STEP-1 vs SURMOUNT-1: Semaglutide and Tirzepatide for Weight Loss, A Cross-Trial Synthesis

What STEP-1 showed

STEP-1 randomized 1,961 adults with a BMI of 30 or higher, or 27 or higher with at least one weight-related condition, and without diabetes, in a 2:1 ratio to once-weekly subcutaneous semaglutide 2.4 mg or placebo for 68 weeks [1]. The coprimary endpoints were percentage change in body weight and the proportion of participants losing at least 5% [1]. The primary estimand assessed effects regardless of treatment discontinuation or rescue intervention [1].

Mean weight change was -14.9% with semaglutide and -2.4% with placebo, an estimated difference of -12.4 percentage points (95% CI -13.4 to -11.5) [1]. Weight reduction of at least 5% was reached by 86.4% of the semaglutide group versus 31.5% on placebo, at least 10% by 69.1% versus 12.0%, and at least 15% by 50.5% versus 4.9% [1].

What SURMOUNT-1 showed

SURMOUNT-1 assigned 2,539 adults with a BMI of 30 or higher, or 27 or higher with at least one weight-related complication, and no diabetes, in a 1:1:1:1 ratio to once-weekly tirzepatide 5 mg, 10 mg, 15 mg or placebo for 72 weeks, including a 20-week dose-escalation period [2]. Coprimary endpoints were the same as in STEP-1: percentage weight change and at least 5% weight reduction [2].

Mean weight change was -15.0% (95% CI -15.9 to -14.2) with 5 mg, -19.5% (-20.4 to -18.5) with 10 mg and -20.9% (-21.8 to -19.9) with 15 mg, versus -3.1% (-4.3 to -1.9) with placebo, with P<0.001 for every comparison against placebo [2]. Baseline mean weight was 104.8 kg, mean BMI 38.0, and 94.5% of participants had a BMI of 30 or higher [2]. The treatment-regimen estimand assessed effects regardless of treatment discontinuation [2].

Can the two trials be compared directly?

Only cautiously. STEP-1 and SURMOUNT-1 used the same coprimary endpoints and the same BMI entry criteria, and both were double-blind and placebo-controlled [1][2]. They differed in duration (68 versus 72 weeks), in randomization scheme (2:1 with one active dose versus 1:1:1:1 with three), and in the escalation period built into the tirzepatide arms [1][2].

One practical point sits inside the numbers: at 5 mg, tirzepatide's 15.0% and semaglutide's 14.9% are essentially the same figure, and the separation appears at 10 and 15 mg [1][2]. The tirzepatide arms also spent 20 weeks of the 72 stepping up to their assigned dose [2].

The drugs are not the same class in the strict sense. Semaglutide is a GLP-1 receptor agonist [4]; tirzepatide activates both the GIP and GLP-1 receptors [5]. Nonclinical studies suggest the added GIP activity may further contribute to regulation of food intake, but whether that explains any difference in weight loss is not established by these trials [5][6][3].

The head-to-head trial: SURMOUNT-5

SURMOUNT-5 was a phase 3b, open-label trial that randomized 751 adults with obesity and no diabetes 1:1 to the maximum tolerated dose of tirzepatide (10 or 15 mg) or the maximum tolerated dose of semaglutide (1.7 or 2.4 mg), once weekly for 72 weeks [3].

The least-squares mean weight change at week 72 was -20.2% (95% CI -21.4 to -19.1) with tirzepatide and -13.7% (-14.9 to -12.6) with semaglutide, P<0.001 [3]. Waist circumference fell 18.4 cm versus 13.0 cm [3]. Participants on tirzepatide were more likely to lose at least 10%, 15%, 20% and 25% of body weight [3]. The most common adverse events in both groups were gastrointestinal and most were mild to moderate [3].

Because SURMOUNT-5 was open-label [3], it did not use the double-blind, placebo-controlled structure of STEP-1 and SURMOUNT-1 [1][2].

How the side effects compare

For Wegovy 2.4 mg injection, pooled across weight-management trials of 2,116 adults treated for up to 68 weeks: nausea 44% versus 16% on placebo, diarrhea 30% versus 16%, vomiting 24% versus 6%, constipation 24% versus 11%, and hair loss 3% versus 1% [4]. Permanent discontinuation for adverse reactions was 6.8% versus 3.2% [4].

For Zepbound 15 mg, pooled across weight-management trials of up to 72 weeks: nausea 28%, vomiting 13%, diarrhea 23% and constipation 11%, versus 8%, 2%, 8% and 5% on placebo, with hair loss in 4% to 5% versus 1% [5]. Discontinuation for adverse reactions was 6.7% versus 3.4% [5].

Those are different trial populations, and the Wegovy label itself states that adverse reaction rates from clinical trials of one drug cannot be directly compared with rates in clinical studies of another drug [4]. Resting heart rate rises by a mean of 1 to 4 bpm with semaglutide and 1 to 3 bpm with tirzepatide [4][5].

Both labels carry a boxed warning for thyroid C-cell tumors in rodents at clinically relevant exposures, state that human relevance is unknown, and contraindicate the drugs in people with a personal or family history of medullary thyroid carcinoma or MEN 2 [4][5]. Both labels state that concomitant use with another GLP-1 receptor agonist is not recommended [4][5].

The two labels also split on one interaction. The tirzepatide label advises switching to a non-oral contraceptive method or adding a barrier method for 4 weeks after starting and after each dose increase [5]. The semaglutide labels carry no such advice, and a semaglutide tablet interaction study found no clinically significant change in ethinyl estradiol or levonorgestrel [4].

Cardiovascular risk: a labeled difference

SELECT enrolled 17,604 adults with established cardiovascular disease and a BMI of 27 or higher but no diabetes, and compared semaglutide 2.4 mg with placebo over a mean follow-up of 39.8 months [7]. Cardiovascular death, nonfatal myocardial infarction or nonfatal stroke occurred in 6.5% of the semaglutide group and 8.0% of the placebo group (hazard ratio 0.80, 95% CI 0.72 to 0.90) [7].

That result is reflected in labeling: the Wegovy label includes an indication to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease who have obesity or overweight [4]. Zepbound's labeled indications cover weight management and sleep apnea [5]. STEP-1 and SURMOUNT-1 themselves reported weight endpoints at 68 and 72 weeks [1][2]; the cardiovascular evidence for semaglutide in this population comes from SELECT, a separate trial [7].

If the person has type 2 diabetes

STEP-1 and SURMOUNT-1 both excluded diabetes, so neither set of numbers carries over to that group [1][2]. The relevant head-to-head is SURPASS-2, an open-label 40-week trial that randomized 1,879 adults with type 2 diabetes to tirzepatide 5, 10 or 15 mg or semaglutide 1 mg [6]. HbA1c fell 2.01, 2.24 and 2.30 points with the three tirzepatide doses versus 1.86 points with semaglutide 1 mg, and weight fell 1.9, 3.6 and 5.5 kg more with the three tirzepatide doses than with semaglutide 1 mg [6].

That comparison used semaglutide 1 mg, a dose used for type 2 diabetes, not the 2.4 mg dose studied in STEP-1 [6][4].