Trial shows weight regain after stopping tirzepatide, continued use adds more loss

Results from an 88-week trial called SURMOUNT-4, published Dec. 11, 2023 in JAMA, show that adults with obesity who stopped taking tirzepatide regained much of the weight they had lost, while those who stayed on the drug kept losing ^[1][4]. Tirzepatide is sold as Zepbound for weight loss and as Mounjaro for type 2 diabetes ^[4].

The trial enrolled 783 adults with a body mass index of 30 or higher, or 27 or higher with a weight-related health condition, and excluded people with diabetes ^[1][3]. Everyone received tirzepatide at the highest dose they could tolerate, either 10 mg or 15 mg once weekly, for a 36-week lead-in period. During that period, participants lost an average of 20.9% of their body weight, down from a mean starting weight of 107.3 kg, or 236.6 lb ^[1][3].

Then 670 participants were randomly assigned, half to continue tirzepatide and half to switch to a placebo injection, for 52 more weeks ^[1][3]. From week 36 to week 88, the continuation group's weight changed by an average of -5.5%, while the placebo group gained an average of 14.0%, a difference of -19.4 percentage points (95% CI, -21.2 to -17.7; P < .001) ^[1][3]. Lilly also reported results using a second statistical method, called the efficacy estimand, showing -6.7% for tirzepatide versus +14.8% for placebo ^[3].

By week 88, 89.5% of people still taking tirzepatide had kept at least 80% of the weight they lost during the lead-in, compared with 16.6% of those on placebo ^[1][3]. Across the full 88 weeks, the average weight reduction was 25.3% with tirzepatide and 9.9% with placebo ^[1][3].

Participants had a mean age of 48, and 71% were women ^[1]. The trial ran at 70 sites in four countries: the United States, including Puerto Rico, Argentina, Brazil and Taiwan ^[1][3]. Gastrointestinal side effects were the most common and were generally mild to moderate. During the lead-in period, nausea occurred in 35.5% of participants, diarrhea in 21.1%, constipation in 20.7% and vomiting in 16.3%. In the blinded period, diarrhea occurred in 10.7% of the tirzepatide group versus 4.8% of the placebo group, nausea in 8.1% versus 2.7%, and vomiting in 5.7% versus 1.2% ^[3]. Treatment was stopped because of a side effect in 7.0% of participants during the lead-in period, and in 1.8% on tirzepatide versus 0.9% on placebo afterward ^[3].

One news account described the placebo group's regain as following a 56-week course of treatment ^[4]; the trial registry and the JAMA report describe a 36-week lead-in period followed by a 52-week blinded period ^[1][2].

Why it matters for patients

The pattern is not unique to tirzepatide. The JAMA paper cites STEP 4, a semaglutide trial with a similar continue-versus-switch design ^[1].

For patients, the practical point is that these drugs appear to suppress weight while they are being taken, and the effect largely fades when they are stopped. The trial did not test lower maintenance doses, skipped doses or a gradual taper after the 36-week lead-in, and those questions have not been answered here. It also excluded people with type 2 diabetes, so the numbers may not describe that group.

What happens beyond 88 weeks of treatment has not been reported. Whether weight regain slows, stops or continues after the first year off the drug is also not yet known.

Zepbound's prescribing information lists reducing excess body weight and maintaining weight reduction long term as part of its approved use, and describes weight reduction and long-term maintenance studies in its clinical studies section ^[5]. The label carries a boxed warning about thyroid C-cell tumors seen in rats, with human relevance unknown, and lists nausea, diarrhea, vomiting, constipation and abdominal pain among the most common adverse reactions ^[5].

Cost and insurance coverage sit outside the trial data, but they often decide whether a treatment continues. The study results themselves say nothing about what a person should do, and decisions about starting, continuing or stopping a GLP-1 or dual-agonist medication are individual medical questions.