Sodium–Glucose Cotransporter 2 Inhibitors, Glucagon-Like Peptide 1 Receptor Agonists, and Frailty Progression in Older Adults With Type 2 Diabetes

OBJECTIVE: Older adults with type 2 diabetes are at high risk for frailty. The effects of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2is) on frailty remain uncertain. RESEARCH DESIGN AND METHODS: Using a 7% random sample of Medicare data, we compared new users of dipeptidyl peptidase 4 inhibitors (DPP-4is), GLP-1RAs, SGLT-2is, and sulfonylureas on 1-year frailty progression, measured by a claims-based frailty index (CFI) (range: 0-1; higher scores indicate greater frailty). Mediation analyses assessed whether cardiovascular or safety events explained differences in frailty progression. RESULTS: Compared with DPP-4i users, the mean CFI change (95% CI) was significantly lower for GLP-1RA (-0.007 [-0.011, -0.004]) and SGLT-2i (-0.005 [-0.008, -0.002]) users; no difference was found for sulfonylurea users. These associations were minimally mediated by cardiovascular or safety events. CONCLUSIONS: GLP-1RAs and SGLT-2is may slow frailty progression through mechanisms independent of cardiovascular benefits. Future trials should confirm these preliminary findings.