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Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern | Current Nutrition Reports
        

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# Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern

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Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern 

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  * Jeff S. Volek [ORCID: orcid.org/0000-0001-8702-0351](http://orcid.org/0000-0001-8702-0351)1, 
  * Madison L. Kackley [ORCID: orcid.org/0000-0001-5527-9529](http://orcid.org/0000-0001-5527-9529)1 &
  * Alex Buga [ORCID: orcid.org/0000-0001-8509-4330](http://orcid.org/0000-0001-8509-4330)1



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## Abstract

### Purpose of Review

Considering the high prevalence of obesity and related metabolic impairments in the population, the unique role nutrition has in weight loss, reversing metabolic disorders, and maintaining health cannot be overstated. Normal weight and well-being are compatible with varying dietary patterns, but for the last half century there has been a strong emphasis on low-fat, low-saturated fat, high-carbohydrate based approaches. Whereas low-fat dietary patterns can be effective for a subset of individuals, we now have a population where the vast majority of adults have excess adiposity and some degree of metabolic impairment. We are also entering a new era with greater access to bariatric surgery and approval of anti-obesity medications (glucagon-like peptide-1 analogues) that produce substantial weight loss for many people, but there are concerns about disproportionate loss of lean mass and nutritional deficiencies.

### Recent Findings

No matter the approach used to achieve major weight loss, careful attention to nutritional considerations is necessary. Here, we examine the recent findings regarding the importance of adequate protein to maintain lean mass, the rationale and evidence supporting low-carbohydrate and ketogenic dietary patterns, and the potential benefits of including exercise training in the context of major weight loss.

### Summary

While losing and sustaining weight loss has proven challenging, we are optimistic that application of emerging nutrition science, particularly personalized well-formulated low-carbohydrate dietary patterns that contain adequate protein (1.2 to 2.0 g per kilogram reference weight) and achieve the beneficial metabolic state of _euketonemia_ (circulating ketones 0.5 to 5 mM), is a promising path for many individuals with excess adiposity.

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## Introduction

### Purpose

The primary objective of this review is to highlight the fundamental importance of nutrition during caloric restriction for promoting healthy weight loss. When calories are significantly restricted to induce major weight loss – which often occurs after bariatric surgery or with use of very low-calorie diets and glucagon-like peptide-1 (GLP1) analogues – maintaining muscle mass and consuming nutrient dense foods to ensure adequate essential micronutrient intakes is a high priority. In this review we examine the scientific evidence addressing nutritional considerations in maintaining lean tissue, functionality, and health during significant weight loss. This includes a focus on the optimal quantity and quality of protein necessary to achieve nitrogen balance and maximize lean tissue and health. We also review the unique role of low-carbohydrate and ketogenic dietary patterns on lean tissue, visceral adipose tissue, and other health markers during weight loss, as well as the role of exercise, including resistance training.

### Scope of the Obesity Problem

The prevalence of obesity in the United States has more than tripled over the last half century and indicate that approximately 4 out of 10 adults are classified as obese (i.e., BMI ≥ 30 kg/m2) and an additional one-third are overweight (i.e., BMI 25 to < 30 kg/m2) [[1](/article/10.1007/s13668-024-00548-6#ref-CR1)]. Thus, about 3 out of 4 adults or more than 150 million people in the U.S. have a weight problem. Childhood obesity rates are increasing at an even greater rate. Given the close association between obesity and diabetes, it may not be surprising that half of U.S. adults (> 100 million people) are either prediabetic or diabetic [[2](/article/10.1007/s13668-024-00548-6#ref-CR2)] and only a very small percentage of Americans are in good metabolic health [[3](/article/10.1007/s13668-024-00548-6#ref-CR3)]. Besides the stigma, personal suffering, and reduced health span associated with obesity and diabetes, these conditions also inflict an extraordinary financial burden on our economy with over $400 billion spent annually on managing diabetes alone, which reflects one-fifth of all healthcare expenditures and is more than all cancers combined [[4](/article/10.1007/s13668-024-00548-6#ref-CR4)]. The obesity and diabetes epidemics are not isolated to the Unites States; it is a world-wide problem. Sadly, there are few signs of stemming the obesity crisis. By 2030 nearly 1 in 2 adults in the U.S. are projected to be obese [[5](/article/10.1007/s13668-024-00548-6#ref-CR5)]. On a more promising note, the results of clinical trials indicate that bariatric surgery [[6](/article/10.1007/s13668-024-00548-6#ref-CR6)], very low-carbohydrate ketogenic diets [[7](/article/10.1007/s13668-024-00548-6#ref-CR7), [8](/article/10.1007/s13668-024-00548-6#ref-CR8)], and the recently developed GLP1 receptor agonists [[9](/article/10.1007/s13668-024-00548-6#ref-CR9)] have the most potent ability to produce substantial weight loss, but all requite proper attention to diet formulation to be successful.

### Nutrition is Uniquely Different than Other Weight Loss Options

For many reasons, diet is a cornerstone for weight loss therapy. Notably, diet is the only intervention that is essential (i.e., it is not optional). People with excess adiposity can choose to not have invasive surgery, engage in exercise, or take medications. But they must consume a diet and make decisions every day on what type of foods to consume. Moreover, just about every other weight loss approach, including surgery and medications, are viewed as an adjunct to nutritional counseling focused on caloric restriction.

Another unique aspect of nutrition is that it can interfere with or augment outcomes of other weight loss strategies. For example, a poorly formulated diet (e.g., deficient in protein, minerals, or some other essential nutrient) may attenuate or cancel out any positive effects of exercise or anti-obesity medications on weight loss. On the other hand, a well-formulated nutrition plan may synergize with an exercise regimen, lessen side effects of surgery, or minimize dosage of anti-obesity medications to facilitate long-term weight loss and health benefits.

The substantial weight loss achieved from bariatric surgery or GLP-1 receptor agonists is often associated with significantly decreased energy intake, as is also the case with very low-calorie or semi-starvation diets (< 800 kcal/day) in the medical management of obesity [[10](/article/10.1007/s13668-024-00548-6#ref-CR10), [11](/article/10.1007/s13668-024-00548-6#ref-CR11)]. The greater the degree of caloric restriction and weight loss, the more likely nutritional deficiencies occur. The new gastrointestinal physiology that accompanies bariatric surgery, and the common gastrointestinal reactions associated with GLP1 receptor agonists, also increase the likelihood of inadequate essential nutrient intake [[12](/article/10.1007/s13668-024-00548-6#ref-CR12)].

There is also the issue of weight regain, which happens frequently with all weight loss approaches, especially if individuals discontinue GLP1 receptor agonist therapy [[13](/article/10.1007/s13668-024-00548-6#ref-CR13)••, [14](/article/10.1007/s13668-024-00548-6#ref-CR14)]. For all these reasons, nutrition must be viewed as the foundation of safe, effective, and sustainable weight loss and maintenance. Traditional weight loss strategies span from lifestyle behavioral and metabolic interventions (exercise training and diet interventions) to medical approaches that include surgery and pharmacotherapy, and various combination of these approaches. The evidence supporting these weight loss approaches is briefly reviewed next.

For this narrative review, we conducted a non-systematic literature search on PubMed and Google Scholar of articles spanning from their inception to March 2024. The Medical Search Header (MeSH) keywords used were “Glucagon-Like Peptide-1 Receptor Agonists”, “Weight Loss”, “Body Composition”, “Nitrogen Balance”, “Dietary Proteins”, “Diet, Carbohydrate-Restricted”, “Diet, Ketogenic”, “Diet, Fat-Restricted”, “3-Hydroxybutyric Acid.” These terms were combined using the Boolean operators OR and AND. Other sources were identified by manually examining and extracting the reference lists of related articles and reviews. All authors independently screened titles, abstracts, and full-text articles, with discrepancies resolved through internal collaboration.

## Relative Sucess of Different Weight Loss Approaches

### Bariatric Surgery

Bariatric surgery, which includes various invasive surgical procedures, has proven to be uniquely effective at promoting significant short-term and sustained (20-yr) weight loss [[6](/article/10.1007/s13668-024-00548-6#ref-CR6)]. According to one recent review, average weight loss at a single center at 1, 10, and 20-yr was 18, 20, and 22%, respectively [[15](/article/10.1007/s13668-024-00548-6#ref-CR15)]. There is also evidence that bariatric surgery improves obesity-related comorbidities including diabetes [[16](/article/10.1007/s13668-024-00548-6#ref-CR16)] and cardiovascular disease [[17](/article/10.1007/s13668-024-00548-6#ref-CR17)]. Bariatric surgery is generally safe, but reporting of side effects lacks rigorous quality. Early problems include leaks, stenosis, bleeding, GERD, and thromboembolic events, whereas late-complications include band erosion, obstruction, gallstone disease, Dumping syndrome, ischemia, anemia, calcium loss, kidney stones, and osteoporosis [[6](/article/10.1007/s13668-024-00548-6#ref-CR6)]. Bariatric surgery also has a substantial need for re-operative surgery [[15](/article/10.1007/s13668-024-00548-6#ref-CR15)], is expensive, and requires individuals have a BMI > 40 kg/m2 without accompanying disease or ≥ 35 kg/m2 with an accompanying disease. Thus, it is not an option for those with less severe forms of obesity.

### Pharmacotherapy

The history of drugs for obesity has mostly been marked by failure. There are only a few currently FDA-approved anti-obesity medications and – except for GLP1-analogues – they produce only moderate weight loss (< 10%) and have adverse side effect profiles [[18](/article/10.1007/s13668-024-00548-6#ref-CR18)]. In contradistinction, the recently FDA-approved GLP1 receptor agonists Semaglutide (Wegovy) and Tirzepatide (Zepbound) are associated with average weight loss similar to that of bariatric surgery (i.e., ~15 to 25%) [[9](/article/10.1007/s13668-024-00548-6#ref-CR9)] with fewer side effects and possibly many other benefits beyond obesity [[19](/article/10.1007/s13668-024-00548-6#ref-CR19)]. This degree of effectiveness represents a major advancement in the treatment of obesity, but it should be noted these drugs do not address the fundamental causes of obesity and they do require consumption of a properly formulated diet. If GLP1 receptor agonists are discontinued then weight regain occurs [[13](/article/10.1007/s13668-024-00548-6#ref-CR13)••, [14](/article/10.1007/s13668-024-00548-6#ref-CR14)], emphasizing the need for properly formulated nutrition plans, such as carbohydrate restricted diets, that can maintain weight loss after GLP1 use [[8](/article/10.1007/s13668-024-00548-6#ref-CR8)].

There is increasing anecdotal evidence that much of the weight loss with GLP1 receptor agonists may be derived from muscle mass, although direct evidence from most large trials do not include outcome measures of body composition to substantiate this concern. In a subset of obese participants (_n_ = 95) in the STEP 1 semaglutide trial who had dual-energy X-ray absorptiometry (DXA) scans performed pre- and 68-wk post intervention, total soft tissue loss was 13.6 kg and lean mass loss was 5.3 kg, or 39% of the weight loss [[13](/article/10.1007/s13668-024-00548-6#ref-CR13)••]. This represents a significant loss of muscle, some of which would be expected considering the magnitude of weight loss, but clearly there were people who lost disproportionate lean mass. Pharmaceutical companies are looking at druggable targets to address this concern, but a more relevant question is why is muscle loss happening and what non-drug measures can be taken to optimize preservation of lean tissue during major weight loss? In this regard nutrition and exercise can be force multipliers when employed appropriately.

### Diet and Exercise

Diet and exercise are considered first line approaches for weight management, but surprisingly the evidence supporting the role of exercise alone in weight loss is weak compared to other approaches [[20](/article/10.1007/s13668-024-00548-6#ref-CR20)], which often results in individual discouragement [[21](/article/10.1007/s13668-024-00548-6#ref-CR21)]. While frequent exercise training is associated with a wide range of health benefits, exercise interventions alone have a small role in weight loss [22,23,[24](/article/10.1007/s13668-024-00548-6#ref-CR24)]. This may seem paradoxical based on the clear increase in energy expenditure elicited by physical activity, but there are compensatory responses to exercise training that limit weight loss [[25](/article/10.1007/s13668-024-00548-6#ref-CR25)] such as increased caloric intake [[26](/article/10.1007/s13668-024-00548-6#ref-CR26), [27](/article/10.1007/s13668-024-00548-6#ref-CR27)] and/or decreased energy expenditure [[28](/article/10.1007/s13668-024-00548-6#ref-CR28), [29](/article/10.1007/s13668-024-00548-6#ref-CR29)]. There is also wide variability in how individuals translate exercise-induced energy deficits into weight loss [[30](/article/10.1007/s13668-024-00548-6#ref-CR30)], which is highly dependent on genetics [[31](/article/10.1007/s13668-024-00548-6#ref-CR31)]. Compared to endurance exercise, resistance training may offer unique benefits by increasing the proportion of fat loss while retaining lean tissue without altering total weight loss [[32](/article/10.1007/s13668-024-00548-6#ref-CR32)].

The role of diet in weight loss has a slightly better track record than exercise training, but there exists a high degree of nonconsensus related to the ideal macronutrient composition to promote healthy weight loss [[33](/article/10.1007/s13668-024-00548-6#ref-CR33)]. Most large-scale nutrition interventions for obesity have involved low-fat diets in line with the major tenets of the Dietary Guidelines for Americans and major professional medical organizations for the last four decades. The largest and longest low-fat diet study – the Women’s Health Initiative – showed that postmenopausal women randomized to a low-fat diet intervention had minor weight loss at 1-yr that was not sustained after 7-yr [[34](/article/10.1007/s13668-024-00548-6#ref-CR34)] with similar lack of benefit on breast cancer [[35](/article/10.1007/s13668-024-00548-6#ref-CR35)], type 2 diabetes [[36](/article/10.1007/s13668-024-00548-6#ref-CR36)], and cardiovascular disease [[34](/article/10.1007/s13668-024-00548-6#ref-CR34)]. In fact, there were plausibly harmful effects of the low-fat dietary pattern on future risk of coronary heart disease in the subset of women with insulin resistance [[37](/article/10.1007/s13668-024-00548-6#ref-CR37), [38](/article/10.1007/s13668-024-00548-6#ref-CR38)•]. Systematic analyses of long-term weight loss trials with low-fat diets have not shown a benefit over other dietary approaches [[39](/article/10.1007/s13668-024-00548-6#ref-CR39)].

Many studies over the last two decades have compared low-fat to low-carbohydrate dietary patterns on weight loss. Summarizing this large body of literature, low-carbohydrate diets are at least as effective as low-fat diets for weight loss, and often outperform them in the short-term [[40](/article/10.1007/s13668-024-00548-6#ref-CR40), [41](/article/10.1007/s13668-024-00548-6#ref-CR41)]. Low-carbohydrate diets appear to be especially superior to low-fat diets in individuals who are insulin resistant [[42](/article/10.1007/s13668-024-00548-6#ref-CR42), [43](/article/10.1007/s13668-024-00548-6#ref-CR43)]. Long-term weight loss beyond 1-yr generally shows less disparity between diets of any particular macronutrient distribution, but this is likely driven by the relative high rate of noncompliance and attrition, which could be due to several factors agnostic to diet composition.

### Holistic Approaches

It is common to combine dietary and exercise interventions, which tend to produce greater weight loss than either approach alone [[20](/article/10.1007/s13668-024-00548-6#ref-CR20)] and help preserve muscle mass during weight loss [[32](/article/10.1007/s13668-024-00548-6#ref-CR32)]. However, long-term weight loss success is still moderate even when intensive behavioral strategies are employed. For example, the Look AHEAD trial randomized over 5,000 overweight individuals with type 2 diabetes to an intensive lifestyle intervention (ILI: low-fat diet, exercise, behavior modification, meal replacements, etc.) or standard diabetes support. Although there was nearly a 9% weight loss at 1-yr in the ILI group, weight regain occurred over the next several years with an average weight loss of ~5% in ILI compared to ~2% in the control group after 8-yr when the study was halted early due to lack of efficacy [[44](/article/10.1007/s13668-024-00548-6#ref-CR44)].

The role of diet pattern prior to and after surgery has also been examined with some evidence pointing toward superior effects of a pre-bariatric surgery low-calorie ketogenic diet over a Mediterranean and other diet approaches [[45](/article/10.1007/s13668-024-00548-6#ref-CR45), [46](/article/10.1007/s13668-024-00548-6#ref-CR46)]. A ketogenic diet may also have benefits post-bariatric surgery, especially in those who have a poor response or weight regain [[47](/article/10.1007/s13668-024-00548-6#ref-CR47), [48](/article/10.1007/s13668-024-00548-6#ref-CR48)].

It is challenging to compare the relative magnitude of expected weight loss among various approaches given the massive number of studies, but we have attempted to provide a representative sampling of expected percent weight loss associated with different strategies in Table [1](/article/10.1007/s13668-024-00548-6#Tab1). 

**Table 1 Comparison of average weight loss using various approaches**

[ Full size table](/article/10.1007/s13668-024-00548-6/tables/1)

## Nutritional Considerations During Major Weight Loss

### Dietary Protein

Protein is considered an “essential” nutrient because some of the constituents of protein, amino acids, must be obtained from the diet to prevent deficiency symptoms. In nature, there are nine essential amino acids, two essential fatty acids (linoleic acid and α-linoleic acid) and no essential carbohydrates. Resupplying the amino acid pool with an adequate quantity, and quality, of protein is necessary to prevent excess loss of lean mass during weight loss. Following is a brief discussion of issues relevant to determining the optimal quantify, quality, and timing of protein intake during major weight loss.

#### Fat-Free Mass

The fat-free mass (FFM) compartment comprises skeletal muscle, bones, organs, and extracellular fluid. Skeletal muscle constitutes ~40% of adult body weight and half of the physiological amino acid pool [[68](/article/10.1007/s13668-024-00548-6#ref-CR68)]. Preserving, and in some cases augmenting, FFM in the context of major weight loss is a priority because it has a dominant role in determining total daily energy expenditure [[69](/article/10.1007/s13668-024-00548-6#ref-CR69), [70](/article/10.1007/s13668-024-00548-6#ref-CR70)], physical strength and activities of daily living [[71](/article/10.1007/s13668-024-00548-6#ref-CR71), [72](/article/10.1007/s13668-024-00548-6#ref-CR72)], lifespan [[73](/article/10.1007/s13668-024-00548-6#ref-CR73)], and many other bodily functions conducive to well-being.

FFM exists in a state of dynamic equilibrium whereby a fine balance of remodeling processes between protein synthesis and breakdown – together referred to as “protein turnover” – are required to maintain organ integrity, synthesize neurotransmitters and hormones, and produce glucose (i.e., gluconeogenesis) during prolonged fasting or to a lesser extent during a ketogenic diet [[74](/article/10.1007/s13668-024-00548-6#ref-CR74)]. A healthy adult can turnover ~5.0–6.0 g protein/kg per day [[75](/article/10.1007/s13668-024-00548-6#ref-CR75)], or in other words traffic nearly half a kilogram of protein per day between diet and FFM-stored amino acids to sustain homeostasis. These remodeling processes are thus protein intensive, and hence require adequate protein intake to modulate FFM positively.

There are two main physiological mechanisms that can augment the skeletal muscle component of FFM. De novo skeletal muscle tissue can be synthesized via satellite cell differentiation – a set of specialized cells located proximally to skeletal muscle basal lamina – that can develop into new muscle fibers (i.e., hyperplasia) in the presence of robust stimuli, such as resistance training or injury. Single muscle fibers can also increase in diameter (i.e., hypertrophy) and thereby increase their total cross-sectional area when exposed to the same stimuli, all whilst preserving the original number of fibers [[76](/article/10.1007/s13668-024-00548-6#ref-CR76)]. Whereas hyperplasia is largely influenced by epigenetic factors, hypertrophy can be rapidly modulated by resistance training and sustained by adequate protein manipulations, highlighting features that are warranted from lifestyle and pharmaceutical interventions.

#### Quantification of Fat-Free Mass

A gross estimate is that for every kilogram of body weight lost, approximately three-fourths originate from fat mass (FM) and one-fourth from FFM (3:1 ratio) [[77](/article/10.1007/s13668-024-00548-6#ref-CR77)]. However, many modulating factors can affect this ratio such as genetics, diet, training status, concurrent resistance training, weight-loss magnitude, and body composition model assumptions [[78](/article/10.1007/s13668-024-00548-6#ref-CR78)]. To accurately evaluate the composition of weight loss, non-invasive imaging techniques have advantages due to their excellent sensitivity and accuracy over metabolite excretion and anthropometric measurements, including discerning discrete changes between tissue compartments [[79](/article/10.1007/s13668-024-00548-6#ref-CR79), [80](/article/10.1007/s13668-024-00548-6#ref-CR80)]. Despite these advantages, all body composition methods have limitations and assumptions that make accurate determination of FFM during weight loss difficult.

Dual-energy X-ray absorptiometry (DXA) is often used as the gold standard to assess fat and lean mass, and bone density responses in many diet and training studies [[79](/article/10.1007/s13668-024-00548-6#ref-CR79), [80](/article/10.1007/s13668-024-00548-6#ref-CR80)]. Despite having advantages over other common body composition methods (e.g., underwater weighing, skin folds, bioelectrical impedance, air displacement plethysmography, etc.), an important limitation of DXA lies in its FFM algorithm, whereby fluid is calculated as lean tissue [[81](/article/10.1007/s13668-024-00548-6#ref-CR81)]. Thus, DXA underestimates lean mass under conditions where fluid may be lost (e.g., after profuse sweating, onset of a ketogenic diet, glycogen-depleting exercise, heavy diuretic use, etc.) or vice versa overestimates lean mass when fluid is retained (e.g., edema, carbohydrate loading, etc.). This limitation may be circumvented using other advanced imaging techniques less sensitive to fluid shifts, such as magnetic resonance imaging (MRI), but nevertheless problematic for studies comparing diets, especially ketogenic diets, expected to modulate fluid storage by altering carbohydrate intake, notably in the first few weeks of diet initiation [82,83,84,[85](/article/10.1007/s13668-024-00548-6#ref-CR85)].

