Recent research on glucagon-like peptide-1 (GLP-1) drugs for weight loss indicates these medications may lead to significant reductions in lean body mass, including muscle. The STEP 1 and SUSTAIN 8 of semaglutide trials found 39–40% of weight lost on the GLP-1 drugs was lean mass. A 2021 meta-analysis of 18 randomized controlled studies showed significant drops in fat-free mass with GLP-1 drugs, including oral and subcutaneous semaglutide and older GLP-1 drugs such as lixisenatide, exenatide, and liraglutide. The meta-analysis focused on both GLP-1 receptor agonists and sodium-glucose cotransporter (SGLT-2) inhibitors.
Sizing up the GLP-1 impact on lean mass: Mixed signals
While some data suggests that GLP-1 drugs are associated with muscle loss, there may be more to the story than meets the eye. In STEP 1 and SUSTAIN 8, the proportion of lean mass to total body mass still increased overall, pointing to an overall improvement in body composition. And data from the SURMOUNT-1 tirzepatide study reached more positive conclusions, concluding that fat mass dropped between 33% and 36% and lean mass by 10% to 11% depending on the age group. In other words, roughly one-quarter of the weight lost in that study was lean mass.
More concerning is the delta in body composition in the STEP study of semaglutide, which found that placebo recipients had no major changes in body composition. But in the SUSTAIN 8 study, recipients of the sodium-glucose cotransporter 2 diabetes drug canagliflozin had similar changes in terms of total fat mass, lean mass, and visceral fat mass compared with those receiving semaglutide.
Overall, a growing number of data points highlight a connection between GLP-1 and potential muscle loss. For instance, a 2020 network meta-analysis by Satoshi Ida and colleagues concluded semaglutide and other GLP-1 receptor agonists markedly decreased fat-free mass versus placebo. On the other hand, a 2023 Chinese study found semaglutide maintained muscle mass. And earlier data suggest that GLP-1 receptor agonists could have a protective effect against muscle wasting by suppressing muscle atrophic factors and boosting myogenic factors.
*Note: Data for ‘Early Phase of Dieting’ and ‘Later Phase of Dieting’ are derived from historical studies, including the Minnesota Semi-Starvation Experiment and Francisco Grande’s research. ‘Water Fasting’ data includes overall lean soft tissue loss, not exclusively muscle mass loss.
The bottom line
While GLP-1 drugs effectively support weight loss, including fat loss, their impact on lean body mass remains less clear. While some high-quality studies, such as the STEP 1 and SUSTAIN 8 studies, show a significant proportion of weight loss as lean mass, data from across studies suggests an overall improvement in body composition for many patients and even potential protective effects against muscle wasting.
Other considerations include the fact that GLP-1 drugs may lower the risk of death from cardiovascular causes, heart attack and stroke. A literature review also found that the proportion of lean body mass reductions varied between 20% and 50% of total weight lost, which is in line with diet-induced weight loss and bariatric surgery. The study found no clear differences between GLP-1 drugs and sodium-glucose cotransporter 2 inhibitors (SGLT2i) in terms of lean body mass loss.