Comparative Safety of Second-Line Antihyperglycemic Agents in Older Adults with Type 2 Diabetes: A Multinational Real-World Evidence From LEGEND-T2DM.
Abstract
BACKGROUND: 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 aimed to evaluate the real-world safety of second-line antihyperglycemic agents among older adults with type 2 diabetes.
METHODS: We conducted a multinational cohort study using nine harmonized electronic health record and claims databases from the U.S. and Europe, applying a consistent analytical framework based on the LEGEND-T2DM initiative. Among adults aged ≥65 years who initiated a second-line agent after metformin monotherapy, we compared safety outcomes across four drug classes: GLP-1 receptor agonists (GLP1RAs), SGLT2 inhibitors (SGLT2Is), DPP-4 inhibitors (DPP4Is), and sulfonylureas (SUs). We used propensity score adjustment, empirical calibration, and prespecified diagnostics to estimate hazard ratios (HRs) for 18 safety outcomes.
RESULTS: In a cohort of 1.8 million older adults, both GLP1RAs and SGLT2Is were linked to significantly lower risks of hypoglycemia (HR 0.21 [95% CI, 0.16-0.27] for GLP1RA vs SU; HR 0.21 [0.13-0.33] for SGLT2I vs SU) and hyperkalemia (HR 0.63 [0.50-0.81] for GLP1RA vs SU; HR 0.75 [0.63-0.90] for SGLT2I vs SU) and peripheral edema (HR 0.81 [0.71-0.92] for GLP1RAs vs. DPP4Is; HR 0.62 [0.46-0.84] for SGLT2Is vs. SU). However, SGLT2Is were associated with a higher risk of diabetic ketoacidosis compared to both…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 8 participants or records.
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