Almost half of adults worldwide now live with excess body fat, a figure projected to climb to 54% by 2035, and it drives type 2 diabetes, hypertension, dyslipidemia, osteoarthritis, and mood disorders. Long-term weight-management medications work best when paired with healthier eating habits and regular physical activity. Semaglutide mimics glucagon-like peptide 1 (GLP-1), whereas cagrilintide mimics the satiety hormone amylin, so each curbs appetite through a distinct pathway. Their combined effect in non-diabetic adults has not been tested in a phase 3 trial; hence, further research is needed.
In a recent study published in the New England Journal of Medicine, a group of researchers evaluated the effectiveness of a combined regimen of cagrilintide and semaglutide in reducing body weight and its safety for adults with obesity but without diabetes. The phase 3a, multicenter, randomized, double-blind, placebo- and active-controlled REDEFINE 1 trial enrolled 3,417 adults across 22 countries. Participants were allocated in a 21:3:3:7 ratio to weekly injections of 1 of 4 regimens: fixed-dose cagrilintide 2.4 mg plus semaglutide 2.4 mg, semaglutide alone, cagrilintide alone, or placebo.
All volunteers also received standardized lifestyle coaching on diet and exercise. Of the 3,417 randomized adults, 2,108 received the drug combination, 302 received semaglutide, 302 received cagrilintide, and 705 received a placebo. The mean age was 47 years; women comprised 67.6%, and most had dyslipidemia or hypertension at baseline. By week 68, 88.2% of those assigned to combination therapy remained on treatment. The combination produced a mean weight reduction of 20.4% under the treatment-policy estimand, versus 3.0% with placebo.
In the trial-product estimand analysis (accounting for treatment adherence), reductions reached 22.7% and 2.3%, respectively, corresponding to an absolute weight loss of -21.6 kg with combination therapy. Notably, 91.9% of the combination group lost at least 5% of baseline weight, while 53.6% lost ≥20%. Further, 34.7% achieved ≥25% loss, and 19.3% achieved ≥30% loss. By contrast, semaglutide alone yielded 14.8% of patients achieving ≥25% weight loss, and cagrilintide alone yielded 6.5%. BMI, waist circumference and waist-to-height ratio improved significantly with combination therapy.
Fat mass decreased by 17.0 kg with the combination, compared to 3.4 kg with the placebo, whereas lean mass decreased by 8.4 kg, compared to 2.6 kg. Cardiometabolic markers also shifted favorably. Systolic blood pressure declined by 9.9 mm Hg with the combination and 3.2 mm Hg with placebo (-6.7 mm Hg difference). Among prediabetic participants, 87.7% reverted to normoglycemia with the combination, compared with 32.2% on placebo. This trial highlights the potential of combining agents with complementary mechanisms to tackle obesity more effectively than single-drug therapies.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Davies MJ, Bajaj HS et al. New Engl J Med. 2025 Jun 22.
Garvey WT, Blüher M et al. New Engl J Med. 2025 Jun 22.
Patel JP, Hardaswani D et al. Cureus. 2025; 17(3):e80321.
