Genetically-proxied GLP1R agonism and cardiometabolic outcomes in East Asian Biobank populations

Introduction Glucagon-like peptide-1 receptor (GLP1R) agonists consistently improve glycaemic control and induce clinically meaningful weight loss, with established cardioprotective effects despite increasing resting heart rate. Mendelian randomization (MR) offers a genetic approach to assess potential causal effects of GLP1R agonism on metabolic and cardiovascular outcomes. However, previous MR studies were conducted in European populations and have relied on genetic instruments weighted by type 2 diabetes risk which may not capture all the effects of targeting GLP1R. Methods Here, we sought to develop genetic instruments for GLP1R agonism using the largest available genome-wide association studies in East Asians for type 2 diabetes, BMI, and resting heart rate. We selected genome-wide significant ( p < 5x10 −8 ), independent ( r 2 < 0.01) variants within ± 150 kb of the GLP1R locus and examined overall and sex-stratified associations with glycaemic traits, adiposity measures, resting heart rate, and cardiovascular outcomes using individual-level data in up to 242,000 individuals from the China Kadoorie Biobank (CKB) and BioBank Japan (BBJ). Results A single variant, rs742762, was genome-wide significant for type 2 diabetes in East Asians. This instrument (rs742762-C) was associated with lower risk of type 2 diabetes, as well as with lower glucose levels, but had no association with BMI, waist circumference or other adiposity measures. Nor were there associations with resting heart rate, or cardiovascular outcomes (after correction for multiple testing). Conclusion These findings underscore the limitations of diabetes-based genetic instruments for GLP1R agonism in East Asian populations and highlight the need for alternative strategies to capture its wider biological effects, particularly related to adiposity traits. Developing more robust instruments will be essential for advancing genetic studies of GLP1R-targeted therapies in diverse populations.