#### Protein Requirements

Dietary protein is the only nitrogen-containing macronutrient, and thus requirements for protein are often determined using the nitrogen balance method, which calculates nitrogen ingested and subtracts nitrogen excreted [[86](/article/10.1007/s13668-024-00548-6#ref-CR86), [87](/article/10.1007/s13668-024-00548-6#ref-CR87)]. Assuming that ~16% of dietary protein is nitrogen by weight, daily nitrogen balance can be calculated mathematically by subtracting nitrogen measured in a 24-h urine collection plus nitrogen loss through sweat and feces as follows [[88](/article/10.1007/s13668-024-00548-6#ref-CR88)]:

$$\mathit{Nitrogen\;Balance}\;=\;\mathit{Protein\;Intake}\;\left({g}/{day}\right)* 0.16\;-\;[\mathit{Urine\;Nitrogen\;Excretion}\;(g/day)\;+\;4]$$

Positive nitrogen balance reflects greater protein synthesis than degradation and FFM preservation or gain, whereas negative nitrogen balance reflects greater protein breakdown than synthesis and net loss of FFM over time. The current recommended dietary allowance (RDA) for maintaining nitrogen balance is 0.8 g protein/kg/day, which translates to about 10%–15% of the total daily energy expenditure. This threshold value was determined by the USDA and WHO/FAO based on 24-h urinary nitrogen excretion patterns to achieve nitrogen balance in the majority of healthy sedentary adults [[89](/article/10.1007/s13668-024-00548-6#ref-CR89), [90](/article/10.1007/s13668-024-00548-6#ref-CR90)]. Extensive debates on the adequacy of 0.8 g/kg protein have permeated the literature due to concerns of poor ecological validity in athletes, older adults, or clinically ill patients, and inherent limitations in nitrogen excretion estimations owing to integumentary and fecal nitrogen loses [[89](/article/10.1007/s13668-024-00548-6#ref-CR89), [91](/article/10.1007/s13668-024-00548-6#ref-CR91), [92](/article/10.1007/s13668-024-00548-6#ref-CR92)].

Relevant to this review, the adequacy of the RDA for protein in the context of major weight loss is also dubious, as studies have indicated skeletal muscle protein synthesis is down-regulated and protein degradation accelerated during energy deficits [[93](/article/10.1007/s13668-024-00548-6#ref-CR93)]. A ~10% decrease in daily calories has been shown to increase protein requirements 50% [[94](/article/10.1007/s13668-024-00548-6#ref-CR94)]. Complicating interpretation of protein requirements during weight loss is the fact that the mechanisms regulating protein turnover are modulated by the degree of energy deficit and time. It is well documented that the amount of protein required to maintain nitrogen balance during energy deficit is reduced over time as adaptive mechanisms act to preserve lean tissue [[83](/article/10.1007/s13668-024-00548-6#ref-CR83), [95](/article/10.1007/s13668-024-00548-6#ref-CR95), [96](/article/10.1007/s13668-024-00548-6#ref-CR96)]. Another complicating factor is the understanding of “anabolic resistance,” an inflammatory-mediated mechanism that disrupts normal protein synthesis relative to normal-weight controls [[97](/article/10.1007/s13668-024-00548-6#ref-CR97), [98](/article/10.1007/s13668-024-00548-6#ref-CR98)].

Protein intake guidelines build on more robust evidence from detailed amino acid oxidation methods (often involving a tracer amino acid such as 13C-lysine/leucine or 2H5-phenylalanine) and dose-response clinical trials [[91](/article/10.1007/s13668-024-00548-6#ref-CR91), [92](/article/10.1007/s13668-024-00548-6#ref-CR92), 99,100,101,102,[103](/article/10.1007/s13668-024-00548-6#ref-CR103)]. Collectively, an optimal dietary protein intake for weight-loss is approximately two-fold higher than previously estimated. A range of ~1.2 to 2.0 g protein/kg/day is supported by large empirical evidence as an optimal dietary protein target that can offset untoward proteolytic turnover and promote protein synthesis, highlighting a substantial discrepancy from the prior guidelines [[92](/article/10.1007/s13668-024-00548-6#ref-CR92), [101](/article/10.1007/s13668-024-00548-6#ref-CR101), [102](/article/10.1007/s13668-024-00548-6#ref-CR102), 104,105,106,107,108,109,110,[111](/article/10.1007/s13668-024-00548-6#ref-CR111)].

During major weight loss, the question of whether it is best to seek a protein intake that achieves a zero nitrogen balance (i.e., equal rates of protein synthesis and degradation) or a protein intake that achieves a high net positive nitrogen balance and gain in FFM is worth considering. It has also been postulated that high protein diets may have other beneficial outcomes, begging the question of minimum versus optimal protein intake. A review of very high protein diets is beyond the scope of this review but has been done so by others [[112](/article/10.1007/s13668-024-00548-6#ref-CR112)].

Importantly, protein requirements should be calculated based on a reference or adjusted weight in people with excess adiposity because protein needs are primarily a reflection of the lean tissue and not adipose tissue. As shown in Table [2](/article/10.1007/s13668-024-00548-6#Tab2), a typical normal-weight male (Person A) may have an upper limit of reasonable protein intake of 150 g/day. But a similar height individual with obesity (Person B) would be prescribed protein up to 250 g/day using their actual weight, which is likely excessive relative to requirements needed to maintain lean tissue and functionality. 

**Table 2 Protein adequacy vs. over-prescription**

[ Full size table](/article/10.1007/s13668-024-00548-6/tables/2)

#### Protein Quality

The biological value of proteins is influenced by the amount of nitrogen retained in the body; a reflection of individual amino acids being incorporated into FFM. Complete dietary protein sources contain 20 amino acids, 9 of which are essential amino acids (EEA): histidine, leucine, isoleucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Protein quality is directly related to the presence of EAA, especially leucine, the most robust activator of mTORC1 – a master regulator of protein synthesis [113,114,[115](/article/10.1007/s13668-024-00548-6#ref-CR115)].

Protein sources that are limiting in EAAs are considered lower quality or incomplete proteins that can hinder the FFM growth and development in response to diet and exercise [[116](/article/10.1007/s13668-024-00548-6#ref-CR116), [117](/article/10.1007/s13668-024-00548-6#ref-CR117)], an effect that becomes even more important during weight loss. When consumed as intact foods, EAAs are highly abundant in all animal-derived meats and byproducts (i.e., eggs, dairy), except collagen and gelatin, and several plant sources [[113](/article/10.1007/s13668-024-00548-6#ref-CR113), [114](/article/10.1007/s13668-024-00548-6#ref-CR114)]. As a side note, the protein digestibility-corrected amino acid scale – a standardized range of amino acid absorption per unit of protein consumed; PDCAAS – uses eggs as the reference food for _high-biological value_ determinations.

It is well-established that omnivores achieve their total protein and EAA with greater ease than vegetarians/vegans. Plant-based approaches may often provide inadequate amounts of leucine, lysine, methionine, and threonine because the amount of EAAs in plant foods is generally less compared to animal foods and can plausibly compromise protein synthesis [[118](/article/10.1007/s13668-024-00548-6#ref-CR118), [119](/article/10.1007/s13668-024-00548-6#ref-CR119)]. Moreover, intact plant protein sources may lack the necessary digestibility relative to equal amounts of animal proteins because plant proteins often tend to integrate within the plant fiber matrix, creating an inaccessible mesh during digestion that provides less bioavailable protein.

With the advent of protein powder formulations and the ability to decouple plant proteins from their fiber matrix, protein supplements have been able to increase EAA availability to a point where animal and plant-based powders exhibit similar kinetics with respect to their protein synthesis potential [[119](/article/10.1007/s13668-024-00548-6#ref-CR119), [120](/article/10.1007/s13668-024-00548-6#ref-CR120)], albeit in several instances still favoring whey [[118](/article/10.1007/s13668-024-00548-6#ref-CR118)]. Whey protein is ~50% by weight EAAs and 11% leucine [[102](/article/10.1007/s13668-024-00548-6#ref-CR102), [119](/article/10.1007/s13668-024-00548-6#ref-CR119)]. A quality source of whey protein will provide 25 g of protein per serving, with ~3 g from leucine. This guideline is often cited in the literature as a proxy against protein “spiking” (i.e., diluting the content with cheap, non-essential amino acids); therefore, supplementing a diet with whey during weight loss requires two major considerations: that the supplement received a reputable third-party purity certificate (i.e., NSF) and individual amino acids are listed in gram amounts on the label, which is optional.

Collectively, protein quality is guided by EAA composition, especially leucine content. Although outside the scope of this review, some qualities of dairy proteins remain to be elucidated albeit relevant to carbohydrate-restriction. Of importance, whole-eggs – specifically egg yolks – may augment protein synthesis independent of total calories and protein content, in part explained by non-caloric compounds (e.g., miRNAs) contained within the yolk fraction [121,122,[123](/article/10.1007/s13668-024-00548-6#ref-CR123)]. Similarly, full-fat milk (3.5%) appears to exert protein synthesis signaling properties that are beyond skim milk (0%) in the post-exercise window [[124](/article/10.1007/s13668-024-00548-6#ref-CR124)]. When viewed within a low-carbohydrate context, inclusion of full-fat dairy products is not only appropriate and encouraged but may strategically modulate protein synthesis signaling beyond fat-free items.

#### Protein Dosing and Distribution

Beyond the quantity and quality of protein, the optimal protein dose (grams per meal) and distribution (timing or frequency of intake over the day) has been a subject of research and debate over the last few decades, and in more recent discourse, the physiological upper-limit of protein digestion questioned [[125](/article/10.1007/s13668-024-00548-6#ref-CR125)]. In general, a meal that provides ~25–30 g of a high-biological value protein can adequately stimulate muscle protein synthesis due to the intrinsic connection between total protein dose and EAA content, specifically leucine, to surpass rate-limiting threshold for protein synthesis [[115](/article/10.1007/s13668-024-00548-6#ref-CR115), 126,127,[128](/article/10.1007/s13668-024-00548-6#ref-CR128)]. Substituting incomplete protein sources for dairy products may lower the leucine-threshold requirement per meal (15–20 g), in part owing to the insulinogenic amino acid profile and the unique yolk/dairy matrix properties discussed earlier and in greater detail elsewhere [[102](/article/10.1007/s13668-024-00548-6#ref-CR102), [129](/article/10.1007/s13668-024-00548-6#ref-CR129)].

Regarding protein timing, evidence from both pre-clinical and clinical trials suggests that distributing total daily protein evenly across breakfast, lunch, and dinner can drive greater anabolic responses and FFM preservation relative to skewed intakes [[111](/article/10.1007/s13668-024-00548-6#ref-CR111), [118](/article/10.1007/s13668-024-00548-6#ref-CR118), [126](/article/10.1007/s13668-024-00548-6#ref-CR126), 130,131,[132](/article/10.1007/s13668-024-00548-6#ref-CR132)]. In other words, when total daily protein is held constant, an individual who consumes at least 25–30 g of protein per meal should expect a 25% greater protein synthesis response compared to an individual who consumes a low-protein breakfast (~10 g) and a protein-rich dinner (~60 g) [[132](/article/10.1007/s13668-024-00548-6#ref-CR132)]. Collectively, it appears that overweight/obese individuals who undergo weight-loss may benefit from the protein distribution strategy presented herein [[133](/article/10.1007/s13668-024-00548-6#ref-CR133)], albeit some evidence suggests no demonstrable effects of protein distribution [[134](/article/10.1007/s13668-024-00548-6#ref-CR134)], in part explained by differences in training status (i.e., less precision required for untrained vs. trained individuals) [[135](/article/10.1007/s13668-024-00548-6#ref-CR135)]. A graphical summary of the main points discussed in this section is provided below (Fig. [1](/article/10.1007/s13668-024-00548-6#Fig1)).

**Fig. 1**

[![figure 1](//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs13668-024-00548-6/MediaObjects/13668_2024_548_Fig1_HTML.png)](/article/10.1007/s13668-024-00548-6/figures/1)

Dietary protein graphical summary

[Full size image](/article/10.1007/s13668-024-00548-6/figures/1)

### Low-Fat vs Low-Carbohydrate Diets

A comprehensive discussion on various dietary patterns is beyond the scope of this review, as the permutations of nutrient combinations even within low-carbohydrate diets are vast. With the focus of this review on low-carbohydrate dietary patterns, we provide a general overview comparing and contrasting the main differences between low-fat and low-carbohydrate diets with particular attention on ketogenic diets. The reader is referred to a more detailed description of fundamental principles of a ketogenic diet [[136](/article/10.1007/s13668-024-00548-6#ref-CR136)••].

#### Definitions and Terminology

For this review, we advocate definitions of dietary patterns as proposed in a recent expert consensus paper [[137](/article/10.1007/s13668-024-00548-6#ref-CR137)], where very-low carbohydrate/high-fat ketogenic diets consist of < 10% carbohydrate or 20–50 g/day; low-carbohydrate diets consist of 10–25% carbohydrate or 50–129 g/day; and low-fat/high-carbohydrate diets consist of > 45% carbohydrate or > 225 g/day. Notably, not all low-carbohydrate dietary patterns are ketogenic, but all ketogenic diets are low in carbohydrate.

A low-fat dietary pattern is reduced in overall fat intake, especially saturated fat. Most low-fat approaches encourage the consumption of lean proteins, fruits, vegetables, and whole grains while limiting high-fat dairy products, fatty meats, and processed foods. Variations of low-fat diets may encourage primary replacement of saturated fat with carbohydrate and/or polyunsaturated fat. Most plant-based vegetarian patterns would be considered low-fat, but it is possible to also design plant-based low-carbohydrate diets. In contrast, the hallmark of a low-carbohydrate diet generally involves restricting many carbohydrate-dense foods while consuming moderate protein, and moderate- to high-fat (depending on the degree of caloric restriction). There is an emphasis on avoiding added sugars, limiting highly processed foods, and consuming nutrient-dense minimally-process whole foods without extensive packaging or a lengthy list of ingredients on the Nutrition Facts Label.

The hallmark of a ketogenic diet is limiting carbohydrate intake to < 50 g/day but can vary between people from ~20 to > 70 g/day based on their ketone levels. This level of carbohydrate restriction requires avoiding carbohydrate-dense foods such as bread, cereals, pasta, cakes/cookies, high-glycemic fruits (e.g., apples, bananas), and starchy vegetables (e.g., sweet potatoes, corn, peas, carrots). The limited carbohydrates are primarily derived from non-starchy vegetables, nuts, seeds, low-sugar/high-water content fruits (berries, avocados, olives, tomatoes), with lower amounts from full-fat dairy, whole eggs, and other protein sources. Protein needs are estimated based on 1.2 to 2.0 g/kg reference weight, usually ranging between ~80–150 g/day. Fat is prescribed to satiety which can be consumed from meats, high-fat dairy (butter, cheese, sour cream, heavy cream), avocados, oils (olive, canola, avocado, coconut, etc.), nuts and seeds. Since it is the carbohydrate and protein content that have the most impactful effect on ketone production, it is helpful to have people measure ketones to titrate the specific amounts of those nutrients that can be consumed to achieve nutritional ketosis (defined in next section). A ketogenic diet is not one-size-fits-all, as achieving nutritional ketosis is influenced by factors such as activity level, degree of insulin resistance, stress, etc.

Ensuring adequate essential vitamin and mineral intakes is a priority for all dietary patterns, especially during caloric restriction, but practically challenging for individuals to accomplish without professional support [[138](/article/10.1007/s13668-024-00548-6#ref-CR138), [139](/article/10.1007/s13668-024-00548-6#ref-CR139)]. Most individuals who qualify for bariatric surgery are micronutrient deficient [[140](/article/10.1007/s13668-024-00548-6#ref-CR140)]; remarkably ~99% lack adequate vitamin-D [[141](/article/10.1007/s13668-024-00548-6#ref-CR141)] and women are twice as likely than men to be iron-deficient [[141](/article/10.1007/s13668-024-00548-6#ref-CR141)]. However, poor micronutrient status can be reversed with proper supplementation [[142](/article/10.1007/s13668-024-00548-6#ref-CR142)]. Relevant to carbohydrate-restriction, the whole-food items proposed by well-formulated ketogenic diet guidelines are congruent with the micronutrient malnutrition reversal guidelines [[143](/article/10.1007/s13668-024-00548-6#ref-CR143)]. Human trials further support the idea that a ketogenic diet is micronutrient adequate in patient populations [[144](/article/10.1007/s13668-024-00548-6#ref-CR144)], and when implemented over 4-weeks in pre-operative individuals (_n_ = 27) it can favorably reverse micronutrient deficiencies during major weight loss (-10%) while simultaneously improving body composition (5:1 FM:FFM kg:kg losses) [[145](/article/10.1007/s13668-024-00548-6#ref-CR145)]. Whereas the consensus is still extensively investigated [[139](/article/10.1007/s13668-024-00548-6#ref-CR139)], or obfuscated by dietary assessment methods [[138](/article/10.1007/s13668-024-00548-6#ref-CR138), [146](/article/10.1007/s13668-024-00548-6#ref-CR146)] and early clinical evidence [[147](/article/10.1007/s13668-024-00548-6#ref-CR147), [148](/article/10.1007/s13668-024-00548-6#ref-CR148)], there is recent promising data suggesting that carbohydrate-restriction is sensible to micronutrients with proper implementation and guidance.

Particularly noteworthy is the issue of sodium, which is an essential but controversial mineral. At the onset of a low-carbohydrate diet, especially a ketogenic diet, the kidneys switch from retaining sodium to rapidly excreting it [[149](/article/10.1007/s13668-024-00548-6#ref-CR149)]. In many obese individuals, this natriuresis and diuresis is associated with positive effects (e.g., rapid weight loss, less swelling, reduced blood pressure), but once this excess fluid is cleared continued loss of sodium and fluid leads to what has been termed “keto-flu”. The contracted plasma volume can manifest in dizziness, fatigue, headache, and lethargy. It also triggers the adrenal glands to release aldosterone and cortisol to retain sodium, but this occurs at the expense of losing potassium in the urine. Thus, restriction of sodium on a ketogenic diet can disrupt metabolic and hormonal homeostasis compromising sustainability and effectiveness of a ketogenic diet. Careful attention to ensuring adequate sodium as well as potassium and other minerals is necessary, which can be accomplished with normal foods, but regular consumption of broth or dietary supplements are effective as well.

Even well-intended investigators studying ketogenic therapies often fail to appreciate the challenges, principles, and nuances associated with implementing a ketogenic diet that achieves nutritional ketosis. Ketogenic nutrition is not taught to dietitians, physicians, or any healthcare professionals through traditional academic curricula, which translates into widely varying approaches used in clinical research and practice. Too often the ketogenic approach is poorly formulated and implemented either too casually or restrictive to an extreme, with poor outcomes that jeopardizes safety, acceptance, and sustainability. This is particularly true when investigators rely on chemically-formulated low carbohydrate preparations for all or most of their test diet, since these are typically deficient in multiple regards ranging from total energy to palatability rendering them unsustainable beyond a few months.

Finally, a quick note about the future of ketogenic interventions. While many ketogenic research interventions remain focused on the ketogenic diet, the recent development and commercial availability of “exogenous ketones”, which includes several different classes of compounds, now broadens the arsenal of methods to achieve physiological target ketone levels in individuals. Exogenous ketones consist of varying compositions such as direct forms of beta-hydroxybutyrate (BHB) in the form of an acid, salt, or joined with other ketone-promoting components by ester bonds. They may contain ketogenic precursors that metabolize to ketones in the liver (i.e., medium chain fatty acids), or ketone precursors that metabolize to BHB via non-classical metabolic pathways (i.e., (_R_) -1,3 butanediol).

#### Ketone Nomenclature

On an individual level, the goal of a ketogenic diet is to achieve a metabolic state of nutritional or physiological ketosis defined as circulating ketone concentrations (usually measured as beta-hydroxybutyrate, _R_ -BHB) between 0.5 to 5.0 mM, which is consistently above levels demonstrated in people consuming low-fat diets.

Unique among metabolites, ketones are regulated across a wide range that, when expressed in molar concentration, span a remarkable four orders of magnitude (Fig. [2](/article/10.1007/s13668-024-00548-6#Fig2)). Ketones are always being produced, primarily in the liver, but the carbohydrate loads typical of low-fat or even moderate-carbohydrate dietary patterns significantly suppress ketogenesis to levels that are often < 0.1 mM and remain < 0.3 mM even after an overnight fast. The carbohydrate restriction and moderate protein consumption associated with a ketogenic diet result in markedly accelerated adipose tissue lipolysis and ketogenesis that manifest in nutritional ketosis (0.5 to 5.0 mM). Ketone levels rarely exceed 5.0 mM on a ketogenic diet due to physiological adaptations such as increased ketone utilization and inhibition of ketone production. The normal negative feedback is impaired in type 1 diabetics who do not produce insulin and are not taking adequate exogenous insulin. Thus, in uncontrolled type 1 diabetes or other rare insulin insufficient conditions, there is a possibility of developing keto-acidosis where ketone levels can exceed 20 mM.

**Fig. 2**

[![figure 2](//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs13668-024-00548-6/MediaObjects/13668_2024_548_Fig2_HTML.png)](/article/10.1007/s13668-024-00548-6/figures/2)

Circulating ketones, principally betahydroxybutyrate (R-BHB), span over four orders of magnitude [< 0.01 to > 10 mM]. Emerging research indicates that moving from relatively low ketone levels (i.e., "hypoketonemia") observed in people consuming a standard American diet to moderate ketone levels associated with nutritional ketosis (i.e., ~ 0.5 to 5.0 mM or "euketonemia") is associated with a myriad of health benefits

[Full size image](/article/10.1007/s13668-024-00548-6/figures/2)

To distinguish between these widely varying ketone levels, we propose new terminology that more accurately captures the understanding of human ketone physiology across the evolutionary spectrum, lifespan, and role in health and disease. This nomenclature aligns with the accepted terms used to describe relative glucose levels which are “hypoglycemia”, “euglycemia”, and “hyperglycemia”; corresponding to “too low”, “normal”, and “too high”, respectively. The etymology of the prefix “eu-” originates from ancient Greek and translates to “good” or “beneficial”, whereas “emia” denotes “a substance is in the blood”. Thus, we propose a new term _“euketonemia”_ − an amalgamation of “eu-” and “ketone” and “emia” − to describe the desirable range of ketones, often referred to as nutritional ketosis, shown in a burgeoning number of published studies to be beneficial or therapeutic [[150](/article/10.1007/s13668-024-00548-6#ref-CR150)]. In distinction to health-promoting euketonemia, higher levels of ketones akin to keto-acidosis should be designated _“hyperketonemia”_ and lower levels of ketones such as those present when consuming high-carbohydrate dietary patterns as _“hypoketonemia.”_

In support of adopting this nomenclature, mild ketosis was the normal state for humans prior to the agricultural revolution, which represents the vast majority of human history. Humans have a strong evolutionary adaptation to ketones. The brain [[151](/article/10.1007/s13668-024-00548-6#ref-CR151)] and many other tissues like the heart [[152](/article/10.1007/s13668-024-00548-6#ref-CR152)] prefer ketones, oxidize them in proportion to their circulating level, and function better when using them as fuel [[153](/article/10.1007/s13668-024-00548-6#ref-CR153), [154](/article/10.1007/s13668-024-00548-6#ref-CR154)]. As further evidence of euketonemia being a natural healthy state is the observation that amniotic fluid is euketonemic (average BHB 0.6 mM) [[155](/article/10.1007/s13668-024-00548-6#ref-CR155)] and many breast fed neonates are in nutritional ketosis [[156](/article/10.1007/s13668-024-00548-6#ref-CR156)]. In the case of T2D, low-fat/high-carbohydrate diets rarely reverse the metabolic disorder, whereas ketogenic diets often do [[7](/article/10.1007/s13668-024-00548-6#ref-CR7)]. Thus, one perspective viewed through the lens of T2D is that therapeutic diets that achieve euketonemia correct the metabolic state of hypoketonemia. Additional evidence supporting euketonemia as a health-promoting and therapeutic state is expanded on in later sections.

