Real-world evidence for comparative safety of second-line antihyperglycemic agents in older adults with type 2 diabetes.

As prescribing of newer antihyperglycemic agents expands, there remains limited comparative safety data for older adults-a population particularly vulnerable to adverse drug events and underrepresented in clinical trials. We conduct a multinational cohort study using nine databases from the U.S. and Europe. Among adults aged ≥65, we compare eighteen safety outcomes across four classes of second-line antihyperglycemic agents. We use propensity score adjustment, empirical calibration, and prespecified diagnostics and estimated hazard ratios. In a cohort of 1.8 million, both GLP-1 receptor agonists and SGLT2 inhibitors are linked to significantly lower risks of hypoglycemia and hyperkalemia than sulfonylureas. GLP-1 receptor agonists show lower risks of peripheral edema than DPP-4 inhibitors. However, SGLT2 inhibitors are associated with a higher risk of diabetic ketoacidosis compared to GLP-1 receptor agonists and sulfonylureas. These results support informed, safety-conscious prescribing in the older adults underrepresented in clinical trials yet highly susceptible to adverse events.