Diabetes and obesity have become significant health concerns globally. Glucagon-like peptide-1 (GLP-1) receptor agonists, medications commonly used in managing type 2 diabetes (T2D), have proven effective not only in lowering blood sugar levels but also in aiding weight loss due to their unique pharmacological properties. A research team from the School of Public Health at the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) conducted a genetic study to investigate how these medications impact weight loss, specifically differentiating between fat mass and muscle mass reduction.
The findings revealed that GLP-1 receptor agonists reduce weight predominantly through decreased fat mass rather than muscle mass. The research was published in Diabetes, Obesity and Metabolism.
Background: GLP-1 receptor agonists are primarily used for T2D treatment but have also been found effective against obesity. They work by mimicking the GLP-1 hormone, which aids in insulin secretion, inhibits glucagon release, and slows gastric emptying to curb appetite—factors that help regulate blood sugar levels and lead to weight loss. Despite their popularity as a pharmaceutical intervention for reducing body mass index (BMI), there were concerns about whether these medications primarily reduce BMI through muscle mass reduction, which could result in physical frailty or sarcopenia.
Research Method and Findings: To understand how GLP-1 receptor agonists affect fat versus muscle, the HKUMed team analyzed genetic data from over 800,000 European participants across multiple genome-wide association studies (GWAS). They identified a specific genetic variant (rs877446) associated with lower BMI and mimicking the effects of GLP-1 receptor agonists. The researchers evaluated this variant’s impact on lean mass, such as appendicular lean mass, whole body fat-free mass, and trunk fat-free mass, alongside various measures of body fat including whole-body fat mass, trunk fat percentage, overall body fat percentage, and waist-to-hip ratio.
Results indicated that participants with genetic profiles mimicking the effects of GLP-1 receptor agonists experienced reductions in both lean (whole-body and trunk fat-free) and fatty tissues. Notably, for every unit decrease in BMI, whole-body fat mass decreased by approximately 7.9 kg, whereas muscle mass reduced by around 6.4 kg. This suggests that these medications result in a greater reduction of body fat compared to muscle mass, leading to an overall decrease in body fat percentage by about 4.5%. These findings support the effectiveness of GLP-1 receptor agonists in reducing fat more than they reduce muscle.
Significance: This study addresses controversies regarding the impact of GLP-1 receptor agonists on body composition as weight-management tools and demonstrates how genetic studies can deepen our understanding of medication effects. It highlights the use of genetics to inform treatment decisions, especially when clinical data is limited. Genetic insights offer valuable guidance for selecting appropriate treatments while considering their health impacts.
“The availability of large-scale human genetic association data allows us to gain crucial insights into drug target effects efficiently and cost-effectively,” remarked Dr Dipender Gill, a Clinical Research Fellow in the Department of Epidemiology and Biostatistics at Imperial College London’s School of Public Health. “This approach can greatly inform clinical studies and enhance patient outcomes.”
