Novo Nordisk’s combination weight loss drug CagriSema failed to outperform Eli Lilly’s Zepbound (tirzepatide) in a head-to-head Phase 3 clinical trial, according to results announced Monday. The study, called REDEFINE 4, showed that CagriSema led to an average of 23% weight loss over 84 weeks, while Zepbound achieved a higher average of 25.5%. Following the announcement, Novo Nordisk’s shares dropped by 15% in pre-market trading.
During a conference call with analysts, Novo Nordisk CEO Maziar Mike Doustdar responded to criticism after one analyst described CagriSema as “obsolete” in light of the new data. Doustdar said, “To say it’s obsolete is quite belittling a fantastic drug, in all honesty.” He also addressed concerns about the drug’s future marketability: “When CagriSema will make it to the market early next year as the first amylin-based product, it will have the best weight loss label than any product marketed at that time.”
CagriSema combines cagrilintide—an amylin agent—with semaglutide and was tested directly against tirzepatide (Zepbound), which is already approved for weight management. Head-to-head trials like this are often used by pharmaceutical companies to compare their products and attempt to increase market share.
Chief Scientific Officer Martin Holst Lange attributed CagriSema’s loss to tirzepatide’s strong performance in the trial. “That’s maybe why we have seen these surprisingly good data for the comparative drug in part—we probably also have to ascribe this to biology,” he said. Holst Lange added that this level of efficacy had not been previously observed with tirzepatide: “So obviously, this is the one off.”
Holst Lange noted that more patients reached the full 15 mg dose in the tirzepatide group than in those taking CagriSema during the trial.
The primary endpoint of REDEFINE 4 was for CagriSema to demonstrate non-inferiority compared with Zepbound; however, it did not meet this goal. When treatment adherence was excluded from analysis, Zepbound still outperformed CagriSema with an average weight loss of 23.6% versus Novo's 20.2%.
Despite these results, Novo executives stated that achieving an average of 23% weight loss remains significant and highlighted that CagriSema could become the first GLP-1/amylin-combination therapy on the market if approved by regulators. According to Novo Nordisk, its application is currently under review by the FDA and a decision is expected by late 2026.
Novo has additional studies underway for CagriSema—including REDEFINE 11—which will test higher doses against placebo and is expected to report results in early 2027. Holst Lange indicated that changes were made mid-program based on earlier readouts from other studies within their clinical development plan.
“We are strongly assuming that there is a further weight loss potential to be had when taking all of these learnings into account; we’ve done that in REDEFINE 11,” Holst Lange said.
While further head-to-head comparisons between CagriSema and Zepbound are possible in future research programs, Holst Lange suggested more data would be needed before proceeding.
The news proved favorable for Eli Lilly investors as company shares rose by about 2.5% following publication of these results. In a note released Monday morning, Truist Securities wrote: “While we do acknowledge that Cagrisema is a potent drug and we continue to keep track of additional trial data, we believe these data maintain LLY’s dominance in obesity landscape at least for the near-future.” They added: “Best-in-class profile coupled with improved access and supply, and increasing demand are expected to support LLY’s position in the landscape, in our view.”
Lilly's tirzepatide previously beat Novo's semaglutide (marketed as Wegovy) in another direct comparison sponsored by Lilly.
In terms of oral therapies for obesity treatment—a growing segment—Novo Nordisk recently launched oral Wegovy after receiving regulatory approval at the end of December 2025. According to CEO Doustdar's comments during recent earnings announcements, more than 100,000 patients have already started using this pill form medication.
Eli Lilly may soon compete directly with its own oral candidate orforglipron; Truist Securities expects FDA approval sometime during Q2.
