SURMOUNT-4 trial finds rapid weight regain after stopping tirzepatide

Adults with obesity who stopped taking tirzepatide after losing weight regained an average of 14.0% of their body weight over the following year, while those who kept taking the drug lost an additional 5.5%, according to results from the phase 3 SURMOUNT-4 randomized withdrawal trial ^[1].

The trial was designed in two phases. During an initial 36-week, open-label lead-in period, 783 participants received once-weekly subcutaneous tirzepatide at the maximum tolerated dose of 10 or 15 mg, along with diet and physical activity ^[1]. At week 36, 670 of those participants were randomly assigned in equal groups either to continue tirzepatide (335 people) or to switch to placebo (335 people) for 52 more weeks ^[1].

Participants who completed the lead-in had a mean weight reduction of 20.9% ^[1]. They had a mean age of 48, 71% were women, and their mean weight was 107.3 kg at the start ^[1]. To enroll, participants had to have a body mass index of at least 30, or at least 27 with a weight-related complication, and they could not have diabetes ^[1]. The study ran at 70 sites in four countries and is registered as NCT04660643 ^[1].

From week 36 to week 88, the mean percent change in weight was -5.5% with continued tirzepatide versus +14.0% with placebo — a difference of -19.4% (95% CI, -21.2% to -17.7%; P < .001) ^[1]. Measured another way, 300 participants (89.5%) still taking tirzepatide at week 88 had maintained at least 80% of the weight they lost during the lead-in, compared with 16.6% of those on placebo (P < .001) ^[1]. Averaged across the full 88 weeks, total mean weight reduction was 25.3% for the tirzepatide group and 9.9% for the placebo group ^[1].

The most common adverse events were mostly mild to moderate gastrointestinal symptoms, which occurred more often with tirzepatide than with placebo ^[1]. The published abstract does not give separate rates for those events.

Why it matters for patients

Tirzepatide is the molecule in Mounjaro and Zepbound. This trial tested what happens when treatment stops, rather than whether the drug works in the first place. The design matters for reading the result: everyone in the study received tirzepatide for 36 weeks first, and only then was half the group switched to placebo. So the 14.0% figure describes what happened to people who had already lost about a fifth of their body weight and then stopped the drug, not what happens to someone who never took it ^[1].

Averages also hide variation. Some participants regained more than 14.0% and some regained less, and the numbers reported are group means ^[1]. The trial enrolled adults without diabetes, so the results may not describe people who take tirzepatide for type 2 diabetes. The study compared continued tirzepatide only with placebo; it did not test tapering, lower maintenance doses, or switching to a different drug, and no results for those approaches appear in this report ^[1].

Cost and coverage questions sit outside the trial itself. A patient who stops because of price, supply, or side effects is in the situation the placebo group was designed to model, though the placebo group stopped without those pressures.

What happens next

The trial's blinded period ended at week 88, and follow-up beyond that point has not been reported ^[1]. Whether weight regain levels off after the first year off the drug, and how repeated cycles of starting and stopping affect health, remain unanswered in this study. Results for lower maintenance doses of tirzepatide also have not been disclosed here ^[1].