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. 2025 Jul 1;8(7):e2523067.
doi: 10.1001/jamanetworkopen.2025.23067.

Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors

Alexander Turchin  1   2 , Lucia C Petito  3 , Emma Hegermiller  4 , Ryan Carnahan  5 , Andrea DeVries  6 , Satyender Goel  3 , M Cecilia Lansang  7 , Marie E McDonnell  1   2 , Vinit Nair  4 , Elisa Priest  8 , Vincent J Willey  9 , Alan F Kaul  10 , Miguel A Hernán  11
Affiliations

Cardiovascular Events in Individuals Treated With Sulfonylureas or Dipeptidyl Peptidase 4 Inhibitors

Alexander Turchin et al. JAMA Netw Open. .

Abstract

Importance: Sulfonylureas are commonly used to treat type 2 diabetes (T2D). Research findings on cardiovascular risk associated with sulfonylureas have been inconsistent.

Objective: To emulate a target trial that compares the risk of cardiovascular events after initiation of treatment with individual sulfonylureas or dipeptidyl peptidase 4 inhibitors (DPP4is).

Design, setting, and participants: This comparative effectiveness research study included individuals with T2D and moderate cardiovascular risk treated with metformin monotherapy who received care at 1 of 10 US health systems or were insured by 1 of 2 large health insurance plans between January 1, 2014, and January 1, 2023. Data were analyzed from July 2024 to March 2025.

Exposure: Initiation of treatment with a sulfonylurea (glimepiride, glipizide, or glyburide) or a DPP4i (reference category) as a second line therapy after metformin.

Main outcomes and measurements: The primary outcome was a 4-point composite of major adverse cardiovascular events (MACE-4): myocardial infarction, ischemic stroke, heart failure hospitalization, or cardiovascular death (from any of these conditions). The 5-year risks of each outcome were estimated.

Results: Among 48 165 eligible individuals (median [IQR] age, 61 [52-69] years; 22 674 female [47.1%]; median [IQR] hemoglobin A1C, 7.8% [7.3%-8.5%]; median [IQR] low-density lipoprotein cholesterol, 89 mg/dL [70-112 mg/dL]), 18 147 started glipizide, 14 282 started glimepiride, 1887 started glyburide, and 13 849 started a DPP4i. Over the median (IQR) follow-up of 37 (20-64) months, 3158 individuals (6.6%) experienced a MACE-4. The estimated 5-year risks of MACE-4 were 8.1% (95% CI, 7.5%-8.7%) for DPP4i, 8.4% (95% CI, 6.8%-9.9%) for glyburide, 8.6% (95% CI, 7.9%-9.2%) for glimepiride, and 9.1% (95% CI, 8.7%-9.7%) for glipizide. Compared with DPP4is, the 5-year risk ratio of MACE-4 was 1.13 (95% CI, 1.03-1.23) for glipizide, 1.07 (95% CI, 0.96-1.16) for glimepiride, and 1.04 (95% CI, 0.83-1.24) for glyburide.

Conclusions and relevance: In this comparative effectiveness research study of sulfonylureas vs DPP4i in patients with T2D, the risk of MACE-4 events was highest for glipizide. These findings suggest that sulfonylureas, glipizide in particular, may not be the optimal agent in treatment of individuals with T2D at moderate cardiovascular risk.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Turchin reported receiving grants from Eli Lilly and personal fees from Novo Nordisk and Proteomics International outside the submitted work. Dr Petito reported receiving grants from Omron Healthcare Co, Ltd (unrelated research support) outside the submitted work. Dr Lansang reported receiving grants from Abbott (investigator-initiated study) and Dexcom (investigator-initiated study) outside the submitted work. Dr Priest reported receiving grants from Boehringer Ingelheim, AstraZeneca, CSL Vifor, and Owkin outside the submitted work. Dr Willey reported being employed by Carelon Research outside the submitted work. Dr Hernán reported receiving personal fees from Cytel and ProPublica, being a consultant to Adigens Health (a company of which he owns equity), and being a member of the ADIALab Advisory Board outside the submitted work; his interests were declared, reviewed, and approved by Harvard University in accordance with its institutional compliance policies. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Selection of Individuals for the Target Trial Emulation, Observational Evaluation of Second Line Therapy Medications in Diabetes Study, 2014-2023
ASCVD indicates atherosclerotic cardiovascular disease; DPP4i, dipeptidyl peptidase-4 inhibitors; eGFR, estimated glomerular filtration rate; HbA1C, hemoglobin A1C; UTI, urinary tract infection. To convert HbA1C to proportion of total hemoglobin, multiply by 0.01; to convert glucose to millimoles per liter, multiply by 0.0555.
Figure 2.
Figure 2.. Cumulative Incidence of Cardiovascular Outcomes by Treatment Group
Both fatal and nonfatal events are included in panels B, C, and D. In panel C, the blue line (glipizide) cannot be easily seen because it almost fully overlaps with the orange line (glimepiride). DPP4i indicates dipeptidyl peptidase-4 inhibitor; MACE-4, major adverse cardiovascular events (4-point composite).
Figure 3.
Figure 3.. Subgroup Analyses for the Primary Outcome
DPP4i indicates dipeptidyl peptidase-4 inhibitor; eGFR, estimated glomerular filtration rate; HbA1C, hemoglobin A1C. To convert HbA1C to proportion of total hemoglobin, multiply by 0.01.
See this image and copyright information in PMC

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