GLP-1 receptor agonists reduce more fat than muscle mass

Glucagon-like peptide-1 (GLP-1) receptor agonists likely induce weight loss by reducing more fat mass than muscle mass, a research team from the University of Hong Kong (HKU) has found.

In what the authors believe to be the largest drug-target Mendelian randomization study to date assessing the relative effects of genetically proxied GLP-1 receptor agonism on muscle and fat mass, genetic data of over one million individuals of European ancestry obtained from several relevant genome-wide association studies (GWAS) were used. [Diabetes Obes Metab 2025;doi:10.1111/dom.16171]

Consistent with previous randomized controlled trials, results showed that genetically proxied GLP-1 receptor agonism is associated with a reduction in body mass index (BMI) and, importantly, this reduction appears to be predominantly due to a loss of fat mass rather than lean mass, as evidenced by the reduction in body fat percentage.  

Genetically proxied GLP-1 receptor agonism using rs877446, the index variant in GLP-1 receptors, was significantly associated with reduction in both whole-body fat-free mass (β, -0.56 per standard deviation [SD] of BMI reduction; 95 percent confidence interval [CI], -0.84 to -0.28) and trunk fat-free mass (β, -0.46 per SD; 95 percent CI, -0.74 to -0.18), but not significantly with appendicular lean mass (β, -0.40 per SD; 95 percent CI, -0.82 to 0.03). For fat-related phenotypes, genetically proxied GLP-1 receptor agonism was significantly associated with lower whole-body fat mass, trunk fat mass, trunk fat percentage and body fat percentage. Sensitivity analyses using rs1042044, the commonly used variant, yielded similar findings.

“This study highlights the use of genetics in understanding medication effects, especially when corresponding clinical experimental evidence is limited,” said lead investigator, Professor Ryan Shiu-Lun Au Yeung of the School of Public Health, Faculty of Medicine, HKU. “Genetic insights can guide us in making informed decisions about treatments and their impact on health.”

“The availability of large-scale human genetic association data allows us to gain valuable insights into drug target effects in a timely and cost-efficient manner. This approach can greatly inform further clinical studies and improve patient outcomes,” remarked senior author of the study, Dr Dipender Gill of the Department of Epidemiology and Biostatistics at the School of Public Health, Imperial College London, UK.

“The study has provided genetic evidence against recent concerns that GLP-1 receptor agonists induce weight loss primarily through reductions in muscle mass,” the authors concluded. Nevertheless, as the study was restricted to the European population, further investigations are warranted to determine their applicability to populations of different ethnicities (eg, Asians), demographic characteristics (eg, adolescents following the US FDA’s approval of GLP-1 receptor agonists for weight management in individuals aged ≥12 years) and frailty status.