INDIANAPOLIS – Detailed results from SURMOUNT-4, which showed Zepbound™ (tirzepatide) injection achieved superior mean percent change in body weight compared to placebo in adults with obesity or overweight with weight-related comorbidities, excluding type 2 diabetes, were published in The Journal of the American Medical Association (JAMA). Zepbound met the primary endpoint of mean percent change in body weight, and all key secondary endpoints for both estimandsi,ii, compared to placebo 52 weeks after randomization.
Study Design
SURMOUNT-4, a phase 3 study evaluating the safety and efficacy of Zepbound compared to placebo, had two periods.
- Lead-in period: 36-week open-label period during which participants took Zepbound at the maximum tolerated dose.
- Double-blind treatment period: 52-week treatment period during which participants were randomized to either continue on Zepbound or switch to placebo.
SURMOUNT-4 utilized a maximum tolerated dose of 10 mg or 15 mg once-weekly. The starting dose of 2.5 mg Zepbound was increased by 2.5 mg every four weeks until maximum tolerated dose was achieved. Participants who tolerated 15 mg continued on 15 mg as their maximum tolerated dose. Participants who tolerated 10 mg but did not tolerate 15 mg continued on 10 mg as their maximum tolerated dose.
“Patients, providers and the public do not always understand obesity is a chronic disease that often requires ongoing treatment, which can mean that treatment is stopped once weight goals are met,” said Jeff Emmick, MD, Ph.D., senior vice president, product development, Lilly. “However, studies like SURMOUNT-4 show that continued therapy can help people living with obesity maintain their weight loss.”
Detailed Results
After 36 weeks of open-label Zepbound, participants, who would then go on to be randomized to Zepbound or placebo in the double-blind period, experienced a mean weight reduction of 20.9% from mean body weight of 236.6 lb. (107.3 kg) at study entry. Primary and key secondary endpoints assessed efficacy during the double-blind period (week 36 to week 88) and over the course of the entire treatment period (week 0 to week 88). For both estimands, Zepbound met the primary endpoint and all key secondary endpoints, including:
| Efficacy Estimand Results at 88 Weeks | Treatment-Regimen Estimand Results at 88 Weeks | |||
| Zepbound | Placebo | Zepbound | Placebo | |
| Primary Endpoint | ||||
| Mean percent change in weight from week 36 (randomization) to week 88* | -6.7 % | 14.8 %
| -5.5 %
| 14.0 % |
| Key Secondary Endpoints | ||||
| The mean change in body weight from week 36* | -5.7 kg
| 11.9 kg
| -4.7 kg
| 11.1 kg |
| Percentage of participants who maintained ≥80% of weight lost during the lead-in period* | 93.4 % | 13.5 % | 89.5 % | 16.6 % |
| The mean change in waist circumference from week 36* | -4.6 cm | 8.3 cm | -4.3 cm | 7.8 cm |
| Percentage of participants who achieved ≥20% weight reduction from week 0* | 72.6 % | 11.6 % | 69.5 % | 12.6 % |
| Additional Secondary and Exploratory Endpoints | ||||
| Percent change in body weight from week 0
| -26.0 %
| -9.5 %
| -25.3 %
| -9.9 %
|
| Percentage of participants who achieved ≥25% weight reduction from week 0 | 56.6 % | 4.0 % | 54.5 % | 5.0 % |
*Tested for superiority, controlled for type 1 error.
Additional secondary endpoints showed that Zepbound was also associated with improvements in BMI, fasting insulin, lipids, blood pressure, and health-related quality of life.
The overall safety profile of tirzepatide in SURMOUNT-4 was similar to previously reported SURMOUNT and SURPASS trials. The most commonly reported adverse events in SURMOUNT-4 were gastrointestinal-related and generally mild to moderate in severity. During the Zepbound lead-in treatment period, the most frequent adverse events were nausea (35.5%), diarrhea (21.1%), constipation (20.7%) and vomiting (16.3%). During the double-blind period, the most frequent adverse events for Zepbound and placebo, respectively, were diarrhea (10.7% vs 4.8%), nausea (8.1% vs 2.7%), vomiting (5.7% vs 1.2%), COVID-19 (14.0% vs 14.9%) and upper respiratory infection (2.4% vs 5.4%). Treatment discontinuation due to an adverse event occurred in 7.0% of enrolled participants during the 36-week open-label lead-in treatment period, mainly due to gastrointestinal events. After the open-label lead-in period, treatment discontinuation rates due to adverse events were 1.8% (Zepbound) and 0.9% (placebo).