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

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.