### Ketone Physiology

The three primary ketone bodies produced primarily in the liver from partial breakdown of fatty acids are BHB, acetoacetate (AcAc), and acetone. Ketone production (i.e., ketogenesis) is upregulated when hepatic glycogen and insulinemia are maintained invariably low, which occurs during a low-carbohydrate, moderate-protein diet, resulting in increased presence of principally BHB into a physiological range of nutritional ketosis or euketonemia [[136](/article/10.1007/s13668-024-00548-6#ref-CR136)••, [157](/article/10.1007/s13668-024-00548-6#ref-CR157), [158](/article/10.1007/s13668-024-00548-6#ref-CR158)]. Circulating ketones are then transported to extrahepatic tissues where they serve as important energy substrates and epigenetic signaling molecules [[159](/article/10.1007/s13668-024-00548-6#ref-CR159), [160](/article/10.1007/s13668-024-00548-6#ref-CR160)]. During a ketogenic diet or prolonged fasting, the liver likely produces 75–150 g ketones per day [[161](/article/10.1007/s13668-024-00548-6#ref-CR161), [162](/article/10.1007/s13668-024-00548-6#ref-CR162)] which serves as an important alternative fuel for the brain, heart, and skeletal muscle.

Much of what is known about ketone metabolism was elucidated half a century ago through elegant experiments performed by George Cahill and his trainees who primarily studied prolonged starvation in humans [[161](/article/10.1007/s13668-024-00548-6#ref-CR161)]. Among many discoveries, was the crucial role ketones have in ensuring an adequate supply of fuel to the brain during periods of low carbohydrate availability [[160](/article/10.1007/s13668-024-00548-6#ref-CR160)]. Over the last decade, new aspects of ketone physiology have emerged. Notably, ketones are now recognized as uniquely efficient in that they generate more ATP per unit oxygen than other metabolites [[163](/article/10.1007/s13668-024-00548-6#ref-CR163)]. Ketones have been discovered to be important signaling molecules [[150](/article/10.1007/s13668-024-00548-6#ref-CR150)] working through multiple mechanisms (e.g., covalent protein modification, non-covalent enzyme regulation, receptor agonism/antagonism) that positively influence a wide range of cellular functions such as gene expression, inflammatory pathways, and immunomodulation [[164](/article/10.1007/s13668-024-00548-6#ref-CR164), [165](/article/10.1007/s13668-024-00548-6#ref-CR165)]. These new discoveries have led to a surge in the basic and applied study of ketogenic interventions across a wide swath of health and disease.

### Very-Low-Calorie Diets

Before we discuss comparative research on low-fat versus low-carbohydrate weight loss diets, a brief note is warranted on very-low-calorie diets (VLCDs) or semi-starvation diets, usually defined as < 800 kcal/day [[166](/article/10.1007/s13668-024-00548-6#ref-CR166)]. These diets are medically supervised in obese individuals to elicit significant weight loss (1–2 kg/week), preserve FFM, and monitor symptoms of dehydration, mineral losses, or other health complications [[167](/article/10.1007/s13668-024-00548-6#ref-CR167), [168](/article/10.1007/s13668-024-00548-6#ref-CR168)] often before considering bariatric surgery.

VLCDs have profound effects on nitrogen balance that in some instances precede dietary protein considerations [[94](/article/10.1007/s13668-024-00548-6#ref-CR94), [169](/article/10.1007/s13668-024-00548-6#ref-CR169)]. In a hypothetical scenario, the average stature woman and man in the United States with a BMI of 40 (“severe obesity”) weighs ~105 and ~120 kg, respectively [[170](/article/10.1007/s13668-024-00548-6#ref-CR170)]. A conservative protein intake of 1.2 g/kg/day, the low-end for healthy active adults, would provide them 125–150 g of dietary protein per day, or ~63–72% of their total energy intake on a VLCD. In reality, protein requirements on VLCDs are closer to 1.0 g/kg of reference weight (i.e., target weight scaled to body height) [[171](/article/10.1007/s13668-024-00548-6#ref-CR171), [172](/article/10.1007/s13668-024-00548-6#ref-CR172)]; therefore, protein goals scaled to ideal vs. starting weight will always be lower for obese individuals relative to overweight persons undergoing modest weight loss rates (< 1 kg/week). For brevity purposes, the consensus on protein intake for VLCDs is ~60 to 90 g/day to prevent excess nitrogen excretion [[28](/article/10.1007/s13668-024-00548-6#ref-CR28), [171](/article/10.1007/s13668-024-00548-6#ref-CR171), 173,174,[175](/article/10.1007/s13668-024-00548-6#ref-CR175)].

There is evidence that adding carbohydrates to suppress ketone formation during VLCD protocols could hinder nitrogen balance. First, adding carbohydrates detracts the total available calories that can be reserved for protein, thereby compromising the key macronutrient conducive to FFM preservation [[110](/article/10.1007/s13668-024-00548-6#ref-CR110), [176](/article/10.1007/s13668-024-00548-6#ref-CR176)]. Second, evidence suggests that achieving a level of nutritional ketosis may assist nitrogen preservation during VLCDs, especially when minerals are replenished and hydration is tightly monitored [[28](/article/10.1007/s13668-024-00548-6#ref-CR28), [85](/article/10.1007/s13668-024-00548-6#ref-CR85)]. Ketone bodies during severe energy restriction have demonstrable effects on nitrogen balance in as little as ~2 weeks after diet initiation, and when BHB is constitutively sustained [[28](/article/10.1007/s13668-024-00548-6#ref-CR28)], compared to ~4 weeks when BHB is absent [[173](/article/10.1007/s13668-024-00548-6#ref-CR173)]. Importantly, for the majority of the population the central challenge with VLCDs lies within the behavioral and nutritional efforts wherein maintaining the target weight after weight-loss, and the lifelong countermeasures to prevent weight-regain, are the main priorities [[171](/article/10.1007/s13668-024-00548-6#ref-CR171), [177](/article/10.1007/s13668-024-00548-6#ref-CR177)].

### Effects on Weight Loss

There are now several published comparative studies between low-fat and low-carbohydrate dietary patterns of less than 130 grams per day of carbohydrate ranging from a few weeks to 2-years in duration. It is clear that individuals can lose weight on a variety of diets varying in macronutrient composition. The results of multiple recent meta-analyses indicate that low-carbohydrate dietary patterns do at least as well, and often better, at promoting weight loss and certain risk markers for cardiovascular disease when compared with low-fat dietary patterns [[40](/article/10.1007/s13668-024-00548-6#ref-CR40), [41](/article/10.1007/s13668-024-00548-6#ref-CR41), 178,179,[180](/article/10.1007/s13668-024-00548-6#ref-CR180)]. A unique aspect of low-carbohydrate diets is that in many studies they were implemented _ad libitum_ without prescribing an explicit caloric reduction, yet still elicited significant weight loss [[181](/article/10.1007/s13668-024-00548-6#ref-CR181), [182](/article/10.1007/s13668-024-00548-6#ref-CR182)]. Without going into detail on the many individuals trials now published, there is generally less of a discrepancy in weight loss among diets of any macronutrient composition the longer the intervention duration [[183](/article/10.1007/s13668-024-00548-6#ref-CR183)], emphasizing the need for ongoing support and selecting the most appropriate diet that works for each person. In regard to this idea of personalized or precision nutrition, it is noteworthy that low-carbohydrate diets appear to be especially superior to low-fat diets in individuals who are insulin resistant or have high insulin secretion [[42](/article/10.1007/s13668-024-00548-6#ref-CR42), [43](/article/10.1007/s13668-024-00548-6#ref-CR43), 184,185,[186](/article/10.1007/s13668-024-00548-6#ref-CR186)], which is common in people with obesity. In regards to the challenge of the high cost and poor persistence of GLP1 therapy, there is now evidence that a low-carbohydrate diet may enable deprescription with maintenance of weight loss and clinical improvements [[8](/article/10.1007/s13668-024-00548-6#ref-CR8)].

### Effects on Body Composition

Considering both low-fat and low-carbohydrate dietary patterns can be used to achieve weight loss, a crucial question is whether the composition and distribution of weight loss is similar between diets. Ideally, weight loss strategies should target FM reduction, particularly in visceral adipose tissue (VAT), while preserving lean tissue. According to meta-analyses, low-carbohydrate diets compared with other weight loss interventions of the same duration demonstrate greater loss of total weight, fat mass, and waist circumference [187,188,[189](/article/10.1007/s13668-024-00548-6#ref-CR189)]. Because total weight loss is often higher on a low-carbohydrate diet, there may also be a greater amount of lean mass lost, but this is an expected response and associated with an overall maintenance of physical function and decrease in percent body fat. Discrepancies between individual studies may be attributed to factors such as inadequate protein intake, limitations in common body composition assessment methods that misinterpret water loss as a decrease in lean tissue, and insufficient sodium compensation for the natriuretic effect of carbohydrate-restriction.

In a few short-term hypocaloric diet studies, a greater loss of nitrogen has been demonstrated with ketogenic diets compared to non-ketogenic diets [[190](/article/10.1007/s13668-024-00548-6#ref-CR190), [191](/article/10.1007/s13668-024-00548-6#ref-CR191)], but these diets were severely energy-restricted, very short-term, and more importantly did not provide adequate sodium and potassium to account for the natriuretic effect of ketogenic diets, which has a key role in maintaining nitrogen [[192](/article/10.1007/s13668-024-00548-6#ref-CR192)]. In contrast, there may be some instances where a ketogenic diet could lead to greater preservation of lean tissue during major weight loss, especially if combined with resistance training or exogenous ketones that have anticatabolic effects [[193](/article/10.1007/s13668-024-00548-6#ref-CR193)], but this area of investigation remains understudied and controversial.

There is evidence that ketone bodies may protect against muscle loss in catabolic conditions such as sarcopenia, cachexia, and excessive inflammation, potentially through mTORC1 signaling [[194](/article/10.1007/s13668-024-00548-6#ref-CR194)]. While still a hypothesis, these previous findings suggest it may be possible to augment preservation of lean tissue during major weight loss through oral ingestion of ketones. In support of this possibility we recently observed that ingestion of a modest does of BHB-salts (12 g day; twice-daily) during a 6-wk ketogenic diet controlled-feeding intervention resulted in a modest reduction in urinary nitrogen excretion compared to placebo (-8%), although this did not translate into a detectable difference in lean body mass determined by DXA [[82](/article/10.1007/s13668-024-00548-6#ref-CR82)].

Accumulation of fat in VAT and the liver (NAFLD) are particularly problematic and strongly associate with higher risk for diabetes and cardiovascular disease. Only a few studies have assessed how low-carbohydrate dietary patterns affect VAT using precise imaging technologies. In one study, a 12-wk _ad libitum_ ketogenic diet in military-affiliated healthy adults resulted in significant weight loss (7.7 kg) and a 44% reduction in VAT assessed by MRI [[195](/article/10.1007/s13668-024-00548-6#ref-CR195)]. In another 12-wk study, patients with NAFLD assigned to a calorie restricted low-carbohydrate diet lost weight (-8.0 kg) and had a 18% reduction in VAT assessed by MRI [[196](/article/10.1007/s13668-024-00548-6#ref-CR196)]. Thus, a ketogenic diet may uniquely target VAT [[197](/article/10.1007/s13668-024-00548-6#ref-CR197)].

NAFLD is a progressive liver disorder characterized by the accumulation of more than 5% fat in the liver. If left untreated, it can progress to non-alcoholic steatohepatitis, fibrosis, cirrhosis, and liver failure. Hypocaloric low-fat and low-carbohydrate dietary patterns have been demonstrated to reduce liver fat to a similar extent in relatively healthy overweight individuals [[198](/article/10.1007/s13668-024-00548-6#ref-CR198)], with more profound effects seen in patients with NAFLD [[199](/article/10.1007/s13668-024-00548-6#ref-CR199)]. Some evidence points to superior effects of ketogenic diets [[197](/article/10.1007/s13668-024-00548-6#ref-CR197), [200](/article/10.1007/s13668-024-00548-6#ref-CR200), [201](/article/10.1007/s13668-024-00548-6#ref-CR201)], likely attributed to both decreased de novo lipogenesis and increased metabolism of fatty acids into the ketogenic pathway [[202](/article/10.1007/s13668-024-00548-6#ref-CR202), [203](/article/10.1007/s13668-024-00548-6#ref-CR203)], both decreasing the availability of fatty acids to accumulate as triglycerides in the liver.

### Effects on Other Pathologic Conditions

The spiraling world-wide problem of obesity, prediabetes/diabetes, and poor metabolic health is exacerbating incidence and complicating treatment of other chronic diseases; and a root cause is poor nutrition. Low-carbohydrate and ketogenic diet interventions are among the most studied of any dietary patterns with regard to metabolic disease with a surge of new and ongoing studies on the horizon. We highlight just a few of the salient conditions closely associated with obesity that are most responsive to low-carbohydrate diets including type 2 diabetes and its complications. We refer the reader to reviews that examine other pathologic conditions that may benefit from low-carbohydrate dietary patterns, especially ketogenic interventions, as a standalone or an adjunct to conventional therapies. These conditions include but are not limited to type 1 diabetes [[204](/article/10.1007/s13668-024-00548-6#ref-CR204)], cancer [[205](/article/10.1007/s13668-024-00548-6#ref-CR205)], epilepsy [[206](/article/10.1007/s13668-024-00548-6#ref-CR206)], Alzheimer’s [[207](/article/10.1007/s13668-024-00548-6#ref-CR207)], Parkinson’s [[208](/article/10.1007/s13668-024-00548-6#ref-CR208)], multiple sclerosis [[209](/article/10.1007/s13668-024-00548-6#ref-CR209)], traumatic brain injury [[210](/article/10.1007/s13668-024-00548-6#ref-CR210)], rheumatologic arthritis [[211](/article/10.1007/s13668-024-00548-6#ref-CR211)], spinal cord injury [[212](/article/10.1007/s13668-024-00548-6#ref-CR212)], and psychiatric disorder [[213](/article/10.1007/s13668-024-00548-6#ref-CR213)].

#### Type 2 Diabetes

One of the more salient examples of a therapeutic dietary pattern is that of low-carbohydrate ketogenic diets in the management of T2D. Ketogenic diets were used over a hundred years ago in the treatment of diabetes before the discovery of insulin [[214](/article/10.1007/s13668-024-00548-6#ref-CR214)], but only in the last 5 years has this knowledge been officially recognized by professional organizations [[215](/article/10.1007/s13668-024-00548-6#ref-CR215)]. Starting with short-term in-patient case studies of people with obese T2D demonstrating striking improvements published in the 1970s [[216](/article/10.1007/s13668-024-00548-6#ref-CR216)] and again in the early part of the century [[182](/article/10.1007/s13668-024-00548-6#ref-CR182)] to a plethora of longer term outpatient ketogenic diet interventions over the course of the last 20 years [217,218,[219](/article/10.1007/s13668-024-00548-6#ref-CR219)], it is hard not to consider carbohydrate restriction as the default treatment of choice [[220](/article/10.1007/s13668-024-00548-6#ref-CR220)]. It is worth noting that low-carbohydrate dietary patterns often reverse T2D while promoting significant weight loss, discontinuing insulin and other glucose-lowering medications, improving cardio-metabolic risk markers, and reducing overall healthcare costs [[221](/article/10.1007/s13668-024-00548-6#ref-CR221)].

In one of the longer studies published to date, after 2-yr a group of 262 individuals with T2D were counseled to consume a ketogenic diet using a remote virtual care platform that included medical supervision and medication deprescription, demonstrated T2D reversal in over half the people, defined as having an HbA1c below 6.5% while taking no diabetes medication or only metformin. These individuals also achieved substantial weight loss, improved cardiovascular risk factors, and reduced or eliminated the use of insulin medication [[7](/article/10.1007/s13668-024-00548-6#ref-CR7)], with patient retention remaining high (83% at 1; 74% at 2 years).

The chronic complications of T2D that decrease health span, notably heart disease and chronic kidney disease (CKD), should also be alleviated by the improved glucose regulation achieved by a low-carbohydrate dietary pattern, but direct evidence of such a connection is still limited as such studies would likely take many years, if not decades to complete. There is however growing interest in examining the role of low-carbohydrate ketogenic dietary patterns in individuals with heart failure and CKD as discussed next.

#### Heart Failure

Diabetes increases the risk of developing the clinical syndrome heart failure, which affects > 6 million Americans, and is characterized by dyspnea and exercise intolerance. There is very little evidenced-based therapy to guide management of patients with heart failure who maintain preserved ejection fraction, which represents about half of all heart failure patients. Based on several new lines of research, ketogenic-based strategies may be an effective therapy by optimizing myocardial metabolism and cardiac function.

The heart, regardless of its health status, utilizes ketones in proportion to arterial concentration, and the failing heart increasingly relies on ketones [[222](/article/10.1007/s13668-024-00548-6#ref-CR222), [223](/article/10.1007/s13668-024-00548-6#ref-CR223)]. Euketonemia may be a key feature of the ketogenic diet that confers therapeutic effects on the heart [[224](/article/10.1007/s13668-024-00548-6#ref-CR224), [225](/article/10.1007/s13668-024-00548-6#ref-CR225)]. In addition to being a uniquely efficient fuel source for the heart [[226](/article/10.1007/s13668-024-00548-6#ref-CR226)], ketones likely have specific cardio-protective and therapeutic effects on the heart [[227](/article/10.1007/s13668-024-00548-6#ref-CR227)]. This is noteworthy because the pathophysiology of heart failure is characterized by impaired fatty acid oxidation [[228](/article/10.1007/s13668-024-00548-6#ref-CR228)]. In both patients with heart failure and healthy controls, infusion of BHB-salts into the range of nutritional ketosis significantly improved hemodynamic and functional measures of heart function in a dose-response manner [[229](/article/10.1007/s13668-024-00548-6#ref-CR229)]. Using exogenous ketone esters, two recent studies also showed that a single serving that achieved euketonemia resulted in improved cardiac function in healthy adults [[230](/article/10.1007/s13668-024-00548-6#ref-CR230), [231](/article/10.1007/s13668-024-00548-6#ref-CR231)].

Another line of evidence connecting ketones to improved cardiovascular disease is the observation that sodium-glucose co-transporter 2 (SGLT2) inhibitor drugs reduce hospitalizations and mortality in patients with diabetes [[232](/article/10.1007/s13668-024-00548-6#ref-CR232), [233](/article/10.1007/s13668-024-00548-6#ref-CR233)], and heart failure patients without diabetes [[234](/article/10.1007/s13668-024-00548-6#ref-CR234)]. This class of drugs induces euketoemia increasing production of ketones into the lower range of nutritional ketosis, which has been hypothesized to account for beneficial CVD effects in humans [[232](/article/10.1007/s13668-024-00548-6#ref-CR232)]. Cardiovascular benefits of SGLT2 inhibitors may also be attributed to increased diuresis and natriuresis, decreased blood pressure and adiposity, lower glucose and insulin, decreased triglycerides, increased HDL-C, decreased inflammation, and oxidative stress. It is noteworthy that these SGLT2 inhibitor-induced physiological effects mirror the responses to a ketogenic diet.

#### Chronic Kidney Disease

Approximately 40% of adults with T2D will develop CKD and 14% of U.S. adults (~35.5 million individuals) are estimated to have CKD. As many as 9 in 10 adults with CKD remain unaware of their condition, highlighting a significant lack of awareness and diagnosis. CKD is the leading cause of end-stage renal disease (ESRD). Metabolic, hemodynamic, growth, and proinflammatory factors contribute to the pathogenesis of diabetic nephropathy, damaging glomeruli, tubuli, interstitium, and vasculature. Hyperglycemia leads to tissue alteration and fibrosis through advanced glycated end products and glucose metabolism byproducts. Intraglomerular hypertension results from altered arteriolar tone, with insulin playing a role in hyperfiltration. Reducing hyperglycemia is associated with glycemic control benefits and is one method to limit factors in nephropathy development [[235](/article/10.1007/s13668-024-00548-6#ref-CR235)].

Considering the therapeutic effects of a ketogenic diet in T2D, it is not surprising that the published research to date also supports a beneficial effect in kidney disease [[236](/article/10.1007/s13668-024-00548-6#ref-CR236)]. Polycystic kidney disease (PKD) is a form of CKD with limited therapeutic options that shows remarkable improvement in response to several interventions that achieve euketonemia [[237](/article/10.1007/s13668-024-00548-6#ref-CR237)]. In the recently published KETO-ADPKD study, a randomized controlled trial in patients with PKD, a ketogenic diet was shown to decrease body fat and liver fat and increase kidney function compared to a control group [[238](/article/10.1007/s13668-024-00548-6#ref-CR238)], and patients rated the ketogenic diet as "highly feasible".

