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.


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.


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.


SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

This article contains supplementary material online at https://doi.org/10.2337/figshare.23992563.

This content is only available via PDF.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at https://www.diabetesjournals.org/journals/pages/license.
You do not currently have access to this content.