Lilly starts SURMOUNT-5, the first head-to-head trial against Wegovy

Eli Lilly quietly registered a new phase 3b trial on ClinicalTrials.gov on Friday that will pit its dual-acting drug tirzepatide (sold as Mounjaro for type 2 diabetes) against Novo Nordisk's Wegovy, semaglutide 2.4 mg once weekly, in adults with obesity or excess weight plus a related health condition ^[1].

The study, coded SURMOUNT-5, plans to enroll 700 participants across 61 sites in the U.S., Canada, South America and several European countries ^[1]. It is expected to begin the following Friday and run about 78 weeks, with an estimated primary completion date of February 2025 ^[1]. The main measure is the percentage of body weight lost from baseline after 72 weeks in each group ^[1]. Secondary measures include the share of participants who reach certain weight-loss thresholds ^[1].

To qualify, a person must have a body mass index of at least 30, or at least 27 along with a prior diagnosis of high blood pressure, dyslipidemia, obstructive sleep apnea or cardiovascular disease ^[1]. Those criteria match Wegovy's FDA-approved patient population ^[1]. Lilly did not immediately respond to a request for comment, and it is not clear from the trial posting whether the company designed SURMOUNT-5 to show tirzepatide is better than semaglutide or merely no worse ^[1].

Why head-to-head is unusual

Until now, the two drugs had only been compared indirectly, by lining up results from separate trials run against placebo. In SURMOUNT-1, tirzepatide produced weight reduction of up to 21% in participants without diabetes ^[1]. Wegovy recorded average weight loss of about 15% — a 12.4% difference from placebo — in its own trial in people without diabetes ^[1]. Those trials enrolled different people under different conditions, so as Fierce Pharma noted, without a head-to-head study no one can say for certain how the two compare ^[1].

The drugs also work differently. Wegovy is a GLP-1 receptor agonist, while tirzepatide acts on both GLP-1 and GIP receptors, which in theory could produce a stronger weight-loss effect ^[1].

At the time of the filing, Wegovy had been approved by the FDA for chronic weight management since 2021, while tirzepatide was approved only for type 2 diabetes ^[1]. Lilly had started a rolling FDA submission for tirzepatide in obesity with the goal of launching later in 2023, and may use a different brand name for the obesity version — the same way Novo sells semaglutide injection as Ozempic for diabetes and Wegovy for weight ^[1].

Why it matters for patients

Most people choosing between these medicines, and most doctors and insurers deciding what to cover, have had to rely on cross-trial comparisons that researchers consider unreliable. A single trial that randomly assigns people to one drug or the other, using the same sites and the same measurement rules, is the closest thing to a direct answer about relative weight loss — and about relative side effects, since both arms are tracked the same way.

There are limits. SURMOUNT-5 measures weight change at 72 weeks, not heart attacks, strokes or long-term health outcomes ^[1]. Its 700 participants all meet Wegovy's approved eligibility criteria, so the results speak to that group rather than to everyone who might want a weight-loss drug ^[1]. And the trial is funded and run by the maker of one of the two drugs being tested.

Both medicines had also been in short supply for months as demand surged, though the companies had recently resolved those shortages ^[1]. Lilly has been expanding manufacturing, including a planned $3.7 billion investment in two new active ingredient sites in Indiana and $1.7 billion for a diabetes and obesity plant in North Carolina ^[1].

What happens next

• Late April 2023: SURMOUNT-5 is expected to begin dosing ^[1].
• Near term: results from SURMOUNT-2, which appears to have wrapped up April 10, plus SURMOUNT-3 and SURMOUNT-4, are expected soon ^[1].
• February 2025: estimated primary completion of SURMOUNT-5 ^[1].

What the head-to-head comparison will show is not yet known.