Lower respiratory infections in diabetes: which hypoglycemic agents help and which harm? A drug-target Mendelian randomization study
Abstract
Abstract Objective To compare whether genetically proxied perturbation of major glucose-lowering drug targets is associated with susceptibility to lower respiratory infections and sepsis, with the aim of identifying clinically relevant target-specific differences in people with diabetes. Research Design and Methods We performed a two-sample drug-target Mendelian randomization study using variants proxying insulin signaling, thiazolidinediones, sulfonylureas, metformin-related targets, sodium-glucose cotransporter 2 inhibition, and glucagon-like peptide 1 receptor agonism. Outcomes included bacterial pneumonia, viral pneumonia, respiratory tuberculosis, influenza pneumonia, severe COVID-19, and sepsis from FinnGen and the UK Biobank. Positive-control analyses against type 2 diabetes were used to assess instrument validity before clinical interpretation. Results PPARG/thiazolidinedione proxies showed the clearest adverse pattern, with higher risks of bacterial pneumonia, respiratory tuberculosis, and influenza pneumonia, although estimates were imprecise. In contrast, insulin signaling and selected metformin-related targets were associated with lower risks of bacterial or viral pneumonia. Sulfonylurea proxies showed heterogeneous associations, including higher bacterial pneumonia risk but lower severe COVID-19 susceptibility. Glucagon-like peptide 1 receptor agonist proxies were not associated with infection outcomes. Sodium-glucose cotransporter 2 instruments failed…
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