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Cited by 8Diabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and LipoproteinsDiabetes Management and Research

Glucagon-like peptide 1 receptor agonist discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: target trial emulation

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Xie, Yan, Choi, Taeyoung, Al-Aly, Ziyad·2026·BMJ Medicine
DOI 10.1136/bmjmed-2025-002150PMC PMC13007077
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Abstract

Objectives: To characterise patterns of use of glucagon-like peptide 1 receptor agonists (GLP-1RAs) and assess the associations between various GLP-1RA treatment scenarios and the risk of major adverse cardiovascular events. Design: Target trial emulation. Setting: Electronic healthcare databases of US Department of Veterans Affairs, 1 January 2017 to 31 December 2023. Data obtained from domains in the Veterans Affairs Corporate Data Warehouse. Participants: Veterans Affairs users with type 2 diabetes who started treatment with GLP-1RAs (n=132 551) or sulfonylureas (n=201 136), followed up for three years. Veterans Affairs users were defined as having at least two visits to Veterans Affairs and having used the Veterans Affairs outpatient pharmacy within a year before receiving treatment with GLP-1RAs or sulfonylureas. Interventions: GLP-1RAs or sulfonylureas. In the GLP-1RA arm, treatment status was reassigned every six months, generating 16 prespecified treatment strategies that varied in length of continued use, discontinuation, or interruption. Main outcome measures: Three year cumulative incidence of major adverse cardiovascular events (myocardial infarction, stroke, or all cause death). Results: The cohort included 132 551 incident users of GLP-1RAs and 201 136 incident users of sulfonylureas (defined as no prescription for GLP-1RAs or sulfonylureas within a year of the first prescription). A duration dependent association was found between the use of GLP-1RAs and the cumulative three year risk of major adverse cardiovascular events. Compared with the sulfonylurea reference group, participants who used GLP-1RAs for 0.5, 1, or 1.5 years, before discontinuing for the remainder of the three years, showed incidence risk ratios close to 1.0, with no significant reduction in the risk of major adverse cardiovascular events at three years. Compared with the sulfonylurea group, the reduction in the risk of major adverse cardiovascular events was significant in people who continued to use GLP-1RAs for 2 and 2.5 years, before discontinuing for the remainder of the three years (incidence risk ratio 0.93, 95% confidence interval (CI) 0.88 to 0.98 and 0.85, 0.81 to 0.90, respectively). Participants who continued to use GLP-1RAs for the whole three year follow-up period had the most pronounced risk reduction (incidence risk ratio 0.82, 95% CI 0.78 to 0.85) compared with the sulfonylurea group. Compared with continued use of GLP-1RA, discontinuing treatment for 0.5 years was associated with an increased risk of major adverse cardiovascular events (incidence risk ratio 1.04, 95% CI 1.01 to 1.08); the risk increased progressively with a longer duration of discontinuation, with an incidence risk ratio of 1.14 (1.09 to 1.18) and 1.22 (1.16 to 1.27) for one and two years of discontinuation, respectively. Compared with continued use of GLP-1RA, 0.5 years of interruption was associated with an increased risk of major adverse cardiovascular events; longer durations of interruption were progressively associated with a higher risk of major adverse cardiovascular events, with an incidence risk ratio of 1.12 (95% CI 1.06 to 1.19) and 1.16 (1.11 to 1.22) for one and two years of interrupted use, respectively. Conclusions: The cardiovascular benefit of GLP-1RAs accumulated with continuous use, but even brief periods of discontinuations or interruptions might progressively erode and could ultimately reverse this protection, increasing the risk of cardiovascular events.

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  • In a target trial emulation study, discontinuation or interruption of GLP-1 RA therapy was associated with progressively higher risks of MACE with longer discontinuation (0.5, 1, and 2 years) compared with continued use.

    “discontinuation for 0.5, 1, and 2 years was associated with progressively higher risks of MACE”

    From Weight maintenance after discontinuation of GLP-1 therapies (2026) · cites this paper as [37]

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Cited by

Sorted by citations

Authors
Xie, Y., Choi, T., & Al-Aly, Z.
Affiliations
  • Washington University in St. Louis (US)
  • St. Louis VA Medical Center (US)
  • Clinical Epidemiology Center, Veterans Affairs Saint Louis Health Care System, St Louis, MO, USA
ORCID
Venue
BMJ Medicine
Publisher
BMJ
Published
2026-03
Volume
5
Issue
1
Pages
e002150
ISSN
2754-0413 (ISSN-L)
DOI
10.1136/bmjmed-2025-002150
PMC
PMC13007077
OpenAlex
W7138931708
Cited by
8
References
22
Citations by year
2026: 8
FWCI
40.12
Type
journal article
Language
en
Open access
Licence
Locations
  • BMJ Medicine (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Veterans Affairs
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
GLP-1 receptor agonists, type 2 diabetes, major adverse cardiovascular events, treatment discontinuation, sulfonylureas, treatment duration, myocardial infarction, stroke, all-cause mortality, veterans, target trial emulation, cardiovascular safety, antidiabetic drugs, veterans' health care utilization, veterans' health care costs, veterans' health care access

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