Cardiovascular events in individuals treated with sulfonylureas or dipeptidyl peptidase 4 inhibitors
Open accessAbstract
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 A 1C , 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A recent analysis found that the risk of major adverse cardiovascular events was highest with glipizide.
“a recent analysis found that the risk of major adverse cardiovascular events was highest with glipizide”
From 13. Older Adults: Standards of Care in Diabetes—2026 (2026) · cites this paper as [125]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Sun, H., Saeedi, P., Karuranga, S., Pinkepank, M., Ogurtsova, K., Duncan, B. B., Stein, C., Basit, A., Chan, J. C. N., Mbanya, J. C., et al. (2022) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2021.109119 · Cited by 10,123 · see citing works
Haffner, S. M., Lehto, S., Rönnemaa, T., Pyörälä, K., & Laakso, M. (1998) · New England Journal of Medicine · doi:10.1056/nejm199807233390404 · Cited by 7,000 · see citing works
Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus
Scirica, B. M., Bhatt, D. L., Braunwald, E., Steg, P. G., Davidson, J., Hirshberg, B., Ohman, P., Frederich, R., Wiviott, S. D., Hoffman, E. B., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1307684 · Cited by 3,470 · see citing works
Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available: Table 1.
Hernán, M. A., & Robins, J. M. (2016) · American Journal of Epidemiology · doi:10.1093/aje/kwv254 · Cited by 3,115 · see citing works
Self-citationEffect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes
Green, J. B., Bethel, M. A., Armstrong, P. W., Buse, J. B., Engel, S. S., Garg, J., Josse, R., Kaufman, K. D., Koglin, J., Korn, S., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1501352 · Cited by 2,577 · see citing works
Alogliptin after acute coronary syndrome in patients with type 2 diabetes
White, W. B., Cannon, C. P., Heller, S. R., Nissen, S. E., Bergenstal, R. M., Bakris, G. L., Perez, A. T., Fleck, P. R., Mehta, C. R., Kupfer, S., et al. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1305889 · Cited by 2,502 · see citing works
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome
Pfeffer, M. A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H. C., Køber, L. V., Lawson, F. C., Ping, L., Wei, X., Lewis, E. F., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509225 · Cited by 2,409 · see citing works
Cardiovascular outcomes with ertugliflozin in type 2 diabetes
Cannon, C. P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukiewicz, U., Charbonnel, B., Frederich, R., Gallo, S., Cosentino, F., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2004967 · Cited by 1,514 · see citing works
Rosenstock, J., Perkovic, V., Johansen, O. E., Cooper, M. E., Kahn, S. E., Marx, N., Alexander, J. H., Pencina, M., Toto, R. D., Wanner, C., et al. (2019) · JAMA · doi:10.1001/jama.2018.18269 · Cited by 1,084 · see citing works
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients
Nissen, S. E., Lincoff, A. M., Brennan, D., Ray, K. K., Mason, D., Kastelein, J. J. P., Thompson, P. D., Libby, P., Cho, L., Plutzky, J., et al. (2023) · New England Journal of Medicine · doi:10.1056/nejmoa2215024 · Cited by 988 · see citing works
Risk of cardiovascular events and rofecoxib: cumulative meta-analysis
Jüni, P., Nartey, L., Reichenbach, S., Sterchi, R., Dieppe, P. A., & Egger, M. (2004) · The Lancet · doi:10.1016/s0140-6736(04)17514-4 · Cited by 846 · see citing works
The Incidence of Congestive Heart Failure in Type 2 Diabetes
Nichols, G. A., Gullion, C. M., Koro, C. E., Ephross, S. A., & Brown, J. B. (2004) · Diabetes Care · doi:10.2337/diacare.27.8.1879 · Cited by 812 · see citing works
Zannad, F., Cannon, C. P., Cushman, W. C., Bakris, G. L., Menon, V., Perez, A. T., Fleck, P. R., Mehta, C. R., Kupfer, S., Wilson, C., et al. (2015) · The Lancet · doi:10.1016/s0140-6736(14)62225-x · Cited by 757 · see citing works
