Appraisal of Cagrisema for Treatment of Obesity and Type 2 Diabetes

Mikhail N and Wali S

Published on: 2025-07-17

Abstract

The amylin receptor agonist, cagrilintide and the glucagon-like peptide 1 receptor (GLP-1R) semaglutide lower body weight and reduce hyperglycemia through multiple but overlapping mechanisms. CagriSema is a combination of cagrilintide and semaglutide injected once weekly and is under investigation for treatment of obesity and diabetes in a series of phase 3 trials called REDEFINE. In REDEFINE 1 and 2 trials, the 2 coprimary endpoints were the percent change in body weight and the proportions of participants with a weight reduction of ≥5% with CagriSema therapy after 68 weeks as compared with placebo. All subjects received same lifestyle intervention. In the REDEFINE 1 Study, the effect of CagriSema on body weight was compared with cagrilintide, semaglutide and placebo in overweight/obese subjects without diabetes. Compared with baseline, percent change in weight was -20.4%, -14.9%, -11.5%, and -4.0% with CagriSema, cagrilintide, semaglutide, and placebo, respectively. The difference in weight loss between CagriSema and placebo was -17.3% (95% -18.1 to -16.6%; P< 0.001). Percentage of participants achieving ≥5% weight reduction was 91.9% and 31.5% with CagriSema and placebo, respectively; difference 60.4% (95% CI, 56.4 to 64.5; P< 0.001). In the REDEFINE 2 Study, CagriSema was compared with placebo in overweight/obese patients with type 2 diabetes. After 68 weeks, weight change versus baseline was -13.7% and -3.4% with CagriSema and placebo, respectively. The difference in weight loss was -10.4% (95% CI, -11.2 to -9.5; P <0.001). Percentage of patients achieving ≥5% weight loss was 83.6% and 30.8% in the CagriSema and placebo group, respectively; difference 52.8% (95% CI, 46.7 to 58.9; P<0.001). Reduction in glycated hemoglobin (HbA1c) levels were -1.8% and -0.4% with CagriSema and placebo, respectively with a difference of -1.4% (95% CI, -1.6 to -1.2; P<0.001). CagriSema use was associated with favorable effects on blood pressure, lipids, and physical function. Discontinuation of CagriSema due to adverse effects occurred in 5.9-8.4% of subjects versus 3.0-3.5% with placebo. The most common adverse effects of CagriSema were gastrointestinal (GE) in origin. Hypoglycemia was uncommon with CagriSema but increased in frequency and severity when used in conjunction with sulfonylureas (SUs). CagriSema is a promising drug combination for treatment of obesity with and without diabetes. Further studies are needed to investigate its efficacy and safety in a broader spectrum of patients with diabetes.