SURMOUNT-4 confirms rapid regain after stopping tirzepatide

A phase 3 randomized withdrawal trial published in JAMA found that people with obesity who stopped taking tirzepatide after 36 weeks regained a large share of the weight they had lost, while those who stayed on the drug kept losing ^[1].

The SURMOUNT-4 trial ran at 70 sites in four countries and enrolled adults with a body mass index of 30 or higher, or 27 or higher with a weight-related complication. People with diabetes were excluded ^[1]. All 783 participants first went through a 36-week open-label lead-in, taking a once-weekly injection of tirzepatide at their maximum tolerated dose of either 10 mg or 15 mg ^[1].

What the trial measured

After the lead-in, 670 participants were randomly assigned 1:1 either to keep taking tirzepatide (335 people) or to switch to placebo (335 people) for 52 more weeks, with neither participants nor researchers knowing who got what ^[1]. The randomized group had a mean age of 48 years, was 71% women (473 people), and had a mean starting weight of 107.3 kg (about 237 pounds) ^[1].

During the 36-week lead-in, participants lost an average of 20.9% of their body weight ^[1]. From week 36 to week 88, the tirzepatide group lost another 5.5% on average, while the placebo group gained 14.0% — a difference of 19.4 percentage points (95% CI, −21.2% to −17.7%; P < .001) ^[1].

Another way the researchers framed it: 89.5% of people who stayed on tirzepatide (300 participants) still held on to at least 80% of the weight they had lost during the lead-in at week 88, compared with 16.6% of those switched to placebo (P < .001) ^[1].

Measured across the whole 88 weeks, from the very start of the study, total mean weight reduction was 25.3% with tirzepatide and 9.9% with placebo ^[1]. So the placebo group did not return all the way to baseline in the year they were off the drug, but they gave back most of their loss ^[1].

The most common side effects were gastrointestinal, mostly mild to moderate, and occurred more often with tirzepatide than placebo ^[1]. The published abstract does not break out specific rates of nausea, vomiting or diarrhea, so those figures are not available here ^[1].

Why it matters for patients

The authors' conclusion is blunt: withdrawing tirzepatide "led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction" ^[1]. In practice, that means the roughly 21% weight loss seen after 36 weeks was not a one-time reset — it depended on staying on the medication ^[1].

That has real consequences for people whose access to these drugs is tied to insurance approval, employer coverage, supply, or out-of-pocket cost. If coverage lapses or someone decides to stop, this trial gives a concrete estimate of what a year off the drug looked like for study participants: an average 14.0% gain in body weight ^[1].

It also shows that weight loss did not fully plateau at 36 weeks. People who continued treatment lost an additional 5.5% over the following year, reaching 25.3% total ^[1].

A few limits are worth noting. Everyone in the trial had already tolerated 36 weeks of tirzepatide at 10 mg or 15 mg before randomization, so the results describe people who did well on the drug early on ^[1]. The trial excluded people with diabetes ^[1]. It was conducted with Eli Lilly involvement — several authors are listed as Lilly employees and shareholders, and others reported grants or personal fees from the company ^[1]. The trial is registered as NCT04660643 ^[1].

The study also does not report what happens to people who stop and then restart, or whether a lower maintenance dose would work as well. Those questions are not answered by this trial ^[1].

Decisions about starting, continuing or stopping any medication are between a patient and their clinician.