9. Pharmacologic Approaches to Glycemic Treatment: <i>Standards of Care in Diabetes—2024</i>
American Diabetes Association Professional Practice Committee, ElSayed, N. A., Aleppo, G., Bannuru, R. R., Bruemmer, D., Collins, B. S., Ekhlaspour, L., Gaglia, J. L., Hilliard, M. E., Johnson, E. L., et al. (2024) · Diabetes Care · doi:10.2337/dc24-s009 · Cited by 662 · see citing works
Rosenstock, J., Kahn, S. E., Johansen, O. E., Zinman, B., Espeland, M. A., Woerle, H. J., Pfarr, E., Keller, A., Mattheus, M., Baanstra, D., et al. (2019) · JAMA · doi:10.1001/jama.2019.13772 · Cited by 612 · see citing works
Xu, G., Liu, B., Sun, Y., Du, Y., Snetselaar, L., Hu, F. B., & Bao, W. (2018) · BMJ · doi:10.1136/bmj.k1497 · Cited by 549 · see citing works
Hong, J., Zhang, Y., Lai, S., Lv, A., Su, Q., Dong, Y., Zhou, Z., Tang, W., Zhao, J., Cui, L., et al. (2013) · Diabetes Care · doi:10.2337/dc12-0719 · Cited by 366 · see citing works
Ticagrelor in patients with stable coronary disease and diabetes
Steg, P. G., Bhatt, D. L., Simon, T., Fox, K., Mehta, S. R., Harrington, R. A., Held, C., Andersson, M., Himmelmann, A., Ridderstråle, W., et al. (2019) · New England Journal of Medicine · doi:10.1056/nejmoa1908077 · Cited by 365 · see citing works
Young, J. G., Stensrud, M. J., Tchetgen, E. J. T., & Hernán, M. Á. (2020) · Statistics in Medicine · doi:10.1002/sim.8471 · Cited by 335 · see citing works
Self-citationA Systematic Review and Meta-Analysis of Hypoglycemia and Cardiovascular Events
Gangji, A. S., Cukierman, T., Gerstein, H. C., Goldsmith, C. H., & Clase, C. M. (2007) · Diabetes Care · doi:10.2337/dc06-1789 · Cited by 308 · see citing works
Cardiovascular risk assessment in patients with diabetes
Bertoluci, M. C., & Rocha, V. Z. (2017) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-017-0225-1 · Cited by 260 · see citing works
On the Treatment of Grouped Observations in Life Studies
Thompson, W. A. (1977) · Biometrics · doi:10.2307/2529360 · Cited by 226 · see citing works
Klepzig, H. (1999) · European Heart Journal · doi:10.1053/euhj.1998.1242 · Cited by 224 · see citing works
Mortality risk among sulfonylureas: a systematic review and network meta-analysis
Simpson, S. H., Lee, J., Choi, S., Vandermeer, B., Abdelmoneim, A. S., & Featherstone, T. R. (2014) · The Lancet Diabetes & Endocrinology · doi:10.1016/s2213-8587(14)70213-x · Cited by 222 · see citing works
Development and Validation of a High‐Quality Composite Real‐World Mortality Endpoint
Curtis, M. D., Griffith, S. D., Tucker, M., Taylor, M. D., Capra, W. B., Carrigan, G. J., Holzman, B., Torres, A. Z., You, P., Arnieri, B., et al. (2018) · Health Services Research · doi:10.1111/1475-6773.12872 · Cited by 216 · see citing works
Prospective Study of Type 1 and Type 2 Diabetes and Risk of Stroke Subtypes
Janghorbani, M., Hu, F. B., Willett, W. C., Li, T. Y., Manson, J. E., Logroscino, G., & Rexrode, K. M. (2007) · Diabetes Care · doi:10.2337/dc06-2363 · Cited by 212 · see citing works
Dunlay, S. M., Givertz, M. M., Aguilar, D., Allen, L. A., Chan, M., Desai, A. S., Deswal, A., Dickson, V. V., Kosiborod, M. N., Lekavich, C. L., et al. (2019) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2019.05.007 · Cited by 145 · see citing works
Schopman, J. E., Simon, A. C. R., Hoefnagel, S. J. M., Hoekstra, J. B. L., Scholten, R. J. P. M., & Holleman, F. (2013) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.2470 · Cited by 120 · see citing works
Mulnier, H. E., Seaman, H. E., Raleigh, V. S., Soedamah‐Muthu, S. S., Colhoun, H. M., Lawrenson, R. A., & de Vries, C. S. (2006) · Diabetologia · doi:10.1007/s00125-006-0493-z · Cited by 117 · see citing works
Is impairment of ischaemic preconditioning by sulfonylurea drugs clinically important?
