Beyond weight loss: Preserving muscle health in the incretin era

Abstract

Incretin-based therapies have transformed the treatment of type 2 diabetes and obesity.¹ As the field has evolved from glucagon-like peptide-1 (GLP-1) receptor agonists to the glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist tirzepatide and, more recently, highly potent multi-agonists, the clinical challenge has begun to shift. The question is no longer whether substantial weight loss can be achieved, but whether it can be achieved while preserving muscle health, particularly in older adults. Retatrutide, an investigational triple GIP/GLP-1/glucagon receptor agonist, exemplifies this therapeutic progress. In a phase 2 body-composition sub-study involving people with type 2 diabetes, pooled 8-mg retatrutide regimens reduced body weight by approximately 16.8 kg over 36 weeks, compared with 2.1 kg with placebo and 0.8 kg with dulaglutide 1.5 mg.² Dual-energy X-ray absorptiometry (DXA) demonstrated an accompanying reduction of approximately 6.5 kg in lean mass, while most of the remaining weight loss reflected reductions in fat mass (Figure 1). This Commentary argues that the next challenge in the incretin era is not simply greater weight loss, but healthier weight loss—maximizing fat loss while preserving muscle health, particularly in older adults with type 2 diabetes.

Across clinical trials, reductions in lean or fat-free mass have consistently accounted for approximately one-quarter to two-fifths of total weight loss with incretin receptor agonists.³ Whether this proportion is excessive remains debated. More importantly, the clinical relevance of lean-mass loss depends not only on its relative contribution to weight loss but also on its absolute magnitude and, critically, on the vulnerability of the individual receiving treatment. The clinical role of incretin receptor agonists is also expanding rapidly. Beyond glycemic and weight management, these agents reduce cardiovascular, heart failure, and chronic kidney disease risks, and have shown benefits in obstructive sleep apnea and metabolic dysfunction-associated steatohepatitis (MASH). As a result, they are increasingly prescribed across a broader range of clinical settings and for longer durations. Consequently, growing numbers of older adults—including those with pre-existing declines in muscle mass and function—are likely to receive these therapies, making preservation of muscle health an increasingly important clinical priority.

Older adults with type 2 diabetes are particularly vulnerable to muscle loss during rapid weight reduction. Sarcopenia—defined by the 2025 Asian Working Group for Sarcopenia (AWGS) as low muscle mass accompanied by low muscle strength—is more prevalent in people with diabetes and is associated with insulin resistance, falls, fractures, disability, loss of independence and mortality.⁴ Reflecting these concerns, AWGS 2025 shifted its focus from sarcopenia to muscle health and introduced BMI-adjusted cut-offs for appendicular skeletal muscle mass alongside conventional height-adjusted indices, which may reduce the risk that sarcopenia is overlooked when excess adiposity masks low muscle mass.⁴ AWGS 2025 also identified sarcopenic obesity—the coexistence of excess adiposity with impaired muscle mass and function—as a priority for future research.⁴ As increasingly potent incretin-based therapies are introduced into rapidly aging populations, particularly in Japan, the convergence of pharmacologically induced weight loss and pre-existing muscle vulnerability is likely to emerge as an important clinical challenge. Body composition alone does not define clinical benefit. What ultimately matters is not how much lean mass is retained, but whether patients preserve strength, mobility and independence—a shift reflected in AWGS 2025, which emphasizes physical performance as an outcome to be monitored rather than a diagnostic criterion.⁴ Importantly, whole-body lean mass—a common trial endpoint—is an imperfect surrogate for skeletal muscle. DXA estimates lean mass rather than directly measuring muscle tissue, and the estimate includes body water and other non-muscle components. Consequently, an early decline may partly reflect changes in hydration rather than true muscle loss. Conversely, preserved lean mass does not necessarily indicate preserved muscle health. Muscle strength may decline despite stable lean mass, while fat accumulation within and around muscle (myosteatosis) can impair physical performance and metabolic function. Muscle quality, therefore, is at least as important as muscle quantity. A stable DXA measurement is reassuring only if accompanied by preserved strength and physical performance.

While resistance exercise and adequate nutritional support remain the foundation of muscle preservation during weight loss, a new pharmacological strategy is emerging: combining potent incretin-based therapies with agents designed to preserve muscle. This approach aims not to reduce weight loss but to shift tissue loss preferentially towards fat while minimizing the loss of skeletal muscle (Figure 2). This proof-of-concept has recently been provided by two phase 2 trials. In a phase 2 study to evaluate efficacy and safety of apitegromab for the treatment of adults who are overweight or obese (EMBRAZE), adding apitegromab—an intravenous antibody that inhibits myostatin activation—to tirzepatide preserved an additional 1.9 kg of lean mass over 24 weeks: Lean-mass loss was 1.6 kg with apitegromab versus 3.5 kg with placebo (54.9% relative preservation), while total weight loss was similar between groups.⁵ In a phase 2 study to assess the safety and efficacy of bimagrumab and semaglutide in adults who are overweight or obese (BELIEVE), adding bimagrumab—an antibody targeting activin type II receptors—to semaglutide reduced the decline in total-body lean mass to approximately 2%, compared with approximately 7% with semaglutide alone, despite greater overall weight loss.⁶ Bimagrumab monotherapy also increased lean mass while reducing fat mass, consistent with activin type II receptor signaling in both skeletal muscle and adipose tissue. Both combinations remain investigational, and the cross-trial comparisons in Figure 1 are illustrative rather than head-to-head. Beyond these agents, an expanding pipeline—including trevogrumab, garetosmab and enobosarm—suggests that muscle-preserving therapies may become an important adjunct to future incretin-based strategies.³

