Frailty is important in diabetes management but its impact on the cardiovascular (CV) effectiveness of SGLT-2i and GLP-1 RA as used in routine care is unexplored. Using Medicare claims data, we identified three pairwise 1:1 propensity score (PS) matched cohorts of people with type 2 diabetes who initiated a SGLT-2i, a GLP-1 RA, or a DPP-4i between 04/2013-12/2018. The primary outcome was a composite of major adverse CV events (MACE) including acute myocardial infarction, ischemic stroke, hospitalization for heart failure, or all-cause mortality. We estimated hazard ratios (HR) and absolute rate differences (RD) per 1`000 person-years, with their 95% CI, in each PS-matched cohort by level of frailty, using a validated claims-based frailty index (3 strata: non-frail, <0.15; pre-frail, 0.15-0.24; frail, ≥0.25) , controlling for >150 baseline covariates. We used the Wald test for homogeneity to assess treatment heterogeneity across strata. The HR for MACE associated with SGLT-2i vs. DPP4i (n=91`141 PS-matched pairs) was 0.82 (95% CI 0.72 to 0.93) in frail, 0.71 (0.67 to 0.75) in pre-frail, and 0.78 (0.71 to 0.86) in non-frail people (p for homogeneity=0.033) . The HR for MACE associated with GLP-1 RA vs. DPP4i (n=90`988 pairs) was 0.84 (0.76 to 0.93) in frail, 0.77 (95% CI 0.73 to 0.81) in pre-frail, and 0.82 (0.74 to 0.91) in non-frail people (p for h.=0.150) . The HR for MACE associated with SGLT-2i versus GLP-1 RA (n=67`067 pairs) was 0.87 (0.75 to 1.01) in frail, 0.93 (95% CI 0.87 to 1.01) in pre-frail, and 0.90 (0.79 to 1.03) in non-frail people (p for h.=0.692) . Compared to DPP-4i, the absolute benefit of either SGLT-2i or GLP-1 RA was largest in frail people [RD, -25.0 (-42.1 to -7.9) , p for h.<0.001, NNT=20; and RD, -24.9 (-39.0 to -10.7) , p for h.<0.001, NNT=21; respectively]. While, compared to DPP4i, SGLT-2i and GLP-1 RA were associated with similar relative risk reductions in MACE among people with and without frailty, their absolute benefits were largest in frail people.


A.Kutz: Research Support; Novo Nordisk. C.Gopalakrishnan: None. D.H.Kim: None. E.Patorno: Research Support; Boehringer Ingelheim International GmbH, National Institutes of Health, Patient-Centered Outcomes Research Institute.


National Institute on Aging (K08AG055670)

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