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.