Novo Nordisk’s CagriSema Delivers Up to 22.7% Weight Loss in Obese or Overweight Adults, REDEFINE 1 Trial Results Published in NEJM
In a significant advancement for the treatment of obesity and overweight, Novo Nordisk today announced the publication of pivotal Phase 3 REDEFINE 1 trial results in the New England Journal of Medicine (NEJM). The investigational dual hormone therapy CagriSema, a combination of semaglutide (GLP-1 receptor agonist) and cagrilintide (amylin analogue), demonstrated clinically meaningful and statistically significant weight loss of up to 22.7% over 68 weeks among adults with obesity or overweight and at least one weight-related medical condition, but without diabetes.
The findings, which were also presented during a scientific symposium at the American Diabetes Association’s (ADA) 85th Scientific Sessions, underscore CagriSema’s potential as a new generation anti-obesity treatment that surpasses currently available pharmacotherapies in both efficacy and tolerability.
REDEFINE 1: A Major Step Forward in Obesity Treatment
The REDEFINE 1 trial evaluated the efficacy and safety of once-weekly subcutaneous CagriSema 2.4 mg / 2.4 mg combined with lifestyle interventions in adult participants with obesity or overweight and weight-related comorbidities, excluding those with type 2 diabetes. The study met both co-primary endpoints, demonstrating a significant reduction in body weight and favorable safety outcomes compared to placebo.
In terms of raw numbers, individuals treated with CagriSema experienced an average weight reduction of 22.7% at 68 weeks under the trial product estimand, which assumes full adherence to the treatment protocol. In contrast, participants receiving placebo achieved only 2.3% weight loss. Even when factoring in treatment discontinuation and non-adherence, under the treatment policy estimand, patients in the CagriSema arm still lost 20.4% of their baseline body weight compared to 3.0% in the placebo group.
Clinical Impact: BMI Reduction and Obesity Resolution
One of the most compelling secondary outcomes was the extent to which CagriSema helped participants transition out of the obesity category. At the start of the trial, participants had an average body mass index (BMI) of 38 kg/m². By week 68, 50.7% of those treated with CagriSema had reduced their BMI below 30, the clinical threshold for obesity. In contrast, only 10.2% of participants in the placebo group achieved this milestone.
Additionally, CagriSema delivered impressive results across higher weight-loss thresholds:
- Under the trial product estimand:
- 40.4% of participants lost 25% or more of their body weight
- 23.1% achieved a ≥30% weight reduction
- Under the treatment policy estimand:
- 34.7% achieved ≥25% weight loss
- 19.3% lost ≥30% of their body weight
These results position CagriSema among the most efficacious anti-obesity interventions to date, including surgical options in some cases.
Body Composition Analysis: Fat vs. Lean Mass Reduction
Beyond total weight loss, the REDEFINE 1 trial also included a prespecified analysis of body composition in a subset of 252 participants. This analysis revealed that CagriSema promoted preferential loss of fat over lean tissue:
- Fat mass decreased by 35.7% in the CagriSema group, compared to 5.7% in the placebo group
- Lean soft-tissue mass decreased by 14.4% vs. 4.3%, respectively
This selective fat loss suggests that CagriSema preserves metabolic health and physical function, a key concern in obesity management.
Real-World Relevance and Dosing Flexibility
Importantly, the study protocol allowed investigators some flexibility in dose adjustments, enabling tailored titration to balance efficacy with tolerability. According to Dr. Timothy Garvey, lead investigator and professor of medicine at the University of Alabama at Birmingham, this design better mimics real-world clinical practice where dose individualization is often necessary. “These findings are relatable to clinical settings, where physicians adjust dosing based on patient needs and judgment,” Dr. Garvey noted.
Safety Profile: Consistent with GLP-1 Class
The safety data from REDEFINE 1 and REDEFINE 2 reinforce CagriSema’s favorable tolerability profile. Overall, discontinuation due to adverse events (AEs) was relatively low:
- 6% in the CagriSema group vs. 3.7% for placebo in REDEFINE 1
- 8.4% with CagriSema vs. 3% with placebo in REDEFINE 2
The most frequently reported AEs were gastrointestinal in nature, including:
- Nausea: 55.0% (CagriSema) vs. 12.6% (placebo)
- Constipation: 30.7% vs. 11.6%
- Vomiting: 26.1% vs. 4.1%
These events were mostly transient and mild to moderate, consistent with known effects of GLP-1 receptor agonists.
REDEFINE 2: Efficacy in Patients with Type 2 Diabetes
Alongside REDEFINE 1, Novo Nordisk also published results from REDEFINE 2, a companion Phase 3 trial in adults with type 2 diabetes and obesity. REDEFINE 2 confirmed CagriSema’s efficacy in this patient population, albeit with somewhat lower weight loss due to the metabolic challenges associated with diabetes.
- Under the trial product estimand:
- CagriSema led to 15.7% weight loss vs. 3.1% with placebo
- Under the treatment policy estimand:
- CagriSema achieved 13.7% weight loss vs. 3.4% with placebo
The percentage of participants reaching key weight-loss thresholds was also notable:
- ≥5% weight loss: 83.6% (CagriSema) vs. 30.8% (placebo)
- ≥10%: 65.6% vs. 10.3%
- ≥15%: 43.9% vs. 2.4%
- ≥20%: 22.9% vs. 0.5%
Safety results in REDEFINE 2 mirrored those of REDEFINE 1, with gastrointestinal issues as the most common AEs.
Future Directions: The REDEFINE Program Continues
Novo Nordisk’s investment in the CagriSema program is far from over. The company recently initiated the REDEFINE 11 trial, with the first patient visit in June 2025. This study will explore the potential for even greater weight loss and long-term safety, with an extended duration and protocol enhancements building on the success of REDEFINE 1 and 2.
“We’re encouraged by what we’ve seen so far,” said Martin Holst Lange, executive vice president and head of Development at Novo Nordisk. “REDEFINE 1 and 2 have not only confirmed the efficacy of CagriSema but also demonstrated its tolerability across diverse patient populations. We’re committed to uncovering the full potential of this combination therapy.”
A New Frontier in Weight Management
The publication of REDEFINE 1 and REDEFINE 2 in NEJM and presentation at ADA marks a watershed moment for obesity pharmacotherapy. With weight loss outcomes exceeding 20% and a manageable safety profile, CagriSema stands out as a highly promising next-generation therapy. As the global obesity epidemic continues to worsen, treatments like CagriSema offer new hope for millions of patients struggling with excess weight and its associated health risks.
Pending regulatory review, CagriSema could soon join Novo Nordisk’s growing portfolio of metabolic disease therapies, redefining how we approach long-term weight management in clinical practice.
