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Cited by 47Diabetes Treatment and ManagementHeart Failure Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

Comparative Effectiveness of Second-Line Antihyperglycemic Agents for Cardiovascular Outcomes

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Khera, Rohan, Aminorroaya, Arya, Dhingra, Lovedeep Singh, Thangaraj, Phyllis M., Pedroso Camargos, Aline, Bu, Fan, Ding, Xiyu, Nishimura, Akihiko +46 more·2024·Journal of the American College of Cardiology
DOI 10.1016/j.jacc.2024.05.069PMC PMC12045554

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Abstract

Background Sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes mellitus (T2DM). However, their effectiveness relative to each other and other second-line antihyperglycemic agents is unknown, without any major ongoing head-to-head clinical trials. Objectives The aim of this study was to compare the cardiovascular effectiveness of SGLT2is, GLP-1 RAs, dipeptidyl peptidase-4 inhibitors (DPP4is), and clinical sulfonylureas (SUs) as second-line antihyperglycemic agents in T2DM. Methods Across the LEGEND-T2DM (Large-Scale Evidence Generation and Evaluation Across a Network of Databases for Type 2 Diabetes Mellitus) network, 10 federated international data sources were included, spanning 1992 to 2021. In total, 1,492,855 patients with T2DM and cardiovascular disease (CVD) on metformin monotherapy were identified who initiated 1 of 4 second-line agents (SGLT2is, GLP-1 RAs, DPP4is, or SUs). Large-scale propensity score models were used to conduct an active-comparator target trial emulation for pairwise comparisons. After evaluating empirical equipoise and population generalizability, on-treatment Cox proportional hazards models were fit for 3-point MACE (myocardial infarction, stroke, and death) and 4-point MACE (3-point MACE plus heart failure hospitalization) risk and HR estimates were combined using random-effects meta-analysis. Results Over 5.2 million patient-years of follow-up and 489 million patient-days of time at risk, patients experienced 25,982 3-point MACE and 41,447 4-point MACE. SGLT2is and GLP-1 RAs were associated with lower 3-point MACE risk than DPP4is (HR: 0.89 [95% CI: 0.79-1.00] and 0.83 [95% CI: 0.70-0.98]) and SUs (HR: 0.76 [95% CI: 0.65-0.89] and 0.72 [95% CI: 0.58-0.88]). DPP4is were associated with lower 3-point MACE risk than SUs (HR: 0.87; 95% CI: 0.79-0.95). The pattern for 3-point MACE was also observed for the 4-point MACE outcome. There were no significant differences between SGLT2is and GLP-1 RAs for 3-point or 4-point MACE (HR: 1.06 [95% CI: 0.96-1.17] and 1.05 [95% CI: 0.97-1.13]). Conclusions In patients with T2DM and CVD, comparable cardiovascular risk reduction was found with SGLT2is and GLP-1 RAs, with both agents more effective than DPP4is, which in turn were more effective than SUs. These findings suggest that the use of SGLT2is and GLP-1 RAs should be prioritized as second-line agents in those with established CVD.

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  • The OHDSI network and its open-source analytic tools have been previously used to generate reliable evidence in medicine, including ophthalmology.

    “The OHDSI network and its open-source analytic tools have been previously used to generate reliable evidence in medicine, including ophthalmology.”

    From Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy (2025) · cites this paper as [11]

    The Methods (Data Sources and Statistical Analysis; page not provided) describe an OHDSI-standardized, federated diabetes study with publicly available analytic code and diagnostics intended to ensure reliable estimates. This supports prior use in medicine, but the paper does not report an ophthalmology application. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • GLP-1RAs offer well-documented benefits in reducing cardiovascular and kidney complications.

    “GLP-1RAs, approved by the US Food and Drug Administration (FDA) for type 2 diabetes (T2D) treatment in 2017, offer well-documented benefits in reducing cardiovascular and kidney complications.”

    From Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy (2025) · cites this paper as [11]

    The Results (Comparative Effectiveness for Primary Endpoints; page not provided) associate GLP-1RAs with lower cardiovascular-event risk than DPP-4 inhibitors and sulfonylureas. The Study Outcomes section lists cardiovascular outcomes only; our copy does not report a reduction in kidney complications, so that part of the claim is unsupported. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Authors
Khera, R., Aminorroaya, A., Dhingra, L. S., Thangaraj, P. M., Pedroso Camargos, A., Bu, F., Ding, X., Nishimura, A., Anand, T. V., Arshad, F., Blacketer, C., Chai, Y., Chattopadhyay, S., Cook, M., Dorr, D. A., Duarte-Salles, T., DuVall, S. L., Falconer, T., French, T. E., Hanchrow, E. E., Kaur, G., Lau, W. C. Y., Li, J., Li, K., Liu, Y., Lu, Y., Man, K. K. C., Matheny, M. E., Mathioudakis, N., McLeggon, J.-A., McLemore, M. F., Minty, E., Morales, D. R., Nagy, P., Ostropolets, A., Pistillo, A., Phan, T.-P., Pratt, N., Reyes, C., Richter, L., Ross, J. S., Ruan, E., Seager, S. L., Simon, K. R., Viernes, B., Yang, J., Yin, C., You, S. C., Zhou, J. J., Ryan, P. B., Schuemie, M. J., Krumholz, H. M., Hripcsak, G., & Suchard, M. A.
Affiliations
  • Yale New Haven Hospital (US)
  • Yale University (US)
  • University of Michigan (US)
  • Johns Hopkins University (US)
  • Columbia University Irving Medical Center (US)
  • University of California, Los Angeles (US)
  • Janssen (United States) (US)
  • University of Hong Kong (HK)
  • Oregon Health & Science University (US)
  • United States Department of Veterans Affairs (US)
  • VA Tennessee Valley Healthcare System (US)
  • University of Dundee (GB)
  • University College London Hospitals NHS Foundation Trust (GB)
  • IQVIA (United States) (US)
  • University of Calgary (CA)
  • Institut Universitari d'Investigació en Atenció Primària Jordi Gol (ES)
  • Taipei Medical University (TW)
  • University of South Australia (AU)
  • IQVIA (United Kingdom) (GB)
  • Yonsei University (KR)
  • Johnson & Johnson (United States) (US)
Corresponding author
  • Khera, Rohan
  • Suchard, Marc A.
ORCID
Venue
Journal of the American College of Cardiology
Publisher
Elsevier BV
Published
2024-09
Volume
84
Issue
10
Pages
904-917
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2024.05.069
PMC
PMC12045554
OpenAlex
W4401882956
Cited by
47
References
16
Citations by year
2026: 27 · 2025: 17 · 2024: 3
FWCI
13.78
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Discovery Research Portal (University of Dundee) (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
  • Discovery Research Portal (University of Dundee) (submittedVersion, cc-by-nc-nd)
Funders
  • US Department of Veterans Affairs
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, sulfonylureas, major adverse cardiovascular events, cardiovascular outcomes, heart failure hospitalization, metformin monotherapy, target trial emulation

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