CHICAGO — CagriSema, a new weekly injection from Novo Nordisk combining the amylin analogue cagrilintide with the GLP-1 receptor agonist semaglutide, significantly reduced weight and improved glycemic control and cardiometabolic measures in individuals with overweight/obesity and both overweight/obesity and type 2 diabetes, new research showed.
In REDEFINE 1, patients with overweight/obesity without diabetes who were treated with CagriSema achieved a 20.4% weight loss at 68 weeks, compared to 3% for those on placebo. In REDEFINE 2, patients with overweight/obesity and those with both overweight/obesity and diabetes who were treated with CagriSema achieved 13.7% weight loss at 68 weeks, compared to 3.4% of those on placebo.
Both phase 3 studies were presented at the American Diabetes Association (ADA) 85th Scientific Sessions and simultaneously published online in the The New England Journal of Medicine.
The weight loss was not as large as has been seen with some GLP-1s alone, such as with tirzepatide, nor did it meet Novo Nordisk’s projections of a 25% reduction.
However, study investigator Timothy Garvey, MD, professor of medicine and director of the Diabetes Research Center at the University of Alabama at Birmingham, who presented data from REDEFINE 1, said in a press release that CagriSema “provided weight loss in the highest range of efficacy observed with existing weight loss interventions,” and that “regardless of dose adjustments participants lost significant weight.”
Asked to comment by Medscape Medical News, Samar Hafida, MBCCh, vice president of the ADA’s Obesity Association, said a 20% reduction was not disappointing.
The focus on weight loss percentage is misplaced, said Hafida, who is also assistant professor of medicine at the Boston University Chobanian & Avedisian School of Medicine in Massachusetts.
“It’s too much of a numbers game,” she added. “Sometimes 10% loss in total body weight leads to amazing outcomes.”
Study presenter, Louis Aronne, MD, the Sanford I. Weill professor of metabolic research at Weill-Cornell Medical College, New York, New York, agreed.
Release of top-line results in March fueled disappointment in some quarters, in particular on Wall Street, he said, but he countered: “These are spectacular results.”
For patients with obesity and diabetes, CagriSema looked to be “best in class,” said Aronne, adding “I’d ask anyone criticizing this to do better.”
REDEFINE 1
The REDEFINE 1 trial enrolled 3417 adults without diabetes with a BMI ≥ 30 or ≥ 27 with one obesity-related complication. A total of 2108 participants were randomly assigned to receive CagriSema, a fixed dose combination of 2.4 mg of cagrilintide with 2.4 mg of semaglutide; 302 to receive 2.4 mg of semaglutide alone; 302 to receive 2.4 mg of cagrilintide alone; and 705 to receive placebo.
Almost three-quarters of patients in each group were White, about 18% were Asian, and 70% were female. The mean BMI was 38.
Investigators were allowed to adjust dose based on side effects, and, in some cases, due to excessive weight loss. At week 68, slightly more than half of those getting CagriSema were receiving the maximum dose, compared to 71% of the semaglutide group and 82% of the cagrilintide group.
CagriSema patients lost more weight than those taking either component alone: 20.4% for the combination vs 11.5% with cagrilintide, 14.9% with semaglutide, and 3% with placebo. About half of those who had obesity at baseline were considered nonobese at the end of the study (with 23% moving to normal weight).
A concern with GLP-1s has been loss of muscle mass co-occurring with fat loss. To gauge where weight loss was occurring, researchers prespecified that 252 of the participants would receive DEXA scans. The scans showed that 67% of total weight loss corresponded to fat mass and 33% to lean soft-tissue mass.
“That’s reassuring,” said Garvey, during his presentation.
REDEFINE 2
The REDEFINE 2 trial enrolled 1206 adults with overweight/obesity and type 2 diabetes, 904 of whom were randomized to CagriSema and 302 to placebo. The mean age was 56, half were men, two-thirds were White, and 346 (29%) were Asian. Patients’ mean BMI was 36.2, and the mean A1C was 8.0%. Forty-one percent of patients were taking one glucose-lowering medication, and 40% were taking two such medications, most commonly metformin (85.9% of patients), SGLT2 inhibitors (33.4%), and sulfonylureas (26.9%).
Sixty-six percent of those taking CagriSema had a greater than 10% weight reduction, compared to only 10% of patients in the placebo group. Patients taking CagriSema also had a reduction of A1C of 1.8%, compared to 0.4% for placebo.
Thirty-five percent of those taking CagriSema had a reduction in glucose-lowering medication intensity, compared to 8% of those taking placebo. The treatment group also had greater increases in time spent in glycemic target range, moving from 44% at baseline to 87% at the study’s end.
“The results are robust,” said Caroline Apovian, MD, professor of medicine at Harvard Medical School and co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital, Boston.
“Roughly speaking, adding cagrilintide to semaglutide increases total weight loss by an average of 5%,” Apovian told Medscape Medical News.
But it was still not as powerful an additive effect as would have been expected, said Aronne. It’s not clear why, but there could be physiological reasons — such as a potential limit to dual agonism — he said.
He also noted that the make-up of the trial populations in both REDEFINE 1 and 2 could affect results. For instance, both had a large proportion of Asians, who tend to be leaner to start, and thus might not lose as much weight.
Will Side Effects be Limiting?
Overall, 92% of patients taking CagriSema in REDEFINE 1 and 90% of those in REDEFINE 2 had an adverse event. Side effects led 6% of patients in REDEFINE 1 and 8% of those in REDEFINE 2 to stop taking the medication.
As seen with previous studies of GLP-1s, the most common adverse events were gastrointestinal, including nausea, constipation, and vomiting.
Apovian said that adverse events “have limited real world use of semaglutide and tirzepatide,” but that they have been managed through close physician follow-up and consultations with dietitians for recommendations that “mitigate some of these side effects.”
Clinicians have also used slower titration to reduce side effects, she said.
Apovian expects CagriSema to be another option for obesity treatment. “We have seen in the real world the benefit of having [both] semaglutide and tirzepatide as patients who may lose less weight than expected or have side effects [on one] can then do well with the other agent,” she said.
“Until research provides more data on precision obesity care, we will not really know beforehand which patient will do well with which agent,” she said.
Hafida said that until access improves, the choices will be limited also. Even if she and her patient agree that a particular medication is the best treatment, “there’s nothing I can do if their insurance is not going to cover it,” said Hafida.
Novo Nordisk has said it would seek FDA approval for CagriSema in early 2026.
The studies were funded by Novo Nordisk. Aronne made multiple disclosures, including advisory and consulting roles from Eli Lilly and Novo Nordisk. Garvey disclosed that he is an adviser for Boehringer-Ingelheim, Eli Lilly, and Novo Nordisk, among other companies. Apovian has served as an advisory board member Eli Lilly, L-Nutra, Novo Nordisk, and Nutrisystem, among others. Hafida reported no conflicts.
Alicia Ault is a Saint Petersburg, Florida-based freelance journalist whose work has appeared in many health and science publications, including Smithsonian.com. You can find her on X @aliciaault and on Bluesky @aliciaault.bsky.social.