Cagrilintide-semaglutide tied to weight loss in adults with obesity, T2D

Combination treatment with cagrilintide and semaglutide significantly reduced body weight in patients with overweight or obesity and type 2 diabetes (T2D), according to the REDEFINE 2 trial presented at EASD 2025.

For the treatment policy estimand, the mean percent change in body weight from baseline to week 68, which is the first primary endpoint of the study, was significantly greater in patients receiving cagrilintide-semaglutide compared with placebo (-13.7 percent vs -3.4 percent; estimated treatment difference [ETD], -10.4 percent; p<0.0001).

Similarly, the trial-product estimand yielded comparable results, with the cagrilintide-semaglutide group achieving a 15.7-percent reduction in body weight compared with a 3.1-percent reduction in the placebo group (ETD, -12.6 percent; p<0.0001).

At week 68, significantly more patients on cagrilintide-semaglutide also achieved the second primary endpoint of ≥5 percent weight loss than those on placebo (89.7 percent vs 30.2 percent).

Furthermore, a higher percentage of patients in the cagrilintide-semaglutide group achieved weight loss thresholds of ≥10, ≥15, and ≥20 percent (74.1 percent vs 9.1 percent, 51.6 percent vs 1.5 percent, and 29.2 percent vs 0.2 percent, respectively) than those in the placebo group.

Overall, treatment with “once-weekly cagrilintide-semaglutide (at a dose of 2.4 mg each) provided clinically meaningful weight reduction in adults with overweight or obesity and T2D,” said lead author Prof Melanie Davies from the University of Leicester, UK.

This phase IIIa, multicentre, double-blind, placebo-controlled trial included 1,206 patients (mean age 56 years, 52.8 percent male) with overweight or obesity (mean BMI 36.2 kg/m²) and T2D (mean HbA_1c 8 percent), with a T2D duration of 8.5 years. Participants were randomized in a 3:1 ratio to receive once-weekly cagrilintide-semaglutide (2.4 mg each; n=904) or placebo (n=302) in addition to lifestyle intervention for 68 weeks. [EASD 2025, abstract 73]

Glycaemic parameters

From baseline to week 68, the mean HbA_1c level was significantly reduced by 1.8 percent in the cagrilintide-semaglutide group compared with 0.4 percent in the placebo group (ETD, -1.4 percent; p<0.0001), with more patients on the combination regimen achieving an HbA_1c threshold of <7 (89.6 percent vs 22.6 percent) or ≤6.5 percent (81 percent vs 12.1 percent).

Moreover, nearly half of cagrilintide-semaglutide recipients achieved normoglycaemia (HbA_1c of <5.7 percent) compared with placebo recipients (39.2 percent vs 2.6 percent).

In a subgroup of 199 patients using continuous glucose monitoring (CGM), the percentage of time spent in the glycaemic target range (>3.9–10 mmol/L or >70–180 mg/dL) increased from 43.6 percent at baseline to 86.8 percent at week 68 with cagrilintide-semaglutide compared with 41.3 percent at baseline and 50.2 percent at week 68 with placebo.

Davies noted that the CGM data showed little changes in glycaemic stability at baseline and at weeks 24 and 68. In contrast, cagrilintide-semaglutide showed a significant flattening of the glucose curves by week 24, which persisted through week 68.

“Cagrilintide-semaglutide (2.4 mg each) provided clinically relevant improvements in glycaemic parameters, including HbA_1c and CGM metrics, achieving near-normoglycaemic control,” said Davies.

Additional endpoints

In terms of cardiometabolic parameters, cagrilintide-semaglutide recipients had greater reductions in systolic blood pressure (-7.6 vs -2.2 mm Hg), hsCRP* (-65.5 percent vs -22.2 percent), triglycerides (-32.7 percent vs -8.2 percent), and VLDL** (-32 percent vs -7.8 percent), along with a notable increase in HDL*** (14.1 percent vs 3.8 percent) than placebo recipients at week 68.

Regarding quality of life, a significant improvement in physical functioning, measured by the mean change in SF-36v2 scores from baseline to week 68, was observed in the cagrilintide-semaglutide compared with the placebo group (5.2 vs 3; ETD, 2.2; p<0.0001). In fact, those with poor physical function at baseline showed even greater improvement with the combination regimen than with placebo at the end of the study (8.4 vs 3.2; ETD, 5.2; p<0.0027).

Safety

Adverse events (AEs) occurred in 90.2 percent of patients in the cagrilintide-semaglutide group vs 85.4 percent in the placebo group.