ADA 2025: CagriSema Demonstrates Dual Benefit in Obesity and Type 2 Diabetes

Data from REDEFINE 1 and REDEFINE 2 indicate coadministration of cagrilintide 2.4 mg and semaglutide 2.4 mg (CagriSema) was associated with weight reductions in the highest range of existing weight loss interventions.

Presented at the 85th Scientific Sessions of the American Diabetes Association (ADA 2025) and simultaneously published in the New England Journal of Medicine, results of the Novo Nordisk-sponsored trials offer the greatest insight yet into the effects of CagriSema, which is a combination of cagrilintide, a dual amylin and calcitonin receptor agonist, and semaglutide, a GLP-1 receptor agonist.1,2,3

“In REDEFINE 1, participants saw significant and clinically meaningful weight loss under a protocol that allowed investigators to maintain patients on a submaximal dose if deemed best for the patient. We also witnessed low, single-digit discontinuation rates due to adverse events in both REDEFINE 1 and 2,” said Martin Holst Lange, executive vice president and head of Development at Novo Nordisk.3 “These results reinforce our confidence in CagriSema, and we continue to study the potential of this combination through the REDEFINE trials.”

REDEFINE 1

A phase 3a, 68-week, double-blind trial, REDEFINE 1 randomized 3417 adults in a 21:3:3:7 ratio to receive once-weekly CagriSema (n=2108), semaglutide 2.4 mg alone (n=302), cagrilintide 2.4 mg alone (n=302), or placebo (n=705), all alongside standardized lifestyle interventions.1

For inclusion, patients need to be adults with a BMI of 30 kg/m2 or greater, or 27 or greater with at least one obesity-related comorbidity, such as hypertension, dyslipidemia, or obstructive sleep apnea. Patients were excluded if they had type 1 or type 2 diabetes.1

The primary outcomes of interest were the relative change in body weight and a reduction of 5% or more in body weight from baseline to week 68 with CagriSema as compared with placebo.1

Results of the trial suggested patients receiving CagriSema achieved a mean body weight reduction of 20.4%, compared to 3.0% with placebo at week 68, which correlates to an estimated treatment difference of –17.3 percentage points (95% CI, –18.1 to –16.6; P <.001). Additionally, the CagriSema group had a significantly greater proportion of participants achieving weight loss of at least 5%, 20%, 25%, and 30% compared with placebo (P <.001 for all thresholds). Of note, 50.7% of patients receiving CagriSema reached the BMI threshold for non-obesity by the end of the trial relative to 10.2% of the placebo group.1

Safety data suggested gastrointestinal adverse events were the most common side effects, which occurred among 79.6% of participants on CagriSema and 39.9% on placebo. Investigators pointed out events, which included nausea, vomiting, and diarrhea, were mostly mild to moderate in severity and transient.

REDEFINE 2

A phase 3a, double-blind, randomized trial, REDEFINE-2 randomized 1206 participants from 12 countries in a 3:1 ratio to receive once-weekly cagrilintide-semaglutide or placebo, along with lifestyle intervention, for 68 weeks. For inclusion in the trial, patients needed to be adults with a BMI of 27 kg/m2 or more, an HbA1c of 7% to 10%, and type 2 diabetes.2

The study population had a mean age of 56.0 years, 52.8% were men, 66.4% were White, and 28.7% were Asian. When examining clinic factors at baseline, the study population had a mean body weight of 102.2 kg, mean BMI of 36.2 kg/m2, mean waist circumference of 115.8 cm, and a mean HbA1c of 8.0%.2

The primary endpoints of interest for REDEFINE 2 were the percent change in body weight and the percentage of patients with a reduction in body weight of 5% or more from baseline to week 68.2

At week 68, patients in the CagriSema group experienced a mean weight reduction of 13.7%, compared to 3.4% with placebo, which correlates to an estimated treatment difference of −10.4 percentage points (95% CI, −11.2 to −9.5; P <.001), with significantly more participants on CagriSema achieved weight loss of at least 5%, 10%, 15%, and 20% (P <.001 for all comparisons). Investigators also highlighted improvements in glycemic control, 73.5% of patients in the CagriSema group achieving an HbA1c of ≤6.5% compared to 15.9% in the placebo group.2

"In REDEFINE 1, CagriSema provided weight loss in the highest range of efficacy observed with existing weight loss interventions,” said lead investigator Timothy Garvey, MD, 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.”

References:

1. Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. The New England Journal of Medicine. Published online June 22, 2025. doi: 10.1056/NEJMoa2502081

2. Davies MJ, Bajaj HS, Broholm C. Cagrilintide–Semaglutide in Adults with Overweight or Obesity and Type 2 Diabetes. The New England Journal of Medicine. Published online June 22, 2025. doi: 10.1056/NEJMoa2502082

3. Novo Nordisk. Novo Nordisk A/S: CagriSema 2.4 mg / 2.4 mg demonstrated 22.7% mean weight reduction in adults with overweight or obesity in REDEFINE 1, published in New England Journal of Medicine. Novo Nordisk. Published June 22, 2025. Accessed June 22, 2025. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916353