When individuals with overweight or obesity discontinue GLP-1 receptor agonists (RAs), they regain approximately 60% of their weight within 1 year following GLP-1 RA discontinuation. Approximately 25% of the weight loss achieved with these medications appears to persist with long-term findings, with significant implications for how clinicians counsel patients at the point of discontinuation.

These are the two central findings of a meta-analysis of 48 studies, including 36 randomized controlled trials, conducted by British researchers led by medical students Brajan Budini and Steven Luo from the School of Clinical Medicine, University of Cambridge, Cambridge, England. The results were published in eClinical Medicine, which is a part of The Lancet Discovery Science.

“Discontinuation of GLP-1 RAs is associated with predictable and slowing weight gain, which appears to plateau below pretreatment levels,” the authors concluded in their study, suggesting that some weight loss may be retained over time.

Half Discontinue

It remains unclear whether regaining weight is caused by an increase in fat mass, lean mass, or fat alone. Earlier studies have shown that fat-free mass — including muscle — can account for up to 40% of the total weight lost during treatment.

More than 1 billion people worldwide have obesity. Most GLP-1 RAs achieve weight reductions of 15%-20% of body weight. However, approximately half of those who begin treatment stop treatment within the first year. After 2 years, only one quarter of the patients continued treatment with weight-loss injections.

Poor adherence is driven by two main factors.

• First, many patients experience adverse effects, including gastrointestinal symptoms, fatigue, dizziness, and exhaustion.
• Second, and likely more importantly, GLP-1 RAs for obesity, unlike those used for type 2 diabetes, are not routinely covered by statutory health insurance and must be paid by patients. Treatment costs can reach up to €300 per month.

Predictive Model

Researchers examined how weight changes over the long term after discontinuation of GLP-1 RAs. For the meta-analysis, they identified 48 relevant studies that addressed this question.

Because most studies included only a few weeks of follow-up after treatment cessation, the researchers selected six randomized controlled trials encompassing more than 3200 participants, in which weight was tracked for up to 1 year after discontinuation of GLP-1 RA.

The researchers used these data to model patterns of weight regain, including projections over 52 weeks.

Similar Trajectories

Their predictive model found that after stopping treatment, weight gain is initially relatively rapid and slows progressively over time. At 52 weeks, the participants had, on average, regained 60% of the kilograms lost during treatment.

After 60 weeks, the weight gain began to plateau, stabilizing at approximately 75% of the initial weight. For example, an individual who lost 20 kg during treatment would still weigh approximately 5 kg less in the long term.

The calculated trajectories were similar across all three agents studied: semaglutide, liraglutide, and tirzepatide, which also activate the glucose-dependent insulinotropic polypeptide receptor in addition to the GLP-1 receptor.

The study had several limitations. First, the model could only be informed by the data collected within the first year of GLP-1 RA discontinuation. Second, the analysis was restricted to studies in which the average weight loss during treatment was at least 3 kg.

Sustained Effects

“Drugs such as Ozempic and Wegovy act like brakes on our appetite, making us feel full sooner, which means we eat less and therefore lose weight. When people stop taking them, they are essentially taking their foot off the brake, and this can lead to rapid weight regain,” Budini said in a press release.

According to the authors, the fact that patients do not return to their original weight even 1 year later may have several explanations. One probable reason is that GLP-1 RAs, through their appetite-suppressing effect, could help individuals develop healthier eating habits, for example, eating smaller portions or more balanced meals. Patients may maintain these new habits even after the end of therapy. It is also conceivable that the medications have long-term effects within the body; for example, GLP-1 RAs may also facilitate long-term physiologic adaptations, such as altering hormone levels and hypothalamic resetting, the researchers noted.

Gradual Tapering

“When stopping weight-loss drugs, doctors and patients should be aware of the potential for weight regain and consider ways to mitigate this risk,” Luo, study author, said in a press release.

“Our projections show that even though people regain most of the weight they have lost, they still maintain some of the weight loss, but what we currently don’t know is if the same proportion of lean mass is recovered. If the regained weight is disproportionately fat, individuals may ultimately be worse off than before in their fat-to-lean mass ratio, which may have adverse consequences for their health,” Budini added.

In their study, the researchers highlighted potential strategies to prevent these effects. “Current evidence suggests that adopting an individualized dose-tapering approach can limit weight regain, but more research is needed to develop strategies for reliable long-term weight management after GLP-1 RA cessation,” the authors wrote.

This story was translated from Medscape’s German edition, part of the Medscape Professional Network.