Ways to reduce muscle loss when using incretin-like drugs to treat obesity

Glucagon‐like peptide‐1 and GIP are hormones that exert an incretin effect, in which an oral glucose load induces a stronger insulin response than an isoglycemic intravenous glucose load.5 Similar to endogenous incretin hormones, IMDs have pleiotropic effects on the gastrointestinal tract, the central nervous system, and other organ systems. In general, IMDs have a significant effect on the regulation of body weight by suppressing appetite and slowing gastric emptying.5 It is widely recognized that restricted caloric intake leading to weight reduction is usually accompanied by loss of muscle mass6 and that such loss can be detrimental.3, 4 Thus, steps to monitor and minimize loss of muscle mass and function are essential components of a comprehensive obesity treatment program.

The central goals of obesity treatment are long‐term reduction of excess and abnormal adiposity, as well as complications associated with excess body weight, such as cardiovascular disease (Figure 1).8, 9 Unfortunately, most patients who use anti‐obesity medications, including IMDs, for this purpose regain much of their former weight after stopping therapy.10, 11 Specifically, at the end of the weight reduction phase, most patients will have lower energy expenditure owing to various adaptations, including lower muscle mass, reduced basal metabolic rate, and possibly improved muscle efficiency (Figure 2).13 Because muscle is more metabolically active than adipose tissue, reductions in muscle mass lead to reduced energy expenditure and consequently reduced energy deficit, rendering weight maintenance more difficult. Furthermore, it is likely the body weight regained after stopping treatment is disproportionately composed of adipose tissue, with little regain of lean mass and little increase in energy expenditure.14, 15 This process can lead to weight cycling, which is particularly common in young and middle‐aged women (<60 years), who are also the most common type of patients seeking obesity treatment.16 Severe weight cycling is associated with an increased risk of muscle loss and sarcopenic obesity,15, 17 which has been reported in as many as 20% of young women (≥18 years of age) seeking obesity treatment.18

On average, people with obesity have a higher absolute skeletal muscle mass and strength than those with a normal weight, especially in weight‐bearing muscles.9, 19, 20 However, a substantial percentage of people with obesity have low muscle mass.21 Furthermore, when muscle strength is normalized to body weight, it is lower in people living with obesity.19 Another factor is that prediabetes and type 2 diabetes (T2D) are common in people with obesity, and T2D is associated with lower muscle mass and more rapid age‐related declines in muscle mass.22, 23, 24, 25 In addition, it is widely recognized that excess and abnormal adiposity has detrimental effects on muscle strength and structure, as well as cardiovascular disease, due to multiple mechanisms, including myosteatosis.19, 26, 27

Low muscle mass is often unrecognized and is independently associated with increased risk of mortality and morbidity, reduced quality of life, increased risk of T2D, and other adverse health outcomes.3, 4, 8, 28, 29 A recent study estimated that 15.9% of the US adult population (≥20 years old) had obesity with low muscle mass, representing almost 30 million people.21 These individuals—and especially women and those with T2D, prediabetes, or metabolic dysfunction‐associated steatotic liver disease (MASLD)—are already at high risk of sarcopenia (age‐related loss of skeletal muscle function and mass),30, 31 sarcopenic obesity (the co‐existence of excess adiposity and low muscle mass/function, which can occur at any age32), and the serious negative health outcomes accompanying those conditions (Figure 3).16, 21, 28, 29, 33

Interpretation of muscle loss in phase 3 trials of IMDs necessitates a clear understanding of body composition terminology and its application. According to precise definitions, lean mass includes lean soft tissues, not bone mass (Figure 4).34 Fat‐free mass, in contrast, includes the sum of lean mass and bone mass. Unfortunately, the terms "lean mass" and "fat‐free mass" are often mistakenly used interchangeably, which ignores these critical distinctions. Compounding this issue, many studies fail to explain dual‐energy X‐ray absorptiometry (DXA) methods in sufficient detail, making it challenging to determine which body composition compartment is being assessed and whether the terminology is used accurately.

In a pivotal trial of semaglutide for the treatment of obesity (Semaglutide Treatment Effect in People with Obesity‐1; STEP‐1), a subset of participants had body composition analyzed by DXA before and at the end of the 68‐week treatment period (see supplementary appendix in Wilding et al.35). In the semaglutide‐treated (2.4 mg once weekly) group, body weight was reduced by an average of 17.32 kg during the treatment period (vs. 2.65 kg in the placebo group); this included a 6.92‐kg mean reduction in total lean mass (vs. 1.48 kg in the placebo group). Thus, in the semaglutide group, 40% of the reduction in body weight was due to a reduction in lean mass. Perhaps more importantly, 6.92 kg represents 13.2% of the average total lean mass at baseline (52.4 kg). Although muscle usually accounts for about one‐half of lean mass, it is not possible to determine from this publication the actual proportion of lean mass that was muscle versus other non‐fat tissues such as the liver, heart, and other organs and tissues. However, it is reasonable to conclude that muscle loss accounted for at least half of the reduction in lean mass during the STEP‐1 trial.36, 37, 38 On this basis, a conservative estimate is that participants in the semaglutide group lost at least 10% of their muscle mass during the 68‐week treatment period.

