June 22, 2025
5 min read
Key takeaways:
- CagriSema is a once-weekly combination of semaglutide and cagrilinitide.
- For adults with overweight or obesity, weight loss was up to 22.7% in those without diabetes and 13.7% in those with diabetes.
CHICAGO — The combination of once-weekly cagrilintide 2.4 mg and semaglutide 2.4 mg conferred greater weight loss at 68 weeks compared with placebo in patients with overweight or obesity with or without diabetes, researchers reported.
Results of the REDEFINE 1 trial comparing cagrilintide/semaglutide (CagriSema, Novo Nordisk) with placebo in patients with overweight or obesity and the REDEFINE 2 trial comparing CagriSema with placebo in patients with obesity and type 2 diabetes were presented at the American Diabetes Association Scientific Sessions and simultaneously published in The New England Journal of Medicine.
“[CagriSema] is a combination of a GLP-1 and an amylin analog,” Melanie J. Davies, CBE, MB, ChB, MD, FRCP, FRCGP, professor of diabetes medicine at the University of Leicester, United Kingdom, who presented the results of REDEFINE 2, told Healio. “Amylin analogs have been around, but not a long-acting one like this. We were wanting to look at the effects on weight and, in REDEFINE 2, glycemic control.”
REDEFINE 1
For REDEFINE 1, resesarchers randomly assigned in a 21:3:3:7 ratio 3,417 participants with overweight or obesity but without diabetes (mean age, 47 years; 67.6% women) to receive subcutaneous administration of CagriSema, semaglutide 2.4 mg alone (Wegovy, Novo Nordisk), cagrilintide 2.4 mg alone or placebo, respectively. All had a BMI of 30 kg/m2 or greater or 27 kg/m2 or greater with at least one obesity-related complication. The primary outcomes were change in body weight and percentage of patients with at least 5% reduction of body weight at 68 weeks.
At 68 weeks, the estimated mean percent change in body weight was –20.4% in the CagriSema group compared with –3% in the placebo group (estimated difference, –17.3 percentage points; 95% CI, –18.1 to –16.6; P < .001), according to W. Timothy Garvey, MD, FACE, MABOM, endocrinologist and professor at the University of Alabama (UAB) at Birmingham and principal investigator of the UAB Diabetes Research Center.
Average weight loss at 68 weeks was 11.5% in the cagrilintide-only group and 14.9% in the semaglutide-only group.
W. Timothy Garvey
Among participants who were fully adherent to their regimen, mean weight loss was –22.7% in the CagriSema group, and 40.4% of participants assigned CagriSema who were fully adherent lost at least 25% of body weight at 68 weeks.
Compared with the placebo group, the CagriSema group more often achieved weight loss of 5%, 20%, 25% and 30% at 68 weeks (P < .001 for all), Garvey and colleagues found.
The percentage of participants who achieved at least 25% weight loss was 34.7% in the CagriSema group, 14.8% in the semaglutide group and 6.5% in the cagrilintide group, while the percentage that achieved at least 30% weight loss was 19.3% in the CagriSema group, 8.7% in the semaglutide group and 1.6% in the cagrilintide group, according to the researchers.
Systolic blood pressure fell –9.9 mm Hg in the CagriSema group compared with –3.2 mm Hg in the placebo group (estimated between-group difference, 6.7 mm Hg; 95% CI, 7.8 to 5.6; P < .001) and diastolic BP fell –5.1 mm Hg in the CagriSema group and –1.9 mm Hg in the placebo group (estimated between-group difference, 3.2 mm Hg; 95% CI, 3.9 to 2.5), according to Garvey and colleagues. The researchers also found that the CagriSema group had greater changes in HbA1c, glucose, insulin, lipid and C-reactive protein levels than the placebo group.
In participants with prediabetes, 87.7% of the CagriSema group and 32.2% of the placebo group achieved normoglycemia by 68 weeks.
