Hypoglycemic Agent Targets and Susceptibility to Lower Respiratory Infection: A Pharmacogenomic Mendelian Randomization Study

Abstract

Background/Objectives: Patients with type 2 diabetes face heightened risks of lower respiratory tract infections, but whether distinct glucose-lowering drug targets differentially alter pulmonary susceptibility remains unclear. We investigated how genetically proxied perturbations of major antidiabetic targets relate to respiratory infection and sepsis risks. Methods: Using two-sample drug-target Mendelian randomization, we examined genetic instruments proxying six antidiabetic pathways: insulin (INSR), sulfonylureas (KCNJ11/ABCC8), thiazolidinediones (PPARG), GLP-1 receptor agonists (GLP1R), SGLT2 inhibitors (SLC5A2), and metformin (GPD1, GPD2, PRKAG2). Associations were calibrated to standardized glycemic decrements and tested across 13 respiratory infection and sepsis GWAS outcomes. Analyses incorporated functional-variant comparisons, a type 2 diabetes positive control, and linkage disequilibrium adjustment. Results: Genetically proxied glucose lowering through PPARG showed consistent nominal associations with increased respiratory infection risk. Per 0.1 mmol/L lower glucose, the primary proxy and Pro12Ala functional variant were associated with higher odds of influenza and pneumonia (odds ratio [OR] 1.53, 95% CI 1.16–2.02, p = 0.003; and OR 1.53, 95% CI 1.13–2.06, p = 0.006) and other acute lower respiratory infections (OR 1.78, 95% CI 1.14–2.77, p = 0.011; and OR 1.87, 95% CI 1.16–3.01, p = 0.010). PPARG primary and functional proxies agreed in direction for 10/13 outcomes, whereas potassium-channel proxies agreed for only 3/13. Other targets showed distinct, heterogeneous patterns. Crucially, all signals were nominal and none survived false discovery rate correction (q ≥ 0.05). Conclusions: Genetically proxied glucose-lowering pathways exhibit divergent associations with respiratory infection susceptibility. While findings do not support class-wide causal risks, the repeated PPARG pattern highlights target-specific pulmonary immune mechanisms warranting functional and clinical investigation.