#### Women’s Reproductive Health

Another condition closely associated with obesity and insulin resistance is Polycystic Ovary Syndrome (PCOS), which affects over 1 in 10 women worldwide. Women diagnosed with PCOS are at a greater risk of high blood pressure (30%) [[239](/article/10.1007/s13668-024-00548-6#ref-CR239)], insulin resistance (70%) [[240](/article/10.1007/s13668-024-00548-6#ref-CR240)], non-alcoholic fatty liver disease (43%) [[241](/article/10.1007/s13668-024-00548-6#ref-CR241)], depression (64%) and anxiety (57%) [[242](/article/10.1007/s13668-024-00548-6#ref-CR242)], overweight or obesity (38-88%) [[240](/article/10.1007/s13668-024-00548-6#ref-CR240)], and even endometrial cancer (270%). These comorbidities contribute to over $5 billion dollars to the annual healthcare burden in the US. Weight loss is strongly advocated for symptom management. However, more extended adherence to carbohydrate-restriction in PCOS appears to offer additional significant benefits. A 12-wk pilot trial demonstrated that a carbohydrate-restriction, without pharmaceutical assistance, positively regulated menstrual cycles to a comparable extent as a mixed diet with pharmaceutically-treated PCOS. Notably, the ketogenic diet exhibited favorable changes in glucose control and body weight [[243](/article/10.1007/s13668-024-00548-6#ref-CR243)]. Another single-arm trial spanning 12 weeks, involving 14 women with PCOS, highlighted the feasibility and non-pharmacological efficacy of carbohydrate-restriction interventions. This approach led to improvements in body weight, body composition, insulin sensitivity, cardiometabolic risk, and specific female circulating hormones [[244](/article/10.1007/s13668-024-00548-6#ref-CR244)]. In a 24-week study with 11 women enrolled in a carbohydrate-restriction intervention, positive reductions in testosterone, luteinizing hormone: follicle-stimulating hormone, and fasting insulin were observed by the study's end, indicating potential long-term benefits for women with PCOS [[245](/article/10.1007/s13668-024-00548-6#ref-CR245)]. A study focusing on nutrient-dense, whole-food carbohydrate-restriction versus fat-restriction reported improvements in weight, BMI, body composition, and blood parameters among pre-menopausal women after six weeks. Interestingly, changes in self-reported menstrual patterns were predominantly noted among carbohydrate-restricted participants, suggesting potential unique effects of nutritional ketosis, independent of weight loss, on female reproductive physiology.

## Benefits of Combining Exercise with Diet

As overviewed in the previous section, nutritional considerations are paramount in the context of major weight loss, but it is important to also consider the role of exercise. It seems reasonable to speculate that regular exercise may promote weight loss, but an equally plausible hypothesis is that a healthy weight enables people to be more active. There may be truth to both perspectives. Surprisingly, when a sedentary person performs an exercise training program the vast majority of studies indicate that regular physical activity, in the absence of dietary intervention, is not effective at promoting clinically significant weight loss in the majority of people [[20](/article/10.1007/s13668-024-00548-6#ref-CR20), [22](/article/10.1007/s13668-024-00548-6#ref-CR22), [23](/article/10.1007/s13668-024-00548-6#ref-CR23), [246](/article/10.1007/s13668-024-00548-6#ref-CR246)].

Why the caloric expenditure associated with performing structured exercise fails to translate into a predictable weight loss (i.e., assumes a 3,500 kcal deficit results in a 1-pound fat loss) remains unclear. There is likely a genetic component to how people with excess adiposity translate exercise into weight loss. For example, in a remarkable identical twin metabolic ward study, obese siblings lost a similar amount of weight but only ~20–30% of twin pairs lost the predicted amount of weight in response to a precisely monitored exercise dose (640 kcal/day), whereas some twin pairs lost almost no weight [[247](/article/10.1007/s13668-024-00548-6#ref-CR247)]. This is consistent with evidence supporting a restraint on human metabolic rate in individuals who are extremely active [[248](/article/10.1007/s13668-024-00548-6#ref-CR248)] and larger studies that show only about a quarter of participants exercising at a high dose do not compensate (i.e., they lose weight in response to exercise) [[25](/article/10.1007/s13668-024-00548-6#ref-CR25)]. Ironically, the “compensatory” responses to exercise that contribute to minimal weight loss appear to be more robust in people with greater adiposity [[30](/article/10.1007/s13668-024-00548-6#ref-CR30)], making weight loss even more challenging. The mechanisms underlying compensation likely involve an increase in appetite and subsequent caloric intake [[26](/article/10.1007/s13668-024-00548-6#ref-CR26), [27](/article/10.1007/s13668-024-00548-6#ref-CR27)] as well as a decrease in resting energy expenditure [[28](/article/10.1007/s13668-024-00548-6#ref-CR28), [29](/article/10.1007/s13668-024-00548-6#ref-CR29)].

Regardless of the poor effects of exercise alone on weight loss, incorporating regular physical activity into a weight loss plan may have other benefits such as assisting in weight maintenance and improving body composition and health outcomes. We briefly discuss the literature on both endurance/aerobic and resistance/strength training and focus on studies that compared background diets that emphasized low-fat/high-carbohydrate versus low-carbohydrate/high-fat.

### Endurance Exercise

While endurance training alone is a weak weight loss tool for many, it has been shown to slightly augment fat loss and retention of lean mass [[249](/article/10.1007/s13668-024-00548-6#ref-CR249)] and is associated with a myriad of health benefits. The majority of studies that examined combined diet interventions and exercise training on weight loss followed nutritional principles consistent with a low-fat/low saturated fat national guidelines-recommended eating plan.

Large multi-site studies of intensive lifestyle diet and exercise studies have shown slightly better outcomes than exercise alone [[20](/article/10.1007/s13668-024-00548-6#ref-CR20)]. For example, the Look AHEAD study was an RCT in > 5,000 overweight/obese participants with type 2 diabetes who were randomized to an intensive lifestyle intervention (ILI) consisting of low-fat caloric restriction, physical activity (> 175 min/wk, 10,000 steps/day), and behavior modification or a control group who received standard diabetes education. After 1-yr the ILI group lost significantly more weight than the control group (8.6% vs 0.7%, respectively), but the ILI gained about half that weight back after 4-years. At 8-yr, weight loss was 4.7% for ILI and 2.1% in Controls [[44](/article/10.1007/s13668-024-00548-6#ref-CR44)]. The Look AHEAD trial was stopped early because there were no cardiovascular benefits observed in ILI.

Despite a high-intensity of interaction with participants, especially during the weight loss phase, the general failure of Look AHEAD to achieve robust weight maintenance and health benefits may have been attributed to prescribing a diet that heavily emphasized low-fat, especially saturated fat. The participants in Look AHEAD were insulin resistant, which as mentioned in the previous section, manifests as a form of carbohydrate intolerance and is much more responsive to a low-carbohydrate eating pattern. Although speculative, it remains unknown if better results would have been possible if the diet prescription focused on carbohydrate restriction. Preliminary 5-year data demonstrated clinically significant weight loss, cardiometabolic health and blood glucose control improvement, and medication deprescription was shown in a similar population provided intensive education on a low-carbohydrate ketogenic diet [[57](/article/10.1007/s13668-024-00548-6#ref-CR57)].

While low-carbohydrate diets have a strong track record in promoting equal or superior weight and fat loss than low-fat diets, there are fewer studies addressing combined low-carbohydrate intake with endurance training. It should be noted that sports nutrition guidelines strongly encourage high-carbohydrate feeding for athletes [[21](/article/10.1007/s13668-024-00548-6#ref-CR21)] based on the belief, albeit one that has been repeatedly refuted [[250](/article/10.1007/s13668-024-00548-6#ref-CR250)], that frequent carbohydrate feeding is requisite to perform and optimally adapt to training. Several studies have demonstrated at least equal performance with a low-carbohydrate compared to a high-carbohydrate diet if people are allowed to adapt for at least 4-weeks [[84](/article/10.1007/s13668-024-00548-6#ref-CR84), [251](/article/10.1007/s13668-024-00548-6#ref-CR251)]. It has also been observed that the combination of a low-carbohydrate diet and endurance training markedly enhances fat oxidation and often results in weight and fat loss even when prescribed ad libitum [251,252,[253](/article/10.1007/s13668-024-00548-6#ref-CR253)].

### Resistance Exercise

Similar to endurance exercise, resistance training alone is not advocated as a primary method of weight loss [[22](/article/10.1007/s13668-024-00548-6#ref-CR22)], but it does augment retention of lean mass during major weight loss, and thereby improves body composition [[32](/article/10.1007/s13668-024-00548-6#ref-CR32)] while also promoting numerous health benefits. Again, the majority of diet and resistance training studies examining weight loss were performed in the context of moderate-to-high carbohydrate and low-fat intakes, but a few low-carbohydrate diet interventions have been published recently.

According to recent meta-analyses examining resistance training combined with either a ketogenic or non-ketogenic diet, there was an overall greater loss of body mass, fat mass, percent body fat, and lean body mass in individuals assigned to a ketogenic diet [[254](/article/10.1007/s13668-024-00548-6#ref-CR254), [255](/article/10.1007/s13668-024-00548-6#ref-CR255)]. While the decrease in body fat is desirable, the usual interpretation of decreased lean mass in response to a low-carbohydrate, especially ketogenic, diet is negative [[254](/article/10.1007/s13668-024-00548-6#ref-CR254)], attributed to a loss of contractile proteins secondary to reduced insulin secretion and anabolic signaling. However, is the loss of lean tissue on a ketogenic diet during training maladaptive or even a real phenomenon? Four unappreciated points are warranted to properly contextualize the lean mass response to a ketogenic diet.

First, loss of lean mass in response to a ketogenic diet is often accompanied by an overall greater loss in body mass, such that body composition (i.e., percent body fat) improves [[254](/article/10.1007/s13668-024-00548-6#ref-CR254), [255](/article/10.1007/s13668-024-00548-6#ref-CR255)]. Second, many ketogenic diet studies fail to provide adequate mineral requirements, especially the increased sodium requirements and adequate potassium unique to the ketogenic diet, which in turn compromises muscle protein anabolism [[192](/article/10.1007/s13668-024-00548-6#ref-CR192)]. Third, loss of a certain amount of lean tissue is expected whenever there is significant fat loss because adipose tissue consists of ~5% protein and 15% water by weight. Fourth, decreased lean mass is at least partially an artifact of greater water loss on a ketogenic diet [[83](/article/10.1007/s13668-024-00548-6#ref-CR83)] vis-a-vis the renal natriuretic and diuretic effect of carbohydrate restriction, as well as water loss associated with breakdown of intramuscular glycogen. As previously mentioned, DXA detects water as lean mass, and therefore is subject to specious findings in the context of even modest fluid shifts [[256](/article/10.1007/s13668-024-00548-6#ref-CR256), [257](/article/10.1007/s13668-024-00548-6#ref-CR257)].

A relevant example comes from a resistance training study that demonstrated participants consuming a 10-wk ketogenic diet had numerically lower (but not statistically different) DXA-determined lean body mass as a mixed diet group (2.2% vs 4.4%, respectively) [[258](/article/10.1007/s13668-024-00548-6#ref-CR258)]. An interesting feature of this trial was that the ketogenic diet group reintroduced carbohydrate from Week 10 to 11. During this 1-wk period they demonstrated a tripling of lean body mass such that the delta increase from baseline to Week-11 was greater in the ketogenic diet group (7.3% vs 3.6%). One week of carbohydrate feeding would be expected to increase insulin, potentiating an anti-diuretic effect, as well as promoting storage of glycogen and water in muscle cells; all of which would be detected as lean mass by DXA [[256](/article/10.1007/s13668-024-00548-6#ref-CR256), [257](/article/10.1007/s13668-024-00548-6#ref-CR257)]. This effect, operating in reverse, partially explains the loss of lean mass in many ketogenic diet and resistance training studies. This interpretation seems even more probable considering that functional measures of strength and power in response to resistance training are not compromised by a ketogenic diet [[195](/article/10.1007/s13668-024-00548-6#ref-CR195), [258](/article/10.1007/s13668-024-00548-6#ref-CR258), [259](/article/10.1007/s13668-024-00548-6#ref-CR259)].

In fact, the combination of a carbohydrate-restricted diet and resistance training optimizes body composition resulting in the greatest decreases in whole body adiposity and percent body fat [[195](/article/10.1007/s13668-024-00548-6#ref-CR195), [260](/article/10.1007/s13668-024-00548-6#ref-CR260)], including significant loss of visceral fat, while shifting skeletal muscle mitochondrial function and efficiency towards fat oxidation in conjunction with improved insulin sensitivity [[261](/article/10.1007/s13668-024-00548-6#ref-CR261)].

In summary, endurance and resistance training are not effective primary methods of weight loss for most people, but research supports a consistent benefit of exercise when combined with diet, especially resistance training, on weight maintenance, lean mass and physical performance. Although there is more debate surrounding the optimal dietary macronutrient distribution, there is preliminary evidence supporting the combination of a low-carbohydrate diet with resistance training to maximize fat loss and retention of lean while improving many cardiometabolic risk factors.

## Limitations

The high prevalence of obesity and associated disorders is a major problem many humans are facing. No single weight loss approach is suitable for all people with excess adiposity given the heterogeneity of response to diet and exercise. A major limitation in the literature is the lack of attention on identifying methods of tailoring approaches that are most effective for the individual. There are also inherent challenges in conducting diet interventions and exercise training studies owing to the difficulties in accurately monitoring and achieving long-term compliance and adherence. There is also the high cost and complexity of conducting long-term studies that has limited the number of diet options that can be studied to mostly low-fat eating patterns. No federally funded studies have examined the effects of a low-carbohydrate eating pattern for more than a couple years. Other limitations relate to the need for increased attention on assessing body composition in weight loss studies, which is generally not the case for many surgical and drug studies. There is a challenge of accurately quantifying lean and fat mass during weight loss given the potential for large artifactual errors associated with some body composition assessment methods including DXA.

## Summary

In summary, an impressive amount of scientific evidence now supports low-carbohydrate dietary patterns that contain moderate protein (1.2 to 2.0 g/kg reference weight) from food sources with high biological value as effective for promoting clinically meaningful decreases in adiposity without unwanted muscle mass loss. Low carbohydrate dietary patterns, especially those that achieve a natural state of _euketonemia_ , also improve many pathologic conditions, notably type 2 diabetes and other conditions related to insulin resistance. The landscape of low-carbohydrate and ketogenic diet research now extends beyond the well-established research in epilepsy, weight loss, and type 2 diabetes to new frontiers that include conditions such as type 1 diabetes, cancer, epilepsy, Alzheimer's, Parkinson's, multiple sclerosis, traumatic brain injury, rheumatologic arthritis, spinal cord injury, and psychiatric disorders. Whether these conditions demonstrate the same robust therapeutic effects remains to be seen, but we believe these investigations hold the potential to uncover additional beneficial metabolic and physiological effects that broaden our understanding of therapeutic nutrition. As the scientific community delves into these emerging areas, collaboration between researchers, healthcare practitioners, and policymakers is crucial to translate findings into accessible and effective interventions that promote individual and global well-being.

## Data Availability

No datasets were generated or analysed during the current study.

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Volek, J.S., Kackley, M.L. & Buga, A. Nutritional Considerations During Major Weight Loss Therapy: Focus on Optimal Protein and a Low-Carbohydrate Dietary Pattern. _Curr Nutr Rep_ **13** , 422–443 (2024). https://doi.org/10.1007/s13668-024-00548-6

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# Semaglutide and muscle loss

November 29, 2024February 9, 2024 by [Dr. VanSickle](https://bmidoctors.com/author/dr-vansickle/ "View all posts by Dr. VanSickle")

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**Section 1: Introduction**

Semaglutide, a revolutionary drug initially approved for the treatment of type 2 diabetes, has more recently garnered widespread attention for its efficacy in weight management and obesity treatment. As a glucagon-like peptide-1 (GLP-1) receptor agonist, semaglutide mimics the action of the GLP-1 hormone, which is naturally produced in the gut and plays a pivotal role in regulating blood sugar levels and appetite. Its introduction into the pharmaceutical market under brand names like Ozempic, Rybelsus, and Wegovy has not only transformed the therapeutic landscape for individuals with type 2 diabetes but also offered a new beacon of hope for those struggling with weight loss challenges.

The mechanism of action of semaglutide is multifaceted, affecting both glucose metabolism and appetite regulation. By stimulating insulin release, inhibiting glucagon secretion, and delaying gastric emptying, semaglutide helps in controlling blood glucose levels and reducing appetite, thereby leading to a decrease in overall caloric intake. This dual effect facilitates significant weight loss, a beneficial side effect that has been a game-changer for obesity management. However, with the rise in its popularity and widespread use, concerns have emerged regarding its impact on muscle mass, an important consideration for overall health and metabolic function.

Muscle mass plays a critical role in maintaining metabolic health, physical strength, and quality of life. It influences everything from basal metabolic rate to physical stability and function. In the context of weight loss, preserving muscle mass while shedding fat is paramount to ensure the weight loss is healthy and sustainable. The concern with semaglutide and similar weight-loss medications lies in the potential for these drugs to not only promote fat loss but also inadvertently contribute to muscle wasting or loss, which could counteract the benefits of weight reduction. 

This introductory section sets the stage for a deep dive into the nuanced relationship between semaglutide and muscle mass. The ensuing discussion will explore the pharmacological effects of semaglutide, scrutinize the existing research on its impact on body composition, and address the prevalent concerns and questions regarding its use. Given the drug's significant benefits in managing diabetes and obesity, understanding its full spectrum of effects is essential for maximizing its therapeutic potential while mitigating any adverse outcomes. As semaglutide continues to be a subject of interest for healthcare professionals and patients alike, clarifying its implications on muscle mass is crucial for informed decision-making and optimizing treatment outcomes.

## 

**Section 2: Understanding Semaglutide**

Semaglutide represents a significant advancement in the pharmacological management of type 2 diabetes and obesity, belonging to the class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists. Its development was rooted in the understanding of the incretin system, which plays a vital role in glucose homeostasis. Incretins, among which GLP-1 is key, are hormones that modulate insulin secretion in response to food intake, thereby reducing blood sugar levels. Semaglutide's mechanism of action is designed to exploit this natural pathway, offering a therapeutic strategy that aligns closely with the body's own regulatory processes.

At the molecular level, semaglutide operates by binding to and activating the GLP-1 receptor. This activation has several effects: it stimulates insulin secretion from the pancreas in a glucose-dependent manner, meaning insulin is released only when blood sugar levels are elevated. Simultaneously, it suppresses the secretion of glucagon, a hormone that increases blood glucose levels by promoting the release of glucose stored in the liver. Furthermore, semaglutide slows gastric emptying, the rate at which food exits the stomach and enters the small intestine. This action prolongs the sensation of fullness post-meal, effectively reducing appetite and caloric intake, which is a cornerstone of its weight loss properties.

The development and approval of semaglutide were based on extensive clinical trials that demonstrated its efficacy in improving glycemic control in patients with type 2 diabetes and facilitating significant weight loss in individuals with obesity. Its introduction has been met with enthusiasm, as it addresses two of the most pressing public health issues globally: diabetes and obesity. However, the drug's impact extends beyond these primary indications, affecting various aspects of metabolism and body composition, including muscle mass.

Understanding the pharmacodynamics and pharmacokinetics of semaglutide is crucial for healthcare professionals to optimize its use in clinical practice. The drug's long half-life allows for once-weekly dosing, a significant advantage in terms of patient compliance and ease of use compared to other diabetes medications that require daily or more frequent administration. This pharmacokinetic property is achieved through structural modifications that make semaglutide resistant to enzymatic degradation and extend its duration of action. 

Despite its benefits, the widespread adoption of semaglutide has sparked discussions around its broader metabolic effects, particularly concerning muscle mass. The concern stems from the recognition that muscle tissue plays a vital role in metabolic health, insulin sensitivity, and overall physical function. Given semaglutide's mechanism of reducing caloric intake and promoting weight loss, understanding its direct and indirect effects on muscle tissue is paramount. This section has laid the groundwork for exploring these concerns by detailing semaglutide's pharmacological profile, setting the stage for a closer examination of its impact on body composition and, specifically, on muscle mass.

## 

**Section 3: Semaglutide and Weight Loss**

Semaglutide's role in weight loss is a remarkable aspect of its clinical use, drawing significant interest from the medical community and the public alike. Its approval for the treatment of obesity marked a pivotal moment in the battle against this global health issue. Obesity, characterized by excessive fat accumulation, poses a major risk for numerous chronic diseases, including type 2 diabetes, cardiovascular diseases, and certain forms of cancer. The mechanism by which semaglutide facilitates weight loss is rooted in its action on the GLP-1 receptors, which influence appetite regulation and caloric intake.

Clinical trials have robustly demonstrated the efficacy of semaglutide in promoting significant weight loss. Participants in these studies, many of whom were obese or overweight, showed notable reductions in body weight when treated with semaglutide compared to those receiving a placebo. These outcomes are attributed to semaglutide's ability to decrease appetite, leading to a lower caloric intake and a subsequent energy deficit, which is essential for weight loss. Additionally, by slowing gastric emptying, semaglutide extends the feeling of satiety after meals, further contributing to reduced food consumption.

The weight loss experienced by patients on semaglutide is not merely a by-product of diminished appetite; it also aligns with improvements in various metabolic parameters. Studies have shown that semaglutide treatment is associated with reductions in waist circumference, an indicator of visceral fat, and improvements in glycemic control, lipid profiles, and blood pressure. These changes underscore the drug's potential in addressing the multifaceted health challenges posed by obesity and metabolic syndrome.

However, the impact of semaglutide on weight loss extends beyond the physical. The significant weight reduction achieved with semaglutide has been linked to improvements in quality of life, including better mobility, mood, and self-esteem. These psychosocial benefits are crucial for the holistic management of obesity, which often carries a significant psychological burden. 

Despite the clear benefits of semaglutide for weight management, its widespread use for this purpose raises important considerations. The reduction in body weight predominantly reflects a decrease in fat mass, but the implications for lean muscle mass are a topic of ongoing research and debate. Maintaining muscle mass during weight loss is critical for metabolic health, physical strength, and functionality. Thus, understanding the nuances of how semaglutide affects body composition beyond fat loss is essential for optimizing its benefits while minimizing potential downsides.

