Novo Nordisk's CagriSema Achieves 23% Weight Loss But Misses Non-Inferiority Goal vs Tirzepatide
CagriSema demonstrated 23% weight loss in the REDEFINE 4 trial but failed to meet its primary endpoint of non-inferiority compared to tirzepatide's 25.5% weight loss. The company submitted an FDA application in December 2025 based on earlier pivotal trials.
Novo Nordisk announced headline results from REDEFINE 4, an open-label phase 3 trial comparing CagriSema to tirzepatide in people with obesity. CagriSema 2.4 mg/2.4 mg did not meet the primary endpoint of showing non-inferiority on weight loss compared to tirzepatide 15 mg at 84 weeks. CagriSema achieved 23% weight loss after 84 weeks of treatment.
The 84-week trial investigated CagriSema, a fixed dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg, compared to tirzepatide 15 mg, both administered once-weekly and subcutaneously. The trial included 809 randomised people with obesity and one or more comorbidities and with a mean baseline body weight of 114.2 kg. The trial had an open-label design, meaning that all investigators and participants were aware of the specific drug administered throughout the trial.
When evaluating the effects of treatment, if all people adhered to treatment, people treated with CagriSema 2.4 mg/2.4 mg achieved a weight loss of 23.0% after 84 weeks compared to 25.5% with tirzepatide 15 mg. When applying the treatment-regimen estimand, people treated with CagriSema 2.4 mg/2.4 mg achieved a weight loss of 20.2% compared to 23.6% with tirzepatide at 84 weeks.
In the trial, CagriSema appeared to have a safe and well-tolerated profile. The most common adverse events with CagriSema were gastrointestinal, and the vast majority were mild to moderate and diminished over time, consistent with the GLP-1 receptor agonist class.
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. Additional trials are exploring the full weight loss potential of CagriSema, including higher-dose combinations.
CagriSema for weight management was submitted to the US FDA in December 2025 based on the REDEFINE 1 and REDEFINE 2 pivotal trials, and an FDA decision is anticipated by late 2026. The REDEFINE 11 phase 3 trial exploring CagriSema 2.4/2.4 mg full weight-loss potential in obesity is expected to report data during the first half of 2027, while initiation of the phase 3 CagriSema higher-dose trial is planned for the second half of 2026.
The NDA is based on results from REDEFINE 1, a 68-week, phase 3, randomized, double-blind, placebo-and active-controlled trial that evaluated the efficacy and safety of once-weekly CagriSema compared to semaglutide 2.4 mg alone, cagrilintide 2.4 mg alone, or placebo, all as an adjunct to lifestyle intervention in 3,417 adults with obesity or overweight with one or more obesity-related complications and without diabetes, and REDEFINE 2, a double-blind, randomized, placebo-controlled, 68-week, phase 3 trial that evaluated the efficacy and safety of once-weekly CagriSema versus placebo, as an adjunct to lifestyle intervention in 1,206 adults with type 2 diabetes and either obesity or overweight.
The REDEFINE 1 trial found that when evaluating the treatment effect regardless of whether patients stayed on treatment, those treated with CagriSema achieved weight loss of 20.4% from an average baseline body weight of 236 lb at 68 weeks versus 3.0% from an average baseline body weight of 235 lb for the placebo group which was statistically significant. CagriSema resulted in greater weight loss of 22.7% at 68 weeks versus 2.3% in the placebo group when evaluating the treatment effect if all patients stayed on treatment. 91.9% of participants taking CagriSema achieved a body weight reduction of greater than or equal to 5%, compared to 31.5% for the placebo group. In addition, a supportive secondary analysis showed that about half (54%) of trial participants with obesity at baseline treated with CagriSema reached the threshold for non-obesity (BMI <30 kg/m2) at week 68. In the placebo group, 11.1% reached that threshold at 68 weeks.
Safety data generated in the REDEFINE 1 and 2 trials was comparable with the GLP-1 RA class. Overall, discontinuation rates due to adverse events were low, with 5.9% for CagriSema versus 3.5% for placebo in REDEFINE 1 and 8.4% with CagriSema versus 3% with placebo in REDEFINE 2. In REDEFINE 1, adverse events were mainly gastrointestinal (79.6% in the CagriSema group vs 39.9% with placebo) including nausea (55% vs 12.6%), constipation (30.7% vs 11.6%), and vomiting (26.1% vs 4.1%).
Novo Nordisk also announced headline results from REIMAGINE 2, a phase 3 trial from the global REIMAGINE clinical trial programme. CagriSema demonstrated both superior HbA1c reduction and weight loss at week 68 versus semaglutide, across all tested doses in the trial. CagriSema achieved superior weight loss of up to 14.2%, where up to 43% of the people achieved ≥15% weight loss and up to 24% achieved ≥20% weight loss. CagriSema achieved superior HbA1c reduction of up to 1.91%-points from a mean HbA1c baseline of 8.2%. Superiority was established on both weight loss and HbA1c versus the individual components.
REIMAGINE 2 was a 68-week efficacy and safety trial investigating once-weekly subcutaneous CagriSema in two different doses (2.4 mg/2.4 mg and 1.0 mg/1.0 mg) compared to two different doses of semaglutide (2.4 mg and 1.0 mg), cagrilintide (2.4 mg), and placebo. The trial included 2,728 people with type 2 diabetes inadequately controlled with metformin with or without an SGLT2 inhibitor. Approximately 40% of all people were using an SGLT2 inhibitor before initiating the trial.
When evaluating the effects of treatment, if all people adhered to treatment, and from a mean HbA1c baseline of 8.2%, people treated with CagriSema 2.4 mg/2.4 mg achieved superior HbA1c reduction of 1.91%-points after 68 weeks compared to 1.76%-points with semaglutide 2.4 mg. From a mean baseline body weight of 101 kg, people treated with CagriSema 2.4 mg/2.4 mg achieved superior weight loss of 14.2% after 68 weeks compared to 10.2% with semaglutide 2.4 mg. No weight loss plateau was observed at week 68 for CagriSema. With CagriSema 2.4 mg/2.4 mg, 43% of the people achieved ≥15% weight loss and 24% achieved ≥20% weight loss.
When applying the treatment-regimen estimand, people treated with CagriSema 2.4 mg/2.4 mg achieved superior HbA1c reduction of 1.80%-points after 68 weeks compared to 1.68%-points with semaglutide 2.4 mg. In addition, people treated with CagriSema 2.4 mg/2.4 mg achieved superior weight loss of 12.9% after 68 weeks compared to 9.2% with semaglutide 2.4 mg.
Following the results of REIMAGINE 1 and REDEFINE 3, Novo Nordisk will approach authorities to discuss the regulatory pathway for CagriSema in type 2 diabetes. The detailed results from REIMAGINE 2 will be presented at a scientific conference in 2026.
CagriSema is a fixed-dose combination of a long-acting amylin analogue, cagrilintide 2.4 mg and semaglutide 2.4 mg. The two molecules induce weight loss by reducing hunger, increasing feelings of fullness and thereby help people eat less and reduce their calorie intake. Once-weekly subcutaneous CagriSema is being investigated by Novo Nordisk as a treatment for adults with overweight or obesity (REDEFINE programme) and as a treatment for adults with type 2 diabetes (REIMAGINE programme).