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. 2023 Nov 1;46(11):2004-2014.
doi: 10.2337/dc23-0671.

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

Alexander Kutz  1 , Dae Hyun Kim  1   2   3 , Deborah J Wexler  4 , Jun Liu  1 , Sebastian Schneeweiss  1 , Robert J Glynn  1 , Elisabetta Patorno  1
Affiliations

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

Alexander Kutz et al. Diabetes Care. .

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.

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Conflict of interest statement

Duality of Interest. D.H.K. has been supported by grants from the National Institute on Aging for unrelated work and receives personal fees from Alosa Health and VillageMD. D.J.W. serves on data monitoring committees for Novo Nordisk. S.S. is participating in investigator-initiated grants to the Brigham and Women’s Hospital from Boehringer Ingelheim and UCB unrelated to the topic of this study; is a consultant to Aetion Inc., a software manufacturer in which he owns equity; and is an advisor to Temedica GmbH, a patient-oriented data generation company. R.J.G. has been supported by the grants from AstraZeneca, Kowa, Novartis, and Pfizer not related to the topic of this work. E.P. is an investigator of a research grant to the Brigham and Women’s Hospital from Boehringer Ingelheim not related to the topic of this work and was supported by a research grant (5U01FD007213) from the U.S. Food and Drug Administration for unrelated work. No other potential conflicts of interest relevant to this article were reported.

Figures

None
Graphical abstract
Figure 1
Figure 1
Cumulative incidence plots of the primary cardiovascular effectiveness outcome in older adults with T2D newly treated with SGLT-2is, GLP-1RAs, or DPP-4is by frailty status. Graphs illustrate cumulative incidence plots stratified by frailty status for the SGLT-2i vs. DPP-4i cohort and GLP-1RA vs. DPP-4i cohort. A and C: Not frail. B and D: Frail. The primary cardiovascular effectiveness outcome was time to the first occurrence of a composite of hospitalization for acute myocardial infarction or ischemic stroke, HHF, or all-cause mortality.
Figure 2
Figure 2
Cumulative incidence plots of the primary safety outcome in older adults with T2D newly treated with SGLT-2is, GLP-1RAs, or DPP-4is by frailty status. Graphs illustrate cumulative incidence plots stratified by frailty status for the SGLT-2i vs. DPP-4i cohort and GLP-1RA vs. DPP-4i cohort. A and C: Not frail. B and D: Frail. The primary safety outcome was time to the first hospitalization for acute kidney injury, occurrence of hospital or emergency department admission for hypoglycemia, DKA, severe genital or urinary tract infection, lower-limb amputation, nonvertebral fracture, acute pancreatitis, or nonmalignant biliary event.
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