CATEGORY: DIET & WEIGHT
Adults with obesity had already lost about a fifth of their body weight on tirzepatide. Then some of them were quietly switched to a placebo, and over the following year they regained 14% of their body weight, while those who kept taking the drug lost a further 5.5%.1 By week 88 the continuing group stood 25.3% below its starting weight. The switched group stood 9.9% below: still lighter than at the beginning, with most of the loss back on.
Thirty-Six Weeks on the Drug, Then a Sealed Reassignment
The trial, SURMOUNT-4, enrolled 783 adults at 70 sites in four countries. Each had a body mass index of 30 or higher, or 27 or higher alongside a weight-related health problem. They averaged 107.3 kg and 48 years of age, and 71% were women. Everyone started on tirzepatide, a once-weekly injection that mimics two gut hormones, GIP and GLP-1. Both hormones slow the emptying of the stomach and dampen appetite. Across 36 weeks at 10 or 15 mg, the group lost an average of 20.9% of body weight. The 670 who finished that stretch were then sorted at random into two arms for a further 52 weeks: keep the drug, or move to identical-looking placebo injections. Neither the participants nor the study staff knew who had been moved. Random sorting is what makes the week-88 gap a fact about the drug being continued or withdrawn, rather than about the kind of person who stops. Eli Lilly, which makes tirzepatide, ran the trial, with Louis Aronne of Weill Cornell Medicine as principal investigator, and the results appeared in JAMA.
Five Percent Further Down, or Fourteen Percent Back Up
From the moment of that split to week 88, weight moved by −5.5% among those who continued and by +14.0% among those switched, a difference of 19.4 percentage points (95% confidence interval 17.7 to 21.2). Another view of the same result: 300 of the people still taking the drug, 89.5% of them, held on to at least 80% of the weight they had lost, against 16.6% of the placebo group. Some of the improvements in cardiometabolic risk factors that had arrived with the weight loss faded as the weight returned. A thermostat is a fair picture of it. Tirzepatide is a hand holding the body’s appetite setting lower, and the setting holds for as long as the hand stays there. Let go and the dial drifts back, not the whole way within a year, but most of it. The commonest side effects were gastrointestinal: nausea, diarrhea, constipation and vomiting, mostly mild to moderate, and more frequent on the drug.
Regain Was the Anticipated Result
The investigators did not present the regain as a surprise. They counted at least five trials across several classes of weight-loss medication, this one included, in which weight came back substantially once treatment stopped. Obesity, in their framing, is a chronic condition that these drugs manage rather than cure, much as blood pressure drugs manage hypertension. The trial was built to measure how much of tirzepatide’s effect depends on staying on it. Most of it, was the answer. What went untested is whether anything short of stopping outright would hold the weight off: a lower dose, a less frequent injection, a structured lifestyle program. The only comparison was full-dose tirzepatide against none. An earlier withdrawal trial of semaglutide, a related once-weekly GLP-1 drug, traced the same arc. There, 803 adults with overweight or obesity lost 10.6% of their body weight during a 20-week run-in, then were divided at random between continuing the drug and switching to placebo; over the next 48 weeks the continuing group lost another 7.9% while the placebo group regained 6.9%, a gap of 14.8 percentage points.2
Key Takeaways
- Switched to placebo after 36 weeks on tirzepatide, adults regained 14% of their body weight over the following year, while those who continued lost another 5.5%.
- At week 88 the continuing group was 25.3% below its starting weight and the withdrawn group 9.9% below it. Nearly nine in ten who stayed on the drug kept at least 80% of what they had lost, against about one in six who stopped.
- A randomized withdrawal trial of semaglutide traced the same pattern, and the authors treat regain after stopping as the expected course for weight-loss medication.
References
- Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38–48. link
- Rubino D, Abrahamsson N, Davies M, et al. Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: the STEP 4 randomized clinical trial. JAMA. 2021;325(14):1414–1425. link