SURMOUNT Study Results: SURMOUNT-1 to -4 Compared

What each SURMOUNT trial tested

SURMOUNT-1 and SURMOUNT-3 enrolled adults with obesity, or overweight plus a weight-related condition, and excluded people with diabetes [1][3]. SURMOUNT-2 enrolled adults with type 2 diabetes, a BMI of at least 27 and an HbA1c of 7% to 10% [2]. SURMOUNT-1 and SURMOUNT-2 compared tirzepatide with placebo for 72 weeks; SURMOUNT-3 did the same after a 12-week intensive lifestyle intervention, randomizing only people who had lost at least 5.0% of body weight during that lead-in [1][2][3]. SURMOUNT-5 was built differently, as an open-label comparison against semaglutide rather than placebo [4].

Tirzepatide is a dual GIP and GLP-1 receptor agonist, and Zepbound is the product labeled to reduce excess body weight and maintain that reduction long term in adults with obesity, or overweight plus a weight-related condition, alongside a reduced-calorie diet and increased physical activity [5].

SURMOUNT-1: 2,539 adults randomized

The design: adults randomized 1:1:1:1 to tirzepatide 5, 10 or 15 mg or placebo for 72 weeks, including a 20-week dose-escalation period, with diabetes as an exclusion criterion. Mean baseline weight was 104.8 kg and mean BMI 38.0 [1].

At week 72, counting everyone randomized whether or not they stayed on treatment (the treatment-regimen estimand), weight changed by -15.0% with 5 mg, -19.5% with 10 mg and -20.9% with 15 mg, against -3.1% with placebo (P<0.001 for all comparisons) [1]. At 15 mg, weight loss exceeded placebo by 17.8 percentage points [1]. The coprimary endpoints were percent change in weight and the proportion of participants losing at least 5% [1].

SURMOUNT-2: 938 adults with type 2 diabetes

The design: 938 adults with a BMI of at least 27 and an HbA1c of 7% to 10% were randomized to tirzepatide 10 mg (312 people), 15 mg (311) or placebo (315) for 72 weeks. Mean baseline weight was 100.7 kg, BMI 36.1 and HbA1c 8.02% [2].

At week 72, weight changed by -12.8% with 10 mg and -14.7% with 15 mg, against -3.2% with placebo, giving treatment differences of -9.6 and -11.6 percentage points [2]. SURMOUNT-1 and SURMOUNT-2 were separately randomized against their own placebo groups, so comparing 20.9% with 14.7% compares two populations; it does not measure how much of the gap diabetes itself accounts for [1][2].

SURMOUNT-3: 579 adults after a lifestyle program

The design: adults who had lost at least 5.0% of body weight during a 12-week intensive lifestyle intervention were randomized 1:1 to tirzepatide at the maximum tolerated dose (10 or 15 mg) or placebo for 72 weeks, 579 people in total [3].

The result: from randomization to week 72, weight changed by -18.4% with tirzepatide and +2.5% with placebo, a difference of -20.8 percentage points. A further 5% or more of body weight was lost by 87.5% of the tirzepatide group versus 16.5% of the placebo group [3].

Two details matter when reading that figure. It is measured from randomization, so it captures the drug phase rather than the total change from each person's starting weight, and entry required at least a 5.0% loss first, so total loss from the original baseline was larger than 18.4% [3]. The dose was also the maximum tolerated dose of 10 or 15 mg, not a fixed 15 mg [3].

SURMOUNT-5: the head-to-head with semaglutide

One SURMOUNT trial compared drugs rather than using placebo. SURMOUNT-5 randomized 751 adults with obesity and no diabetes, open-label, to the maximum tolerated dose of tirzepatide (10 or 15 mg) or semaglutide (1.7 or 2.4 mg) for 72 weeks. Weight change was -20.2% with tirzepatide and -13.7% with semaglutide, waist circumference fell 18.4 cm versus 13.0 cm, and more tirzepatide participants lost at least 10%, 15%, 20% and 25% of body weight [4]. Because the trial was open-label, participants and investigators knew which drug was being taken, unlike the double-blind placebo-controlled SURMOUNT-1 and -2 [1][2][4].

Side effects reported in the tirzepatide trials

The most common adverse events in SURMOUNT-3 were gastrointestinal, and most were mild to moderate [3]. The Zepbound label, pooling its weight-management trials of up to 72 weeks, reports these rates at 15 mg versus placebo: nausea 28% vs 8%, vomiting 13% vs 2%, diarrhea 23% vs 8%, constipation 11% vs 5%. Treatment was permanently discontinued for adverse reactions in 6.7% on 15 mg versus 3.4% on placebo, and hair loss was reported by 4% to 5% versus 1% [5].

The label carries a boxed warning based on thyroid C-cell tumors in rodents, with human relevance unknown, and contraindicates tirzepatide in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [5].

What this comparison does not cover

The endpoints reported from these trials are weight change and safety over 72 weeks [1][2][3][4]. None of them was designed to test whether tirzepatide reduces heart attacks or strokes in adults with obesity but no diabetes, and none followed participants beyond 72 weeks of randomized treatment [1][2][3][4].