Coadministered Cagrilintide and Semaglutide in Adults with Overweight or Obesity

The REDEFINE-1 trial was the registrational phase 3, randomized, double-blind, placebo- and active-controlled study evaluating the CagriSema combination — weekly co-administration of cagrilintide 2.4 mg (long-acting amylin analogue) with semaglutide 2.4 mg (GLP-1 agonist) — in adults with overweight or obesity without type 2 diabetes. 3,417 participants with BMI >=30 (or >=27 with comorbidity) were randomized to CagriSema, cagrilintide, semaglutide, or weekly subcutaneous placebo over 68 weeks.

The primary endpoint was percentage change in body weight at 68 weeks:

• CagriSema: -20.4% vs. -3.0% with placebo (estimated difference -17.3 percentage points; P<0.001)
• With full adherence, mean loss was 22.7%
• 60% of patients on CagriSema achieved >=20% weight loss (vs. ~5% with placebo)
• 40.4% achieved >=25% and 23% achieved >=30% — levels previously associated only with bariatric surgery
• CagriSema was superior to both cagrilintide and semaglutide alone

Cardiometabolic benefits were robust: significant improvements in systolic blood pressure, waist circumference, lipid profile, and glycemic control (88% of prediabetic patients returned to normoglycemia). Gastrointestinal events were more common with CagriSema (79.6% vs. 39.9% with placebo), but predominantly mild to moderate and transient.

REDEFINE-1 established CagriSema as a new gold-standard therapy for obesity, surpassing the best results of current monotherapies (semaglutide ~15%, tirzepatide ~20-22%) and approaching bariatric surgery results. The combination demonstrated that simultaneous agonism of GLP-1 and amylin — pathways with complementary anorexigenic signaling (hypothalamus vs. brainstem) — produces a synergistic effect, validating a new therapeutic platform based on peptide combinations.