Discontinuing GLP-1 drugs can rapidly reverse the cardiovascular benefits Washing medicine

After a rapid increase in the popularity of GLP-1 drugs for diabetes and weight loss, such as semaglutide and terzapatide, nearly one in eight adults in the United States now takes the drug, which also offers cardiovascular benefits. However, when patients stop taking these drugs, not only do they regain weight, but according to a new study, they also have an increased risk of heart attack, stroke and death compared to those who stay on the drug.

In the study, researchers at Washington University School of Medicine in St. Louis followed more than 333,000 American veterans with type 2 diabetes for three years. Compared with continuous use, they found that stopping or interrupting GLP-1 therapy for six months was associated with a significant increase in the risk of major cardiovascular events. The longer the gap in treatment, the greater the risk—a 22% increase in heart attack, stroke, and death two years after GLP-1s, largely because the cardiovascular benefits disappear during treatment.

The results, which appear in the March 18 issue of BMJ Medicine, show that the consequences of stopping GLP-1 drugs go beyond weight regain, increase cardiovascular risk, and highlight the importance of continued treatment for lasting heart protection.

“There is a lot of excitement about starting GLP-1 medications, but not nearly as much attention as to what happens when people stop,” said senior author Ziad Al-Ali, MD, a clinical epidemiologist at WashU Medicine and director of research and development services at the VA St. Louis Healthcare System. “Many quit after a few months because of costs, side effects, or deficiency. When they stop, it’s not just the weight that comes back; they experience a resurgence in inflammation, blood pressure, and cholesterol; the weight returns; not the metabolic changes.”

“Our data suggest that this metabolic whiplash is detrimental to cardiovascular health.” Al Ali added. “Resuming the medication helped restore some protection, but only partially, indicating that discontinuation leaves a lasting scar.”

The benefits of GLP-1 develop slowly, and wear off quickly

GLP-1 drugs include the semaglutide drugs Ozempic and Vigovi and the terzapatide drugs Monjaro and Zipbound. After about half of users stopped taking GLP-1s immediately after starting treatment, Al Aly wanted to know the consequences of stopping GLP-1 drugs on heart health, particularly the risk of major adverse events including heart attack, stroke and death. The study of 333,687 veterans compared 132,551 participants who were prescribed GLP-1s for their type 2 diabetes with 201,136 participants who were prescribed sulfonylureas, another treatment for diabetes, and followed patient outcomes for up to three years. Sulfonylureas include the drugs glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Diabetes and others).

The researchers evaluated the treatment status of GLP-1 users every six months. During the study, 26% of GLP-1 users stopped taking the drug and about 23% experienced interruptions of six months or more when resuming treatment.

Al-Aly and colleagues found a beneficial association between continued use of GLP-1s and fewer cardiovascular events. At the end of the trial, compared to the sulfonylurea group, the participants who continuously took GLP-1 drugs throughout the three-year period of the study had a significant reduction in risk – 18%, or approximately 4 fewer heart disease events per 100 people in three years. Those who continued GLP-1 therapy for two to two and a half years before stopping for the remainder of the study also achieved a significant risk reduction (7% and 15%, respectively). Those who took GLP-1 for less than 18 months before stopping did not see a significant risk reduction compared to the sulfonylureas group at the end of the trial.

Those who interrupted GLP-1 therapy and then restarted it before the end of the three-year trial period experienced less benefit than those who remained on the drug, consistent with smaller reductions in cardiovascular risk with longer treatment intervals. Compared to continuous use of GLP-1s for three years, which corresponded to an 18% risk reduction, GLP-1 users who discontinued and then resumed achieved an average risk reduction of 12%. Interrupting just six months before resuming treatment still reduces cardiovascular benefits, leading to a 4% to 8% increase in risk compared with continued use.

Discontinuing GLP-1 use for one or two years without resuming use increased the risk of cardiovascular events by 14% or 22%, respectively, compared with remaining on the drug. In other words, any benefits gained while taking GLP-1 drugs are quickly lost when patients stop.

These findings highlight the importance of maintaining continuous GLP-1 therapy to maintain cardiovascular benefits and indicate that strategies to minimize treatment discontinuation should be developed to maximize the cardioprotective effects of GLP-1s.

“Clinicians should treat GLP-1 therapy as an important outcome in its own right — not an afterthought,” said El Ali. “Health systems need plans to help people continue taking their medications indefinitely, given that GLP-1s are treating chronic conditions. These include proactive management of side effects, clear communication about the long-term nature of treatment, infrastructure to identify and support patients to reduce risk, and address the cost barriers that create unnecessary barriers to many GLP-1 therapies.”

These measures are especially important, Al Ali noted, because the cardioprotection provided by GLP-1 drugs builds slowly, but wears off quickly. As little as one year off medication was more than enough for study participants to lose the benefits accrued over years of continuous treatment. Once lost, these gains are not fully regained upon resumption of treatment.