Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor (GLP-1R) agonists reduce the risk of major adverse cardiovascular and kidney events in individuals with various cardiometabolic conditions. The long-term efficacy and safety of these therapies, especially in low- and moderate-risk populations, remain uncertain.

Methods: We conducted a biobank-scale analysis using genetic instruments derived from naturally occurring genetic variations in the genes encoding the targets of SGLT2 inhibitors (SLC5A2) and GLP-1R agonists (GLP1R) that associated with HbA1c levels. This Mendelian randomization study utilized data from the All of Us Research Program, which includes whole genome sequencing and electronic health records of 633,547 participants.

Results: Higher SGLT2 inhibitor genetic instrument scores were associated with a lower risk of heart failure (OR: 0.97, 95% CI: 0.96 to 0.99) and chronic kidney disease (OR: 0.98, 95% CI: 0.96 to 0.99). Higher GLP-1R agonist genetic instrument scores were linked to reduced risks of heart failure (OR: 0.97, 95% CI: 0.96 to 0.99), chronic kidney disease (OR: 0.96, 95% CI: 0.95 to 0.98), and coronary artery disease (OR: 0.98, 95% CI: 0.96 to 0.99). We did not detect associations between the GLP1-R agonist instrument and multiple endocrine neoplasia or medullary thyroid carcinoma. PheWAS identified associations between the SGLT2 inhibitor and GLP-1R agonist genetic instruments and a lower risk of diabetes, but no other phenotypes.

Conclusions: Long-term, primary prevention with an SGLT2 inhibitor or GLP-1R agonist would safely lower the risk of major adverse cardiovascular and kidney events in low- to moderate-risk adults.