GLP-1 Discontinuation Tied to Loss of Cardiovascular Protection

Stopping GLP-1 receptor agonist therapy, even briefly, is associated with a measurable increase in risk of major adverse cardiovascular events in adults with type 2 diabetes, according to a cohort study of more than 300,000 published in BMJ Medicine.

The findings add important clinical context to the widely documented problem of GLP-1 discontinuation and suggest the cardiovascular consequences of stopping treatment extend well beyond weight regain.¹

“There is enormous exuberance about starting GLP-1 drugs, but not nearly enough attention to what happens when people stop,” said lead investigator Ziyad Al-Aly, MD, a Washington University in St. Louis School of Medicine clinical epidemiologist and chief of the Research and Development Service at the VA Saint Louis Health Care System. “Many quit after a few months because of cost, side effects or shortages. When they stop, it’s not just weight that comes back; they experience a resurgence in inflammation, blood pressure, and cholesterol. Weight regain is visible; the metabolic reversal is not.”

Leveraging VA Data to Understand GLP-1 Benefits

The analysis used a target emulation trial design drawing on data from 333,687 US veterans with type 2 diabetes. Researchers compared 132,551 patients prescribed GLP-1 receptor agonists, including semaglutide and tirzepatide, with 201,136 patients prescribed sulfonylureas. Treatment status was evaluated every 6 months over a 3-year follow-up period. The primary outcome was a composite of major adverse cardiovascular events, including myocardial infarction, stroke, and death.¹

Continuous GLP-1 use over the full 3-year period was associated with the greatest cardiovascular benefit, corresponding to an 18% reduction in major adverse cardiovascular events compared with sulfonylurea use, or 4 fewer events per 100 patients over 3 years. Benefit was also observed among patients who used GLP-1s for 2 to 2.5 years before discontinuing (7% and 15% risk reduction, respectively). Patients who stopped within 18 months saw no significant risk reduction at the end of follow-up compared with the sulfonylurea group.¹

Interruptions followed by resumption of treatment also diminished benefit. Compared to continuous use, a gap of 6 months before restarting was associated with a 4% to 8% increase in cardiovascular risk relative to uninterrupted therapy. Discontinuation of 1 or 2 years without resumption corresponded to a 14% or 22% increased risk, respectively, compared to staying on the drug. Restarting treatment restored some protection, a finding the investigators characterized as evidence of a lasting effect from the period of discontinuation.¹

Over the course of the study, 26% of GLP-1 users stopped treatment entirely and approximately 23% experienced an interruption of 6 months or more before resuming.¹

Clinical Implications for Adherence and Access

The study is observational and subject to limitations inherent in real-world claims-based data, including potential confounding by indication and differences in baseline characteristics between GLP-1 and sulfonylurea users. The cohort was drawn exclusively from the VA population, which skews male and older, limiting generalizability. Additionally, the use of sulfonylureas as the comparator group, rather than placebo, shapes the magnitude of relative risk estimates.

The investigators called for health systems to treat GLP-1 adherence as a primary clinical outcome, including proactive side effect management, patient counseling about the long-term nature of treatment, and structural approaches to addressing the cost barriers that drive discontinuation.¹

“Health systems need plans in place to help people continue their medication indefinitely, recognizing that GLP-1s treat chronic conditions,” Al-Aly added. “That includes proactive management of side effects, candid conversations about the long-term nature of treatment, infrastructure to identify and support patients at risk of stopping and addressing the cost barriers that make GLP-1 therapy unsustainable for many.”

References

1. Xie Y, Choi T, Al-Aly Z. GLP-1RA discontinuation and risks of major adverse cardiovascular events in adults with type 2 diabetes: a target emulation trial. BMJ Med. 2026;5(1):e002150. doi:10.1136/bmjmed-2025-002150

2. Washington University School of Medicine in St. Louis. Stopping GLP-1 drugs can quickly erase cardiovascular benefits. EurekAlert! Published March 18, 2026. Accessed March 20, 2026. https://www.eurekalert.org/news-releases/1120133