REDEFINE 1 Trial Finds Cagrilintide–Semaglutide Combo Delivers Over 20% Weight Loss in Majority of Sufferers

Outcomes of the Section IIIa REDEFINE 1 trial (NCT05567796) present {that a} once-weekly mixture of cagrilintide and semaglutide (CagriSema) produced unprecedented weight reduction in adults with obese or weight problems, in accordance with trial investigators. These findings, revealed by The New England Journal of Medication (NEJM), demonstrated that greater than half of members within the trial achieved physique weight reductions of 20% or extra.^1,2

“The imply weight discount noticed with cagrilintide–semaglutide is within the highest vary of that noticed with current weight-loss interventions,” the research authors wrote in NEJM. “We posit that these results on physique weight in all probability outcome from the complementary impact of the 2 molecules on urge for food regulation by means of direct actions in mind areas identified to be concerned in hedonic and homeostatic urge for food regulation, such because the hypothalamus, hindbrain, and septum.”¹

• Semaglutide, a glucagon-like peptide-1 receptor agonist, was initially authorised in June 2021 for persistent weight administration in these with weight problems or obese and at the least one weight-related situation, together with hypertension, kind 2 diabetes, or excessive ldl cholesterol, along with eating regimen and elevated train.³
• Semaglutide has additionally been authorised by the FDA in each long-acting injectable (Wegovy and Ozempic) and each day oral pill (Rybelsus) formulations.
• Wegovy is indicated for weight reduction and weight upkeep in sufferers aged 12 years and older with weight problems; and for decreasing main cardiovascular occasion (MACE) dangers in adults with kind 2 diabetes with identified coronary heart illness.
• Ozempic is indicated to deal with kind 2 diabetes in adults to assist management blood sugar ranges together with eating regimen and train; for decreasing MACE dangers in adults with kind 2 diabetes with identified coronary heart illness; and to decrease the danger of kidney operate decline, kidney failure, and demise attributable to heart problems in adults with persistent kidney illness and kind 2 diabetes.
• Rybelsus is indicated to assist management blood sugar ranges in adults with kind 2 diabetes.
• Cagrilintide is a long-acting human amylin analogue, which has been discovered to be a promising strategy to weight reduction as a result of pure amylin is a pancreatic hormone that produces satiety.

“As soon as-weekly cagrilintide, a long-acting amylin analog that’s non-selective for the [calcitonin G protein-coupled receptor (CTR)] and amylin receptors, has proven promising weight-loss results in addition to enchancment in cardiometabolic elements,” wrote the authors of a research revealed by Cardiology in Assessment. “Cagrilintide 4.5 mg was proven to supply superior weight reduction than liraglutide 3.0 mg over a 26-week interval. Cagrilintide has been proven to be secure and tolerable each alone and together with the GLP-1 receptor analog semaglutide. The complementary MOAs of amylin-analog and GLP-1 receptor agonists look like a promising mixture remedy with larger weight reduction than some other at the moment authorised AOM and the potential to additional shut the hole with bariatric surgical procedure outcomes.”⁴

REDEFINE 1 Trial Design and Affected person Profile

• The 68-week, multicenter, double-blind, placebo- and active-controlled REDEFINE 1 trial, enrolled 3417 grownup sufferers with out diabetes and who’ve a body-mass index (BMI) of 30 or extra or a BMI of 27 or extra with at the least one obesity-related complication.
• Individuals had been randomly assigned in a 21:3:3:7 ratio to obtain the mix remedy with semaglutide administered at a dose of two.4 mg and cagrilintide at a dose of two.4 mg (n = 2108), semaglutide alone at a dose of two.4 mg (n = 302), cagrilintide alone at a dose of two.4 mg (n = 302), or placebo (n = 705), in addition to life-style interventions in every cohort.
• The trial’s coprimary endpoints had been relative change in physique weight and weight lack of 5% or extra from baseline by means of week 68 within the CagriSema cohort in comparison with placebo.
• Confirmatory secondary endpoints included weight lack of 20% or extra, 25% or extra, and 30% or extra.

Versatile Dosing Technique Helps Individualized Affected person Response

• Outcomes present that from baseline to week 68, sufferers within the CagriSema cohort achieved an estimated imply % change in physique weight of –20.4% in comparison with –3.0% within the placebo cohort (estimated distinction, –17.3 proportion factors; 95% confidence interval, –18.1 to –16.6; P
• The CagriSema cohort was discovered to be extra prone to attain weight-loss targets of 5% or extra, 20% or extra, 25% or extra, and 30% or extra in comparison with placebo.

“On this trial, a mixture strategy led to 60% of members reaching the goal weight lack of 20% or extra, and roughly one in 4 members (23%) had a weight lack of 30% or extra on the premise of the trial-product estimand (i.e., when members had been handled as supposed),” the research authors wrote in NEJM. “Statistical superiority of cagrilintide–semaglutide over placebo was noticed for all confirmatory secondary finish factors within the testing hierarchy, together with systolic blood strain and waist circumference; enhancements in lipid ranges had been additionally noticed.”¹

Security Profile Constant With GLP-1-Primarily based Therapies

• When it comes to security, gastrointestinal hostile occasions (AEs) had been reported in 79.6% of members within the CagriSema cohort in comparison with 39.9% within the placebo cohort.
• Probably the most continuously reported AEs included nausea, vomiting, diarrhea, constipation, or belly ache, which had been principally mild-to-moderate in severity and dissipated over time.

“On this trial, substantial body-weight loss was noticed, even though some members who had been randomly assigned to cagrilintide–semaglutide didn’t attain the goal dose of two.4 mg of every of the medication within the mixture or full the trial receiving this dose,” the research authors wrote. “This discovering means that doses under the goal is likely to be extremely efficient for some sufferers and that dose reductions primarily based on the medical judgment of research website investigators could also be acceptable; it additionally highlights the person responsiveness and variability within the medical response to therapy. These findings could also be related for medical apply, since dosing is commonly adjusted on the premise of particular person wants and medical judgment to attain the diploma of weight reduction that promotes well being. Additional analyses investigating the connection between weight-loss response and dose are warranted.”¹

References

1. Garvey W., et al. Coadministered Cagrilintide and Semaglutide in Adults with Chubby or Weight problems. N Engl J Med 2025; DOI: 10.1056/NEJMoa2502081.

2. A Analysis Examine to See How Effectively CagriSema Helps Individuals With Extra Physique Weight Lose Weight (REDEFINE 1). ClinicalTrials.gov. Up to date Could 28, 2025. Accessed June 30, 2025. https://clinicaltrials.gov/research/NCT05567796

3. FDA Approves New Drug Therapy for Continual Weight Administration, First Since 2014. FDA. Information launch. 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 Lengthy-Appearing Amylin Analog for the Therapy of Weight problems. Cardiology in Assessment 32(1):p 83-90, January/February 2024. DOI: 10.1097/CRD.0000000000000513.