Once-weekly subcutaneous administration of a fixed-dose combination of cagrilintide and semaglutide resulted in clinically meaningful weight loss and improved glycemic control in adults with obesity and type 2 diabetes, according to results from the REDEFINE 2 trial presented at the American Diabetes Association’s 85th Scientific Sessions and published in The New England Journal of Medicine.
In the double-blind, placebo-controlled phase 3a trial, 1206 patients were randomized 3:1 to receive once-weekly injections of cagrilintide 2.4 mg and semaglutide 2.4 mg (n = 904) or placebo (n = 302) for 68 weeks, in conjunction with lifestyle intervention. The coprimary end points were the percentage change in body weight and the proportion of patients achieving at least 5% weight loss.
By week 68, patients in the treatment group had a mean weight reduction of 13.7%, compared with 3.4% in the placebo group (difference, −10.4 percentage points; 95% CI, −11.2 to −9.5; P < .001). Clinically meaningful weight loss was more common among those receiving the active drug: 83.6% achieved ≥5% weight loss, 65.6% achieved ≥10%, 43.8% achieved ≥15%, and 22.9% achieved ≥20%, compared with 30.8%, 10.3%, 2.4%, and 0.5%, respectively, in the placebo group (all P < .001).
Improvements were also observed in glycemic outcomes. The mean reduction in glycated hemoglobin (HbA1c) was 1.8 percentage points with cagrilintide–semaglutide versus 0.4 percentage points with placebo (difference, −1.4; 95% CI, −1.6 to −1.2; P < .001). At week 68, 73.5% of patients in the treatment group achieved an HbA1c ≤6.5%, compared with 15.9% in the placebo group.
Among a subgroup of 199 patients undergoing continuous glucose monitoring, time in the target glycemic range (70–180 mg/dL) increased from 43.6% at baseline to 86.8% at week 68 in the treatment group. In the placebo group, time in range increased from 41.3% to 50.2%. The percentage of time below range (<70 mg/dL) remained <1% in both groups.
Additional treatment effects favored cagrilintide–semaglutide, including a reduction in waist circumference (−11.9 cm vs −3.6 cm), systolic blood pressure (−6.5 mm Hg vs −2.4 mm Hg), and improved physical function scores on both the IWQOL-Lite-CT (+16.1 vs +10.4) and the SF-36v2 (+5.0 vs +3.1) (all P < .001).
Gastrointestinal disorders were the most frequently reported adverse events, occurring in 72.5% of patients in the treatment group and 34.4% in the placebo group. These events were generally mild to moderate and occurred primarily during dose escalation. Adverse events led to treatment discontinuation in 8.4% of patients receiving cagrilintide–semaglutide, compared with 3.0% of those receiving placebo. Nausea and vomiting were the most common causes of discontinuation in the treatment group.
Hypoglycemia was infrequent. Level 2 hypoglycemic events (blood glucose <54 mg/dL) occurred in 6.0% of patients receiving cagrilintide–semaglutide and in 3.3% of those receiving placebo. Two level 3 events occurred in the treatment group, both in patients receiving concomitant sulfonylureas.
Although only 61.9% of patients in the treatment group were receiving the full 2.4-mg maintenance dose by the end of the trial, 75.9% received the maximum dose at some point. Weight and glycemic outcomes remained consistent regardless of final dose.
The fixed-dose combination of cagrilintide and semaglutide may represent a promising therapeutic option for adults with type 2 diabetes and overweight or obesity. Long-term studies are needed to assess durability of effect and safety.
Full trial results and disclosures are available in the published study.
