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