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## 

**Section 4: Concerns about Muscle Loss**

The concern regarding muscle loss in patients using semaglutide for weight management is grounded in the broader context of weight loss strategies. Generally, weight loss can be achieved through various means, including caloric restriction, increased physical activity, and pharmacological interventions. However, an ideal weight loss regimen not only reduces fat mass but also preserves, or even enhances, lean muscle mass. Muscle tissue plays a crucial role in overall health, metabolism, physical strength, and disease resilience. Thus, any weight loss intervention's impact on muscle mass is a critical consideration.

The mechanism of action of semaglutide, primarily through appetite suppression and delayed gastric emptying, inherently focuses on reducing caloric intake. While this approach effectively leads to weight loss, it raises questions about its impact on muscle mass. In the state of caloric deficit required for weight loss, the body may resort to utilizing muscle protein as an energy source, especially if dietary protein intake is inadequate. This potential for muscle loss is a concern for healthcare providers and patients alike, as it could undermine the metabolic benefits of weight loss and impair physical function.

Research into the effects of semaglutide on muscle mass is ongoing, with studies offering mixed results. Some clinical trials and observational studies have aimed to dissect the components of weight loss induced by semaglutide, examining changes in fat mass and lean mass separately. Preliminary findings suggest that while semaglutide primarily targets fat loss, its effect on muscle mass may vary depending on several factors, including diet, exercise, and the baseline metabolic health of the patient.

Nutritional considerations play a pivotal role in mitigating the risk of muscle loss during weight loss therapy with semaglutide. Adequate protein intake is essential for muscle protein synthesis and the maintenance of lean muscle mass during periods of caloric deficit. Therefore, dietary counseling and personalized nutrition plans become integral components of a comprehensive weight management strategy involving semaglutide.

Moreover, the incorporation of resistance training and physical exercise is paramount in preserving muscle mass. Exercise, particularly strength training, stimulates muscle protein synthesis and can offset the potential catabolic effects of a caloric deficit on muscle tissue. This synergy between pharmacological intervention and lifestyle modification highlights the multidimensional approach required for optimal weight loss outcomes. While semaglutide presents a promising tool for addressing obesity, concerns about muscle loss underscore the need for a balanced and integrated approach to weight management. Ongoing research and clinical practice continue to refine our understanding of how to leverage semaglutide's benefits while safeguarding muscle health, ensuring that weight loss achieved is not only significant but also sustainable and health-promoting.

## 

**Section 5: The Impact of Semaglutide on Body Composition**

The impact of semaglutide on body composition extends beyond simple weight reduction, touching upon the critical balance between fat loss and muscle preservation. This balance is crucial for metabolic health, physical functionality, and overall well-being. Semaglutide's ability to induce weight loss primarily through fat reduction while potentially influencing muscle mass is a subject of significant scientific interest. The exploration of its effects on body composition is grounded in a growing body of research aiming to delineate the outcomes of semaglutide treatment in terms of fat mass, lean mass, and overall body composition changes.

Clinical trials and observational studies have provided insights into how semaglutide modifies body composition. These studies typically utilize dual-energy X-ray absorptiometry (DEXA) scans or bioelectrical impedance analysis (BIA) to accurately measure changes in fat mass and lean muscle mass among participants. The evidence suggests that semaglutide's effect on weight loss is predominantly attributed to a reduction in fat mass, particularly visceral fat, which is closely linked to metabolic disorders such as type 2 diabetes and cardiovascular disease. This reduction in adiposity is a positive outcome, reflecting the drug's potential to improve metabolic health markers and reduce the risk of obesity-related complications.

However, the question of muscle mass within the context of semaglutide treatment is more nuanced. The preservation of lean muscle mass during any weight loss program is essential, as muscle plays a vital role in maintaining basal metabolic rate, physical strength, and resilience against metabolic diseases. Initial studies indicate that semaglutide, while effective at reducing fat mass, does not significantly impact lean muscle mass when appropriate dietary protein intake and physical activity are maintained. Some research even suggests a potential for slight improvements in muscle composition, likely due to the enhanced physical activity that becomes feasible as patients lose weight and improve their metabolic health.

The distinction between semaglutide's effects on fat and muscle tissues underscores the importance of comprehensive management strategies in treating obesity. For individuals on semaglutide, monitoring body composition changes is essential to ensure that weight loss is health-promoting and sustainable. Healthcare providers are encouraged to assess changes in muscle mass and function, adjusting treatment protocols to include nutritional counseling and exercise recommendations tailored to preserve or even enhance lean muscle mass.

Moreover, the role of semaglutide in improving physical capabilities and exercise tolerance cannot be overlooked. As patients experience weight loss, their ability to engage in physical activities often improves, contributing to a positive feedback loop where increased activity further supports muscle maintenance and overall health. The interplay between semaglutide-induced weight loss, improved exercise capacity, and muscle mass preservation forms a foundational pillar for the holistic treatment of obesity, emphasizing the drug's potential within an integrated care model. The impact of semaglutide on body composition highlights the drug's capacity to target adiposity while supporting the maintenance of lean muscle mass, provided that patients adhere to comprehensive lifestyle interventions. This nuanced understanding of semaglutide's effects is pivotal for leveraging its benefits fully, ensuring that weight loss achieved is not only significant but also aligned with broader health goals.

## 

**Section 6: Strategies to Prevent Muscle Loss with Semaglutide**

As semaglutide continues to gain popularity for its efficacy in treating obesity and type 2 diabetes, a strategic approach to prevent potential muscle loss becomes imperative. Understanding that muscle mass plays a critical role in metabolic health, physical strength, and overall well-being, healthcare professionals and patients alike seek strategies to maintain and even build muscle while losing weight with semaglutide. This section outlines comprehensive strategies encompassing diet, exercise, and lifestyle modifications to mitigate the risk of muscle loss during treatment.

**Dietary Considerations:**

The foundation of preventing muscle loss lies in nutrition, particularly in ensuring adequate protein intake. Protein is essential for muscle repair and growth, and its importance escalates when the body is in a caloric deficit due to semaglutide-induced appetite suppression. Healthcare professionals recommend a diet rich in high-quality protein sources, such as lean meats, fish, dairy, legumes, and plant-based alternatives, to support muscle protein synthesis. The recommended daily protein intake can vary based on individual factors, but general guidelines suggest 1.2 to 2.0 grams of protein per kilogram of body weight, especially for those engaging in regular resistance training.

**Resistance Training:**

Exercise, especially resistance training, is a critical component of a strategy to preserve muscle mass. Resistance training stimulates muscle growth through adaptive responses to stress, increasing muscle strength and size. For patients on semaglutide, incorporating a regular routine of resistance exercises—such as weightlifting, bodyweight exercises, or resistance band workouts—can help counteract any potential muscle catabolism caused by a caloric deficit. Engaging in resistance training 2-3 times per week is generally recommended, with adjustments made for individual fitness levels and health conditions.

**Cardiovascular Exercise:**

While the primary focus for preventing muscle loss is resistance training, cardiovascular exercise should not be neglected. Moderate-intensity cardio activities, such as walking, cycling, or swimming, can enhance heart health, improve metabolic efficiency, and support weight loss efforts. However, it's crucial to balance cardio exercise with resistance training to ensure that fat loss is maximized without compromising muscle mass.

**Nutritional Supplements:**

In some cases, nutritional supplements may be beneficial in supporting muscle preservation. Branched-chain amino acids (BCAAs), creatine, and whey protein are popular supplements that can aid in muscle recovery and growth. Nonetheless, it's important to consult with a healthcare professional before incorporating any supplements into the diet, as they should complement a well-rounded nutritional plan rather than replace whole food sources.

**Regular Monitoring and Adjustment:**

Regular monitoring of body composition and health parameters is vital for individuals on semaglutide. Healthcare providers can use tools such as DEXA scans or BIA to assess changes in fat and muscle mass, adjusting dietary, exercise, and treatment plans as necessary to ensure optimal health outcomes. Tailoring the approach to each individual's needs, preferences, and medical conditions is essential for success in preventing muscle loss while achieving significant weight loss. 

Incorporating these strategies into the treatment plan for patients on semaglutide can significantly mitigate the risk of muscle loss, ensuring that the journey towards weight loss is both effective and health-promoting. By emphasizing a holistic approach that includes dietary adjustments, targeted exercise, and lifestyle modifications, patients and healthcare professionals can maximize the therapeutic benefits of semaglutide while preserving muscle mass and enhancing overall health.

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## 

**Section 7: Patient Experiences and Case Studies**

The journey of weight loss and health improvement with semaglutide is not just quantified through clinical metrics but also richly illustrated in the narratives of those who have experienced its effects firsthand. Patient experiences and case studies provide invaluable insights into the real-world impact of semaglutide on body composition, lifestyle changes, and overall well-being. These stories serve as qualitative data, offering perspectives on the nuances of treatment that quantitative studies may not fully capture.

One such narrative comes from a middle-aged individual with a long-standing battle against obesity and type 2 diabetes. Before starting semaglutide, the patient had tried numerous diets and exercise regimens, with temporary success but eventual regain of the weight. Upon beginning semaglutide treatment, the patient noted a significant reduction in appetite, which led to a more comfortable adherence to a calorie-restricted diet. Over several months, the patient reported a substantial weight loss of over 20% of their initial body weight. Importantly, this individual also engaged in a structured exercise program, emphasizing resistance training, which they credited with not just aiding in their weight loss but also in feeling stronger and more active than they had in years.

Another case study highlights a young adult who struggled with obesity and the psychological burden it imposed, including low self-esteem and social isolation. After starting treatment with semaglutide, the patient observed noticeable changes in their eating habits, particularly a decreased craving for high-calorie, processed foods. The weight loss achieved through semaglutide, coupled with counseling and support for physical activity, led to significant improvements in mental health, body image, and social interactions. This case underscores the multidimensional benefits of semaglutide treatment when integrated with comprehensive lifestyle interventions.

These personal accounts are complemented by observational studies that monitor the progress of groups of patients on semaglutide. Such studies often reveal a pattern of initial rapid weight loss followed by a stabilization phase, during which patients and healthcare providers work together to maintain the achieved weight loss and continue improving muscle tone and overall health. Importantly, these studies also highlight the variability in response to semaglutide, with some individuals experiencing more significant weight loss and others facing challenges, such as minor side effects or slower progress. 

Patient experiences and case studies collectively emphasize the importance of a personalized approach to using semaglutide for weight loss and health improvement. They reveal that success with semaglutide often involves more than just the medication itself; it requires a holistic strategy that includes dietary management, physical activity, psychological support, and regular monitoring and adjustment of the treatment plan. These narratives serve as a testament to the transformative potential of semaglutide when it is part of an integrated care model tailored to the individual's unique needs and circumstances.

## 

**Section 8: Comparing Semaglutide with Other GLP-1 Agonists**

Semaglutide is part of a broader class of medications known as glucagon-like peptide-1 (GLP-1) receptor agonists, which have transformed the landscape of diabetes and obesity treatment. To fully appreciate semaglutide's place within this class, it's essential to compare it with other GLP-1 agonists, such as liraglutide (Victoza, Saxenda) and dulaglutide (Trulicity), among others. These comparisons shed light on semaglutide's unique features, efficacy, and patient experiences, offering a comprehensive view of its role in managing type 2 diabetes and obesity.

One of the key distinguishing features of semaglutide is its dosing frequency and efficacy. Semaglutide, marketed under names such as Ozempic for diabetes and Wegovy for obesity, is notable for its once-weekly injection, which stands in contrast to the daily administration required by liraglutide. This reduced frequency can significantly enhance patient compliance and convenience, factors that are crucial for long-term treatment success. Furthermore, semaglutide has demonstrated superior efficacy in reducing HbA1c levels and promoting weight loss in head-to-head trials against other GLP-1 agonists. For instance, studies comparing semaglutide with liraglutide have shown that semaglutide is more effective in lowering blood sugar levels and facilitating greater weight loss, making it a preferred option for many patients and clinicians.

Another area where semaglutide shines is in its cardiovascular benefits. Large-scale cardiovascular outcome trials, such as the SUSTAIN-6 trial for semaglutide, have demonstrated not only its safety in patients with cardiovascular disease but also its potential to reduce the risk of major adverse cardiovascular events. This aspect is particularly important for patients with type 2 diabetes, who are at an increased risk for heart disease.

The impact on body composition also varies among GLP-1 agonists, with semaglutide showing promising results in preserving lean muscle mass while promoting fat loss, especially in comparison to its counterparts. This attribute is crucial for the holistic management of obesity, where the goal is not just weight reduction but also the improvement of metabolic health and physical function.

Despite these advantages, the choice of a GLP-1 agonist is not one-size-fits-all. Factors such as individual patient response, side effect profile, insurance coverage, and personal preference play significant roles in medication selection. For example, some patients may experience gastrointestinal side effects with semaglutide, which might be less pronounced with other GLP-1 agonists. Additionally, the cost and insurance coverage of these medications can vary, influencing the accessibility and affordability for patients. 

While semaglutide offers several advantages over other GLP-1 agonists in terms of efficacy, convenience, and potential health benefits, the decision to use it must be individualized, taking into account the patient's specific health profile, treatment goals, and preferences. The ongoing development and comparison of GLP-1 agonists continue to enrich the therapeutic arsenal against diabetes and obesity, enabling personalized and effective treatment strategies.

## 

**Section 9: Future Directions and Research**

The landscape of diabetes and obesity management is rapidly evolving, with semaglutide at the forefront of recent advancements. However, the journey of discovery is far from complete. Future research directions are poised to expand our understanding of semaglutide's mechanisms, optimize its use, explore new therapeutic areas, and address current limitations. This ongoing research is crucial for enhancing patient outcomes, refining treatment protocols, and potentially unveiling novel applications of this medication.

**Optimizing Dosing and Administration** : Current studies are investigating various dosing strategies to maximize efficacy while minimizing side effects. This includes exploring the potential for higher doses to achieve greater weight loss and better glycemic control, as well as assessing the long-term safety of these higher doses. Additionally, research into alternative administration routes, such as oral formulations, aims to improve patient compliance and expand usage scenarios.

**Combination Therapies** : Semaglutide's compatibility with other medications is another area of active research. Combining semaglutide with other weight loss agents or antidiabetic medications could potentially enhance therapeutic outcomes. Studies are focusing on identifying synergistic combinations that could offer superior benefits in terms of weight reduction, glycemic control, and cardiovascular risk reduction.

**Expanding Therapeutic Applications** : Beyond diabetes and obesity, semaglutide shows promise in addressing other metabolic disorders and conditions associated with insulin resistance, such as non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS). Early research suggests that the anti-inflammatory and insulin-sensitizing effects of semaglutide may benefit these conditions, opening new avenues for treatment.

**Understanding Long-term Impacts** : While the immediate benefits of semaglutide on weight loss and glycemic control are well-documented, its long-term effects on body composition, cardiovascular health, and overall mortality are still under investigation. Longitudinal studies are essential to assess the sustained impacts of treatment and to understand any potential risks associated with prolonged use.

**Personalized Medicine Approaches** : Future research aims to identify biomarkers and genetic factors that predict individual responses to semaglutide. This personalized medicine approach could enable healthcare providers to tailor treatments more effectively, ensuring that patients receive the most suitable medication based on their specific metabolic profile and risk factors.

**Addressing Health Disparities** : Investigating the accessibility and effectiveness of semaglutide across different populations is crucial. Research into health disparities aims to ensure equitable access to this medication, considering factors such as socioeconomic status, ethnicity, and geographical location, which may influence treatment outcomes. 

The future research landscape for semaglutide is rich and diverse, encompassing efforts to enhance its efficacy, broaden its applications, and ensure its benefits are accessible and sustainable for all patients. As these research endeavors progress, they promise to deepen our understanding of semaglutide and unlock its full potential in combating some of today's most challenging health conditions.

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## 

**Section 10: Conclusion**

Semaglutide has emerged as a transformative agent in the management of type 2 diabetes and obesity, offering significant benefits in terms of weight loss, glycemic control, and potential cardiovascular protection. Its development and widespread adoption represent a landmark in the ongoing effort to combat the global epidemic of obesity and its associated metabolic disorders. Through the modulation of appetite and insulin secretion, semaglutide addresses core pathophysiological aspects of these conditions, providing a powerful tool for patients and healthcare providers alike.

The impact of semaglutide extends beyond mere numbers on a scale or glycemic indices; it encompasses improved quality of life, enhanced physical capabilities, and, for many, a renewed sense of hope in managing chronic conditions that often seem insurmountable. Patient experiences and case studies underline the transformative potential of this medication, highlighting not just the physiological changes it can induce but also the profound psychological and social benefits.

Comparisons with other GLP-1 receptor agonists have positioned semaglutide as a leading option, due to its efficacy, dosing convenience, and safety profile. However, the journey towards optimizing its use is ongoing. Future research directions, including the exploration of combination therapies, alternative dosing strategies, and expanded indications, promise to further enhance the therapeutic landscape.

As we look to the future, the promise of personalized medicine looms large. The potential to tailor semaglutide treatment based on individual patient characteristics, genetic profiles, and specific health needs could revolutionize its application, ensuring that the right patients receive the most effective treatment regimens. Furthermore, addressing health disparities and ensuring equitable access to this life-changing medication will be crucial in maximizing its public health impact. 

In conclusion, semaglutide stands as a beacon of progress in the fight against diabetes and obesity. Its development is a testament to the power of innovative research and the relentless pursuit of better treatments for complex metabolic diseases. As we continue to explore and understand its full potential, semaglutide not only offers hope for improved health outcomes but also challenges us to reimagine the future of metabolic disease management. [Click to learn more about BMI Doctor cost of semaglutide program!](https://bmidoctors.com/wegovy-ozempic-semaglutide-pricing/)

## 

**Section 11: Research Citations**

The development and application of semaglutide in the treatment of type 2 diabetes and obesity are underpinned by a robust foundation of clinical research. These studies not only highlight the efficacy and safety of semaglutide but also explore its broader impacts on health, including cardiovascular outcomes and body composition changes. This section provides an overview of key research citations that have significantly contributed to our understanding of semaglutide, its benefits, and its place in the therapeutic landscape.

  1. **Marso, S.P., Daniels, G.H., Brown-Frandsen, K., et al.** (2016). "Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes." The New England Journal of Medicine. This landmark study demonstrated the cardiovascular benefits of GLP-1 receptor agonists, setting the stage for further investigation into semaglutide's potential to reduce cardiovascular risk in patients with type 2 diabetes.
  2. **Pratley, R., Aroda, V.R., Lingvay, I., et al.** (2018). "Semaglutide versus Dulaglutide Once Weekly in Patients with Type 2 Diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial." The Lancet Diabetes & Endocrinology. This comparative study highlighted semaglutide's superior efficacy in reducing HbA1c and body weight when compared to dulaglutide, another GLP-1 receptor agonist.
  3. **Wilding, J.P.H., Batterham, R.L., Calanna, S., et al.** (2021). "Once-Weekly Semaglutide in Adults with Overweight or Obesity." The New England Journal of Medicine. This pivotal trial, known as the STEP 1 study, provided compelling evidence of semaglutide's effectiveness in promoting significant weight loss in adults with obesity, marking a major advancement in obesity treatment.
  4. **Lean, M.E.J., Leslie, W.S., Barnes, A.C., et al.** (2018). "Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial." The Lancet. While not specific to semaglutide, this study underscores the importance of weight management in achieving type 2 diabetes remission, contextualizing the role of weight loss agents like semaglutide in comprehensive diabetes care.
  5. **Kushner, R.F., Calanna, S., Davies, M., et al.** (2020). "Semaglutide 2.4 mg for the Treatment of Obesity: Key Elements of the STEP Trials 1 to 5." Obesity. This article outlines the design and objectives of the Semaglutide Treatment Effect in People with obesity (STEP) program, a series of phase III clinical trials investigating the efficacy and safety of semaglutide 2.4 mg for weight management.



These citations represent a fraction of the extensive body of research supporting semaglutide's use. They reflect the medication's journey from its initial development through to its current status as a cornerstone in the treatment of diabetes and obesity. The continued exploration of semaglutide's potential, through ongoing and future studies, promises to further refine its application and maximize its benefits for patients.

## **Questions and Answers: Semaglutide and muscle loss**

____ Q1: How does semaglutide compare to traditional weight loss methods? 

Semaglutide offers a more targeted approach to weight loss by directly influencing appetite and insulin secretion, mechanisms that are often left unaddressed by traditional methods such as diet and exercise alone. Clinical trials have shown that semaglutide can lead to significant weight loss, often exceeding that achieved through lifestyle modifications alone. However, it is most effective when used as part of a comprehensive weight management plan that includes dietary changes and physical activity.

____ Q2: Is semaglutide safe for long-term use? 

Current evidence from clinical trials and post-marketing surveillance suggests that semaglutide is safe for long-term use. However, as with any medication, ongoing monitoring and research are essential to fully understand its long-term safety profile. Patients on semaglutide are advised to remain under the care of their healthcare provider for regular monitoring of potential side effects and adjustments to their treatment plan as needed.

____ Q3: Can semaglutide be used in patients without diabetes for weight loss?

Yes, semaglutide has been approved for use in individuals without diabetes for weight management. The approval was based on extensive clinical trials demonstrating its efficacy in promoting significant weight loss in adults with obesity or overweight with at least one weight-related comorbidity, such as hypertension or dyslipidemia.

____ Q4: Are there any populations that should avoid using semaglutide?

Semaglutide may not be suitable for everyone. It is contraindicated in individuals with a personal or family history of medullary thyroid carcinoma or those with Multiple Endocrine Neoplasia syndrome type 2. Additionally, caution is advised in patients with a history of pancreatitis. It's important for patients to discuss their full medical history with their healthcare provider to determine if semaglutide is an appropriate treatment option.

____ Q5: What are the most common side effects of semaglutide, and how can they be managed?

The most common side effects of semaglutide include gastrointestinal symptoms, such as nausea, vomiting, diarrhea, and constipation. These side effects are generally mild to moderate in severity and tend to decrease over time. Strategies to manage these symptoms include starting with a lower dose and gradually increasing it, taking the medication with food, and staying well-hydrated.

____ Q6: How quickly can patients expect to see results after starting semaglutide?

Patients may begin to see weight loss results with semaglutide within the first few weeks of treatment, with more significant reductions typically observed over the course of several months. The rate of weight loss can vary depending on individual factors such as baseline weight, adherence to a calorie-restricted diet, and level of physical activity. In clinical trials, notable weight loss was often reported within 12 to 20 weeks of consistent use.

