 62 | 34 | 17 | NA | NA  
  
  * Note: data are presented as mean ± standard deviation, except for orlistat, for which they are presented as median (minimum – maximum).

  * NA: information not available in the original publication; SIB: sibutramine; PLB: placebo.

  * * Difference in weight loss in the treatment group _versus_ the placebo group. ** Completers. *** Difference in weight loss in the treatment group _versus_ the placebo group not available in the article.




#####  table_chart****Table 7**** Most common and specific side effects of the anti obesity pharmacologic agents   


| More than 10% of patients | Specific side effects that deserve attention  
---|---|---  
Sibutramine 10-15 mg | Constipation, xerostomia, insomnia | Tachycardia/increased heart rate, increased blood pressure, headache, anxiety  
Orlistat 120 mg 3 x/day | Diarrhea/steatorrhea/urgency, flatulence, upper respiratory tract infections/flu, headache, hypoglycemia | Hypersensitivity reactions, long-term deficiency of fat-soluble vitamins  
Liraglutide 3.0 mg/day | Nausea and vomiting, diarrhea, constipation | Injection site reactions, increased heart rate, insomnia, cholelithiasis, asthenia and fatigue, hypoglycemia  
Semaglutide 2.4 mg/week | Nausea and vomiting, diarrhea, constipation, abdominal pain, headache, fatigue | Injection site reactions, increased heart rate, cholelithiasis, hypoglycemia  
*Tirzepatide 10 and 15 mg/week | Hypoglycemia (when used with sulfonylureas or insulin), nausea, diarrhea | Hypersensitivity reactions, increased heart rate, injection site reactions  
Naltrexone/Bupropion 360/32 mg/day | Nausea, constipation, headache, vomiting | Suicidal thoughts or actions, seizures, risk of opioid overdose, sudden opioid withdrawal, severe allergic reactions, increased blood pressure or heart rate, hepatitis, manic episodes, narrow-angle glaucoma, hypoglycemia (when used with sulfonylureas or insulin), serotonin syndrome  
  
  * *As of July 2024, tirzepatide was not yet approved to treat obesity in Brazil. Up to this date, the medication has been approved ONLY to treat type 2 diabetes mellitus.




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[Pharmacologic Treatment of Obesity in adults and its impact on comorbidities: 2024 Update and Position Statement of Specialists from the Brazilian Association for the Study of Obesity and Metabolic Syndrome (Abeso) and the Brazilian Society of Endocrinology and Metabolism (SBEM)](https://plu.mx/scielo/a/?doi=10.20945/2359-4292-2024-0422)

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