Abstract 4141896: Genetic Mimics of GLP-1Ra and SGLT2i Therapy, Heart Failure and Chronic Kidney Disease Outcomes

Background: GLP-1 receptor agonists (GLP-1Ra) prevent atherosclerotic and chronic kidney disease (CKD) progression events in type 2 diabetes. In obesity without diabetes, GLP-1Ra lower the risk of atherosclerotic cardiovascular events. Less is known about the effects of GLP-1Ra on heart failure (HF) events and CKD progression events in people without type 2 diabetes and the benefits of adding GLP-1Ra to standard-of-care SGLT2 inhibitor therapy. Objective: Assess the association between genetic mimics of GLP1-Ra and SGLT2 inhibitor therapy on the risk of coronary artery disease (CAD), HF, and CKD. Methods: We used whole exome sequencing data from the All of Us Research Program to construct genetic instruments mimicking GLP1-Ra and SGLT2i therapy. The genetic instruments included variants in the GLP1R and SLC5A2 genes that associated with lower hemoglobin A1c levels in elastic net regression models with linkage disequilibrium pruning (r 2 < 0.3). Thus, higher genetic scores mimicked lifelong treatment with a GLP-1Ra or SGLT2 inhibitor. Having both higher GLP-1Ra and higher SGLT2i genetic scores mimicked lifelong exposure to combined therapy ( Figure ). Results: We included 245,388 All of Us participants (mean age 55 years, 59% females, 38% males, and 2% other genders). Higher GLP-1Ra genetic scores associated with a lower risk of CAD (OR [95% CI] per 1-standard deviation [SD]: 0.97 [0.95-0.99]; P=0.004), HF (OR [95% CI] per 1-SD: 0.95 [0.93-0.98]; P<0.001) and CKD (OR [95% CI] per 1-SD: 0.95 [0.93-0.97]; P<0.001). The associations between the GLP-1Ra genetic score and HF and CKD were not modified by the SGLT2 inhibitor genetic score ( Figure ). Conclusion: Lifelong exposure to genetic variants mimicking the pharmacologic effects of GLP1-Ra is associated with a lower risk of CAD, HF, and CKD. GLP-1Ra may provide cardio-kidney protection beyond SGLT2i alone. These results also suggest that GLP-1Ra may prevent new-onset CAD, HF and CKD in the general population.