Tirzepatide Tops Semaglutide for Weight Loss in Head-to-Head Trial, Eli Lilly Says

Adults on the obesity medication tirzepatide (Zepbound) lost more weight on average than those on semaglutide (Wegovy) in a head-to-head trial of the two injectables, Eli Lilly announced on Wednesday.

In topline data from the open-label phase IIIb SURMOUNT-5 trial, people on tirzepatide lost 20.2% of their body weight compared with 13.7% with semaglutide after 72 weeks.

Those treated with tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, lost on average 50.3 lb (22.8 kg) while those treated with semaglutide lost 33.1 lb (15 kg), translating to a 47% greater relative weight loss with tirzepatide.

All of the five key secondary endpoints favored tirzepatide, as well. For example, 31.6% of those on tirzepatide achieved at least 25% body weight loss compared with 16.1% of those on semaglutide, the company said.

The findings are congruent with recently reported real-world data that found a 6.9% greater weight loss at 1 year with tirzepatide versus semaglutide.

Average weight lost in SURMOUNT-5 was also reflective of data from the clinical trials that underpinned FDA approval for both agents. In SURMOUNT-1, people taking 15 mg of tirzepatide lost on average 22.5% of body weight — representing a mean loss of 52 lb (24 kg) by week 72. And in STEP 1, people on semaglutide lost an average 14.9% of baseline body weight after 68 weeks and an average of 33.7 lb (15.3 kg).

“Given the increased interest around obesity medications, we conducted this study to help healthcare providers and patients make informed decisions about treatment choice,” said Leonard Glass, MD, senior vice president of global medical affairs at Lilly Cardiometabolic Health, in a statement.

Approved in 2022 for type 2 diabetes (under the name Mounjaro) and in 2023 for chronic weight management along with diet and exercise, tirzepatide is the only once-weekly dual GIP/GLP-1 receptor agonist on the market.

Semaglutide, a GLP-1 receptor agonist manufactured by Novo Nordisk, currently holds three indications: type 2 diabetes (approved in 2017 under the trade name Ozempic), chronic weight management (approved in 2021), and cardiovascular disease risk reduction (approved in 2024).

A total of 751 participants from the U.S. and Puerto Rico were included in SURMOUNT-5. Randomized in a 1:1 ratio, participants were treated with a maximum tolerated dose of tirzepatide (10 mg or 15 mg) or semaglutide (1.7 mg or 2.4 mg). The cohort included adults with obesity, or overweight with at least one of the following comorbidities: hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease, but without diabetes.

No unexpected safety events occurred during the trial and tirzepatide’s overall safety profile was comparable to prior SURMOUNT trials, Eli Lilly said. As expected with GLP-1 receptor agonist-containing agents, the most common adverse events for both drugs were gastrointestinal-related and were generally mild to moderate in severity.

Full study results will be published in a journal and presented at a medical conference next year, according to the drugmaker.

Tirzepatide is currently under FDA review for potential indications in moderate-to-severe obstructive sleep apnea and obesity, as well as heart failure with preserved ejection fraction and obesity.

It was revealed this week that the labeling for tirzepatide no longer includes BMI ranges. Previously, the label outlined usage for adults with obesity (a BMI of ≥30) or overweight (BMI 27 to