medwireNews: Combination treatment with cagrilintide and semaglutide (known as CagriSema) leads to clinically meaningful bodyweight reductions in adults with overweight or obesity, with or without type 2 diabetes, show data from the REDEFINE clinical trials.
The findings of the two phase 3a trials were reported at the 85th ADA Scientific Sessions in Chicago, Illinois, USA, and simultaneously published in The New England Journal of Medicine.
For REDEFINE 1, W Timothy Garvey (University of Alabama at Birmingham, USA) and colleagues enrolled 3417 adults (mean age 47 years, 68% women) without diabetes who had a BMI of 30 kg/m2 or higher, or a BMI of 27 kg/m2 or higher with at least one obesity-related complication.
They were randomly assigned to receive the CagriSema combination of subcutaneous semaglutide 2.4 mg plus cagrilintide 2.4 mg (n=2108), semaglutide monotherapy (n=302), cagrilintide monotherapy (n=302), or placebo (n=705) once weekly for 68 weeks. All groups were also given lifestyle advice.
At baseline, the mean bodyweight was 106.9 kg for the whole cohort. The researchers report that, by week 68, the estimated mean percent reduction in bodyweight from the baseline was significantly greater with CagriSema than with placebo, at 20.4% versus 3.0%. This corresponded to mean weight loss of 26.6 kg and 3.6 kg, respectively.
The mean percent reduction in bodyweight was also significantly greater with CagriSema than with semaglutide and cagrilintide monotherapy, where the reductions were 14.9% and 11.5%, respectively.
In addition, participants receiving CagriSema were significantly more likely than those receiving placebo to reach weight loss targets of at least 5%, 20%, 25%, and 30%. For example, 91.9% of participants in the CagriSema arm had a bodyweight reduction of at least 5% versus 31.5% of those in the placebo arm. For weight loss of at least 30%, the corresponding proportions were 19.3% and 0.4%.
The most common adverse events (AEs) were gastrointestinal in nature and occurred in 79.6% of people given CagriSema and 39.9% of those given placebo. These included nausea, vomiting, diarrhea, constipation, and abdominal pain, which were mainly transient and mild to moderate in severity. Fatigue, dizziness, alopecia, gallbladder-related disorders, and injection-site reactions were also more common with CagriSema than with placebo.
The REDEFINE 2 trial focused on people with type 2 diabetes. In this study, 1206 participants (mean age 56 years, 47% women) with a BMI of at least 27 kg/m2, a mean bodyweight of 102.2 kg, and a glycated hemoglobin level of 7–10% (53–86 mmol/mol) were randomly assigned to receive once-weekly CagriSema (2.4 mg each for each component; n=904) or placebo (n=302), along with lifestyle intervention, for 68 weeks.
Like the participants in REDEFINE 1, those given CagriSema in REDEFINE 2 experienced a significantly greater mean reduction in bodyweight from baseline to week 68 than those given placebo, at 13.7% versus 3.4%.
The proportion meeting weight-loss targets of at least 5%, 10%, 15%, and 20%, was also significantly higher with CagriSema than with placebo, report Melanie Davies (Leicester General Hospital, UK) and co-investigators. Specifically, 83.6% of participants in the CagriSema arm and 30.8% of those in the placebo arm experienced weight loss of 5% or more. For weight loss of 20% or more, the corresponding proportions were 22.9% and 0.5%.
In addition, CagriSema was associated with a significantly greater mean reduction in HbA1c than placebo, at 1.8 percentage points versus 0.4 percentage points. Moreover, almost three-quarters (73.5%) of participants given CagriSema had a glycated hemoglobin level of 6.5% (48 mmol/mol) or lower at week 68 compared with 15.9% of those given placebo, a significant difference.
Among other exploratory endpoints, the researchers found that participants given CagriSema had a significant 4.1 mmHg greater mean reduction in systolic blood pressure relative to those given placebo.
Gastrointestinal AEs were reported by 72.5% of the patients in the CagriSema group and 34.4% of those in the placebo group. As with the participants in REDFINE 1, most of these events were transient, and mild or moderate in severity, Davies et al remark.
Hypoglycemia events were uncommon, with level 2 hypoglycemic episodes reported in 6.0% of the patients in the CagriSema group and in 3.3% of those in the placebo group; level 3 episodes occurred in two (0.2%) patients in the CagriSema group, both of whom were also receiving sulfonylureas, and none of the placebo group.
The authors conclude: “These findings support the use of cagrilintide–semaglutide as a promising treatment option in this population with type 2 diabetes.”
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N Engl J Med 2025; doi:10.1056/NEJMoa2502081
N Engl J Med 2025; doi:10.1056/NEJMoa2502082
ADA 85th Scientific Sessions; Chicago, Illinois, USA: 20–23 June