Lilly reports up to 22.5% weight loss in the first SURMOUNT-1 topline

Eli Lilly reported topline results on April 28, 2022 from SURMOUNT-1, showing that its once-weekly injection tirzepatide produced average weight reductions of 16.0% to 22.5% over 72 weeks in adults with obesity or overweight who did not have type 2 diabetes ^[1]. The drug, not yet approved for any use at the time and then under regulatory review as a diabetes treatment, later reached the U.S. market as Mounjaro for type 2 diabetes and Zepbound for weight management ^[1].

SURMOUNT-1 randomized 2,539 participants across the U.S., Argentina, Brazil, China, India, Japan, Mexico, Russia and Taiwan in equal groups to tirzepatide 5 mg, 10 mg, 15 mg or placebo, all on top of a reduced-calorie diet and more physical activity ^[1]. Participants qualified if they had obesity, or overweight plus at least one of high blood pressure, abnormal cholesterol, obstructive sleep apnea or cardiovascular disease ^[1]. Average starting weight was 231 lb (105 kg) ^[1]. Everyone in the drug groups started at 2.5 mg weekly and stepped up every four weeks to their assigned maintenance dose ^[1].

The numbers

Lilly reported results two ways. Under the "efficacy estimand," which measures effects before people stop the study drug, average weight loss was 16.0% (35 lb or 16 kg) on 5 mg, 21.4% (49 lb or 22 kg) on 10 mg and 22.5% (52 lb or 24 kg) on 15 mg, versus 2.4% (5 lb or 2 kg) on placebo ^[1]. At least 5% weight loss was reached by 89% of the 5 mg group and 96% of the 10 mg and 15 mg groups, compared with 28% on placebo ^[1]. Losses of 20% or more were reached by 55% (10 mg) and 63% (15 mg), versus 1.3% on placebo; 32% of the 5 mg group hit that mark, though that analysis was not controlled for statistical error ^[1].

Under the "treatment-regimen estimand," which counts everyone regardless of whether they stopped treatment, the figures were lower: 15.0%, 19.5% and 20.9% for the three doses, versus 3.1% for placebo ^[1]. Weight loss of 20% or more occurred in 50% (10 mg) and 57% (15 mg) of participants, compared with 3.1% on placebo ^[1].

Side effects were mostly digestive and generally mild to moderate, showing up largely while doses were being raised ^[1]. Across the 5 mg, 10 mg and 15 mg groups, nausea was reported by 24.6%, 33.3% and 31.0%; diarrhea by 18.7%, 21.2% and 23.0%; vomiting by 8.3%, 10.7% and 12.2%; and constipation by 16.8%, 17.1% and 11.7%, versus placebo rates of 9.5%, 7.3%, 1.7% and 5.8% ^[1]. Discontinuation because of side effects was 4.3%, 7.1% and 6.2% on tirzepatide and 2.6% on placebo, while overall dropout was highest in the placebo group at 26.4% ^[1].

Why it matters for patients

Before this readout, no phase 3 obesity drug trial had reported average weight loss above 20% ^[1]. Lilly's Jeff Emmick called tirzepatide "the first investigational medicine to deliver more than 20 percent weight loss on average in a phase 3 study" ^[1]. That raised the ceiling for what people and clinicians might expect from a prescription weight-loss medicine, and it set a benchmark that later drugs have been measured against.

Two caveats sit in the same release. The size of the reported benefit depends on which analysis is used, with the more conservative treatment-regimen numbers running roughly 1.5 to 2 percentage points lower at each dose ^[1]. And the higher doses came with more nausea and vomiting, which is why dosing was raised in steps over months ^[1]. Topline company data are also not the same as peer-reviewed results; Lilly said the full data would go to a medical meeting and a journal ^[1].

Investors reacted: Lilly shares rose about 3% the day of the announcement, with one Wells Fargo analyst projecting about $4 billion in peak sales ^[2].

What happens next

Participants who had prediabetes at enrollment stayed in SURMOUNT-1 for another 104 weeks past the 72-week mark, to test whether tirzepatide slows progression to type 2 diabetes over three years ^[1]. Lilly said results from SURMOUNT-2, -3 and -4 were expected in 2023 ^[1]. The SURMOUNT program had enrolled more than 5,000 people across six trials ^[1].