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NEW ORLEANS — CagriSema (Novo Nordisk), a novel, once-weekly injectable combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide, increased benefits in weight loss and A1c in patients with type 2 diabetes (T2D) compared to placebo or either of the individual therapies taken separately, according to a trio of phase 3 clinical trials. 

These benefits extended to patients with T2D on insulin.

Since CagriSema showed greater reductions in weight and A1c than semaglutide at the same dose level, it allows us “to expand our toolkit in the management of people living with diabetes,” said Akshay Jain, MD, of the Department of Medicine, University of British Columbia, Vancouver, Canada, lead author of REIMAGINE 2, one of the three trials evaluating CagriSema’s effects.

The double-blind, randomized REIMAGINE trials looked at CagriSema compared to placebo in patients with T2D (trial 1); CagriSema compared to either cagrilintide or semaglutide alone in patients with T2D plus overweight/obesity (trial 2); and the combination therapy compared to placebo in patients with T2D who use insulin (trial 3). 

The findings of all three trials were presented at the American Diabetes Association (ADA) 2026 Scientific Sessions. Each study was also published separately this week in The Lancet. 

These trials follow the REDEFINE trials that looked at CagriSema compared to placebo in patients with obesity, and in patients with obesity and T2D. The results, presented last year at ADA 2025, showed weight-loss, glycemic control, and cardiometabolic benefits in both trials, although weight loss was less than hoped for.

Combination CagriSema vs Placebo 

For the REIMAGINE 1 study, 189 patients with T2D uncontrolled by diet or exercise in six countries were randomly assigned to receive a fixed-dose, once-weekly injection of CagriSema at 2.4 mg for each drug (n = 62) , at 1.0 mg for each drug (n = 63), or placebo (n = 64). 

Of the patients, 54% were male, mean baseline A1c was 7.8%, and mean BMI was 35.2.

For the primary outcome, the estimated mean reductions in A1c over 40 weeks of treatment was 1.8% in the 2.4-mg CagriSema group and 1.5% in the 1.0-mg combination group, vs -0.1% in the placebo group (both dose groups, P < .0001) according to the efficacy estimand.

In terms of the estimated mean relative change in body weight, the change at week 40 was 13.8% in the 2.4-mg treatment group and 11.8% in the 1-mg group, vs 1.4% reduction in the placebo group (both, P < .0001).

The safety profile of CagriSema was consistent with that of GLP-1 receptor agonists and multi-agonists, with no new safety or tolerability issues identified, first author Vanita R. Aroda, MD, of the Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, said in presenting the findings.

Furthermore, no level 3 hypoglycemic events occurred in any treatment arm.

Combination vs Monotherapy 

The REIMAGINE 2 study enrolled 2728 patients in 30 countries with T2D and overweight or obesity. All patients had blood glucose that was not well controlled with metformin, with or without an SGLT2 inhibitor.

Of the participants, 57.1% were male, mean baseline A1c was 8.2%, and mean BMI was 35.1; 39% were on SGLT2 inhibitors, and 98% were on metformin at baseline.

Patients were randomized to receive once-weekly CagriSema 2.4 mg (n = 603), semaglutide 2.4 mg alone (n = 605), cagrilintide 2.4 mg alone (n = 152), CagriSema 1.0 mg (n = 595), semaglutide 1.0 mg alone (n = 609), or placebo (n = 149). 

For the primary endpoint, after 68 weeks of treatment, those treated with CagriSema 2.4 mg had a significantly greater mean reduction in A1c vs those treated with semaglutide 2.4 mg alone (-1.91% vs -1.75, for an estimated treatment difference of -0.16%; P = .0035), according to the efficacy estimand.

In comparisons of change in body weight, those receiving CagriSema 2.4 mg had a reduction of 14.2% at 68 weeks, compared with a reduction of 10.2% with semaglutide 2.4 mg alone and 8.4% with cagrilintide alone (P < .0001 for each vs CagriSema). Weight loss in the placebo group was 1.5%.

The safety profiles between the treatment groups were similar, with adverse events (AEs) ranging from 78.5% in the semaglutide 1.0 mg group to 86.9% in the CagriSema 2.4 mg group, consistent with the GLP-1 receptor agonist class and with previous data for cagrilintide. The rate of AEs was 70.5% in the placebo group.

“This was the first study in [T2D] to compare the efficacy and safety of CagriSema versus its individual components (semaglutide and cagrilintide) or placebo,” Jain said.

Overall, “CagriSema provided added benefits versus its monocomponents in adults with [T2D] inadequately controlled on metformin and SGLT2 inhibitors,” he concluded.

Comparison With Tirzepatide Anticipated 

Echoing comments expressed during the session about interest in further head-to-head comparisons, Andre J. Scheen, MD, of the Division of Diabetes, Nutrition and Metabolic Disorders, CHU Liège, Belgium, wrote in an editorial published concurrently with the study in The Lancet, that “from a clinical point of view, a comparison with the dual agonist tirzepatide would be of major interest.”