The prevalence of gastrointestinal side effects such as nausea, vomiting, diarrhea, constipation, abdominal pain or hepatobiliary conditions was 79.6% in the CagriSema group and 39.9% in the placebo group, with most events being mild to moderate and temporary, the researchers found.
REDEFINE 2
For REDEFINE 2, Davies and colleagues randomly assigned in a 3:1 ratio 1,206 participants with a BMI of 27 kg/m2 or greater and type 2 diabetes with an HbA1c of 7% to 10% to receive CagriSema or placebo, respectively. The primary endpoints were the same as in REDEFINE 1.
The mean age was 55.9 years in the CagriSema group and 56.5 years in the placebo group. Women comprised 47.5% of the CagriSema group and 46.4% of the placebo group.
At 68 weeks, in the treatment policy estimand, the estimated mean percent change in body weight was –13.7% in the CagriSema group compared with –3.4% in the placebo group (estimated difference, –10.4 percentage points; 95% CI, –11.2 to –9.5; P < .001), according to the researchers. For the trial-product estimand, the estimated mean percent change in body weight was –15.7% in the CagriSema group and –3.1% in the placebo group (estimated difference, –12.6 percentage points; 95% CI, –13.4 to –11.7), Davies and colleagues reported.
Participants in the CagriSema group were more likely than those in the placebo group to achieve weight loss of 5% (83.6% vs. 30.8%) and 20% (22.9% vs. 0.5%) at 68 weeks (P < .001 for both), the researchers found.
Changes in waist circumference and BMI also favored the CagriSema group, according to Davies and colleagues.
“The agent was able to achieve robust and clinically meaningful weight loss in patients with type 2 diabetes,” Davies told Healio. “In past studies, the weight loss we see in patients with type 2 diabetes is around 30% to 40% less than we see in people without diabetes. So 13.7% is amongst the best we’ve ever seen with a therapy, in terms of weight loss, in type 2 diabetes.”
The CagriSema group had greater reduction in HbA1c than the placebo group in the treatment-policy estimand (–1.8 percentage points vs. –0.4 percentage points; estimated difference, –1.4; 95% CI, –1.6 to –1.2; P < .001), Davies and colleagues found.
An HbA1c of 6.5% or less at 68 weeks was achieved by 73.5% of the CagriSema group and 15.9% of the placebo group, according to the researchers.
For the 199 participants with continuous glucose monitoring, the mean percentage of time spent in the glycemic target range at 86 weeks was 86.8% in the CagriSema group and 50.2% in the placebo group; both groups were below the target range less than 1% of the time, according to Davies and colleagues.
Change in systolic BP at 68 weeks favored the CagriSema group (estimated difference, –4.1 mm Hg; 95% CI, –6 to –2.1; P < .001), as did changes in diastolic BP, C-reactive protein and lipids, the researchers found.
Gastrointestinal adverse events occurred in 72.5% of the CagriSema group and 34.4% of the placebo group, and most events were mild to moderate and temporary, according to the results.
“We’ve got very powerful agents that are able to lower HbA1c and weight in patients with type 2 diabetes,” Davies told Healio. “These results are amongst the best we’ve ever seen. This is the second dual-approach agent after tirzepatide (Mounjaro/Zepbound, Eli Lilly) to show really good results. What sets [CagriSema] apart is the mechanism of action, with the amylin analog. In the continuous glucose monitoring subgroup, we saw it was very effective from a glycemic control perspective.”
The results on BP and other cardiovascular risk factors were encouraging, and “we haven’t seen it in human studies yet, but we know that it may impact on the metabolic adaptation that we see,” Davies told Healio. “It does seem to have an impact on energy expenditure that perhaps the other agents don’t have, and a theoretical benefit on body composition and bone. We will see if that bears out in the future.”
References:
For more information:
Melanie J. Davies, MD, can be reached at melanie.davies@uhl-tr.nhs.uk.