In a pivotal trial of tirzepatide (Study of Tirzepatide in Participants with Obesity of Overweight; SURMOUNT‐1) for obesity, a subset of participants also had body composition analyzed by DXA before and at the end of the 72‐week treatment period (see supplementary appendix in Jastreboff et al.2). In the pooled tirzepatide‐treated (5, 10, or 15 mg once weekly) DXA subgroup, participants lost 10.9% of their lean mass during the treatment period. However, in the overall trial, tirzepatide‐treated patients lost 15% to 20.9% of their body weight. On a percentage basis, the loss of lean mass was similar to that reported among the semaglutide‐treated participants in the STEP‐1 trial. The estimated loss of skeletal muscle in these two major trials (10% or more during 68–72 weeks of treatment) approximates the average decline in muscle mass during 20 years of aging‐related muscle loss in adults older than 30 years, estimated at 3%–5% per decade (Figure 5).39

In earlier studies of modest weight reduction by non‐pharmacologic caloric restriction, declines in lean mass typically accounted for 10%–30% of the total body weight reduction.6 However, this percentage is not a constant and is expected to trend higher in people rapidly experiencing large weight reductions, as observed after bariatric surgery.40 It can also vary by sex, race, ethnicity, physical activity level, and other variables.6, 41 Although participants in the active‐treatment groups of the STEP‐1 and SURMOUNT‐1 trials experienced proportionately large declines in lean mass, those declines may be consistent with declines in lean mass expected in people experiencing large weight reductions.40 Or they could be due to characteristics of participants enrolled in the trials or other trial‐related factors. In the absence of additional studies or analyses, it is premature to speculate that the observed declines in lean mass were due to anything other than reduced caloric intake and possibly inadequate intake of specific macro‐ or micronutrients (in the context of low levels of physical activity).

Available evidence suggests that IMD therapy has beneficial effects on muscle structure and function in animal models and humans.42, 43, 44, 45, 46, 47, 48, 49, 50, 51 It is unclear whether those effects are sufficient to counteract the loss of muscle mass seen in clinical trials. However, there is evidence that exercise has beneficial effects when added to IMD therapy52 or to weight reduction induced by caloric restriction.53, 54, 55 It could be a decade or more before long‐term follow‐up studies evaluate the long‐term risk of sarcopenia or sarcopenic obesity associated with IMD therapy. Given the existing elevated risk in people with obesity,7 and taking into account current research gaps, efforts to minimize that risk should be a routine part of current obesity care.

Adequate nutrition is essential for the maintenance of muscle mass.63 Comprehensive obesity guidelines provide clear recommendations regarding macronutrient intake, a personalized approach to nutrition, and a comprehensive approach to management.53, 54, 55, 64 As noted in several guidelines, individualized nutrition education and medical nutrition therapy from a registered dietitian (RD) should be offered as core components of any obesity treatment plan.53, 54, 55, 65 If an RD is not accessible, the prescribing clinic should provide nutrition education and support.

In the setting of caloric restriction associated with IMD therapy, many patients may have inadequate protein intake. Thus, protein intake should be monitored to ensure it is adequate. Currently, the Institute of Medicine Recommended Dietary Allowance for protein in healthy people is 0.8 g/kg body weight/day.66 Higher amounts have been recommended for healthy people older than 65 years (1.2–1.5 g/kg body weight).67 Guidelines for the management of patients after bariatric surgery recommend a minimal protein intake of 60 g/day and up to 1.5 g/kg ideal body weight.68 Clinical nutrition guidelines from the Joslin Diabetes Center recommend protein intake of 1.0–1.5 g/kg of adjusted body weight, in which adjusted body weight is ideal body weight plus 0.25 × excess body weight.69 Protein intake should be adapted to meet the individual needs of each patient.67, 68, 70, 71 Furthermore, protein quality (as reflected by the content of essential amino acids and protein digestibility) affects the ability of dietary protein to support muscle protein synthesis.72 Thus, nutrition education and support should include individualized guidance on how patients can incorporate high‐quality protein sources in their diet.

Still unclear is the role of protein supplementation beyond recommended levels as a stand‐alone intervention to preserve muscle mass during caloric restriction or during maintenance of a reduced body weight. Studies addressing this issue have had mixed results, and many study designs make it difficult to apply the results to specific patient types such as people living with obesity on calorie‐restricted diets.73, 74 There are no current guidelines that recommend protein supplementation for these purposes beyond ensuring adequate protein intake on an individual basis.

