SURMOUNT-3 shows tirzepatide adds to successful lifestyle change

Detailed results from the phase 3 SURMOUNT-3 trial, published in Nature Medicine and presented at ObesityWeek 2023 on October 15, show that adding tirzepatide after a successful intensive diet-and-exercise program produced large additional weight loss, while people on placebo slowly regained ^[1][2].

The trial started with 806 adults with obesity, or overweight plus at least one weight-related health problem, excluding type 2 diabetes, at sites in the U.S. including Puerto Rico, plus Argentina and Brazil ^[2]. All went through a 12-week intensive lifestyle lead-in with a low-calorie diet, exercise and counseling sessions ^[2][3]. The 579 people who lost at least 5% of their body weight were then randomly assigned 1:1 to once-weekly tirzepatide or placebo for 72 weeks ^[1][2]. Mean body weight at study entry was 241.4 lb (109.5 kg), and the lead-in produced an average 6.9% loss, about 16.8 lb (7.6 kg) ^[2].

What the numbers showed

Under the treatment-regimen analysis, which counts everyone regardless of whether they stuck with treatment, weight change from randomization to week 72 was −18.4% with tirzepatide versus +2.5% with placebo, a difference of −20.8 percentage points (95% CI −23.2 to −18.5; P < 0.001) ^[1][3]. The efficacy analysis, which focuses on people while on treatment, showed −21.1% versus +3.3%, a difference of −24.5 percentage points (95% CI −26.1 to −22.8) ^[2][3].

The second co-primary endpoint, losing at least another 5% after the lead-in, was reached by 87.5% on tirzepatide versus 16.5% on placebo (odds ratio 34.6; 95% CI 19.2 to 62.6) ^[1][3]. Additional weight loss of 20% or more was reached by 44.7% versus 2.2% ^[2]. Among those on tirzepatide, 94.0% kept at least 80% of the weight they had lost during the lead-in, compared with 43.8% on placebo ^[2]. Waist circumference fell 14.6 cm with tirzepatide and rose 0.2 cm with placebo ^[2].

Counting from study entry through 84 weeks total, mean weight loss was 26.6%, or 64.4 lb (29.2 kg), with tirzepatide, versus 3.8%, or 9.0 lb (4.1 kg), with placebo ^[2].

Dosing started at 2.5 mg weekly and increased by 2.5 mg every four weeks to a maximum tolerated dose of 10 mg or 15 mg ^[2]. Side effects were mostly stomach-related and mild to moderate ^[1]. Rates for tirzepatide versus placebo were nausea 39.7% vs 14.0%, diarrhea 31.0% vs 9.2%, constipation 23.0% vs 6.8%, COVID-19 23.0% vs 25.3%, and vomiting 18.1% vs 1.4% ^[2][3]. Side effects led 10.5% of the tirzepatide group and 2.1% of the placebo group to stop study treatment ^[2][3].

Why it matters for patients

SURMOUNT-3 answers a narrow but practical question: what happens when someone who has already succeeded at diet and exercise adds a medication? The placebo group's pattern, regaining 2.5% on average even while staying in the trial, illustrates a point Lilly's Jeff Emmick framed as "the difficulty some people face maintaining weight loss with diet and exercise alone" ^[2].

Some cautions belong with the numbers. Everyone in the randomized phase had already proven they could lose 5% with lifestyle change, so results may not transfer to people who did not clear that bar. People with type 2 diabetes were excluded ^[2]. The trial ran 72 weeks after randomization; nothing in these results shows what happens after the drug stops. The study was conducted by Eli Lilly, and several authors are Lilly employees and shareholders ^[1]. A correction to the paper was later published in Nature Medicine in June 2024 ^[1].

The two sources also describe the lead-in counseling differently, as "frequent" sessions in Lilly's release and "weekly" in one trade report ^[2][3].

What happens next

Topline SURMOUNT-3 and SURMOUNT-4 data were announced July 27, 2023, with full SURMOUNT-3 results published October 15, 2023 ^[2]. As of that date, tirzepatide was under review by the FDA and the European Medicines Agency for chronic weight management; it was already approved as Mounjaro for type 2 diabetes on May 13, 2022 ^[2]. Trials in heart failure with preserved ejection fraction, obstructive sleep apnea, NASH, chronic kidney disease and obesity-related illness and death were ongoing ^[2].