REDEFINE 1 trial: CagriSema results in 22.7% mean weight reduction in adults with overweight or obesity

Outcomes from Novo Nordisk's phase 3 REDEFINE 1 trial - evaluating the efficacy and safety of investigational CagriSema plus lifestyle interventions - met its co-primary endpoints and achieved statistically significant and clinically meaningful weight loss at 68 weeks in patients taking CagriSema versus placebo.

REDEFINE 1 is evaluating the efficacy and safety of investigational CagriSema plus lifestyle interventions for weight loss in adults with obesity or overweight who have a weight-related medical complication and without diabetes.

These data, along with the related phase 3 REDEFINE 2 study conducted in adults with overweight or obesity and type 2 diabetes, were presented during a scientific symposium at the American Diabetes Association's® (ADA) 85th Scientific Sessions.

CagriSema is an investigational product that combines the GLP-1 RA, semaglutide, with an amylin analogue, cagrilintide. The REDEFINE 1 trial found that treatment with CagriSema resulted in greater weight loss of 22.7% at 68 weeks versus 2.3% in the placebo group (estimated difference [95% CI] -20.4 [-21.1 to -19.7]; p<0.001) if all patients adhered to treatment.

When evaluating the treatment effect regardless of adherence, those treated with CagriSema achieved statistically significant weight loss of 20.4% at 68 weeks versus 3.0% for the placebo group (estimated difference [95% CI] -17.3 [-18.1 to -16.6]; p<0.001). In addition, a supportive secondary analysis showed that half (50.7%) of trial participants with obesity treated with CagriSema reached the threshold for non-obesity (BMI <30 kg/m2) at the end of treatment, from a mean BMI of 38 kg/m2 at the start of treatment. In the placebo group, 10.2% reached that threshold at 68 weeks.

Select confirmatory secondary endpoints showed that if all participants adhered to treatment 40.4% of those receiving CagriSema achieved a body-weight reduction of ≥25% ([95% CI] 39.5 (37.1 to 41.9); p<0.001). Additionally, 23.1% lost ≥30% of their body weight ([95% CI] 22.7 (20.7 to 24.7); p<0.001). When applying the treatment policy estimand, 34.7% of participants treated with CagriSema achieved ≥25% body-weight reduction ([95% CI] 33.7 (31.5 to 35.9); p<0.001) and 19.3% achieved ≥30% body-weight reduction ([95% CI] 18.9 (17.1 to 20.7); p<0.001).

In a prespecified analysis of 252 participants, the relative reduction in fat and lean soft-tissue mass from baseline to week 68 was -35.7% (fat mass) and -14.4% (lean soft-tissue mass) for those treated with CagriSema versus -5.7% and -4.3% for the placebo group, respectively.

"In REDEFINE 1, CagriSema provided weight loss in the highest range of efficacy observed with existing weight loss interventions," said lead investigator, Dr Timothy Garvey, professor of medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham. "Investigators were allowed some flexibility in dose adjustments to balance efficacy and safety, but regardless of dose adjustments participants lost significant weight. These findings are relatable to clinical practice, where dosing is often adjusted based on individual needs and clinical judgement."

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 6% for CagriSema versus 3.7% for placebo in REDEFINE 1 and 8.4% with CagriSema versus 3% with placebo in REDEFINE 2.1,3 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%), vomiting (26.1% vs 4.1%) and were mostly transient and mild-to-moderate in severity.

Results from REDEFINE 2, a phase 3 study that evaluated the efficacy and safety of CagriSema plus lifestyle interventions in adults with obesity and type 2 diabetes, were also simultaneously presented during a scientific symposium at the ADA's Scientific Sessions. In REDEFINE 2, if all participants adhered to treatment, the estimated mean change in body weight from baseline to week 68 was -15.7% with CagriSema versus -3.1% with placebo (estimated difference [95% CI] -12.6% [-13.4 to -11.7]; p<0.001).

When applying the treatment policy estimand, the estimated mean change in body weight from baseline to week 68 was -13.7% with CagriSema versus -3.4% with placebo (estimated difference [95% CI] -10.4% [-11.2 to -9.5]; p<0.001). A greater proportion of participants receiving CagriSema, compared with placebo, reduced their body weight by >5% (83.6% vs 30.8% of participants; p<0.001), ≥10% (65.6% vs 10.3%), ≥15% (43.9% vs 2.4%), and ≥20% (22.9% vs 0.5%; p<0.001).3 The safety results from CagriSema in REDEFINE 2 were similar to those reported in REDEFINE 1.

The REDEFINE clinical programme will continue to assess the efficacy and safety of CagriSema. Most recently, Novo Nordisk initiated the REDEFINE 11 trial with the first patient visit occurring in early June 2025. REDEFINE 11 will explore further weight loss potential and safety of CagriSema 2.4 mg / 2.4 mg through a longer trial duration and other protocol changes compared to REDEFINE 1 and 2.

CagriSema is not approved in the US for weight loss.

The findings were also reported in the paper, 'Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity', published in the New England journal of medicine. To access this paper, please click here (log-in maybe required)