Genetic evidence that diabetes drug GLP-1 receptor agonists achieve weight loss primarily by reducing fat mass more than muscle

GLP-1 receptor agonists are pharmaceutical treatments primarily for T2D and more recently, obesity. They function by mimicking the action of GLP-1 hormone, which plays a crucial role in stimulating insulin secretion, inhibiting glucagon secretion, and delaying gastric emptying to suppress appetite, thereby regulating blood sugar levels and resulting in weight loss. Their application as a pharmacological intervention for weight reduction has gained popularity worldwide. However, concerns have been raised over whether GLP-1 receptor agonists reduce weight (often measured by body mass index, or BMI) mainly via muscle mass loss, which could lead to physical frailty or sarcopenia.

To study how GLP-1 receptor agonists affect muscle and fat, the HKUMed research team used genetic data of over 800,000 European participants from different genome wide association studies (GWAS). They identified a specific genetic variant (rs877446) linked to lower BMI that mimicked the effect of GLP-1 receptor agonists. The team examined the effect of this variant on different types of lean mass, including appendicular lean mass, whole body fat-free mass, and trunk fat-free mass, as well as various measures of body fat, such as whole-body fat mass, trunk fat mass, trunk fat percentage, body fat percentage, and waist-to-hip ratio.

The research team found that participants with genetic makeup mimicking the effect of GLP-1 receptor agonists leads to reductions in both lean mass (whole-body fat-free mass and trunk fat-free mass) and body fat (whole-body fat mass, trunk fat percentage and body fat percentage). Specifically, for each unit reduction in BMI, whole-body fat mass decreases by about 7.9 kg, while muscle mass reduces by about 6.4 kg. This indicates that GLP-1 receptor agonists lead to greater reduction in overall body fat than that in muscle mass, resulting in an overall body fat percentage decrease of around 4.5%. This supports the effectiveness of GLP-1 receptor agonists in reducing fat more than muscle.

This study clarifies the controversy regarding the effect of GLP-1 receptor agonists on body composition as a weight-management medication, and showcases how a genetic approach can enhance our understanding of how medications work.

'This study highlights the use of genetics in understanding medication effects, especially when corresponding clinical experimental evidence is limited,' said Professor Ryan Au Yeung Shiu-lun, Assistant Professor in the School of Public Health, HKUMed. '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 Dr Dipender Gill, Clinical Research Fellow in the Department of Epidemiology and Biostatistics at the School of Public Health of Imperial College London, a senior author of the study.

About the research team The study was led by Professor Ryan Au Yeung Shiu-lun, Assistant Professor in the School of Public Health, HKUMed; and Dr Dipender Gill, Clinical Research Fellow in the Department of Epidemiology and Biostatistics at the School of Public Health of Imperial College. Liang Yiwen, a PhD student in the same School was the first author of the study. Other research team members from HKUMed included Professor Eric Wan Yuk-fai and Dr Luo Shan from the Department of Family Medicine and Primary Care, School of Clinical Medicine; and Professor Cheung Ching-lung from the Department of Pharmacology and Pharmacy.