Real-World Study Shows Limited Weight Regain After Stopping GLP-1s; New Obesity Drugs in Development

A new study from Cleveland Clinic offers a more hopeful perspective on what happens when patients stop using injectable GLP-1 medications like Ozempic, Wegovy or Zepbound. The study, published in the journal Diabetes, Obesity and Metabolism, found that patients did not experience significant weight regain in the year after stopping a GLP-1, contrasting with previous clinical trials that suggested a discouraging "rebound" effect.

The study looked at nearly 8,000 adults in Ohio and Florida who used semaglutide or tirzepatide for three to 12 months before stopping. Unlike tightly controlled clinical trials, the researchers looked at "real-world" outcomes where patients often switch from one medication to another. Among those treated specifically for obesity, the average weight loss before stopping was 8.4%; one year later, they had regained just 0.5% on average.

An estimated 27% of patients transitioned to different medications, including older-generation obesity drugs, while another 20% eventually restarted their original medication once insurance issues or side effects were resolved. Another 14% transitioned to intensive lifestyle modification programs, working closely with dietitians and exercise specialists. Patients who maintained their weight tended to remain engaged with the healthcare system, whether through alternative prescriptions or structured lifestyle support, the researchers noted.

"Our real-world data show that many patients who stop semaglutide or tirzepatide restart the medication or transition to another obesity treatment, which may explain why they regain less weight than patients in randomized trials," said lead study author Dr. Hamlet Gasoyan. This suggests that the rebound seen in clinical trials may be a result of patients being left without alternative support, a scenario that doesn't have to happen in clinical practice, researchers say.

The study had some limitations. "We included adult patients from a single large integrated health system in Ohio and Florida," the authors noted. "Patient characteristics and healthcare delivery patterns vary across the U.S., which may limit the generalizability of our findings." Some of the observed weight reduction may be associated with other interventions that the researchers were unable to capture.

Meanwhile, next-generation obesity treatments continue to advance through clinical development. Retatrutide, developed by Eli Lilly, is a "triple agonist" that targets GLP-1, GIP, and glucagon receptors. In a phase 2 obesity trial, higher doses produced very large average weight reductions at 48 weeks.

Roche's obesity drug candidate petrelintide showed up to 10.7% weight loss over 42 weeks in the Phase 2 ZUPREME-1 trial. The trial evaluated petrelintide versus placebo in 493 obese participants with a mean BMI of 37 kg/m². The Phase 2 ZUPREME-1 trial showed petrelintide led to significant weight loss with low discontinuation and a favorable safety profile.