Recent micronutrient guidelines emphasize that an adequate supply of all essential trace elements and vitamins (micronutrients) is essential for the metabolism of foods supplying protein and energy.75 Unfortunately, an analysis of National Health and Nutrition Examination Survey (NHANES) data suggests that more than 40% of US adults have inadequate intake of micronutrients.61 The recent micronutrient guidelines provide detailed information about the signs of micronutrient deficiency as well as how to assess and correct micronutrient levels.75 Another set of guidelines addressing nutrition after bariatric surgery also provides a reasonable template for a clinical approach to this issue.68

IMD therapy for obesity is associated with reduced appetite, temporary food aversion, and changes in taste preferences, especially during the initial stages of therapy.76 If patients receiving IMD therapy are unable to maintain a diet containing sufficient high‐quality protein and micronutrients, oral nutritional supplements (ONS) may be an effective and scalable option. With guidance from the clinical team, these products can be integrated into a comprehensive obesity treatment plan without undermining weight reduction efforts.4, 54 ONS provide protein, energy, and micronutrients for people who are not meeting their nutrition needs by food alone, and some are formulated with ingredients intended to support muscle health, as discussed in detail elsewhere.4 Use of ONS products is supported by extensive research and clinical guidelines.77, 78, 79 Note that dietary supplements are distinct from ONS and typically provide only specified types and amounts of individual nutrients, and they often have less research supporting their efficacy and safety.80, 81, 82, 83 Several randomized controlled trials have shown beneficial effects of ONS products on functional outcomes in various clinical scenarios,84, 85, 86 including significantly better leg strength in older (≥65 years), community‐dwelling adults at risk of malnutrition.87 Ongoing trials are evaluating the role of ONS to support muscle health in people with obesity.88

Both aerobic exercise and resistance training are widely recommended as essential components of a comprehensive obesity care plan.53, 54, 55, 89 Some guidelines recognize that resistance training can promote the maintenance of muscle mass and function during weight reduction therapy and promote weight maintenance after cessation of weight reduction therapy.53, 54, 55 In addition, several systematic reviews and meta‐analyses concluded that resistance training was effective for maintaining muscle mass during caloric restriction in people with overweight or obesity.90, 91, 92, 93 Another systematic review found similar results after bariatric surgery.94 These results are also supported by a randomized clinical trial of older adults living with frailty or reduced muscle mass induced by weight reduction.95 A study of maintenance therapy after low‐calorie weight reduction showed that exercise in combination with IMD therapy is associated with greater loss of adiposity and improvements in glycemic parameters and cardiorespiratory fitness versus IMD therapy alone or exercise alone.96 Furthermore, a long‐term follow‐up study of people with obesity who were treated with an IMD has shown that discontinuation of therapy was accompanied by weight regain as well as the return of cardiometabolic risk factors (e.g., high blood pressure and prediabetes).11 However, evidence suggests that when IMD therapy is accompanied by supervised exercise, those adverse effects occurring after treatment discontinuation can be attenuated.52

A program of physical activity that includes resistance training should take into account numerous patient‐specific factors including age, baseline fitness level, nutritional status, existing cardiovascular disease or risk factors, joint health and overall mobility, respiratory health, other comorbidities, medications, patient preferences, access to fitness equipment or resources, patient motivation, and psychological factors.97, 98 Guidance on the development of individualized goals and physical activity programs can be found in guidelines from the American College of Sports Medicine and the Physical Activity Guidelines for Americans.97, 98 The latter guidelines recommend at least 150–300 min per week of moderate‐intensity exercise or 75–150 min of vigorous‐intensity exercise as well as muscle‐strengthening activities on two or more days per week. It also notes the importance of working all the major muscle groups: legs, hips, back, abdomen, chest, shoulders, and arms.97 A practical consideration for developing resistance training plans is that muscle loss during weight reduction may affect some muscles more than others, and this effect may depend on the person's sex and age.99

A related question is whether a high‐protein diet increases the benefit of resistance training with respect to preserving muscle mass during caloric restriction in people with obesity. Several trials, systemic reviews, and meta‐analyses have addressed this question, but most of them studied older adults or people without obesity.100, 101, 102, 103 Because physical activity increases muscle protein synthesis, it is likely to increase protein needs. At the least, available studies reinforce the importance of maintaining adequate protein intake during caloric restriction in people with obesity.32 Other advantages of higher protein intake in this setting include increased satiety and energy expenditure, both of which contribute to weight reduction and maintenance of lower weight.104 Fortuitously, the two key strategies for preserving muscle mass and function during caloric restriction—nutrition and physical exercise—also have beneficial effects on bone,105, 106, 107 potentially reducing the risk for osteosarcopenic obesity.108

Skeletal muscle also functions as an endocrine organ. Muscle contraction during exercise triggers the release of numerous autocrine, paracrine, and endocrine mediators collectively known as myokines.109 These humoral factors have been shown to have beneficial effects on cognition, lipid and glucose metabolism, adipocyte function, bone structure, endothelial function, immune function, and skin structure.109 Though human research on this topic is limited, preclinical studies suggest that loss of muscle mass or function can detrimentally affect numerous physiological systems.109