CagriSema Achieves 23% Weight Loss but Misses Noninferiority vs Tirzepatide in REDEFINE 4

CagriSema, a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg administered once weekly, achieved a 23.0% mean weight loss at 84 weeks in adults with obesity in the phase 3 REDEFINE 4 trial but did not meet its primary endpoint of demonstrating noninferiority to tirzepatide 15 mg for weight reduction, according to Novo Nordisk.

REDEFINE 4 was an 84-week, open-label, head-to-head phase 3 trial enrolling 809 adults with obesity and at least one comorbidity. Participants had a mean baseline body weight of 114.2 kg. All participants and investigators were aware of treatment allocation throughout the study.

Using the efficacy estimand, defined according to the trial protocol and regardless of dose modification, participants treated with CagriSema 2.4 mg/2.4 mg achieved a mean weight loss of 23.0% at week 84 compared with 25.5% among those treated with tirzepatide 15 mg. When applying the treatment-regimen estimand, which assesses treatment effect regardless of adherence, mean weight loss was 20.2% with CagriSema versus 23.6% with tirzepatide at 84 weeks. The difference did not meet the predefined criteria for noninferiority.

In the trial, CagriSema appeared to have a safe and well-tolerated profile. The most common adverse events were gastrointestinal in nature. The majority were mild to moderate in severity and diminished over time, consistent with the glucagon-like peptide-1 receptor agonist class.

“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. 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”, said Martin Holst Lange, executive vice president, R&D and chief scientific officer at Novo Nordisk.

CagriSema for weight management was submitted to the US Food and Drug Administration in December 2025 based on data from the pivotal REDEFINE 1 and REDEFINE 2 trials, with a regulatory decision anticipated by late 2026.

CagriSema is under investigation as a once-weekly subcutaneous treatment for adults with overweight or obesity in the REDEFINE program and for adults with type 2 diabetes in the REIMAGINE program. The combination pairs a long-acting amylin analogue, cagrilintide 2.4 mg, with semaglutide 2.4 mg. The two agents are designed to promote weight loss by reducing hunger and increasing satiety, thereby decreasing caloric intake.

The broader REDEFINE phase 3 program includes multiple trials evaluating efficacy, safety, cardiovascular outcomes, body composition, and maintenance of weight loss. REDEFINE 1 and REDEFINE 2 enrolled approximately 4 600 adults with overweight or obesity, with or without type 2 diabetes. Additional trials, including REDEFINE 11 and a higher-dose CagriSema 2.4 mg/7.2 mg study, are ongoing or planned to further assess the combination’s weight-loss potential.

Reference: Novo Nordisk A/S: 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#