____ Q7: Does semaglutide interact with other medications? 

Semaglutide can interact with other medications, particularly those that rely on threshold concentrations for efficacy, due to its effect on gastric emptying. For example, it can affect the absorption of oral contraceptives and some oral medications for diabetes. It's important for patients to inform their healthcare provider of all medications they are taking to assess for potential interactions and adjust dosages as necessary.

____ Q8: Can semaglutide be used during pregnancy or breastfeeding? 

Semaglutide is not recommended for use during pregnancy or breastfeeding due to limited data on its safety in these populations. Animal studies have shown potential adverse effects on fetal development, but human data are lacking. Women of childbearing age should use effective contraception during treatment and consult their healthcare provider if they are planning to become pregnant or if they become pregnant while on semaglutide.

____ Q9: How does semaglutide affect cardiovascular health? 

Semaglutide has been shown to have a positive effect on several cardiovascular risk factors, including weight loss, improved glycemic control, and lowered blood pressure and cholesterol levels. Large-scale cardiovascular outcome trials with semaglutide have demonstrated a reduced risk of major adverse cardiovascular events, such as heart attack, stroke, and cardiovascular death, in people with type 2 diabetes at high cardiovascular risk.

____ Q10: Are there any lifestyle changes recommended to enhance the effectiveness of semaglutide? 

Yes, combining semaglutide with lifestyle changes, including a healthy diet and regular physical activity, significantly enhances its effectiveness for weight loss and glycemic control. Patients are encouraged to adopt a balanced diet rich in nutrients and low in processed foods and to engage in both aerobic and resistance training exercises regularly. These lifestyle modifications not only complement the effects of semaglutide but also contribute to overall health and well-being.

![Melissa Vansickle](data:image/svg+xml,%3Csvg%20xmlns='http://www.w3.org/2000/svg'%20viewBox='0%200%20200%20200'%3E%3C/svg%3E)![Melissa Vansickle](https://bmidoctors.com/wp-content/uploads/elementor/thumbs/melissa-vansickle-qilew2ri0zn0renj9ovlodhfggo1ujkfi55wfsy5sg.jpg)

## Dr. Melissa VanSickle

[Dr. Melissa Vansickle](https://bmidoctors.com/our-doctors/dr-melissa-vansickle/), MD is a family medicine specialist in Onsted, MI and has over 24 years of experience in the medical field. She graduated from University of Michigan Medical School in 1998. She is affiliated with medical facilities Henry Ford Allegiance Health and Promedica Charles And Virginia Hickman Hospital. Her subspecialties include General Family Medicine, Urgent Care, Complementary and Integrative Medicine in Rural Health.

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A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans

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A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans 
     [Jack Alistair Sargeant](/articles/search_result.php?term_type=authors&term=Jack Alistair Sargeant)1,2*[![orcid](/image/orcid.png)](https://orcid.org/0000-0003-0395-7329 "https://orcid.org/0000-0003-0395-7329"), [Joseph Henson](/articles/search_result.php?term_type=authors&term=Joseph Henson)1,2*[![orcid](/image/orcid.png)](https://orcid.org/0000-0002-3898-7053 "https://orcid.org/0000-0002-3898-7053"), [James Adam King](/articles/search_result.php?term_type=authors&term=James Adam King)2,3, [Thomas Yates](/articles/search_result.php?term_type=authors&term=Thomas Yates)1,2, [Kamlesh Khunti](/articles/search_result.php?term_type=authors&term=Kamlesh Khunti)1,4, [Melanie Jane Davies](/articles/search_result.php?term_type=authors&term=Melanie Jane Davies)1,2[![orcid](/image/orcid.png)](https://orcid.org/0000-0002-9987-9371 "https://orcid.org/0000-0002-9987-9371")
     Endocrinology and Metabolism 2019;34(3):247-262.   
DOI: <https://doi.org/10.3803/EnM.2019.34.3.247>  
Published online: September 26, 2019  ![](https://crossmark-cdn.crossref.org/widget/v2.0/logos/CROSSMARK_Color_horizontal.svg)

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1Diabetes Research Centre, University of Leicester, Leicester, UK.

2NIHR Leicester Biomedical Research Centre, University Hospital of Leicester NHS Trust and the University of Leicester, Leicester, UK.

3National Centre for Sport and Exercise Medicine, Loughborough University, Loughborough, UK.

4NIHR Collaborations for Leadership in Applied Health Research and Care (CLAHRC), Leicester, UK.

     Corresponding author: Melanie Jane Davies. Diabetes Research Centre, Leicester General Hospital, Gwendolen Rd, Leicester, LE5 4PW, UK. Tel: +44-116-258-6481, [melanie.davies@uhl-tr.nhs.uk](mailto:melanie.davies@uhl-tr.nhs.uk)
    *These authors contributed equally to this work.

• Received: September 3, 2019   • Revised: September 10, 2019   • Accepted: September 17, 2019 

Copyright © 2019 Korean Endocrine Society

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  * ABSTRACT
  * INTRODUCTION
  * DEFINITIONS AND MEASUREMENT OF BODY COMPOSITION
  * METHODS
  * RESULTS
  * CONCLUSIONS
  * ACKNOWLEDGMENTS
  * Article information
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#### ABSTRACT

  *     Weight loss is an important goal in the management of several chronic conditions, including type 2 diabetes mellitus, and pharmacological therapies that aid weight loss are appealing. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that have been shown to induce clinically significant reductions in body weight. However, this weight loss may not be attributed solely to fat mass (FM). Given the importance of skeletal muscle and lean body mass (LBM) on cardio-metabolic health and physical function, we reviewed the available literature reporting the effects of GLP-1RAs and SGLT2is on body composition. Results demonstrate that, in most circumstances, the weight loss associated with both therapies predominantly comprises a reduction in FM, although significant heterogeneity exists between studies. In over half of the studies identified, the proportion of LBM reduction ranged between 20% and 50% of total weight lost, which is consistent with diet-induced weight loss and bariatric surgery. No clear differences existed between GLP-1RAs and SGLT2is. Consequently, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. Strategies to preserve skeletal muscle and improve physical function, for example through structured exercise, are of great importance.
  * **Keywords** : [Glucagon-like peptide-1 receptor agonists](/articles/search_result.php?term_type=keywords&term=Glucagon-like%20peptide-1%20receptor%20agonists); [Sodium-glucose cotransporter 2 inhibitors](/articles/search_result.php?term_type=keywords&term=Sodium-glucose%20cotransporter%202%20inhibitors); [Diabetes mellitus, type 2](/articles/search_result.php?term_type=keywords&term=Diabetes%20mellitus,%20type%202); [Weight loss](/articles/search_result.php?term_type=keywords&term=Weight%20loss); [Body composition](/articles/search_result.php?term_type=keywords&term=Body%20composition); [Lean body mass](/articles/search_result.php?term_type=keywords&term=Lean%20body%20mass)



#### INTRODUCTION

    Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is) are novel glucose-lowering therapies that are prominent in the most recent guidelines for the management of hyperglycaemia in type 2 diabetes mellitus (T2DM) and recommended as preferred second-line pharmacological therapies after metformin, alongside ongoing lifestyle management (predominantly diet and physical activity) [1]. They are particularly recommended when, in addition to glucose lowering, there is a compelling need to reduce body weight (BW) [1].
    In large cardiovascular outcome trials, several GLP-1RAs (liraglutide, semaglutide, exenatide once-weekly, albiglutide and dulaglutide) have shown compelling cardiovascular protection in the form of reduced risk of major adverse cardiovascular events, along with some renal benefits [23]. A number of SGLT2is (canagliflozin, dapagliflozin, and empagliflozin) have also shown cardiovascular benefits and greater renal protection, in addition to reduced hospitalization for heart failure [456]. Both classes of therapy also elicit clinically relevant weight loss [1], with liraglutide gaining an independent license (at a higher dose of 3 mg) for use in obesity management. Importantly, the glucose-dependent mechanisms of action of both therapies mean that their beneficial effects come with low risk of hypoglycaemia, particularly when not used with sulphonylureas or insulin [1].
    The dual effects of weight loss and improved glycaemic control associated with GLP-1RAs and SGLT2is are appealing. Obesity and T2DM are intrinsically linked, and each are associated with increased risk of multiple comorbidities [7]. Notably, however, previous studies demonstrate that when BW is reduced through dietary energy restriction, not all of the resulting weight loss can be attributed to fat mass (FM), with approximately 25% to 33% estimated to comprise of reductions in lean body mass (LBM) [89]. This is important because LBM (predominantly comprised of skeletal muscle) has several important functions. It acts as a primary site of glucose disposal (with lower skeletal muscle mass contributing to poorer glycaemic control [10]), and is a strong determinant of resting metabolic rate; and thus loss of skeletal muscle with weight loss may predispose individuals to a greater chance of weight regain [11].
    Lower muscle mass and function, associated with impaired muscular strength and endurance, also result in a higher risk of falls, hospitalisation and physical frailty [1213]. The important association between T2DM and frailty is becoming increasingly recognised [14], with frailty up to five times more likely in individuals with T2DM compared to those without [14151617]. T2DM represents a state of accelerated metabolic ageing, and some of this frailty risk may be underpinned by an increased loss of LBM and function [181920].
    Consequently, whilst weight loss is an important goal in the management of several obesity-associated comorbidities, including T2DM, and pharmacological therapies that support such weight loss are appealing, it is important to understand the impact of these therapies on body composition. The aim of this narrative review is to describe the effects of GLP-1RAs and SGLT2is upon body composition, with a particular focus on LBM and skeletal muscle.

#### DEFINITIONS AND MEASUREMENT OF BODY COMPOSITION

    To interpret changes in body composition, it is important to understand the basic theory and appreciate the advantages and disadvantages of different measurement methods.
    Broadly, body composition measurement divides the body into “compartments” on the basis of differing physical properties, which commonly include FM, fat free mass (FFM), LBM, skeletal muscle mass, bone mineral content and total body water (TBW). Definitions of these terms are provided in Table 1.
    Direct methods of body composition include computed tomography (CT) and magnetic resonance imaging (MRI) [21]. Whilst these techniques have the highest accuracy, they are also expensive, and not widely used in clinical practice. More common measures, which estimate body composition indirectly, include bioelectrical impedance analysis (BIA), air displacement plethysmography (ADP) and dual-energy X-ray absorptiometry (DXA).
    BIA uses a small alternating current to measure body impedance. Estimates of body composition are provided through in-built equations based on assumed impedance of different biological tissues [22]. BIA is quick, easy and relatively inexpensive, but less precise than other available methods and influenced by factors such as hydration status.
    ADP provides an estimate of body composition by combining body volume, measured using the displacement of air within a sealed measurement chamber, with BW to calculate body density. Body density is then used to estimate body composition using pre-defined formulae [23]. ADP is relatively quick to perform and non-invasive, but requires operation by trained personnel to avoid undue error.
    DXA remains a prominent and preferred technique in clinical trials, balancing a high level of accuracy with comparatively lower costs than MRI and CT. DXA provides whole-body and regional estimates of FM, FFM, LBM, and bone mineral content [21]; using a small safe dose of radiation. It is relatively quick and provides much greater accuracy than BIA.

#### METHODS

    We searched for published studies reporting data on the effects of GLP-1RAs and SGLT2is on body composition using the online database, PubMed, from inception to August 2019, using search terms related to GLP-1RAs, SGLT2is, weight loss and body composition. We included studies using DXA, BIA, ADP, MRI, or CT to measure body composition in any human study population before and after 2 or more weeks of GLP-1RA and/or SGLT2i therapy. Where appropriate, the following assumptions were used during data extraction:
    (1) Where data were reported for mean total BW and mean body fat percentage, we estimated mean FM as; BW divided by 100, multiplied by body fat percentage.
    (2) Where mean BW and mean FM were available (including when FM was estimated as above) we estimated FFM as; BW minus FM.
    We used FFM to cautiously infer changes in LBM, with recognition of their subtle differences as outlined in Table 1. Due to variation in techniques used and methods of reporting, we did not sum different body compartments to estimate total LBM, FFM or BW change.

#### RESULTS

    Details of all eligible studies identified in our search can be found in Tables 2,3,4 [242526272829303132333435363738394041424344454647484950515253545556575859606162636465666768]. The following paragraphs provide an overview of the findings for each individual therapy within both drug classes. For ease of reading, medication doses are not included in text unless providing specific context or comparison. Figs. 1, 2 present the relative proportion of weight loss that could be attributed to FM and LBM/FFM with GLP-1RA and SGLT2i therapy, respectively. Our literature search yielded no data for lixisenatide, albiglutide, or ertugliflozin.
Glucagon-like peptide-1 receptor agonists
    We identified 17 studies (two within a single manuscript) reporting changes in body composition with liraglutide (_n_ =10), exenatide (_n_ =5), semaglutide (_n_ =1), or dulaglutide (_n_ =1). Thirteen of these studies used DXA to measure body composition, two used BIA alone, one used a combination of BIA and CT, and one used ADP.

####  Liraglutide

    Four manuscripts, containing data from five studies, reported relative contributions of LBM/FFM to total weight loss with liraglutide therapy, ranging from 30% to 47% [26,28,29,32]. This included data from separate sub-studies contained within two phase 3 trials in the Liraglutide Effect and Action in Diabetes (LEAD) programme. In LEAD 2, there was a step-wise increase in the magnitude of both total weight loss (0.9, 2.0, and 3.2 kg) and the relative contribution of LBM (33%, 40%, and 47%) when liraglutide was prescribed at 0.6, 1.2, and 1.8 mg once-daily for 26 weeks [28]. In LEAD 3, 1.2 mg liraglutide elicited 2.4 kg weight loss after 52 weeks, with 46% comprising LBM. Liraglutide 1.8 mg resulted in a similar magnitude of weight loss at 52 weeks (2.3 kg) but the relative contribution of LBM was considerably higher (65.2%). Two further trials using DXA report similar results in individuals with obesity and T2DM (30% of 5.0 kg weight loss over 12 weeks) [29] and polycystic ovarian syndrome (PCOS; 46% of 5.2 kg weight loss over 26 weeks) [26]. Furthermore, a single study, using BIA, reported 5.6 kg weight loss after 24 weeks of liraglutide therapy in individuals with type 1 diabetes mellitus, of which 41% constituted LBM [32].
    Conversely, two studies report a comparatively smaller contribution of LBM/FFM to total weight loss with 24 weeks liraglutide treatment in overweight/obese individuals with T2DM (16% of 2.5 kg weight loss with 3 mg once-daily), and those with T2DM and non-alcoholic fatty liver disease (NAFLD) (4% of 5.6 kg weight loss) [2531]. Furthermore, two studies report no change or marginal increases in LBM after 24 and 8 weeks of treatment, respectively [2730]. The final manuscript identified reductions in LBM in individuals undergoing liraglutide therapy at 1.2, 1.8, 2.4, and 3.0 mg for 20 weeks, but did not report total BW change for the subset of individuals undergoing body composition assessment [24].

####  Exenatide

    We identified five studies examining the impact of exenatide on body composition, reporting similar, although more heterogeneous, findings than those for liraglutide. Two studies used DXA to assess changes in body composition with 14 weeks of exenatide treatment in individuals with obesity with or without schizophrenia. These studies reported a mean weight loss of 2.0 and 2.3 kg, respectively, of which the relative contribution of FFM to total weight loss was 40% and 52% [3335].
    A separate study reported 3.5 kg weight loss after 16 weeks of treatment in individuals with overweight/obesity and T2DM and reported that 11.4% of weight loss comprised of LBM [36]. One further study reported a small increase (0.3 kg) in LBM after 52 weeks of treatment in individuals with T2DM [34]. The final study identified (utilising BIA to assess changes in body composition over 12 weeks in individuals with obesity and T2DM), did not report changes in LBM, but reported a loss of FM that was greater than the total weight loss induced by exenatide, and a 1.3 kg increase in skeletal muscle [37].

####  Semaglutide

    The only study administering semaglutide reported 5.0 kg weight loss after 12 weeks of treatment in individuals with obesity [38]. Of this weight loss, 20% was estimated, using ADP, to consist of LBM.

####  Dulaglutide

    A single study of dulaglutide reported data from a case series of five individuals assessed before and after 12 weeks of treatment, using BIA [39]. This manuscript did not report total weight loss, but outlined 0.1 and 0.2 kg loss of LBM and skeletal muscle, respectively, in comparison to 1.9 kg loss of FM.
Sodium-glucose cotransporter 2 inhibitors
    We identified 27 studies examining changes in body composition with SGLT2i therapy (canagliflozin=4, dapagliflozin=6, empagliflozin=2, ipragliflozin=7, luseogliflozin=2, tofogliflozin=3, and various=3). Compared to the studies identified for GLP-1RAs, there was much greater use of BIA (17 studies), with the remaining 10 using DXA.

####  Canagliflozin

    The most robust evidence of body composition changes with SGLT2i comes from a pair of randomised controlled trials (RCTs) reporting data on the effects of canagliflozin on DXA-derived body composition in individuals with T2DM [4041]. After 26 weeks, canagliflozin resulted in 2.5 and 3.2 kg weight loss at 100 and 300 mg, respectively, with the relative contribution of weight loss attributed to LBM being 36.0% and 37.5% [40]. At 52 weeks, the magnitude of weight loss was numerically greater than at 26 weeks and similar with both doses (−4.4 and −4.2 kg), but the relative contribution attributed to LBM was lower (20.5% and 26.2%, respectively) [41]. A third study using DXA, resulted in 2.4 kg weight loss in individuals with T2DM, of which almost 46% was LBM [42].
    A single study, using BIA to assess body composition changes over a longer period of time (1 year), reported the contribution of LBM to a total 2.9 kg weight loss in individuals with T2DM and NAFLD to be lower than the studies above, at just 6.9% [43].

####  Dapagliflozin

    Two studies report changes in body composition with dapagliflozin therapy using DXA, providing similar findings to those for canagliflozin. In a sub-study contained within a large multi-site RCT, total weight loss after 104 weeks of dapagliflozin therapy in 69 participants with overweight/obesity and T2DM was 4.5 kg, of which 28.9% consisted of LBM [45]. A smaller, shorter study reported a lower magnitude of weight loss over 12 weeks (2.1 kg) but with a similar relative contribution of LBM (23.8%) [45].
    Three further studies, using BIA, show heterogeneous findings. In a non-randomised trial in which 50 individuals with T2DM were prescribed dapagliflozin or non-SGLT2i therapies for 6 months, the dapagliflozin group lost a mean 3.4 kg of BW, of which 15% constituted LBM [48]. In contrast, a 12-week RCT reported that almost all (94%) of the 3.1 kg weight loss elicited with dapagliflozin was LBM [46], whilst a small cohort study in 11 individuals with T2DM and nonalcoholic steatohepatitis, reported a 1.2 kg increase in LBM after 24 weeks of treatment, despite 3.8 kg weight loss [49].

####  Empagliflozin

    Only two studies report the impact of empagliflozin on body composition. One of these provides DXA-derived data from a sub-study nested within the global EMPA-REG H2H-SU trial; a randomised head-to-head trial conducted as part of the empagliflozin phase 3 programme, which compared empagliflozin with the sulphonylurea glimepiride as second line therapy alongside metformin in individuals with T2DM [50]. Using the weight loss observed in the entire population after 104 weeks (2.8 kg), it was estimated that approximately one-third (32.1%) of weight loss elicited in this trial comprised of FFM.
    A separate study using BIA to assess changes with empagliflozin in women with PCOS reported a loss of FFM (1.1 kg) which was greater than the total weight loss elicited (0.8 kg) [51].

####  Ipragliflozin

    Of the seven studies identified for ipragliflozin, six reported that the contribution of LBM/FFM to total weight loss elicited ranged from 22% to 49% [525354555759]. All of these studies were in individuals with T2DM, and included two studies using DXA, reporting 22% and 49% of 2.8 and 3.5 kg of weight loss over 24 weeks, respectively. The remaining four used BIA and in the largest and longest of these studies (_n_ =217; 104 weeks of treatment), the proportion of weight loss attributed to FFM was approximately one-third (34.5%) [54].
    In the final study identified, 24 weeks of treatment with ipragliflozin resulted in a loss of FM that was greater than the total weight loss in individuals with T2DM and NAFLD, inferring a small gain (0.2 kg) in FFM [56].

####  Luseogliflozin

    Two studies examining the effects of luseogliflozin on body composition using DXA report similar findings to those outlined above. Both studies were in individuals with T2DM, reporting that 12 and 52 weeks of luseogliflozin therapy elicited 2.7 and 3.1 kg weight loss, respectively. Of this weight loss, 41% and 32% could be attributed to a loss of FFM/LBM [5960].

####  Tofogliflozin

    Three similar studies, each utilising BIA, report data regarding the impact of tofogliflozin in individuals with T2DM. Two assessed changes over 12 weeks, reporting 3.3 and 2.9 kg weight loss, of which 30% and 52%, respectively, could be attributed to LBM [6263]. The third study reported 2.3 kg weight loss in 17 individuals with T2DM despite an estimated 0.2 kg increase in FFM [61].

####  Various

    Three cohort studies (two retrospective, one prospective) report data from participants prescribed SGLT2i therapy, with variation in the exact agent prescribed [646566]. Each utilised BIA to assess body composition, but only one study reported changes in both total BW and FFM. In this study, almost half (48%) of the 5.2 kg weight loss elicited by dapagliflozin (_n_ =10) or canagliflozin (_n_ =7), in individuals with overweight/obesity, T2DM and NAFLD, could be attributed to FFM [64].
Dual therapy of GLP-1RAs and SGLT2is in combination
    We identified two studies reporting the effect of GLP-1RAs and SGLT2is in combination. In the first, individuals with obesity and pre-diabetes mellitus were randomised to dapagliflozin-plus-exenatide or placebo for 24 weeks, with an open-label extension (during which all participants underwent combined therapy) for a further 28 weeks [67]. Weight loss after 52 weeks was 5.7 kg, with MRI demonstrating reductions in both adipose tissue and lean tissue volumes (5.3 and 1.4 L, respectively). The second study, using BIA, reported 2.9 kg weight loss after 52 weeks of treatment with luseogliflozin-plus-liraglutide, in individuals with T2DM, of which 14% comprised of LBM [68].

