Key Takeaways
- Unprecedented Weight Loss Outcomes. In the REDEFINE 1 trial, 60% of participants receiving once-weekly CagriSema (cagrilintide–semaglutide) achieved at least 20% weight loss, and 23% lost 30% or more, which is among the most significant results seen with any anti-obesity medication to date.
- Broad Metabolic and Cardiovascular Benefits. The combination therapy significantly improved systolic blood pressure, waist circumference, lipid levels, and glycemic control, with 88% of participants with prediabetes returning to normoglycemia.
- Flexible Dosing Shows Promise. Substantial weight loss was observed even among patients who did not reach the full target dose, suggesting individual responsiveness and the potential for personalized, lower-dose regimens in clinical practice.
Results of the Phase IIIa REDEFINE 1 trial (NCT05567796) show that a once-weekly combination of cagrilintide and semaglutide (CagriSema) produced unprecedented weight loss in adults with overweight or obesity, according to trial investigators. These findings, published by The New England Journal of Medicine (NEJM), demonstrated that more than half of participants in the trial achieved body weight reductions of 20% or more.1,2
Cagrilintide and Semaglutide Combination Achieves Significant Weight Loss Through Dual Mechanisms of Action
“The mean weight reduction observed with cagrilintide–semaglutide is in the highest range of that observed with existing weight-loss interventions,” the study authors wrote in NEJM. “We posit that these effects on body weight probably result from the complementary effect of the two molecules on appetite regulation through direct actions in brain regions known to be involved in hedonic and homeostatic appetite regulation, such as the hypothalamus, hindbrain, and septum.”1
- Semaglutide, a glucagon-like peptide-1 receptor agonist, was initially approved in June 2021 for chronic weight management in those with obesity or overweight and at least one weight-related condition, including high blood pressure, type 2 diabetes, or high cholesterol, in addition to diet and increased exercise.3
- Semaglutide has also been approved by the FDA in both long-acting injectable (Wegovy and Ozempic) and daily oral tablet (Rybelsus) formulations.
- Wegovy is indicated for weight loss and weight maintenance in patients aged 12 years and older with obesity; and for reducing major cardiovascular event (MACE) risks in adults with type 2 diabetes with known heart disease.
- Ozempic is indicated to treat type 2 diabetes in adults to help control blood sugar levels along with diet and exercise; for reducing MACE risks in adults with type 2 diabetes with known heart disease; and to lower the risk of kidney function decline, kidney failure, and death due to cardiovascular disease in adults with chronic kidney disease and type 2 diabetes.
- Rybelsus is indicated to help control blood sugar levels in adults with type 2 diabetes.
- Cagrilintide is a long-acting human amylin analogue, which has been found to be a promising approach to weight loss because natural amylin is a pancreatic hormone that produces satiety.
“Once-weekly cagrilintide, a long-acting amylin analog that is non-selective for the [calcitonin G protein-coupled receptor (CTR)] and amylin receptors, has shown promising weight-loss effects as well as improvement in cardiometabolic factors,” wrote the authors of a study published by Cardiology in Review. “Cagrilintide 4.5 mg was shown to produce superior weight loss than liraglutide 3.0 mg over a 26-week period. Cagrilintide has been shown to be safe and tolerable both alone and in combination with the GLP-1 receptor analog semaglutide. The complementary MOAs of amylin-analog and GLP-1 receptor agonists appear to be a promising combination therapy with greater weight loss than any other currently approved AOM and the potential to further close the gap with bariatric surgery outcomes.”4
REDEFINE 1 Trial Design and Patient Profile
- The 68-week, multicenter, double-blind, placebo- and active-controlled REDEFINE 1 trial, enrolled 3417 adult patients without diabetes and who have a body-mass index (BMI) of 30 or more or a BMI of 27 or more with at least one obesity-related complication.
- Participants were randomly assigned in a 21:3:3:7 ratio to receive the combination therapy with semaglutide administered at a dose of 2.4 mg and cagrilintide at a dose of 2.4 mg (n = 2108), semaglutide alone at a dose of 2.4 mg (n = 302), cagrilintide alone at a dose of 2.4 mg (n = 302), or placebo (n = 705), as well as lifestyle interventions in each cohort.
- The trial’s coprimary endpoints were relative change in body weight and weight loss of 5% or more from baseline through week 68 in the CagriSema cohort compared to placebo.
- Confirmatory secondary endpoints included weight loss of 20% or more, 25% or more, and 30% or more.
Flexible Dosing Strategy Supports Individualized Patient Response
- Results show that from baseline to week 68, patients in the CagriSema cohort achieved an estimated mean percent change in body weight of –20.4% compared to –3.0% in the placebo cohort (estimated difference, –17.3 percentage points; 95% confidence interval, –18.1 to –16.6; P<0.001).
- The CagriSema cohort was found to be more likely to reach weight-loss targets of 5% or more, 20% or more, 25% or more, and 30% or more compared to placebo.
“In this trial, a combination approach led to 60% of participants reaching the target weight loss of 20% or more, and approximately one in four participants (23%) had a weight loss of 30% or more on the basis of the trial-product estimand (i.e., when participants were treated as intended),” the study authors wrote in NEJM. “Statistical superiority of cagrilintide–semaglutide over placebo was observed for all confirmatory secondary end points in the testing hierarchy, including systolic blood pressure and waist circumference; improvements in lipid levels were also observed.”1
Safety Profile Consistent With GLP-1-Based Therapies
- In terms of safety, gastrointestinal adverse events (AEs) were reported in 79.6% of participants in the CagriSema cohort compared to 39.9% in the placebo cohort.
- The most frequently reported AEs included nausea, vomiting, diarrhea, constipation, or abdominal pain, which were mostly mild-to-moderate in severity and dissipated over time.
“In this trial, substantial body-weight loss was observed, despite the fact that some participants who were randomly assigned to cagrilintide–semaglutide did not reach the target dose of 2.4 mg of each of the drugs in the combination or complete the trial receiving this dose,” the study authors wrote. “This finding suggests that doses below the target might be highly effective for some patients and that dose reductions based on the clinical judgment of study site investigators may be appropriate; it also highlights the individual responsiveness and variability in the clinical response to treatment. These findings may be relevant for clinical practice, since dosing is often adjusted on the basis of individual needs and clinical judgment to achieve the degree of weight loss that promotes health. Further analyses investigating the relationship between weight-loss response and dose are warranted.”1
References
1. Garvey W., et al. Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2025; DOI: 10.1056/NEJMoa2502081.
2. A Research Study to See How Well CagriSema Helps People With Excess Body Weight Lose Weight (REDEFINE 1). ClinicalTrials.gov. Updated May 28, 2025. Accessed June 30, 2025. https://clinicaltrials.gov/study/NCT05567796
3. FDA Approves New Drug Treatment for Chronic Weight Management, First Since 2014. FDA. News release. June 4, 2021. Accessed June 30, 2025. https://www.fda.gov/news-events/press-announcements/fda-approves-new-drug-treatment-chronic-weight-management-first-2014
4. D’Ascanio, Antonella M. BS; Mullally, Jamie A. MD; Frishman, William H. MD. Cagrilintide: A Long-Acting Amylin Analog for the Treatment of Obesity. Cardiology in Review 32(1):p 83-90, January/February 2024. DOI: 10.1097/CRD.0000000000000513.
