Sarcopenia in Asian Patients in the Era of SGLT2i and GLP-1RA: A Clinical Concern?

Dear Editor, The advent of glucagon-like peptide-1 receptor agonists (GLP-1RA), sodium–glucose cotransporter-2 inhibitors (SGLT2i), and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists has expanded therapeutic options for type 2 diabetes mellitus, with substantial benefits for glycemic control, weight reduction, and cardiometabolic risk reduction. However, their effects on lean body mass warrant closer attention, particularly in Asian populations where sarcopenic obesity (SO) is increasingly recognized.[1,2] Evidence from randomized trials suggests that pharmacologic weight loss with these agents reflects loss of both fat and lean mass rather than adipose tissue alone. In STEP-1, semaglutide produced 14.9% weight loss (approximately 15.3 kg), with a reduction in lean mass, although the relative proportion of lean mass increased because fat loss was greater.[3] Similarly, in SURMOUNT-1, tirzepatide produced 20.9% weight loss (approximately 23.6 kg), with a 10.9% reduction in lean mass, and about 25% of the lost weight was attributable to lean mass.[4] In parallel, SGLT2i such as dapagliflozin, canagliflozin, and empagliflozin have been associated with modest weight loss and small reductions in lean mass [Table 1].[15]Table 1: Clinical studies evaluating changes in body composition with SGLT2 inhibitors, GLP-1 receptor agonists, and dual GLP-1/GIP agonistsThis issue may be especially relevant in Asian populations, where lower lean mass and greater visceral adiposity at a given body mass index increase vulnerability to SO.[16] Sarcopenia is defined not only by reduced muscle quantity but also by impaired muscle strength and/or physical performance, making functional assessment essential when lean mass declines are observed.[17] Sarcopenia should be assessed using the Asian Working Group for Sarcopenia 2019 consensus criteria, which incorporate muscle strength, muscle mass, and physical performance. In clinical practice, handgrip strength is commonly used to assess muscle strength, dual-energy X-ray absorptiometry to assess muscle mass, and gait speed or chair-rise testing to assess physical performance. Low muscle strength is generally considered the initial step in case identification, followed by confirmation of low muscle mass and severity grading based on impaired physical performance.[17,18] Thus, treatment-associated reductions in lean mass may have important clinical implications in patients with preexisting frailty or low baseline muscle reserve. At the same time, available evidence suggests that these therapies mainly reduce fat mass, whereas functional measures are often preserved. In the SLIM LIVER study, semaglutide reduced psoas muscle volume, but physical function remained stable, indicating that short-term muscle loss does not necessarily imply functional decline.[14] The main limitation of current evidence is that most data come from subgroup analyses, short-term studies, or trials conducted in non-Asian populations. Although Asian trials such as STEP-6, STEP-7, and SURMOUNT-CN demonstrated significant weight loss with incretin-based therapy, body-composition outcomes were inconsistently reported, leaving an important evidence gap.[19] Moreover, heterogeneity in measurement methods, including dual-energy X-ray absorptiometry, bioelectrical impedance analysis, and computed tomography, limits direct comparison across studies. Accordingly, these agents should not be withheld on the basis of theoretical concerns about sarcopenia. Rather, they should be used with a balanced approach that includes nutritional support, resistance exercise, and functional monitoring, particularly in older adults, frail patients, and those with low baseline muscle reserve. In practical terms, baseline assessment of handgrip strength and physical performance, followed by periodic reassessment during treatment, may help identify patients at higher risk. Adequate protein intake and structured resistance training should be encouraged wherever feasible.[20] In summary, GLP-1RA, SGLT2i, and dual GLP-1/GIP agonists offer major metabolic benefits, but their effects on lean mass warrant attention in Asian patients at risk of sarcopenia. Future studies in Asian populations should incorporate prespecified body-composition and functional endpoints, using region-specific diagnostic criteria, to determine whether treatment-related changes in lean mass are clinically meaningful. A balanced approach that combines pharmacotherapy with nutritional and exercise strategies, plus functional monitoring when feasible, may help maximize benefit while minimizing muscle-related harm. Acknowledgment Not applicable.