Published Nov 11, 2026 | 4:04 PM ⚊ Updated Nov 11, 2026 | 4:04 PM
The association between treatment discontinuation and adverse cardiovascular outcomes was more pronounced among people with obesity.
Synopsis: A study of more than 80,000 people with type 2 diabetes in Italy found that discontinuing GLP-1 drugs was associated with twice the risk of heart attack, stroke or death compared with continued treatment. The association was stronger among people with obesity, but researchers cautioned that the findings do not establish causation.
People with type 2 diabetes who discontinue glucagon-like peptide-1 receptor agonists (GLP-1 RAs) may face a substantially higher risk of cardiovascular events and death than those who continue treatment, according to a study published in The Lancet Regional Health – Europe.
The study analysed health records of 80,302 people with type 2 diabetes who received care at 301 diabetes clinics across Italy between 2004 and 2024. It found that stopping GLP-1 treatment was associated with approximately twice the risk of a combined outcome of non-fatal heart attack, non-fatal stroke or death from any cause.
“Among people with T2D and free of CVD starting a therapy with a GLP-1RA, interruption of therapy was associated with greater incidence of a composite of myocardial infarction, stroke, or death from any cause in comparison with individuals persistent on therapy, with a consistently higher risk of death from any cause,” said the authors.
After adjusting for differences in participants’ baseline characteristics through propensity score matching, researchers compared two groups of 28,713 people each.
The incidence of the combined cardiovascular and mortality outcome was 3.94 events per 100 person-years among those who discontinued treatment, compared with 1.96 events per 100 person-years among those who continued. This translated into a hazard ratio of 2.03, indicating approximately twice the risk among those who stopped treatment.
For death from any cause, the incidence was 2.23 events per 100 person-years in the discontinuation group, compared with 0.48 events per 100 person-years among those who continued treatment. The hazard ratio was 4.81.
The association between treatment discontinuation and adverse cardiovascular outcomes was more pronounced among people with obesity.
When researchers analysed the findings according to body mass index (BMI), the hazard ratio for the combined outcome was 2.27 among people with a BMI of 30 or above, compared with 1.61 among those with a BMI below 30.
The researchers suggested that people with obesity could be more vulnerable to the cardiovascular consequences of stopping GLP-1 treatment, potentially because of their higher underlying cardiovascular risk or the loss of some benefits associated with these medicines.
The study also found that changes in conventional cardiovascular risk factors did not fully explain the higher risk observed after treatment discontinuation.
Although people who stopped medication had higher levels of some risk factors than those who continued, changes in blood glucose control, body weight, blood pressure and lipid levels did not meaningfully distinguish those who subsequently experienced cardiovascular events from those who did not.
“The comparison within the discontinuation group evidenced only small differences in risk factors between people subsequently having or not a primary endpoint,” said the authors.
They added that this could indicate people at higher risk of cardiovascular events or death after discontinuing GLP-1 treatment are not necessarily those whose conventional cardiovascular risk factors deteriorate.
GLP-1 receptor agonists are used to manage type 2 diabetes and obesity because they help improve blood glucose control, promote weight loss and reduce cardiovascular risk.
However, discontinuation is common in routine clinical practice. Previous studies have reported discontinuation rates ranging from 37% to 81%, with around 20% to 50% of patients stopping treatment within the first year.
The researchers identified gastrointestinal side effects, perceived lack of effectiveness, high treatment costs and inconvenience as common reasons for discontinuation.
“A substantial proportion of individuals discontinue these agents, often within the first year of therapy,” said the authors.
Stopping these medicines is also frequently associated with weight regain and deterioration in cardiometabolic risk factors, including blood glucose levels, blood pressure and lipid profiles.
“Consequently, people stopping GLP-1RA quickly regain most of the weight previously lost, independent of the treatment indication, a phenomenon accompanied by the concomitant deterioration of multiple cardiovascular risk factors,” said the authors.
They suggested that more flexible dose-escalation strategies could improve treatment tolerability and prevent unnecessary discontinuation.
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Despite the increased risks observed, the researchers cautioned that the observational nature of the study does not establish that stopping GLP-1 medicines directly causes heart attacks, strokes or death.
They could not determine why individual patients discontinued treatment or fully account for other underlying health conditions that might have influenced both treatment decisions and subsequent outcomes.
“The observational nature of this work is inherently associated with the risk of residual confounding and reverse causation,” said the authors.
They also noted that the magnitude of the association with all-cause mortality was larger than the cardiovascular benefits observed in randomised trials of GLP-1 medicines. This suggests that factors other than treatment discontinuation itself could have contributed to the findings.
“The observational nature of the study prevents distinguishing whether treatment discontinuation directly contributes to increased cardiovascular risk or rather identifies patients with worsening overall clinical status,” said the authors.
They added that discontinuation “may represent a marker of higher underlying risk rather than a direct cause of adverse outcomes.”
The findings may also not apply to people taking GLP-1 medicines exclusively for obesity without diabetes. The study primarily included people with type 2 diabetes and did not establish whether the association extends to other patients.
The researchers concluded that continued treatment may be important for maintaining the cardiovascular and mortality benefits associated with GLP-1 receptor agonists. However, they said further prospective studies are needed to establish whether discontinuation itself contributes to the increased risk.
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(Edited by Fayisa CA)
