Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes

Abstract

OBJECTIVE To evaluate the comparative cardiovascular effectiveness and safety of sodium–glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. RESEARCH DESIGN AND METHODS We performed three 1:1 propensity score–matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013–2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. RESULTS Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69–0.75), corresponding to an incidence rate difference (IRD) of −13.35 (95% CI −15.06 to −11.64). IRD ranged from −6.74 (95% CI −8.61 to −4.87) in nonfrail to −27.24 (95% CI −41.64 to −12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71–0.77) and an IRD of −15.49 (95% CI −17.46 to −13.52). IRD in the lowest frailty stratum was −7.02 (95% CI −9.23 to −4.81) and −25.88 (95% CI −38.30 to −13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. CONCLUSIONS SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.