SURMOUNT-1 reports 20.9% average weight loss and reshapes the obesity field

Results from SURMOUNT-1, a phase 3 trial of once-weekly tirzepatide in adults with obesity or overweight and without diabetes, were published June 4, 2022. Over 72 weeks, average weight change was -15.0% with the 5 mg dose, -19.5% with 10 mg and -20.9% with 15 mg, compared with -3.1% for placebo (P<0.001 for all comparisons) ^[1].

The trial randomly assigned 2,539 adults in a 1:1:1:1 ratio to tirzepatide 5 mg, 10 mg, 15 mg, or placebo, given as a weekly injection under the skin for 72 weeks, including a 20-week period of gradually stepping up the dose ^[1]. To enroll, participants needed a body mass index (BMI) of 30 or higher, or 27 or higher plus at least one weight-related complication; people with diabetes were excluded ^[1]. At the start, mean body weight was 104.8 kg (about 231 pounds), mean BMI was 38.0, and 94.5% of participants had a BMI of 30 or higher ^[1]. The study is registered as NCT04184622 and was supported by Eli Lilly ^[1][2].

The numbers behind the averages

The two co-primary endpoints were percentage change in weight and the share of people losing at least 5% of body weight. On the second measure, 85% of the 5 mg group, 89% of the 10 mg group and 91% of the 15 mg group reached 5% or more, versus 35% on placebo ^[1].

The more striking figures were at the higher thresholds. Half of the 10 mg group (50%) and 57% of the 15 mg group lost at least 20% of their body weight, compared with 3% of the placebo group ^[1]. For someone starting at the trial's average weight, a 20.9% reduction works out to roughly 22 kg, or about 48 pounds. The authors also reported improvements in all prespecified cardiometabolic measures with tirzepatide, though the abstract does not list the individual values ^[1].

Side effects followed the pattern seen with this drug class. The most common adverse events were gastrointestinal, most were mild to moderate, and they occurred mainly during the dose-escalation period ^[1]. Adverse events led people to stop treatment in 4.3% of the 5 mg group, 7.1% of the 10 mg group, 6.2% of the 15 mg group and 2.6% of the placebo group ^[1]. Notably, the highest discontinuation rate was in the 10 mg group rather than the top dose.

The results were analyzed using a "treatment-regimen estimand," which measures effects regardless of whether people stopped treatment, in the intention-to-treat population ^[1]. An accompanying New England Journal of Medicine editorial was titled "Shifting Tides Offer New Hope For Obesity" ^[1].

Why it matters for patients

Tirzepatide is the molecule sold as Mounjaro and Zepbound. It acts on two gut hormone receptors, GIP and GLP-1, rather than GLP-1 alone as semaglutide (Ozempic, Wegovy, Rybelsus) does ^[1]. SURMOUNT-1 was the first phase 3 obesity trial to report average weight loss above 20% at the top dose, which raised the ceiling for what people and clinicians consider possible from a medication ^[1].

Averages hide a wide range. Even at 15 mg, 9% of participants did not reach 5% weight loss, and the trial does not tell any one person what to expect ^[1]. The dose-escalation phase is also where most stomach and bowel side effects showed up, and a small but real share of people stopped because of side effects ^[1].

What happens next

These sources cover 72 weeks of treatment only. What happens to weight after the trial ends, whether tirzepatide reduces heart attacks, strokes or deaths, and how it performs head-to-head against other drugs are not addressed here and are not yet known from this publication ^[1]. The sources also do not describe any regulatory decision or US approval status for tirzepatide in obesity, or its price and insurance coverage.