Stopping GLP-1 drugs can quickly erase cardiovascular benefits

Following a rapid increase in popularity of GLP-1 drugs for diabetes and weight loss, such as semaglutide and tirzepatide, approximately one in eight U.S. adults now take these medications, which also provide cardiovascular benefits. However, when patients stop taking these drugs, they not only regain weight, but, according to a new study, they also incur increased risk of heart attack, stroke, and death compared to staying on the medication.

In the study, researchers at Washington University School of Medicine in St. Louis followed more than 333,000 U.S. veterans with type 2 diabetes for three years. Compared to continued use, they found that stopping or interrupting GLP-1 treatment for as little as six months was linked to a significant increase in the risk of major cardiovascular events.

The longer the gap in treatment, the bigger the jump in risk—up to a 22% increase for heart attack, stroke, and death after two years off GLP-1s, largely erasing the cardiovascular benefits gained during treatment.

The results, which appear in BMJ Medicine, show that the consequences of stopping GLP-1 drugs go beyond weight regain, extending to increased cardiovascular risk, and underscore the importance of continuous treatment for sustained heart protection.

“There is enormous exuberance about starting GLP-1 drugs, but not nearly enough attention to what happens when people stop,” said senior author Ziyad Al-Aly, MD, a WashU 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.”

“Our data suggest this metabolic whiplash is detrimental to heart health,” Al-Aly added. “Restarting the medication helped restore some protection, but only partially, showing that discontinuation leaves a lasting scar.”

GLP-1 benefits build slowly, erode quickly

GLP-1 medications include the semaglutide drugs Ozempic and Wegovy and the tirzepatide drugs Mounjaro and Zepbound. After noticing about half of users stop taking GLP-1s shortly after starting treatment, Al-Aly wanted to understand the consequences of discontinuing GLP-1 medications on cardiovascular health, particularly the risk of major adverse cardiovascular 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 the patients’ outcomes for up to three years. Sulfonylureas include the medications glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Diabeta and others).

The researchers evaluated the treatment status of GLP-1 users every six months. Over the course of the study, 26% of GLP-1 users stopped taking the medication and about 23% had an interruption of six months or more followed by resuming treatment.

Al-Aly and colleagues found a beneficial relationship between the continuous use of GLP-1s and fewer cardiovascular events.

At the end of the trial, compared to the group taking sulfonylureas, participants who consistently took GLP-1 medications for the entire three-year period of the study had the most pronounced reduction in risk—18%, or roughly four fewer major cardiovascular events per 100 people over three years.

Those who continued GLP-1 treatment for two or two-and-a-half years before discontinuing for the remainder of the study also gained significant risk reduction (7% and 15%, respectively). Those who took GLP-1s for less than 18 months before discontinuing saw no significant risk reduction compared to the group on sulfonylureas at the end of the trial.

Those who interrupted GLP-1 treatment and subsequently resumed before the end of the three-year trial period experienced less benefit compared to those who stayed on the medication, with longer gaps in treatment corresponding to smaller reductions in cardiovascular risk.

Compared to continued use of GLP-1s for three years, which corresponded to an 18% risk reduction, GLP-1 users who experienced interruption and subsequently resumed gained a 12% risk reduction on average.

An interruption of just six months before resuming treatment still reduced the cardiovascular benefit, leading to a 4% to 8% increase in risk compared to continuous use.

Discontinuations of one or two years without resuming GLP-1 use resulted in a 14% or 22% increased risk of cardiovascular events, respectively, compared to staying on the drugs. In other words, any benefits gained over the course of taking GLP-1 medications are quickly lost when patients stop.

These findings highlight the importance of maintaining continuous GLP-1 treatment to sustain cardiovascular benefits and indicate that strategies to reduce treatment discontinuity should be developed to maximize the cardioprotective effects of GLP-1s.

“Clinicians should treat adherence to GLP-1 treatment as an important outcome in its own right—not an afterthought,” Al-Aly said.

“Health systems need plans in place to help people continue their medication indefinitely, recognizing that GLP-1s treat chronic conditions. 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.”

These measures are especially important, Al-Aly noted, because the cardiovascular protection provided by GLP-1 medication builds slowly, but it erodes quickly.

As little as one year off the drug was more than enough for study participants to lose benefits cultivated over years of continuous treatment. Once lost, those gains were not fully restored by resuming treatment.