American Diabetes Association
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Comparative cardiovascular effectiveness and safety of SGLT-2 inhibitors, GLP-1 receptor agonists and DPP-4 inhibitors according to frailty in type 2 diabetes

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posted on 2023-09-07, 19:45 authored by Alexander Kutz, Dae Hyun Kim, Deborah J. Wexler, Jun Liu, Sebastian Schneeweiss, Robert J. Glynn, Elisabetta Patorno


To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose-cotransporter-2-inhibitors (SGLT-2i), glucagon-like-peptide-1-receptor-agonists (GLP-1RA) and dipeptidyl-peptidase-4-inhibitors (DPP-4i) 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-2i, GLP-1RA, or DPP-4i. 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-4i, the overall HR for the primary effectiveness outcome associated with SGLT-2i (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--11.64). IRD ranged from -6.74 (95% CI, -8.61--4.87) in non-frail to -27.24 (95% CI, -41.64--12.84) in frail people (Pinteraction<0.01). Consistent benefits were observed for GLP-1RA compared with DPP-4i (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--13.52). IRD in the lowest frailty stratum was -7.02 (95% CI, -9.23--4.81) and -25.88 (95% CI, -38.30--13.46) in the highest (Pinteraction<0.01). Results for SGLT-2i versus GLP-1RA (n=89,865) were comparable. Severe adverse events were not more frequent with SGLT-2i or GLP-1RA than DPP-4i.


SGLT-2i and GLP-1RA safely improved cardiovascular outcomes and all-cause mortality with largest absolute benefits among frail people.


This study was supported by a grant (DB-2020C2-20326) from the Patient Centered Outcomes Research Institute, by the Brigham and Women's Hospital and Harvard Medical School. Dr. Kutz was supported by a Postdoc.Mobility grant (P400PM_194479 / 1) from the Swiss National Science Foundation and by an educational grant from Novo Nordisk. Dr. Patorno was supported by a career development grant (K08AG055670) from the National Institute on Aging.


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