Genetic Evidence for the Benefits and Risks of Glucose-Lowering Drugs on Cardiovascular-Kidney-Metabolic Syndrome: A Drug-Target Mendelian Randomization Study.

BACKGROUND

To explore the potential benefits and risks of glucose-lowering drugs on cardiovascular-kidney-metabolic (CKM) syndrome outcomes using drug-target Mendelian randomization (MR).

METHODS

Genetic instruments for eight glucose-lowering drugs were identified from variants associated with glycated hemoglobin (HbA1c) and drug target gene expression. We employed two-sample MR and meta-analysis to estimate associations with nine CKM syndrome-related diseases, including coronary artery disease (CAD), myocardial infarction (MI), stroke, heart failure (HF), atrial fibrillation (AF), venous thromboembolism (VTE), peripheral artery disease (PAD), chronic kidney disease (CKD), and metabolic syndrome (MetS), using data from UK Biobank, FinnGen, and other large GWAS consortia. Supplementary analyses included summary-data-based MR (SMR) and colocalization.

RESULTS

Genetic proxies for sodium-glucose cotransporter 2 inhibitors (SGLT2i) were associated with reduced risks of CAD (OR 0.85, 95% CI 0.73-0.98), HF (OR 0.66, 95% CI 0.44-0.98), and MetS (OR 0.64, 95% CI 0.50-0.82). GLP-1 receptor agonists (GLP-1RA) were linked to lower risks of CAD (OR 0.90, 95% CI 0.84-0.96), HF (OR 0.92, 95% CI 0.86-0.99), and CKD (OR 0.87, 95% CI 0.79-0.95). Metformin showed protective association with CAD (OR 0.51, 95% CI 0.40-0.66) and PAD (OR 0.99, 95% CI 0.99-1.00). Sulfonylureas showed a modest association with reduced CAD (OR 0.98, 95% CI 0.96-1.00). Conversely, insulin was associated with a higher risk of MetS (OR 1.07, 95% CI 1.02-1.13), and thiazolidinediones (TZDs) with an increased risk of HF (OR 1.12, 95% CI 1.05-1.20). SMR provided additional evidence for protective roles of GLP1R and VEGFA for CAD, KCNJ11 for HF, ABCC8 for HF and AF, and PRKAB1 for multiple cardiovascular outcomes. The detrimental effects of INSR on MetS and SERPINE1 on CKD and MetS were also verified.

CONCLUSIONS

This study provides genetic evidence revealing the potential benefits and risks of certain glucose-lowering drugs in the management of CKM syndrome. These findings may inform target validation, drug repurposing, and personalized therapies for CKM syndrome.