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 GLP1RAs (HR 2.03 [1.38-2.99]) and SUs (HR 1.64 [1.27-2.11]). GLP1RAs had significantly higher risks of nausea (HR 0.63 [0.55-0.72]) and vomiting (HR 0.63 [0.57-0.69]) relative to SGLT2Is. Results were consistent across both on-treatment and intent-to-treat sensitivity analyses.

Conclusion: In older adults with type 2 diabetes, GLP1RAs and SGLT2Is demonstrated more favorable safety profiles than SUs and DPP4Is across multiple clinically relevant outcomes. These results support more informed, safety-conscious prescribing in a population underrepresented in clinical trials yet highly susceptible to adverse effects.

Figure 1.

Study design scheme

Figure 2.

Meta-analytic safety profiles comparing new users of SGLT2I to GLP1RA, DPP4I, and SU across 18 outcomes. Points and lines identify HR estimates with their 95% CIs, respectively. Outcomes in orange signify that the p<0.05 and outcomes in red mean statistically significant after Bonferroni correction (p<0.00277778) for the multiple testing. The result for all-cause mortality in the GLP1RA vs SU comparison was not presented because there was no valid result after the study diagnostic process.

Figure 3.

Safety profiles comparing new users of SGLT2I to GLP1RA, DPP4I, and SU across 18 outcomes from the intent-to-treat follow-up. Points and lines identify HR estimates with their 95% CIs, respectively. Outcomes in orange signify that the p<0.05 and outcomes in red mean statistically significant after Bonferroni correction (p<0.00277778) for the multiple testing. The result for all-cause mortality in the GLP1RA vs SU comparison was not presented because there was no valid result after the study diagnostic process.