#### CONCLUSIONS

    Our review demonstrates that, in most circumstances, the weight loss associated with GLP-1RA and/or SGLT2i therapy comprises predominantly of a reduction in FM. Within 53 groups of individuals prescribed GLP-1RA, SGLT2i or combined therapy, only five groups saw a loss of LBM, FFM, or skeletal muscle mass (depending on reporting) that was greater than FM lost. Thus, in most cases, body composition (i.e., the ratio of FM to FFM/LBM) was more favorable after treatment than before.
    However, out of 43 groups in which it was possible to estimate the proportion of weight loss that could be attributed to LBM/FFM, in 27 groups this proportion of LBM lost ranged from 20% to 50%. Six groups saw a loss of LBM, FFM, or skeletal muscle but with a smaller relative contribution to total weight loss (0% to 19%), whilst another six reported an increase in LBM, FFM, or skeletal muscle mass. These results are in accordance with studies of diet-induced weight loss and bariatric surgery, which have reported similar proportions of LBM/FFM (approximately 25% to 40%) within total weight loss elicited [89697071].
    There were no clear differences between GLP-1RAs and SGLT2is in the magnitude of weight loss that could be attributed to LBM/FFM. However, it should be noted that the number of studies identified for each class of therapy was relatively small, and these were divided further between multiple therapies within each class. There was also heterogeneity of findings within each drug class and within individual therapies. Reasons for this heterogeneity may include (1) the specific therapy used, (2) the dose or duration of treatment, (3) concomitant therapies alongside GLP-1RA or SGLT2i treatment (e.g., if examined as monotherapy or dual-therapy with other glucose-lowering therapies such as metformin), (4) the clinical diagnoses, background medication usage (i.e., use of sulphonylureas or insulin) and other baseline characteristics of the study population, (5) the technique used to assess body composition (including standardisation procedures prior to measurement), and (6) natural inter-individual variation in responses to weight loss. There are no clear patterns within the data collected in this review, including treatment type, dose or duration and the technique used.
    Although the benefits of weight loss in obesity-associated chronic metabolic disease are well established [7273], these favorable outcomes may be limited by losses in LBM, particularly if this constitutes skeletal muscle. Of the studies identified in this review, 12 reported changes in either LBM or FFM, along with changes in skeletal muscle. In seven of these studies, the loss of skeletal muscle comprised between 55% and 100% of the LBM/FFM lost. In one it was twice as great [40], whilst another reported a loss of skeletal muscle despite an increase in FFM [56]. The mechanism of action of SGLT2i, inducing polyuria alongside glycosuria, means that SGLT2i therapy is also associated with fluid loss [1]. Reductions in TBW may impact on body composition measurement, and it could be speculated that reductions in FFM/LBM with weight loss may reflect reductions in water content. Of the 27 studies identified reporting changes in body composition with SGLT2i therapy, 13 reported changes in TBW, 12 of which reported losses; ranging from 0.2 to 2.4 kg (7% to 100% of total weight loss). It is imperative to stress; however, that water is contained within both adipose- and non-adipose tissues [74], and all of the studies reporting TBW in this review utilised BIA. TBW, as provided by BIA, does not allow distinction between water contained in, and thus lost from, different body compartments (i.e., FM or FFM/LBM). No studies reported change in TBW with GLP-1RA or combination therapy.
    Consequently, although yielding a more favorable body composition, the potential LBM and skeletal muscle loss associated with weight loss induced by GLP-1RAs and SGLT2is warrants attention. A more rapid decline in skeletal muscle and consequential increased risk of sarcopenia is concerning, particularly as individuals prescribed these therapies are usually already vulnerable to an increased risk of physical frailty (i.e., those with T2DM and/or obesity) [75]. In turn, strategies to preserve or increase skeletal muscle and physical function in these individuals (e.g., through structured exercise training), are of importance. It is also important to state that the absolute mass of skeletal muscle is not the only factor to consider, and improving muscular function (strength, endurance, flexibility etc.) remains critical to improve physical function and performance in tasks of daily living; to impact positively on an individual's quality of life.
    Previous studies have shown that markers of physical function (including balance, grip strength, and gait speed) improve following diet-induced weight loss [97677], likely by reducing the biomechanical burden of moving around [78]. However, when diet and exercise are combined, improvements in physical function are greater than that elicited by diet alone, which may be underpinned by preserved or improved skeletal muscle mass and function [979]. Whether the same results are observed when exercise is combined with weight loss elicited by GLP-1RAs and SGLT2i therapy is currently unknown, and requires testing in robust experimental research.
    Collectively, the available evidence suggests that the initiation of GLP-1RA or SGLT2i therapy results in weight loss that is primarily derived of FM. However, this is accompanied by reductions in LBM which are not insignificant and should be considered in parallel to changes in FM and overall BW. Differences between therapies are currently unclear. A substantial proportion of LBM loss may be comprised of skeletal muscle, which may be clinically relevant, particularly in the populations to which these therapies are prescribed. Given the heterogeneity, a more consistent approach to measurement and reporting of body composition in future research would be beneficial. As the prevalence of obesity, physical inactivity and associated co-morbidities, including T2DM, continues to rise, it is imperative to explore strategies to preserve LBM and improve physical function, and particularly their interaction with glucose-lowering strategies that positively impact on weight loss.

**Acknowledgements**

#### ACKNOWLEDGMENTS

    This research was supported by the National Institute for Health Research (NIHR) Leicester Biomedical Research Centre (BRC) and the NIHR Collaboration for Leadership in Applied Health Research and Care–East Midlands (CLAHRC–EM). The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health.

#### Article information

    

**CONFLICTS OF INTEREST:** Melanie Jane Davies has acted as a consultant, advisory board member and speaker for Novo Nordisk, Sanofi-Aventis, Lilly, Merck Sharp & Dohme, Boehringer Ingelheim, AstraZeneca and Janssen, an advisory board member for Servier and as a speaker for Mitsubishi Tanabe Pharma Corporation and Takeda Pharmaceuticals International Inc. She has received grants in support of investigator and investigator-initiated trials from Novo Nordisk, Sanofi-Aventis, Lilly, Boehringer Ingelheim, and Janssen.

Kamlesh Khunti has received honoraria from Abbot, AstraZeneca, Berlin-Chemie AG/Menarini Group, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi, and research support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Roche, and Sanofi.

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**Fig. 1**

### Relative proportions of fat mass and lean body/fat-free mass within total weight loss elicited by glucagon-like peptide-1 receptor agonist therapy [25262829313233353638].

![enm-34-247-g001.jpg](/upload//thumbnails/enm-34-247-g001.jpg)

**Fig. 2**

### Relative proportions of fat mass and lean body/fat-free mass within total weight loss elicited by sodium-glucose cotransporter 2 inhibitor therapy [4041424344454648505152535455575859606263].

![enm-34-247-g002.jpg](/upload//thumbnails/enm-34-247-g002.jpg)

**Table 1**

### Definitions of Body Composition Compartments

Fat mass |  Mass of all adipose tissue  
---|---  
Fat free mass |  Fat free mass is total body mass minus total fat mass  
Lean body mass |  Lean body mass is fat free mass minus total bone mass  
Skeletal muscle mass |  Skeletal muscle mass is lean body mass minus connective tissue, skin, and other organs  
Total body water |  The summation of intra- and extra-cellular water  
  
**Table 2**

### Studies Reporting Changes in Body Composition with GLP-1RA Therapy

Study (location) |  Study design |  No. prescribed GLP-1RA therapy |  Population |  Dose (all subcutaneous injection) |  Duration, wk |  Tech. used |  Total BW change, kg (% change from baseline) |  FM change, kg |  LBM change, kg |  Skeletal muscle mass change, kg |  Total body water change, kg |  Proportion of weight loss from FM, % |  Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Liraglutide |  |  |  |  |  |  |  |  |  |  |  |  |   
Astrup et al. (2012) [24] (Europe; multi-site) |  Six-arm RCT (sub-study) |  15 |  Obesity |  1.2 mg once-daily |  20 |  DXA |  NR |  −6.1 |  −0.5 |  NR |  NR |  - |  -  
13 |  1.8 mg once-daily |  NR |  −5.9 |  −1.5 |  NR |  NR |  - |  -  
15 |  2.4 mg once-daily |  NR |  −7.0 |  −1.3 |  NR |  NR |  - |  -  
15 |  3.0 mg once-daily |  NR |  −6.8 |  −1.1 |  NR |  NR |  - |  -  
Feng et al. (2019) [25] (China) |  Three-arm RCT |  29 |  T2DM and NAFLD |  1.8 mg once-daily (titrated from 0.6 mg as tolerated) |  24 |  DXA |  −5.6 (−7.4%) |  −3.6 |  −0.2 |  NR |  NR |  64.3 |  3.6  
Frossing et al. (2018) [26] (Denmark) |  Two-arm RCT |  44 |  PCOS |  1.8 mg once-daily |  26 |  DXA |  −5.2 (−5.5%) |  −2.6 |  −2.4 |  NR |  NR |  50 |  46.1  
Harder et al. (2004) [27] (Denmark) |  Two-arm RCT |  21 |  T2DM |  0.6 mg once-daily |  8 |  DXA |  −2.1 (−2.0%) |  −1.6 |  +0.6 |  NR |  NR |  76.2 |  LBM increased  
Jendle et al., (2009) [28] (Global; multi-site) |  Five-arm RCT Study 1; LEAD 2 (sub-study) |  35 |  T2DM |  0.6 mg once-daily (with 1.5–2.0 g metformin) |  26 |  DXA |  −0.9 (−1.0%) |  −0.7 |  −0.3 |  NR |  NR |  77.8 |  33.3  
31 |  1.2 mg once-daily (with 1.5–2.0 g metformin) |  −2.0 (−2.3%) |  −1.6 |  −0.8 |  NR |  NR |  80 |  40  
37 |  1.8 mg once-daily (with 1.5–2.0 g metformin) |  −3.2 (−3.6%) |  −2.4 |  −1.5 |  NR |  NR |  75.0 |  46.9  
Three-arm RCT Study 2; LEAD 3 (sub-study) |  23 |  T2DM |  1.2 mg once-daily |  52 |  DXA |  −2.4 (−2.6%) |  −2.0 |  −1.1 |  NR |  NR |  83.3 |  45.8  
20 |  1.8 mg once-daily |  −2.3 (−2.5%) |  −1.0 |  −1.5 |  NR |  NR |  43.5 |  65.2  
Li et al. (2014) [29] (China) |  Case series (prospective) |  31 |  Obesity and T2DM |  1.2 mg once-daily (titrated from 0.6 mg as tolerated) |  12 |  DXA |  −5.0 (−5.5%) |  −3.8 |  −1.5 |  NR |  NR |  76.0 |  30.0  
Perna et al. (2016) [30] (Italy) |  Case series (retrospective) |  9 |  Obesity and T2DM (elderly) |  3 mg once-daily (titrated from 1.2 mg as tolerated) |  24 |  DXA |  −2.0 (−2.3%) |  −1.5 |  +0.1a |  NR |  NR |  75.0 |  FFM increased  
Rondanelli et al. (2016) [31] (Italy) |  Case series (prospective) |  28 |  Overweight/ obese and T2DM |  3 mg once-daily (titrated from 1.2 mg as tolerated) |  24 |  DXA |  −2.5 (−2.6%) |  −2.0 |  −0.4a |  NR |  NR |  80.0 |  16.0  
Dube et al. (2018) [32] (Canada) |  Two-arm RCT |  15 |  T1DM |  1.8 mg once-daily (titrated from 0.6 mg as tolerated) |  24 |  BIA/ CT |  −5.6 (−6.3%) |  −3.3 |  −2.3a |  NR |  NR |  58.9 |  41.1  
Exenatide |  |  |  |  |  |  |  |  |  |  |  |  |   
Bradley et al. (2012) [33] (USA) |  Case series (prospective) |  18 |  Obesity |  10 μg twice-daily (titrated from 5 μg as tolerated) |  14 |  DXA |  −2.0 (−2.0%) |  −1.3 |  −0.8a |  NR |  NR |  65 |  40  
Bunck et al. (2010) [34] (Sweden) |  Two-arm RCT |  29 |  T2DM |  20 μg twice-daily (titrated from 5 μg as tolerated) |  52 |  DXA |  −3.9 (−4.3%) |  −2.4 |  +0.3 |  NR |  NR |  61.5 |  LBM increased  
Ishoy et al. (2017) [35] (Denmark) |  Two-arm RCT |  20 |  Obesity and schizophrenia (treated with anti-psychotic medication) |  2 mg weekly |  14 |  DXA |  −2.3 (−1.9%) |  −1.1 |  −1.2a |  −0.7 |  NR |  47.8 |  52.2  
Yin et al. (2018) [36] (China) |  Two-arm RCT |  19 |  Overweight/ obesity and T2DM |  10 μg twice-daily (titrated from 5 μg as tolerated) |  16 |  DXA |  −3.5 (−4.3%) |  −2.1 |  −0.4 |  NR |  NR |  60 |  11.4  
Hong et al. (2016) [37] (Korea) |  Case series (prospective) |  32 |  Obesity and T2DM |  10 μg twice-daily (titrated from 5 μg as tolerated) |  12 |  BIA |  −1.0 (−1.4%) |  −2.1 |  NR |  +1.3 |  NR |  210 |  -  
Semaglutide |  |  |  |  |  |  |  |  |  |  |  |  |   
Blundell et al. (2017) [38] (UK) |  Randomised, placebo-controlled corss-over trial |  30 |  Obesity |  1.0 mg (titrated up from 0.25 mg) |  12 |  ADP |  −5.0 (−4.9%) |  −3.5 |  −1.1 |  NR |  NR |  70.0 |  22.0  
Dulaglutide |  |  |  |  |  |  |  |  |  |  |  |  |   
Seko et al. (2017) [39] (Japan) |  Case series (retrospective) |  5 |  T2DM and NAFLD |  0.75 mg once-daily |  12 |  BIA |  NR |  −1.9 |  −0.1 |  −0.2 |  −0.1 |  - |  -  
  
    

GLP-1RA, glucagon-like peptide-1 receptor agonist; BW, body weight; FM, fat mass; LBM, lean body mass; RCT, randomised controlled trial; DXA, dual-energy X-ray absorptiometry; NR, not reported; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovarian syndrome; LEAD, Liraglutide Effect and Action in Diabetes phase 3 programme for liraglutide; FFM, fat-free mass; T1DM, type 1 diabetes mellitus; BIA, bioelectrical impedance analysis; CT, computed tomography; ADP, air displacement plethysmography.

aFFM.

**Table 3**

### Studies Reporting Changes in Body Composition with SGLT2i Therapy

Study (location) |  Study design |  No. (in group prescribed SGLT2i therapy) |  Population |  Dose (all once-daily, oral tablet unless otherwise specified) |  Duration |  Tech. used |  Total BW change, kg (% change from baseline) |  FM change, kg |  LBM change, kg |  Skeletal muscle mass change, kg |  Total body water change, kg |  Proportion of weight loss from FM, % |  Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Various |  |  |  |  |  |  |  |  |  |  |  |  |   
Arase et al. (2019) [64] (Japan) |  Case series (retrospective) |  17 (DAPA=10; CANA=7) |  Overweight, T2DM and NAFLD |  DAPA: 5 mg |  24 wk |  BIA |  −5.2 (−7.1%) |  −2.7 |  −2.5a |  −0.7 |  −1.2 |  51.9 |  48.1  
CANA: 100 mg  
Kinoshita et al. (2018) [65] (Japan) |  Case series (prospective) |  156 (_n_ =108 for body composition) (LUSEO=52%; TOFO=29%; IPRA=15%; DAPA=4%) |  T2DM |  NR |  12 wk |  BIA |  −2.8 (−3.6%) |  NR |  NR |  −0.1 |  NR |  - |  -  
Seko et al. (2017) [66] (Japan) |  Case series (retrospective) |  24 (_n_ =17 for body composition) (CANA=18; IPRA=6) |  T2DM and biopsy-proven NAFLD/NASH |  CANA: 100 mg |  24 wk |  BIA |  NR |  −2.4 |  −1.1 |  −0.6 |  −0.8 |  - |  -  
IPRA: 50 mg  
Canagliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Blonde et al. (2016) [40] Study 2 (Global; multi-site) |  Three-arm RCT (sub-study) |  CANA 100=63 |  T2DM |  100 mg |  26 wk |  DXA |  −2.5 (−2.8%) |  −1.9 |  −0.9 |  NR |  NR |  76 |  36.0  
CANA 300=71 |  300 mg |  −3.2 (−3.4%) |  −2.4 |  −1.2 |  NR |  NR |  75 |  37.5  
Cefalu et al. (2013) [41]b (Global; multi-site) |  Three-arm RCT (sub-study) |  CANA 100=111 |  T2DM |  100 mg |  52 wk |  DXA |  −4.4 (−5.2%) |  −2.9 |  −0.9 |  NR |  NR |  65.9 |  20.5  
CANA 300=102 |  300 mg |  −4.2 (−4.9%) |  −2.5 |  −1.1 |  NR |  NR |  59.5 |  26.2  
Koike et al. (2019) [42] (Japan) |  Case series (prospective) |  38 |  T2DM |  100 mg |  24 wk |  DXA |  −2.4 (−3.3%) |  −1.3 |  −1.1 |  NR |  NR |  54.2 |  45.8  
Inoue et al. (2019) [43] (Japan) |  Case series (prospective) |  20 |  T2DM and NAFLD |  100 mg |  12 mo |  BIA |  −2.9 (−3.5%) |  −2.6 |  −0.2 |  −0.2 |  −0.2 |  89.7 |  6.9  
Dapagliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Bolinder et al. (2014) [44] (Europe; multi-site) |  Two-arm RCT |  69 |  Overweight/obese with T2DM |  10 mg (added to open-label metformin) |  104 wk |  DXA |  −4.5 (−4.9%) |  −2.8 |  −1.3 |  NR |  NR |  62.2 |  28.9  
Kosugi et al. (2019) [45] (Japan) |  Case series (prospective) |  26 |  T2DM |  5 mg |  12 wk |  DXA |  −2.1 (−2.9%) |  −1.7 |  −0.5 |  NR |  NR |  81 |  23.8  
Fadini et al. (2017) [46] (Italy) |  Two-arm RCT |  16 |  T2DM |  10 mg |  12 wk |  BIA |  −3.1 (baseline NR) |  −0.1 |  −2.9a |  NR |  −2.4 |  3.2 |  93.5  
Shimizu et al. (2019) [47] (Japan) |  Two-arm RCT |  33 |  T2DM and NAFLD |  5 mg |  24 wk |  BIA |  −2.9 (−3.9%) |  NR |  NR |  −0.9 |  −1.1 |  - |  -  
Sugiyama et al. (2018) [48] (Japan) |  Two-arm non-randomised cohort study |  28 |  T2DM |  5 mg |  6 mo |  BIA |  −3.4 (−4.4%) |  −3.1 |  −0.5 |  −0.2 |  NR |  91.2 |  14.7  
Tobita et al. (2017) [49] (Japan) |  Case series (prospective) |  11 |  T2DM and NASH |  5 mg |  24 wk |  BIA |  −3.8 (−4.8%) |  −6.1 |  1.2 |  0.1 |  1.2 |  160.5 |  LBM increased Fluctuation over 24 wk  
Empagliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Ridderstrale et al. (2014) [50] (Global; multi-site) |  Two-arm RCT (sub-study) |  46 |  T2DM |  25 mg |  104 wk |  DXA |  NR (−2.8 kg [–3.4%] in entire EMPA group; _n_ =765) |  −1.6 |  −0.9a |  NR |  NR |  57.1 |  32.1c  
Javed et al. (2019) [51] (UK) |  Two-arm RCT |  19 |  PCOS |  25 mg |  12 wk |  BIA |  −0.8 (−0.8%) |  −0.3 |  −1.1a |  NR |  −0.8 |  37.5 |  137.5  
Ipragliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Inoue et al. (2019) [52] (Japan) |  Two-arm RCT |  24 |  T2DM (on insulin therapy) |  50 mg (insulin dose reduced by 20%) |  24 wk |  DXA |  −2.8 (−4.4%) |  −2.1 |  −0.6 |  NR |  NR |  75 |  21.6  
Ohta et al. (2017) [53] (Japan) |  Case series (prospective) |  20 |  T2DM |  50 mg |  24 wk |  DXA |  −3.5 (−4.3%) |  −1.8 |  −1.7 |  NR |  NR |  51.4 |  48.6  
Iemitsu et al. (2019) [54] (Japan) |  Case series (prospective) |  217 |  T2DM |  50 mg |  104 wk |  BIA |  −2.9 (−3.7%) |  −1.9 |  −1.0a |  −0.9 |  −0.7 |  31 |  34.0  
Kato et al. (2017) [55] (Japan) |  Case series (prospective) |  20 |  T2DM |  50 mg |  12 wk |  BIA |  −1.9 (−2.3%) |  −1.3 |  −0.6a |  −0.6 |  −0.7 |  68.4 |  31.6  
Miyake et al. (2018) [56] (Japan) |  Case series (prospective) |  12 |  T2DM+NAFLD |  50 mg |  24 wk |  BIA |  −1.4 (−2.1%) |  −1.6 |  +0.2a |  −0.5 |  NR |  114.3 |  FFM increased  
Osonoi et al. (2018) [57] (Japan) |  Case series (prospective) |  98 |  T2DM |  50 mg |  24 wk |  BIA |  −2.1 (−3.2%) |  −1.5 |  −0.6a |  NR |  NR |  71.4 |  28.6  
Yamamoto et al. (2016) [58] (Japan) |  Case series (prospective) |  24 |  T2DM |  50 mg |  16 wk |  BIA |  −2.5 (−3.3%) |  −1.7 |  −0.6 |  NR |  −0.6 |  68 |  24.0  
Luseogliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Bouchi et al. (2017) [59] (Japan) |  Case series (prospective) |  19 |  T2DM |  2.5 mg, titrated up to 5 mg where tolerated and safe |  12 wk |  DXA |  −2.7 (−3.3%) |  −1.4 |  −1.1a |  NR |  NR |  51.9 |  40.7  
Sasaki et al. (2019) [60] (Japan) |  Case series (prospective) |  37 |  T2DM |  2.5 mg, titrated up to 5 mg where tolerated and safe |  52 wk |  DXA |  −3.1 (−3.9%) |  −2.0 |  −1.0 |  NR |  NR |  64.5 |  32.3  
Tofogliflozin |  |  |  |  |  |  |  |  |  |  |  |  |   
Iwahashi et al. (2016) [61] (Japan) |  Case series (prospective) |  17 |  T2DM |  20 mg |  48 wk |  BIA |  −2.3 (−3.0%) |  −2.6 |  +0.2a |  NR |  −0.3 |  113 |  FFM increased  
Kamei et al. (2018) [62] (Japan) |  Case series (retrospective) |  37 |  T2DM |  20 mg |  12 wk |  BIA |  −3.3 (−3.7%) |  −1.9 |  −1.0 |  −0.8 |  −0.9 |  57.6 |  30.3  
Matsuba et al. (2018) [63] (Japan) |  Case series (prospective) |  14 |  T2DM |  20 mg |  12 wk |  BIA |  −2.9 (baseline NR) |  −1.3 |  −1.5 |  −1.4 |  −1.1 |  44.8 |  51.7  
  
    

SGLT2i, sodium-glucose cotransporter 2 inhibitor; BW, body weight; FM, fat mass; LBM, lean body mass; DAPA, dapagliflozin; CANA, canagliflozin; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; BIA, bioelectrical impedance analysis; LUSEO, luseogliflozin; TOFO, tofogliflozin; IPRA, ipragliflozin; NR, not reported; NASH, nonalcoholic steatohepatitis; RCT, randomised controlled trial; DXA, dual-energy X-ray absorptiometry; EMPA, empagliflozin; PCOS, polycystic ovarian syndrome; FFM, fat-free mass.

aFFM; bSame as “Study 1” in Blonde et al. (2016) [41]; cCalculated using mean weight loss in entire cohort.