Meier, J. J., Gallwitz, B., Schmidt, W. E., Mügge, A., & Nauck, M. A. (2003) · Heart · doi:10.1136/heart.90.1.9 · Cited by 112 · see citing works
A Structural Description of Biases That Generate Immortal Time
Hernán, M. A., Sterne, J. A. C., Higgins, J. P. T., Shrier, I., & Hernández-Díaz, S. (2025) · Epidemiology · doi:10.1097/ede.0000000000001808 · Cited by 99 · see citing works
Self-citationCardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis
Engel, S. S., Golm, G. T., Shapiro, D., Davies, M. J., Kaufman, K. D., & Goldstein, B. J. (2013) · Cardiovascular Diabetology · doi:10.1186/1475-2840-12-3 · Cited by 98 · see citing works
Mishriky, B. M., Cummings, D. M., & Tanenberg, R. J. (2015) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2015.05.025 · Cited by 93 · see citing works
Variations in tissue selectivity amongst insulin secretagogues: a systematic review
Abdelmoneim, A. S., Hasenbank, S., Seubert, J. M., Brocks, D. R., Light, P. E., & Simpson, S. H. (2011) · Diabetes Obesity and Metabolism · doi:10.1111/j.1463-1326.2011.01496.x · Cited by 87 · see citing works
Mulnier, H. E., Seaman, H. E., Raleigh, V. S., Soedamah‐Muthu, S. S., Colhoun, H. M., Lawrenson, R. A., & de Vries, C. S. (2008) · Diabetologia · doi:10.1007/s00125-008-1076-y · Cited by 79 · see citing works
Estimating Absolute Risks in the Presence of Nonadherence
Toh, S., Hernández–Dı́az, S., Logan, R. W., Robins, J. M., & Hernán, M. Á. (2010) · Epidemiology · doi:10.1097/ede.0b013e3181df1b69 · Cited by 66 · see citing works
Self-citationMirel, L. B., Resnick, D. M., Aram, J., & Cox, C. S. (2022) · Statistical Journal of the IAOS · doi:10.3233/sji-210891 · Cited by 32 · see citing works
Changes in Type 2 Diabetes Medication Utilization and Costs in the United States, 2014–2019
Neilson, L. M., Munshi, K. D., Peasah, S. K., Huang, Y., Swart, E. C. S., Henderson, R. R., Manolis, C. H., & Good, C. B. (2021) · Medical Care · doi:10.1097/mlr.0000000000001597 · Cited by 16 · see citing works
Trends in Use of Sulfonylurea Types Among US Adults with Diabetes: NHANES 1999–2020
Shin, J., Echouffo-Tcheugui, J. B., Fang, M., Grams, M. E., & Selvin, E. (2023) · Journal of General Internal Medicine · doi:10.1007/s11606-023-08067-w · Cited by 6 · see citing works
Flagged first, then by citations
1 of the 41 references couldn’t be matched to a known paper.
Research works printed but not linked: 1
- [38]Hollis A. Me-too drugs: is there a problem. ResearchGate. Published December 13, 2004. Accessed June 16, 2025. https://www.researchgate.net/publication/228919661_Me-too_drugs_Is_there_a_problem
Cited by
Sorted by citations
13. Older Adults: Standards of Care in Diabetes—2026
American Diabetes Association Professional Practice Committee for Diabetes*, Bajaj, M., McCoy, R. G., Balapattabi, K., Bannuru, R. R., Bellini, N. J., Bennett, A. K., Beverly, E. A., Briggs Early, K., ChallaSivaKanaka, S., et al. (2026) · Diabetes Care · doi:10.2337/dc26-s013 · Cited by 87 · see citing works
Shariat‐Madar, Z., & Mahdi, F. (2025) · Molecules · doi:10.3390/molecules30224448 · Cited by 13 · see citing works
Cai, M., Li, Y., Guo, M., Dong, H., & Cheng, H. (2025) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2025.178113 · Cited by 4 · see citing works
Insulin resistance and type 2 diabetes as allostatic responses to chronic nutrient excess
Prentki, M., Nolan, C. J., James, D. E., Thorens, B., Rhodes, C. J., Corkey, B. E., Ling, C., Froguel, P., Mathieu, C., Gautier, J., et al. (2026) · Cell Metabolism · doi:10.1016/j.cmet.2026.06.012 · Cited by 4 · see citing works
Reassessing Sulfonylurea Safety in Modern Diabetes Care
Ratzki‐Leewing, A. A., Chen, C., & McCoy, R. G. (2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.23079 · Cited by 3 · see citing works
