CATEGORY: DIET & WEIGHT
Adults with obesity who had lost about a fifth of their body weight on tirzepatide and were then switched to a placebo regained 14% of their body weight over the following year, while those who kept taking the drug lost a further 5.5%, in a randomized trial of 670 people published in JAMA.1 By the end of the 88-week study, people who stayed on tirzepatide were 25.3% below their starting weight; those who had stopped were 9.9% below it—still lighter than when they began, but with most of what they had lost back on.
Thirty-Six Weeks on the Drug, Then a Coin Flip
The trial, called SURMOUNT-4, enrolled 783 adults at 70 sites in four countries. Participants had a body mass index of 30 or higher, or 27 or higher with a weight-related health problem; their average weight was 107.3 kg, their average age 48, and 71% were women. Everyone first took tirzepatide—a once-weekly injection that mimics two gut hormones, GIP and GLP-1, which slow stomach emptying and dampen appetite—at a dose of 10 or 15 mg for 36 weeks, losing an average of 20.9% of their body weight. The 670 who completed that lead-in were then assigned by chance to keep taking tirzepatide or to switch to identical-looking placebo injections for another 52 weeks, with neither participants nor study staff knowing who was on which. Because chance rather than choice decided the groups, the difference in weight at week 88 can be attributed to the drug being continued or withdrawn, not to the kind of person who stops. The trial was run by Eli Lilly, the drug’s manufacturer, with Louis Aronne of Weill Cornell Medicine as principal investigator.
Five Percent Further Down, or Fourteen Percent Back Up
From the moment of randomization to week 88, weight changed by −5.5% in the group that continued tirzepatide and by +14.0% in the group switched to placebo, a difference of 19.4 percentage points (95% confidence interval 17.7 to 21.2). Another way to see it: 300 of the people still on the drug (89.5%) held on to at least 80% of the weight they had lost, compared with 16.6% of those on placebo. The placebo group’s regain also reversed some of the improvements in cardiometabolic risk factors that had come with the weight loss, the authors reported. A useful image is a thermostat. Tirzepatide acts like a hand holding the body’s appetite thermostat at a lower setting; for as long as the hand stays there, the setting holds. Take the hand away and the dial drifts back toward where it was—not all the way within a year, but most of the way. The most common side effects were gastrointestinal: nausea, diarrhea, constipation and vomiting, mostly mild to moderate and more frequent in the tirzepatide group.
Regain Was the Result the Researchers Anticipated
The investigators did not present the regain as a surprise. They pointed out that at least five trials across several classes of weight-loss medication, including this one, had shown that weight is substantially regained once treatment stops, and they framed obesity as a chronic condition in which the drug manages weight rather than curing it, much as blood pressure drugs manage hypertension. The trial was designed to measure how much of tirzepatide’s effect depends on staying on it, and the answer was: most of it. What the trial did not test is whether anything short of stopping outright—a lower dose, a less frequent injection, or a structured lifestyle program—could hold the weight off, because the only comparison was full-dose tirzepatide against none.
The Same Pattern With Semaglutide
The result mirrors an earlier randomized withdrawal trial of semaglutide, a related once-weekly GLP-1 drug. In that study, 803 adults with overweight or obesity lost 10.6% of their body weight during a 20-week run-in, then were assigned by chance to continue semaglutide or switch to placebo; over the following 48 weeks the continuing group lost a further 7.9% while the placebo group regained 6.9%, a gap of 14.8 percentage points.2 Two drugs, two manufacturers, the same trajectory: the weight lost with these medications tracks whether the medication is still being taken.
Key Takeaways
- After 36 weeks on tirzepatide, adults switched to placebo regained 14% of their body weight over the next year, while those who continued lost a further 5.5%.
- At 88 weeks, people who stayed on the drug were 25.3% below their starting weight; those who stopped were 9.9% below it.
- Nearly nine in ten people who continued kept at least 80% of the weight they had lost, compared with about one in six who stopped.
- A randomized withdrawal trial of semaglutide found the same pattern, and the authors describe regain after stopping as the expected course for weight-loss medications.
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