Tirzepatide added to a lifestyle program produced further weight loss in SURMOUNT-3 trial

Tirzepatide produced substantially more weight loss than placebo in adults who had already lost weight through an intensive lifestyle program, according to results from the SURMOUNT-3 trial published in Nature Medicine on October 15, 2023, and presented at ObesityWeek 2023 ^[1][2][3].

The trial enrolled 806 adults with a body mass index of at least 30, or at least 27 with one weight-related health condition, and excluded people with diabetes ^[1][2][3]. All of them entered a 12-week intensive lifestyle program that included a low-calorie diet, exercise and frequent counseling sessions ^[2][3]. Of those, 579 lost at least 5% of their body weight and were randomly assigned to weekly tirzepatide or placebo for 72 more weeks ^[1][2].

Participants started at 2.5 mg of tirzepatide and increased by 2.5 mg every four weeks up to a maximum tolerated dose of 10 mg or 15 mg ^[2]. At study entry, the mean body weight was 241.4 pounds (109.5 kg). The 12-week lifestyle program produced a mean loss of 6.9%, or 7.6 kg (16.8 lb) ^[2].

The trial had two co-primary endpoints. The first looked at average percent weight change from randomization to week 72, counting all participants regardless of whether they stayed on treatment. Tirzepatide produced a change of -18.4%, while placebo produced +2.5% — an estimated difference of -20.8 percentage points (95% CI -23.2 to -18.5; P < 0.001) ^[1][3]. A second analysis, which estimates the effect while participants were taking the assigned treatment, showed -21.1% with tirzepatide and +3.3% with placebo, a difference of -24.5 percentage points (95% CI -26.1 to -22.8; P < .001) ^[2][3]. The two figures reflect different statistical approaches, and the published co-primary result is the -18.4% versus +2.5% comparison ^[1].

The second co-primary endpoint was the share of participants who lost at least another 5% of body weight. That was 87.5% with tirzepatide and 16.5% with placebo (odds ratio 34.6; 95% CI 19.2 to 62.6; P < .001) ^[1][3]. In the on-treatment analysis, 94.4% of the tirzepatide group and 10.7% of the placebo group reached that threshold ^[2]. Over the full 84 weeks from study entry, total mean weight loss was 26.6% (29.2 kg or 64.4 lb) with tirzepatide and 3.8% (4.1 kg or 9.0 lb) with placebo ^[2].

Other results from the trial: 94.0% of participants on tirzepatide maintained at least 80% of the weight they had lost during the lead-in period, compared with 43.8% on placebo, and waist circumference changed by -14.6 cm with tirzepatide versus +0.2 cm with placebo ^[2].

The most common side effects were gastrointestinal and generally mild to moderate, the investigators reported ^[1][2]. Reported by the tirzepatide and placebo groups respectively: nausea 39.7% versus 14.0%, diarrhea 31.0% versus 9.2%, constipation 23.0% versus 6.8%, vomiting 18.1% versus 1.4%, and COVID-19 23.0% versus 25.3% ^[2][3]. Side effects led 10.5% of the tirzepatide group and 2.1% of the placebo group to stop treatment ^[2][3]. Lilly said the overall safety profile was similar to earlier SURMOUNT and SURPASS trials ^[2][3]. A correction to the published paper appeared in June 2024; the PubMed listing does not describe what it changed ^[1].

Why it matters for patients

Most weight-loss drug trials start with people who have not recently lost weight. SURMOUNT-3 tested a different situation: what happens when a medication is added after diet and exercise have already produced at least a 5% loss ^[1][2]. The trial's placebo group gained weight on average over the following 72 weeks, which the researchers and Lilly framed as evidence of how hard maintenance can be ^[1][2].

The results apply to a specific group — adults without diabetes who succeeded in losing at least 5% during a supervised 12-week program ^[1][2]. How the same approach works in people with diabetes, or in people who did not lose weight during such a program, has not been reported for this trial.

The findings also do not answer what happens after the medication is stopped. The trial ran 72 weeks of treatment after randomization, and no post-treatment follow-up data are described in these results ^[1][2].

At the time the results were published, tirzepatide was approved in the United States as Mounjaro for type 2 diabetes and was under review by the FDA and the European Medicines Agency for adults with obesity or overweight with weight-related conditions, so it was not then an approved weight-management option ^[2]. Lilly, which makes the drug, funded the trial and several authors are company employees and shareholders ^[1]. Several academic authors reported payments or advisory roles with Lilly, Novo Nordisk and other companies ^[1].

What happens next

At publication, Lilly said tirzepatide was under FDA and EMA review for chronic weight management, with no decision date disclosed ^[2]. SURMOUNT-4 results were presented at the European Association for the Study of Diabetes annual meeting in October 2023, according to the company ^[2]. Lilly also listed ongoing studies of tirzepatide in heart failure with preserved ejection fraction, obstructive sleep apnea, non-alcoholic steatohepatitis, chronic kidney disease and obesity-related morbidity and mortality ^[2]. The trial is registered as NCT04657016 ^[1][2].