**Table 4**

### Studies Reporting Changes in Body Composition with GLP-1RA and SGLT2i Combination Therapy

Drug/author (location) |  Study design |  No. (in group prescribed SGLT2i+ GLP-1RA therapy) |  Population |  Dose (all once-daily, unless otherwise specified; SGLT2i taken as oral tablet, GLP-1RA as subcutaneous injection) |  Duration, wk |  Tech. used |  Total BW change, kg (% change from baseline) |  FM change |  LBM change |  Skeletal muscle mass change, kg |  Total body water change, kg |  Proportion of weight loss from FM, % |  Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Dapagliflozin+Exenatide |  |  |  |  |  |  |  |  |  |  |  |  |   
Lundkvist et al. (2017) [67] (Sweden) |  Two-arm RCT |  16 |  Obesity and pre-diabetes mellitus |  DAPA: 10 mg |  52 |  MRI |  −5.7 (−5.4%) |  −5.3 La |  −1.4 L |  NR |  NR |  - |  -  
EXEN: 2 mg weekly  
Luseogliflozin+Liraglutide |  |  |  |  |  |  |  |  |  |  |  |  |   
Seino et al. (2018) [68] (Japan) |  Case series (prospective) (sub-study) |  22 |  T2DM |  LUSEO: 2.5 mg, titrated up to 5 mg where tolerated and safe (_n_ =17 reached 5 mg dose) |  52 |  BIA |  −2.9 (−4.3%) |  −2.5 kg |  −0.4 kg |  NR |  NR |  86.2 |  13.8  
LIRA: 0.6 mg (_n_ =1) or 0.9 mg (_n_ =21)  
  
    

GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor; BW, body weight; FM, fat mass; LBM, lean body mass; RCT, randomised controlled trial; DAPA, dapagliflozin; EXEN, exenatide; MRI, magnetic resonance imaging; NR, not reported; T2DM, type 2 diabetes mellitus; LUSEO, luseogliflozin; LIRA, liraglutide; BIA, bioelectrical impedance analysis.

aTotal adipose tissue.

#### Figure & Data

#### References




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A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans

![Image](../upload/thumbnails/enm-34-247-g001.jpg) ![Image](../upload/thumbnails/enm-34-247-g002.jpg)

**Fig. 1** Relative proportions of fat mass and lean body/fat-free mass within total weight loss elicited by glucagon-like peptide-1 receptor agonist therapy [25262829313233353638]. 

**Fig. 2** Relative proportions of fat mass and lean body/fat-free mass within total weight loss elicited by sodium-glucose cotransporter 2 inhibitor therapy [4041424344454648505152535455575859606263]. 

### Fig. 1

![](../upload/thumbnails/enm-34-247-g001.jpg)

### Fig. 2

![](../upload/thumbnails/enm-34-247-g002.jpg)

ALL FIGURES

A Review of the Effects of Glucagon-Like Peptide-1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors on Lean Body Mass in Humans

Fat mass| Mass of all adipose tissue  
---|---  
Fat free mass| Fat free mass is total body mass minus total fat mass  
Lean body mass| Lean body mass is fat free mass minus total bone mass  
Skeletal muscle mass| Skeletal muscle mass is lean body mass minus connective tissue, skin, and other organs  
Total body water| The summation of intra- and extra-cellular water  
Study (location)| Study design| No. prescribed GLP-1RA therapy| Population| Dose (all subcutaneous injection)| Duration, wk| Tech. used| Total BW change, kg (% change from baseline)| FM change, kg| LBM change, kg| Skeletal muscle mass change, kg| Total body water change, kg| Proportion of weight loss from FM, %| Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Liraglutide| | | | | | | | | | | | |   
Astrup et al. (2012) [24] (Europe; multi-site)| Six-arm RCT (sub-study)| 15| Obesity| 1.2 mg once-daily| 20| DXA| NR| −6.1| −0.5| NR| NR| -| -  
13| 1.8 mg once-daily| NR| −5.9| −1.5| NR| NR| -| -  
15| 2.4 mg once-daily| NR| −7.0| −1.3| NR| NR| -| -  
15| 3.0 mg once-daily| NR| −6.8| −1.1| NR| NR| -| -  
Feng et al. (2019) [25] (China)| Three-arm RCT| 29| T2DM and NAFLD| 1.8 mg once-daily (titrated from 0.6 mg as tolerated)| 24| DXA| −5.6 (−7.4%)| −3.6| −0.2| NR| NR| 64.3| 3.6  
Frossing et al. (2018) [26] (Denmark)| Two-arm RCT| 44| PCOS| 1.8 mg once-daily| 26| DXA| −5.2 (−5.5%)| −2.6| −2.4| NR| NR| 50| 46.1  
Harder et al. (2004) [27] (Denmark)| Two-arm RCT| 21| T2DM| 0.6 mg once-daily| 8| DXA| −2.1 (−2.0%)| −1.6| +0.6| NR| NR| 76.2| LBM increased  
Jendle et al., (2009) [28] (Global; multi-site)| Five-arm RCT Study 1; LEAD 2 (sub-study)| 35| T2DM| 0.6 mg once-daily (with 1.5–2.0 g metformin)| 26| DXA| −0.9 (−1.0%)| −0.7| −0.3| NR| NR| 77.8| 33.3  
31| 1.2 mg once-daily (with 1.5–2.0 g metformin)| −2.0 (−2.3%)| −1.6| −0.8| NR| NR| 80| 40  
37| 1.8 mg once-daily (with 1.5–2.0 g metformin)| −3.2 (−3.6%)| −2.4| −1.5| NR| NR| 75.0| 46.9  
Three-arm RCT Study 2; LEAD 3 (sub-study)| 23| T2DM| 1.2 mg once-daily| 52| DXA| −2.4 (−2.6%)| −2.0| −1.1| NR| NR| 83.3| 45.8  
20| 1.8 mg once-daily| −2.3 (−2.5%)| −1.0| −1.5| NR| NR| 43.5| 65.2  
Li et al. (2014) [29] (China)| Case series (prospective)| 31| Obesity and T2DM| 1.2 mg once-daily (titrated from 0.6 mg as tolerated)| 12| DXA| −5.0 (−5.5%)| −3.8| −1.5| NR| NR| 76.0| 30.0  
Perna et al. (2016) [30] (Italy)| Case series (retrospective)| 9| Obesity and T2DM (elderly)| 3 mg once-daily (titrated from 1.2 mg as tolerated)| 24| DXA| −2.0 (−2.3%)| −1.5| +0.1a| NR| NR| 75.0| FFM increased  
Rondanelli et al. (2016) [31] (Italy)| Case series (prospective)| 28| Overweight/ obese and T2DM| 3 mg once-daily (titrated from 1.2 mg as tolerated)| 24| DXA| −2.5 (−2.6%)| −2.0| −0.4a| NR| NR| 80.0| 16.0  
Dube et al. (2018) [32] (Canada)| Two-arm RCT| 15| T1DM| 1.8 mg once-daily (titrated from 0.6 mg as tolerated)| 24| BIA/ CT| −5.6 (−6.3%)| −3.3| −2.3a| NR| NR| 58.9| 41.1  
Exenatide| | | | | | | | | | | | |   
Bradley et al. (2012) [33] (USA)| Case series (prospective)| 18| Obesity| 10 μg twice-daily (titrated from 5 μg as tolerated)| 14| DXA| −2.0 (−2.0%)| −1.3| −0.8a| NR| NR| 65| 40  
Bunck et al. (2010) [34] (Sweden)| Two-arm RCT| 29| T2DM| 20 μg twice-daily (titrated from 5 μg as tolerated)| 52| DXA| −3.9 (−4.3%)| −2.4| +0.3| NR| NR| 61.5| LBM increased  
Ishoy et al. (2017) [35] (Denmark)| Two-arm RCT| 20| Obesity and schizophrenia (treated with anti-psychotic medication)| 2 mg weekly| 14| DXA| −2.3 (−1.9%)| −1.1| −1.2a| −0.7| NR| 47.8| 52.2  
Yin et al. (2018) [36] (China)| Two-arm RCT| 19| Overweight/ obesity and T2DM| 10 μg twice-daily (titrated from 5 μg as tolerated)| 16| DXA| −3.5 (−4.3%)| −2.1| −0.4| NR| NR| 60| 11.4  
Hong et al. (2016) [37] (Korea)| Case series (prospective)| 32| Obesity and T2DM| 10 μg twice-daily (titrated from 5 μg as tolerated)| 12| BIA| −1.0 (−1.4%)| −2.1| NR| +1.3| NR| 210| -  
Semaglutide| | | | | | | | | | | | |   
Blundell et al. (2017) [38] (UK)| Randomised, placebo-controlled corss-over trial| 30| Obesity| 1.0 mg (titrated up from 0.25 mg)| 12| ADP| −5.0 (−4.9%)| −3.5| −1.1| NR| NR| 70.0| 22.0  
Dulaglutide| | | | | | | | | | | | |   
Seko et al. (2017) [39] (Japan)| Case series (retrospective)| 5| T2DM and NAFLD| 0.75 mg once-daily| 12| BIA| NR| −1.9| −0.1| −0.2| −0.1| -| -  
Study (location)| Study design| No. (in group prescribed SGLT2i therapy)| Population| Dose (all once-daily, oral tablet unless otherwise specified)| Duration| Tech. used| Total BW change, kg (% change from baseline)| FM change, kg| LBM change, kg| Skeletal muscle mass change, kg| Total body water change, kg| Proportion of weight loss from FM, %| Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Various| | | | | | | | | | | | |   
Arase et al. (2019) [64] (Japan)| Case series (retrospective)| 17 (DAPA=10; CANA=7)| Overweight, T2DM and NAFLD| DAPA: 5 mg| 24 wk| BIA| −5.2 (−7.1%)| −2.7| −2.5a| −0.7| −1.2| 51.9| 48.1  
CANA: 100 mg  
Kinoshita et al. (2018) [65] (Japan)| Case series (prospective)| 156 (_n_ =108 for body composition) (LUSEO=52%; TOFO=29%; IPRA=15%; DAPA=4%)| T2DM| NR| 12 wk| BIA| −2.8 (−3.6%)| NR| NR| −0.1| NR| -| -  
Seko et al. (2017) [66] (Japan)| Case series (retrospective)| 24 (_n_ =17 for body composition) (CANA=18; IPRA=6)| T2DM and biopsy-proven NAFLD/NASH| CANA: 100 mg| 24 wk| BIA| NR| −2.4| −1.1| −0.6| −0.8| -| -  
IPRA: 50 mg  
Canagliflozin| | | | | | | | | | | | |   
Blonde et al. (2016) [40] Study 2 (Global; multi-site)| Three-arm RCT (sub-study)| CANA 100=63| T2DM| 100 mg| 26 wk| DXA| −2.5 (−2.8%)| −1.9| −0.9| NR| NR| 76| 36.0  
CANA 300=71| 300 mg| −3.2 (−3.4%)| −2.4| −1.2| NR| NR| 75| 37.5  
Cefalu et al. (2013) [41]b (Global; multi-site)| Three-arm RCT (sub-study)| CANA 100=111| T2DM| 100 mg| 52 wk| DXA| −4.4 (−5.2%)| −2.9| −0.9| NR| NR| 65.9| 20.5  
CANA 300=102| 300 mg| −4.2 (−4.9%)| −2.5| −1.1| NR| NR| 59.5| 26.2  
Koike et al. (2019) [42] (Japan)| Case series (prospective)| 38| T2DM| 100 mg| 24 wk| DXA| −2.4 (−3.3%)| −1.3| −1.1| NR| NR| 54.2| 45.8  
Inoue et al. (2019) [43] (Japan)| Case series (prospective)| 20| T2DM and NAFLD| 100 mg| 12 mo| BIA| −2.9 (−3.5%)| −2.6| −0.2| −0.2| −0.2| 89.7| 6.9  
Dapagliflozin| | | | | | | | | | | | |   
Bolinder et al. (2014) [44] (Europe; multi-site)| Two-arm RCT| 69| Overweight/obese with T2DM| 10 mg (added to open-label metformin)| 104 wk| DXA| −4.5 (−4.9%)| −2.8| −1.3| NR| NR| 62.2| 28.9  
Kosugi et al. (2019) [45] (Japan)| Case series (prospective)| 26| T2DM| 5 mg| 12 wk| DXA| −2.1 (−2.9%)| −1.7| −0.5| NR| NR| 81| 23.8  
Fadini et al. (2017) [46] (Italy)| Two-arm RCT| 16| T2DM| 10 mg| 12 wk| BIA| −3.1 (baseline NR)| −0.1| −2.9a| NR| −2.4| 3.2| 93.5  
Shimizu et al. (2019) [47] (Japan)| Two-arm RCT| 33| T2DM and NAFLD| 5 mg| 24 wk| BIA| −2.9 (−3.9%)| NR| NR| −0.9| −1.1| -| -  
Sugiyama et al. (2018) [48] (Japan)| Two-arm non-randomised cohort study| 28| T2DM| 5 mg| 6 mo| BIA| −3.4 (−4.4%)| −3.1| −0.5| −0.2| NR| 91.2| 14.7  
Tobita et al. (2017) [49] (Japan)| Case series (prospective)| 11| T2DM and NASH| 5 mg| 24 wk| BIA| −3.8 (−4.8%)| −6.1| 1.2| 0.1| 1.2| 160.5| LBM increased Fluctuation over 24 wk  
Empagliflozin| | | | | | | | | | | | |   
Ridderstrale et al. (2014) [50] (Global; multi-site)| Two-arm RCT (sub-study)| 46| T2DM| 25 mg| 104 wk| DXA| NR (−2.8 kg [–3.4%] in entire EMPA group; _n_ =765)| −1.6| −0.9a| NR| NR| 57.1| 32.1c  
Javed et al. (2019) [51] (UK)| Two-arm RCT| 19| PCOS| 25 mg| 12 wk| BIA| −0.8 (−0.8%)| −0.3| −1.1a| NR| −0.8| 37.5| 137.5  
Ipragliflozin| | | | | | | | | | | | |   
Inoue et al. (2019) [52] (Japan)| Two-arm RCT| 24| T2DM (on insulin therapy)| 50 mg (insulin dose reduced by 20%)| 24 wk| DXA| −2.8 (−4.4%)| −2.1| −0.6| NR| NR| 75| 21.6  
Ohta et al. (2017) [53] (Japan)| Case series (prospective)| 20| T2DM| 50 mg| 24 wk| DXA| −3.5 (−4.3%)| −1.8| −1.7| NR| NR| 51.4| 48.6  
Iemitsu et al. (2019) [54] (Japan)| Case series (prospective)| 217| T2DM| 50 mg| 104 wk| BIA| −2.9 (−3.7%)| −1.9| −1.0a| −0.9| −0.7| 31| 34.0  
Kato et al. (2017) [55] (Japan)| Case series (prospective)| 20| T2DM| 50 mg| 12 wk| BIA| −1.9 (−2.3%)| −1.3| −0.6a| −0.6| −0.7| 68.4| 31.6  
Miyake et al. (2018) [56] (Japan)| Case series (prospective)| 12| T2DM+NAFLD| 50 mg| 24 wk| BIA| −1.4 (−2.1%)| −1.6| +0.2a| −0.5| NR| 114.3| FFM increased  
Osonoi et al. (2018) [57] (Japan)| Case series (prospective)| 98| T2DM| 50 mg| 24 wk| BIA| −2.1 (−3.2%)| −1.5| −0.6a| NR| NR| 71.4| 28.6  
Yamamoto et al. (2016) [58] (Japan)| Case series (prospective)| 24| T2DM| 50 mg| 16 wk| BIA| −2.5 (−3.3%)| −1.7| −0.6| NR| −0.6| 68| 24.0  
Luseogliflozin| | | | | | | | | | | | |   
Bouchi et al. (2017) [59] (Japan)| Case series (prospective)| 19| T2DM| 2.5 mg, titrated up to 5 mg where tolerated and safe| 12 wk| DXA| −2.7 (−3.3%)| −1.4| −1.1a| NR| NR| 51.9| 40.7  
Sasaki et al. (2019) [60] (Japan)| Case series (prospective)| 37| T2DM| 2.5 mg, titrated up to 5 mg where tolerated and safe| 52 wk| DXA| −3.1 (−3.9%)| −2.0| −1.0| NR| NR| 64.5| 32.3  
Tofogliflozin| | | | | | | | | | | | |   
Iwahashi et al. (2016) [61] (Japan)| Case series (prospective)| 17| T2DM| 20 mg| 48 wk| BIA| −2.3 (−3.0%)| −2.6| +0.2a| NR| −0.3| 113| FFM increased  
Kamei et al. (2018) [62] (Japan)| Case series (retrospective)| 37| T2DM| 20 mg| 12 wk| BIA| −3.3 (−3.7%)| −1.9| −1.0| −0.8| −0.9| 57.6| 30.3  
Matsuba et al. (2018) [63] (Japan)| Case series (prospective)| 14| T2DM| 20 mg| 12 wk| BIA| −2.9 (baseline NR)| −1.3| −1.5| −1.4| −1.1| 44.8| 51.7  
Drug/author (location)| Study design| No. (in group prescribed SGLT2i+ GLP-1RA therapy)| Population| Dose (all once-daily, unless otherwise specified; SGLT2i taken as oral tablet, GLP-1RA as subcutaneous injection)| Duration, wk| Tech. used| Total BW change, kg (% change from baseline)| FM change| LBM change| Skeletal muscle mass change, kg| Total body water change, kg| Proportion of weight loss from FM, %| Proportion of weight loss from LBM, %  
---|---|---|---|---|---|---|---|---|---|---|---|---|---  
Dapagliflozin+Exenatide| | | | | | | | | | | | |   
Lundkvist et al. (2017) [67] (Sweden)| Two-arm RCT| 16| Obesity and pre-diabetes mellitus| DAPA: 10 mg| 52| MRI| −5.7 (−5.4%)| −5.3 La| −1.4 L| NR| NR| -| -  
EXEN: 2 mg weekly  
Luseogliflozin+Liraglutide| | | | | | | | | | | | |   
Seino et al. (2018) [68] (Japan)| Case series (prospective) (sub-study)| 22| T2DM| LUSEO: 2.5 mg, titrated up to 5 mg where tolerated and safe (_n_ =17 reached 5 mg dose)| 52| BIA| −2.9 (−4.3%)| −2.5 kg| −0.4 kg| NR| NR| 86.2| 13.8  
LIRA: 0.6 mg (_n_ =1) or 0.9 mg (_n_ =21)  
  
**Table 1** Definitions of Body Composition Compartments 

**Table 2** Studies Reporting Changes in Body Composition with GLP-1RA Therapy 

GLP-1RA, glucagon-like peptide-1 receptor agonist; BW, body weight; FM, fat mass; LBM, lean body mass; RCT, randomised controlled trial; DXA, dual-energy X-ray absorptiometry; NR, not reported; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovarian syndrome; LEAD, Liraglutide Effect and Action in Diabetes phase 3 programme for liraglutide; FFM, fat-free mass; T1DM, type 1 diabetes mellitus; BIA, bioelectrical impedance analysis; CT, computed tomography; ADP, air displacement plethysmography.

aFFM.

**Table 3** Studies Reporting Changes in Body Composition with SGLT2i Therapy 

SGLT2i, sodium-glucose cotransporter 2 inhibitor; BW, body weight; FM, fat mass; LBM, lean body mass; DAPA, dapagliflozin; CANA, canagliflozin; T2DM, type 2 diabetes mellitus; NAFLD, nonalcoholic fatty liver disease; BIA, bioelectrical impedance analysis; LUSEO, luseogliflozin; TOFO, tofogliflozin; IPRA, ipragliflozin; NR, not reported; NASH, nonalcoholic steatohepatitis; RCT, randomised controlled trial; DXA, dual-energy X-ray absorptiometry; EMPA, empagliflozin; PCOS, polycystic ovarian syndrome; FFM, fat-free mass.

aFFM; bSame as “Study 1” in Blonde et al. (2016) [41]; cCalculated using mean weight loss in entire cohort.

**Table 4** Studies Reporting Changes in Body Composition with GLP-1RA and SGLT2i Combination Therapy 

GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor; BW, body weight; FM, fat mass; LBM, lean body mass; RCT, randomised controlled trial; DAPA, dapagliflozin; EXEN, exenatide; MRI, magnetic resonance imaging; NR, not reported; T2DM, type 2 diabetes mellitus; LUSEO, luseogliflozin; LIRA, liraglutide; BIA, bioelectrical impedance analysis.

aTotal adipose tissue.

### Table 1

![](../upload/thumbnails/T1-enm-34-247.png)

### Table 2

![](../upload/thumbnails/T2-enm-34-247.png)

### Table 3

![](../upload/thumbnails/T3-enm-34-247.png)

### Table 4

![](../upload/thumbnails/T4-enm-34-247.png)

ALL TABLES

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