GLP-1 drugs such as semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound) have surged in popularity for treating diabetes and helping people lose weight, with about one in eight U.S. adults now using these medications, which are also known to provide cardiovascular benefits—but new research suggests that those heart benefits may fade quickly when treatment is stopped. 
Researchers at Washington University School of Medicine in St. Louis tracked more than 333,000 U.S. veterans with type 2 diabetes for three years and found that interrupting or stopping GLP-1 treatment for as little as six months was associated with a meaningful increase in the risk of major cardiovascular events compared with remaining on the medication; the longer patients stayed off treatment, the greater the increase in risk, with the risk of heart attack, stroke and death up to 22% higher after two years without GLP-1 therapy than among people who continued treatment, largely wiping out the cardiovascular protection gained while taking the drugs. 
The findings, published in BMJ Medicine, suggest that stopping GLP-1 medications may have consequences that extend well beyond weight regain and point to the importance of uninterrupted treatment for maintaining 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." 
After observing that about half of users stop taking GLP-1 drugs not long after beginning treatment, Al-Aly set out to examine what happens to cardiovascular health after therapy is discontinued, focusing on major adverse cardiovascular events including heart attack, stroke and death by analyzing data from 333,687 veterans with type 2 diabetes—132,551 prescribed GLP-1 drugs and 201,136 prescribed sulfonylureas, another class of diabetes medications that includes glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Diabeta and others)—with participants followed for up to three years and GLP-1 treatment status reassessed every six months, during which 26% of GLP-1 users stopped taking the medication altogether and another roughly 23% experienced a treatment gap lasting at least six months before eventually restarting therapy. 
The clearest cardiovascular benefit appeared among people who remained on GLP-1 medications throughout the full three-year study period: compared with participants taking sulfonylureas, those who consistently stayed on GLP-1 therapy had an 18% lower risk of major cardiovascular events, translating to about four fewer major cardiovascular events for every 100 people over three years, while participants who stayed on GLP-1 treatment for two years or two-and-a-half years before stopping for the rest of the study also saw meaningful reductions in risk, at 7% and 15%, respectively—by contrast, people who discontinued GLP-1 therapy before reaching 18 months showed no significant reduction in cardiovascular risk compared with those taking sulfonylureas by the end of the study. 
Interrupting treatment and then restarting it also appeared to reduce the cardiovascular benefit, as people who remained on GLP-1 drugs continuously for three years had an 18% reduction in risk while those who stopped temporarily and later resumed treatment saw an average reduction of 12%, and even a six-month interruption before restarting therapy was enough to weaken the benefit, with those treatment gaps associated with a 4% to 8% increase in cardiovascular risk compared with continuous use; longer periods off the drugs were linked to even greater losses of protection, since people who stopped GLP-1 treatment for one year without restarting had a 14% higher risk of cardiovascular events compared with continuous users, and after two years off treatment that increase reached 22%—a pattern suggesting that cardiovascular benefits accumulated during GLP-1 treatment can be lost relatively quickly once the medication is discontinued. 
These findings reinforce the importance of continuous treatment if patients and clinicians want to preserve the cardiovascular effects of GLP-1 therapy and suggest that reducing treatment interruptions could help maximize the drugs' protective effects on the heart. 
"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." Al-Aly noted that this is especially important because cardiovascular protection from GLP-1 treatment appears to accumulate gradually but disappear much more quickly.