SURMOUNT-4 shows rapid weight regain when tirzepatide is stopped

Results from SURMOUNT-4, published in JAMA on December 11, 2023, show that most of the weight people lost on tirzepatide came back within a year of stopping the drug ^[1][3][4]. Participants who stayed on treatment kept nearly all of their loss and lost slightly more ^[1].

The phase 3 trial used a "randomized withdrawal" design at 70 sites in four countries ^[1]. All 783 enrolled adults first took once-weekly tirzepatide for 36 weeks at their maximum tolerated dose, either 10 mg or 15 mg ^[1][3]. Participants had a BMI of 30 or higher, or 27 or higher with a weight-related condition; people with type 2 diabetes were excluded ^[1]. Average age was 48, 71% were women, and average starting weight was 107.3 kg (236.6 lb) ^[1][3].

After the 36-week lead-in, the 670 people who continued were randomly assigned 1:1 to keep taking tirzepatide (335) or switch to placebo (335) for 52 more weeks ^[1]. By the end of the lead-in, average weight reduction was 20.9% ^[1].

What the numbers showed

From week 36 to week 88, the continuation group lost another 5.5% of body weight, while the placebo group gained back 14.0% — a difference of 19.4 percentage points (95% CI, −21.2% to −17.7%; P < .001) ^[1]. Lilly also reported a second analysis method, the "efficacy estimand," which showed −6.7% versus +14.8% over the same stretch ^[3].

A key secondary measure was how many people held onto at least 80% of the weight they had lost during the lead-in. At week 88, 89.5% of the tirzepatide group did, compared with 16.6% of the placebo group (P < .001) ^[1]. Using the efficacy estimand, the figures were 93.4% and 13.5% ^[3].

Over the full 88 weeks, average weight reduction was 25.3% with continued tirzepatide versus 9.9% with placebo ^[1]; Lilly's efficacy-estimand numbers were 26.0% and 9.5% ^[3]. Waist circumference fell 4.3 cm in the continuation group and grew 7.8 cm in the placebo group ^[3]. About 69.5% of continuers reached at least 20% total weight loss, versus 12.6% of those switched to placebo, and 54.5% versus 5.0% reached at least 25% ^[3].

Side effects were mostly gastrointestinal and mild to moderate ^[1]. During the open-label lead-in, the most common were nausea (35.5%), diarrhea (21.1%), constipation (20.7%) and vomiting (16.3%) ^[3]. In the double-blind phase, diarrhea (10.7% vs 4.8%), nausea (8.1% vs 2.7%) and vomiting (5.7% vs 1.2%) were more common with tirzepatide than placebo ^[3]. Discontinuation because of a side effect occurred in 7.0% during the lead-in, then 1.8% on tirzepatide and 0.9% on placebo ^[3].

Why it matters for patients

SURMOUNT-4 is direct evidence that, for most people, weight loss from tirzepatide does not hold on its own after the drug stops. The placebo group still ended the study about 9.9% below their starting weight, but they had given back roughly two-thirds of what they lost ^[1].

That has practical consequences for insurance coverage, drug shortages, cost and any plan built around "finishing" a course of treatment. Lilly's Jeff Emmick framed it as evidence that obesity "is a chronic disease that often requires ongoing treatment" ^[3]. Reuters noted a Novo Nordisk official said in March 2023 that people stopping drugs like Wegovy risk regaining their original weight in about five years ^[4]. Investors read the data as a mixed signal: Lilly shares fell over 4% in morning trading the day the paper appeared ^[4].

The trial ran 88 weeks total, so it does not answer what happens after several years of continuous use. Goldman Sachs analysts said in July that they awaited longer-term data on incretin therapies after multiple years of treatment ^[4]. It also does not tell us whether tapering, a lower maintenance dose, or restarting later changes the pattern — those questions were not tested here.

What happens next

Topline SURMOUNT-4 data were announced July 27, 2023, with full results published in JAMA on December 11, 2023 ^[3][4]. The current Zepbound label carries an indication "to reduce excess body weight and maintain weight reduction long term" in adults with obesity or overweight with a weight-related condition, and its clinical studies section covers long-term maintenance ^[5]. Approved maintenance doses are 5 mg, 10 mg or 15 mg once weekly, with 15 mg the maximum ^[5].