He noted that in the phase 3 REDEFINE 4 trial, patients with obesity treated with CagriSema 2.4 mg showed a 23.0% decrease in bodyweight, compared with 25.5% with tirzepatide 15 mg over 84 weeks, which did not achieve noninferiority.

“Such a head-to-head study that will compare the efficacy and safety of [CagriSema] and tirzepatide in patients with [T2D] would help to better define the future place of [CagriSema] in the management of [T2D],” Scheen wrote. 

Effects in Insulin-Treated T2D 

Finally, the REIMAGINE 3 study evaluated the effects of the CagriSema in patients with T2D treated with insulin — a population known to have a higher risk of weight gain and hypoglycemia. 

That study included 274 patients (58% male) in six countries with T2D and a mean baseline A1c of 8.8%. All patients were receiving stable doses of once-daily basal insulin with or without metformin.

The mean diabetes duration was 14.9 years, mean BMI was 31.6, and the mean age was 59 years.

For the primary endpoint of mean change in A1c from baseline to week 40, the study showed those treated with CagriSema 2.4 mg (n = 90) had a mean reduction of -2.33%, the 1.0-mg group (n = 93) had a reduction of -2.10%, and the placebo group had a reduction of -0.66% (P < .0001 for both doses), according to the efficacy estimand.

In addition, those in the CagriSema groups had mean reductions in body weight of 12% and 10% for the 2.4-mg and 1.0-mg groups, respectively, vs a gain of 1.1% in the placebo group.

In further weight-loss results, at least a 5% reduction in body weight was achieved by 78% in the CagriSema 2.4-mg group, 73% in the 1.0-mg group, and 5% in the placebo group. More than half of treatment groups achieved a targeted ≥ 10% reduction in body weight: 59% for the 2.4-mg group and 51% for 1 mg. Two percent of the placebo group met this threshold.

At least a 15% reduction in body weight was achieved in 33% and 24% in the 2.4-mg and 1.0-mg groups, respectively, over the 40-week study vs 1% with placebo (all P < .0001).

Of note, those treated with both doses of CagriSema also had significantly greater improvements in cardiometabolic parameters, including C-reactive protein and systolic and diastolic blood pressure, vs placebo.

AEs ranged from 71% and 80% in the CagriSema 1.0-mg and 2.4-mg groups, respectively, and 71% in the placebo groups, which were described as mostly mild or moderate gastrointestinal disorders.

No severe hypoglycemia events were reported.

The results with insulin-treated patients indicate “CagriSema, when available, may become a solid option to advance basal insulin therapy in inadequately controlled [T2D] to achieve potentially greater A1c reductions and weight loss than previously shown with a GLP-1 RA,” said first author Julio Rosenstock, MD, of the Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, in presenting the findings.

Potentially Important Shift in Management of T2D 

Noting that findings on cardiovascular outcomes with CagriSema from ongoing studies — including the REDEFINE 3 trial — are still anticipated, the current results suggest a potentially important shift in therapeutic management of T2D, wrote the authors of an editorial accompanying the study in The Lancet.

“If substantiated, REIMAGINE 3 might ultimately be remembered not as another study of glycemic control, but as an early signal of a broader transition in advanced [T2D] care — from progressive insulin replacement towards integrated multihormone approaches addressing the wider cardiometabolic burden of disease,” they said.

Further commenting, Marlon Pragnell, PhD, the ADA’s vice president of research and science, noted that, “it’s great to see such innovation, with multiple therapeutic options in the pipeline right now, and I think we’re heading in the right direction for being able to more precisely treat patients.”

“Whether patients have prediabetes or diabetes or obesity, more choices in effective therapies at a variety of doses will be a win for patients and clinicians, alike.”

The studies were sponsored by Novo Nordisk. 

Aroda reported institutional contracts with Amgen, Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Corcept Therapeutics, Eli Lilly, Fractyl Health, Kailera, Novo Nordisk, Pfizer, Recordati, Rhythm Pharmaceuticals, and Servier; and consulting for Baim Institute for Clinical Research, Mediflix, Roche, and Sanofi. 

Scheen reported speaker fees from Eli Lilly, Novo Nordisk, and Boehringer Ingelheim. 

Jain’s disclosures included advisory panel, speaker’s bureau and/or research support from Abbott, Eli Lilly, Novo Nordisk, Sanofi, AstraZeneca, Dexcom, Eisai, embecta, Roche Canada, and Boehringer Ingelheim. 

Rosenstock’s disclosures include consulting and/or other relationships with Applied Therapeutics, AstraZeneca, Biomea Fusion, Boehringer Ingelheim, Corcept, Eccogene, Ell Lilly, Ferring, Hanmi, Merck, Novartis, Novo Nordisk, Oramed, Pfizer, Regeneron Pharmaceuticals, Regor, Roche, Sanofi, Structure Therapeutics, and Terns. 

Pragnell had no disclosures to report.