Sulfonylureas increase cardiovascular risk versus DPP4is
(2025) · Reactions Weekly · doi:10.1007/s40278-025-87080-6
(2025) · JAMA Network Open · doi:10.1001/jamanetworkopen.2025.51975
Interdisciplinary Approach to Fall Risk Mitigation in an Older Adult with Atrial Fibrillation
Pogge, E. K., Davis, L. E., Tuitele, J., & Bhatia, N. (2026) · The Senior Care Pharmacist · doi:10.4140/tcp.n.2026.21
Risk Factors for Valvulopathy Among Childhood Cancer Survivors
Chen, H., Ph, H., & Chang, C. (2026) · JAMA Oncology · doi:10.1001/jamaoncol.2025.6437
Noninsulin Medications for Type 2 Diabetes
CASTRO-REVOREDO, I. A., & WEBSTER, S. C. M. (2026) · Medical Clinics of North America · doi:10.1016/j.mcna.2025.12.006
Sklepinski, S. M., Ratzki‐Leewing, A. A., Herrin, J. S., SWARNA, K. S., Deng, Y., Polley, E. C., Neumiller, J. J., Galindo, R. J., Umpierrez, G. E., Ross, J. S., et al. (2026) · BMJ Open Diabetes Research & Care · doi:10.1136/bmjdrc-2025-005775
Tomczyk, M. D., Wawrzynosek, C., de Carrillo, D. G., Krzystanek, M., Pantziarka, P., & Jędrzejowska–Szypułka, H. (2026) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2026.119009
Sklepinski, S. M., Herrin, J. S., Neumiller, J. J., Polley, E. C., SWARNA, K. S., Deng, Y., Galindo, R. J., Umpierrez, G. E., Ross, J. S., Brito, J. P., et al. (2026) · Diabetes Obesity and Cardiometabolic CARE · doi:10.2337/doc26-0025
Molecular mechanisms underlying low glycemic index in rice: Insights from Indian landrace diversity
Jayasurya, K., Utharasu, S., Manonmani, S., Manivannan, U., P, R. R., & Vanitha, K. (2026) · Molecular Biology Reports · doi:10.1007/s11033-026-12702-0
- Authors
- Turchin, A., Petito, L. C., Hegermiller, E., Carnahan, R., DeVries, A., Goel, S., Lansang, M. C., McDonnell, M. E., Nair, V., Priest, E., Willey, V. J., Kaul, A. F., Hernán, M. A., BESTMED Study Research Group, Bah, H., Barlocker, J., Bride, D. L., Churchilles, E., Douros, M., Gryzlak, B., Hansen, C. W., Hess, R., Horne, B., Kean, J., Knudson, P., Melendez, V., Ortman, C., Ryu, G.-Y., Sidebottom, A., Smith, C., Song, X., Spinka, C., Stoddard, A., Taylor, B., VanWormer, J., & Zhong, H.
- Affiliations
- Brigham and Women's Hospital (US)
- Northwestern University (US)
- Indus Consulting, Inc, Chicago, Illinois
- University of Iowa (US)
- Humana (United States) (US)
- Cleveland Clinic (US)
- Baylor Scott & White Research Institute (US)
- Carelon Research (United States) (US)
- Medical Outcomes Management, Inc, Sharon, Massachusetts
- CAUSALab, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- for the BESTMED Study Research Group
- Corresponding author
- Turchin, Alexander
- ORCID
- Venue
- JAMA Network Open
- Publisher
- American Medical Association (AMA)
- Published
- 2025-07-24
- Volume
- 8
- Issue
- 7
- Pages
- e2523067
- ISSN
- 2574-3805 (ISSN-L)
- PMC
- PMC12290728
- OpenAlex
- W4412628968
- Cited by
- 14
- References
- 41
- Citations by year
- 2026: 8 · 2025: 6
- FWCI
- 9.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- JAMA Network Open (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- sulfonylureas, DPP-4 inhibitors, type 2 diabetes, major adverse cardiovascular events, cardiovascular risk, glipizide, glimepiride, glibenclamide, metformin, second-line therapy, cardiovascular safety, comparative effectiveness, myocardial infarction, ischemic stroke, heart failure hospitalization, cardiovascular mortality, TARGET trial
- MeSH terms
- Aged, Cardiovascular Diseases, Diabetes Mellitus, Type 2, Female, Glyburide, Glipizide, Humans, Hypoglycemic Agents, Male, Metformin, Middle Aged, Sulfonylurea Compounds, Dipeptidyl-Peptidase IV Inhibitors, Comparative Effectiveness Research
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