More importantly, these studies were not conducted in the populations most likely to benefit from muscle-preserving strategies. In BELIEVE, the mean participant age was 47.5 years, approximately three-quarters of participants were White, and individuals with diabetes were excluded.⁶ Similarly, EMBRAZE excluded people with diabetes, enrolled predominantly women, and had a mean age of approximately 43 years.⁵ Neither study specifically targeted older adults; participants were not selected or systematically evaluated for sarcopenia, and neither was designed to determine whether muscle preservation is greatest in those at highest risk of functional decline. Moreover, EMBRAZE was explicitly a proof-of-concept study. Efficacy analyses were descriptive and made no adjustment for multiplicity.⁵ Accordingly, its findings should be regarded as hypothesis-generating rather than confirmatory.

Follow-up in these studies was relatively short, and body composition—not muscle function—was the primary focus. Functional outcomes were secondary or exploratory, and current evidence does not establish that preserving DXA-measured lean mass translates into better muscle strength, physical performance, or independence. Muscle quality was also rarely assessed. These approaches also present practical and safety considerations. Bimagrumab was associated with muscle spasms, diarrhea, and acne; the long-term safety of activin-pathway inhibition remains uncertain, and adding an intravenous biologic increases treatment complexity, cost, and patient burden.⁶ No pharmacological combination has yet been approved specifically for muscle preservation. Moreover, the durability of lean-mass preservation after treatment discontinuation remains unknown. The key unanswered question is therefore not whether lean mass can be pharmacologically preserved, but whether such preservation translates into sustained muscle function, mobility, and independence in older adults with type 2 diabetes, particularly those with sarcopenia and/or obesity.

Until more definitive evidence becomes available, preservation of muscle health should be an integral component of incretin-based therapy in older adults. Progressive resistance exercise and individualized nutritional support remain the cornerstone, with particular attention to adequate protein and energy intake. Because incretin-induced satiety and delayed gastric emptying may compromise nutritional intake, dietary intake should be assessed proactively and reinforced throughout treatment. Muscle health should also be monitored routinely using complementary measures. In clinical practice, bioelectrical impedance analysis (BIA), an assessment method endorsed by AWGS 2025, is generally more practical than DXA for estimating appendicular skeletal muscle mass.⁴ However, body composition alone is insufficient. Muscle strength and physical performance should be assessed alongside muscle mass using simple, validated measures such as handgrip strength and the five-time chair-stand test.⁴

The pace and extent of weight reduction with incretin receptor agonists should be individualized according to baseline frailty, sarcopenia, the degree of excess adiposity, and the severity of obesity-related complications. In individuals with limited muscle reserve, slower dose escalation and more conservative weight-loss targets may be appropriate. These decisions should also reflect the broad benefits of incretin-based therapies, including improvements in glycemic management, reductions in cardiovascular and kidney risk, and benefits for obesity-related complications. Preservation of muscle health should be integrated into the overall risk–benefit assessment, rather than considered in isolation. For individuals with advanced frailty or sarcopenia and a limited obesity-related disease burden, maintaining body weight or only modest reduction may be more appropriate. These considerations define an important research agenda. Future trials should enroll older adults with type 2 diabetes, particularly those with sarcopenic obesity and individuals from rapidly aging Asian populations. Beyond body composition, studies should evaluate muscle strength, physical performance, and muscle quality. Longer follow-up will be required to assess durability, safety, cost-effectiveness, and treatment burden, and to identify those most likely to benefit—or to be harmed. Ultimately, the success of incretin-based therapy should not be judged by kilograms of weight loss alone, but by the extent to which excess adiposity is reduced while muscle health, physical function, and independence are preserved.

Toshinori Imaizumi declares no conflict of interest. Daisuke Yabe received clinically commissioned/joint research grants from Taisho Pharmaceutical, Boehringer Ingelheim, Kowa, and Tanabe Pharama. Daisuke Yabe also received consulting or speaker fees from Sumitomo Pharma, Tanabe Pharma, Boehringer Ingelheim, Novo Nordisk, Eli Lilly, and Taisho Pharmaceutical.

This article is a commentary on previously published clinical trial data and does not describe any new research involving human participants or animals conducted by the authors. Therefore, the following items are not applicable.

Approval of the research protocol by an Ethics Committee: N/A.

Informed consent: N/A.

Registry and the registration no. of the study/trial: N/A.

Animal studies: N/A.

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.