[Updated on March 18, 2024]
Do GLP-1 drugs lead to loss of muscle mass? The German expression “jein,” spanning both yes and no, captures researchers’ present understanding of the complexity of this issue.
Yes, 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.
In 2024, a growing number of biotech and pharma companies are exploring ways to preserve skeletal muscle mass in those taking GLP-1 agonist drugs for obesity, as Nature Biotechnology noted in early March. These efforts aim to counter the muscle loss that often accompanies the significant weight reduction achieved with medications such as semaglutide (Ozempic) and tirzepatide (Mounjaro). By pairing GLP-1 agonists with muscle-preserving agents targeting pathways like myostatin/activin, apelin and mTOR, companies hope to drive fat loss while maintaining lean muscle tissue.
For instance, BioAge Labs is combining its drug candidate BGE-105 with tirzepatide in a phase 1 study while Regeneron will test its antibody drugs with semaglutide to prevent muscle loss, especially in older patients. Finally, Veru received FDA clearance for a phase 2b trial of enobosarm with GLP-1 drugs to preserve muscle in sarcopenic obese elderly patients.
Sizing up the GLP-1 impact on lean mass: Mixed signals
But 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. For context, some degree of lean muscle mass loss is normal in most weight loss scenarios, as the body tends to shed both fat and some lean tissue when losing weight.
It is true, though, that some semaglutide-related study appear to point to greater-than-average losses in muscle. The STEP study of semaglutide, for instance, found that placebo recipients had no major changes in body composition, while semaglutide recipients appeared to have reductions in both fat and muscle. But the proportion of lean body mass improved in the drug arm. Additionally, in the SUSTAIN 8 study, recipients of the sodium-glucose cotransporter type 2 diabetes drug canagliflozin had similar changes in terms of total fat mass, lean mass, and visceral fat mass compared with those receiving semaglutide.
Still, 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 represents an average value of overall lean soft tissue loss, not exclusively muscle mass loss.
Historical context
To put things into perspective, researchers’ understanding of the nuances of weight loss remains something of a work in progress. While weight loss studies are common, some of the most famous research on the physiological and psychological effects of severe calorie restriction dates to the middle of the last century. The Minnesota Semi-Starvation Experiment, published in 1950, for instance, aimed to determine the physiological effects of severe and prolonged dietary restriction and the effectiveness of dietary rehabilitation strategies for war victims who had undergone starvation. The study observed that 37% of weight loss was from fat during the first 12 weeks of dieting, and in the following 12 weeks, fat loss increased to 70% of the total weight loss.
A modern study, from 2021, shed light on the dynamics of body composition changes during and after a controlled period of fasting combined with physical activity. During a 10-day fast, participants lost an average of 7% of their body weight, with fat mass and lean soft tissues accounting for about 40% and 60% of this weight loss (averaged above as 50%), respectively. It’s worth noting that both of these studies focused solely on men.
The bottom line
While GLP-1 drugs effectively support weight loss, including fat loss, their impact on lean body mass remains unclear. 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.
Filed Under: clinical trials, Gastroenterology
