Lilly's Tirzepatide (Zepbound) Beats Novo's Semaglutide (Wegovy) in Head-to-Head Weight Loss Trial: SURMOUNT-5 Study (2024)

The market for first-generation weight loss treatments has been dominated by two major players, Eli Lilly and Novo Nordisk. But new data provide the clearest evidence yet that one may have an edge.

On Dec 4, 2024, Lilly reported the first data from a head-to-head Phase 3 trial testing Zepbound against Novo’s Wegovy, finding that Zepbound was the superior weight loss agent. By week 72, patients given Zepbound lost 20.2% of their body weight on average, compared to 13.7% for Wegovy, the study’s primary endpoint. That equated to a 47% greater relative weight reduction, Lilly said.

The percentage changes in weight translated to Zepbound patients losing an average of 50.3 pounds. For patients given Wegovy, the average weight loss was 33.1 pounds.

Lilly highlighted one secondary endpoint, finding that 31.6% of people given Zepbound lost at least 25% of their body weight, compared to 16.1% for Wegovy. Lilly said it beat Wegovy on four other secondary endpoints and that more results will be published and presented in 2025.

The topline figures spell a resounding victory for Lilly, which bet on itself when it launched the randomized, controlled trial — called SURMOUNT-5 — more than a year and a half ago in April 2023. At that point, tirzepatide had not been formally approved for weight management in the US, though its diabetes-branded equivalent, Mounjaro, was being used as such off-label.

In the head-to-head trial, the weight loss percentage data are fairly similar to both drugs’ performances in their respective pivotal studies. Wegovy underperformed slightly in SURMOUNT-5, posting a 1.2-percentage point difference in overall weight loss compared to its pivotal trial. Zepbound also showed a 2.3-percentage point gap in weight loss versus its pivotal SURMOUNT-1 trial. However, the slightly weaker efficacy for both drugs could be due to the lower doses used in the latest study.



The data are a lift for Lilly after a bruising third-quarter earnings report sent its shares down 10%. The company lowered the top end of its guidance by $600 million and sales missed Wall Street’s expectations by roughly $800 million.

Now, it can take the data to doctors and payers. Leonard Glass, SVP of global medical affairs for the pharma’s cardiometabolic unit, said in a release that the study was conducted to “help health care providers and patients make informed decisions about treatment choice.”

SURMOUNT-5 randomized 751 participants in the US and Puerto Rico to receive the maximum tolerated dose of either Zepbound or Wegovy, more than the 700 that were expected to enroll.

Lilly did not design the trial to test long-term durability, saying that it would last around 74 weeks. Instead, it’s using the enrollees for another Phase 3 study, testing its oral candidate orforglipron as a maintenance option for people previously given injectables.

People who complete SURMOUNT-5 will be eligible to enter the study of orforglipron, randomized to receive either the pill or placebo, with that trial slated for a readout next year.

The Indianapolis pharma reported no specific side effect figures for SURMOUNT-5, saying that the safety profile of Zepbound was consistent with other studies of tirzepatide. The most common adverse events for both drugs were gastrointestinal-related and were “generally mild to moderate in severity,” Lilly said.


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