CagriSema Did Not Meet Primary End Point of Noninferiority to Tirzepatide

Novo Nordisk announced headline results from the REDEFINE 4 clinical trial, revealing that its experimental combination therapy CagriSema achieved a 23% weight loss in adults with obesity over 84 weeks. Despite this clinically significant reduction, the drug failed to meet its primary end point of demonstrating noninferiority when compared head-to-head against tirzepatide at its highest 15 mg dose.¹

The open-label phase 3 trial, which included 809 participants with a mean baseline weight of 114.2 kg, showed that tirzepatide led to a slightly higher weight loss of 25.5% under the same efficacy estimand.¹

“We are pleased with the weight loss of 23% for CagriSema in this open-label trial. CagriSema has the potential to be the first GLP-1/amylin-combination product to reach the market for people living with obesity, documenting that cagrilintide adds to the existing benefits of semaglutide and offers clinically meaningful additive weight loss effects superior to what has been observed with GLP-1 biology alone,” Martin Holst Lange, executive vice president of R&D and chief scientific officer at Novo Nordisk, said in the news release.¹

For pharmacists evaluating the next generation of metabolic treatments, CagriSema represents a novel approach by combining 2 distinct mechanisms of action into a single once weekly subcutaneous injection. The medication is a fixed-dose combination of 2.4 mg of semaglutide, a well-known glucagon-like peptide-1 (GLP-1) receptor agonist, and 2.4 mg of cagrilintide, a long-acting amylin analog. These molecules work synergistically to reduce hunger and increase feelings of fullness, theoretically offering additive benefits beyond what is observed with GLP-1 therapy alone.^1,2

Results across the REDEFINE program, including the latest head-to-head data, indicate that CagriSema is generally well-tolerated. The most frequently reported adverse events are gastrointestinal, such as nausea or diarrhea, which investigators characterized as mostly mild to moderate. These side effects appear to follow a predictable pattern for the GLP-1 class, typically waning over time as patients adhere to the treatment regimen.^2,3

The REDEFINE 4 results provide further context to earlier pivotal trials that have already been submitted for regulatory review. In the REDEFINE 1 (NCT05567796) trial, which studied more than 3400 adults without type 2 diabetes, the combination therapy demonstrated superior weight loss of 22.7% compared to its individual components and placebo.²

Meanwhile, the REDEFINE 2 (NCT05394519) trial focused on the more challenging patient population of those with both obesity and type 2 diabetes. In that study, patients achieved a weight loss of 15.7% after 68 weeks, with nearly 90% of participants reaching the coprimary endpoint of at least a 5% reduction in body weight.³

Although the failure to meet noninferiority against tirzepatide in REDEFINE 4 highlights the high bar set by current dual-agonist therapies, the manufacturer remains committed to the drug's development. Other studies have previously indicated that tirzepatide alone facilitates greater relative weight loss compared to semaglutide monotherapy, a trend that appears to persist even when semaglutide is paired with an amylin analog.

“Based on the learnings from completed studies, we look forward to the REDEFINE 11 readout and the initiation of the higher-dose CagriSema trial, which are both designed to assess the full weight-loss potential of CagriSema,” Holst Lange said.¹ “The results in the REDEFINE program reinforce our commitment to transforming obesity care through novel products such as CagriSema and zenagamtide with the potential to offer even greater health benefits for patients living with obesity.”

Pharmacists can expect a decision from the FDA regarding the initial approval of CagriSema by late 2026. The submission, which was filed in December 2025, is based primarily on the efficacy and safety data from the REDEFINE 1 and REDEFINE 2 trials. As the landscape for obesity management continues to shift toward multi-receptor agonists, these latest findings underscore both the significant weight-loss potential of combined therapies and the competitive challenges they face from existing market leaders.¹

REFERENCES

1. CagriSema demonstrated 23% weight loss in an open-label head-to-head REDEFINE 4 trial in people with obesity, the primary endpoint was not achieved. News release. Novo Nordisk. February 23, 2026. Accessed February 23, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916501
2. Biscaldi L. CargiSea demonstrates statistically significant, superior weight loss vs placebo. Drug Topics. December 20, 2024. Accessed February 23, 2026. https://www.drugtopics.com/view/cagrisema-demonstrates-statistically-significant-superior-weight-loss-vs-placebo
3. Gallagher A. CargiSema demonstrates significant weight loss at 68 weeks. Drug Topics. March 12, 2025. Accessed February 23, 2026. https://www.drugtopics.com/view/cagrisema-demonstrates-significant-weight-loss-at-68-weeks