A fixed-dose combination of the novel amylin receptor agonist cagrilintide and the approved GLP-1 receptor agonist semaglutide (CagriSema) yields better HbA1c control and weight loss in patients with type 2 diabetes (T2D) than either therapy alone or placebo in three phase III trials from the global REIMAGINE programme presented at ADA 2026. The benefits also extend to patients on insulin therapy.
CagriSema, administered once weekly by injection, performed well at doses of 2.4 or 1.0 mg of each drug across the REIMAGINE 1, 2, and 3 trials.
REIMAGINE 1: CagriSema vs placebo
In the REIMAGINE I trial of 189 patients with early T2D, both the 2.4 mg and 1.0 mg doses of CagriSema led to HbA1c reductions of 1.8 and 1.5 percentage points from baseline to week 40, compared with a reduction of -0.1 percentage point for placebo, corresponding to treatment differences of 1.7 and 1.3 percentage points, respectively (p<0.0001 for both). [Lancet Diabetes Endocrinol 2026:S2213-8587(26)00126-9]
Change in body weight also favoured CagriSema (13.8 percent in the 2.4-mg group and 11.8 percent in the 1-mg group vs 1.4 percent in the placebo group; p<0.0001 for both). “This corresponds to estimated treatment differences of 12.4 and 10.4 percentage points for the higher and lower doses, respectively (p<0.0001 for both),” reported Dr Vanita Aroda from Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts, US.
Traditional cardiometabolic risk factors, including blood pressure and C-reactive protein, also improved, and no new safety signals beyond those previously observed were reported.
Patients in the REIMAGINE 1 trial had T2D inadequately controlled with diet or exercise. They were randomly assigned to receive CagriSema 2.4 mg of each drug (n=62), 1.0 mg of each drug (n=63), or placebo (n=64). At baseline, mean HbA1c was 7.8 percent, mean BMI was 35.2 kg/m², and 54 percent of patients were male.
“In this early disease population of T2D, CagriSema demonstrated fairly robust holistic disease-modifying properties that could be relevant for the course and trajectory of the disease,” said Aroda.
REIMAGINE 2: CagriSema better than either drug alone
CagriSema’s benefits extend beyond the early stage of T2D. In the REIMAGINE 2 trial, the fixed-dose combination reduced HbA1c and body weight more effectively than either drug alone in patients with overweight or obesity who had progressed on standard T2D medications.
After 68 weeks of treatment, patients on CagriSema 2.4 mg had a significantly greater mean reduction in HbA1c than those treated with semaglutide 2.4 mg alone (-1.91 percent vs -1.75 percent, for an estimated treatment difference of -0.16 percent; p=0.0035). [Lancet Diabetes Endocrinol 2026;S2213-8587(26)00125-7]
Patients receiving CagriSema 2.4 mg had the greatest reduction in body weight at 14.2 percent vs 10.2 percent with semaglutide 2.4 mg alone and 8.4 percent with cagrilintide alone (p<0.0001 for each vs CagriSema). Those on placebo only lost 1.5 percent of body weight.
In patients using CGM, CagriSema also improved time in target range and time in tight range. Further, the safety profile of CagriSema was comparable to that reported in previous trials of CagriSema and cagrilintide, and the known safety profile of semaglutide.
“This was the first study in [T2D] comparing the efficacy and safety of CagriSema with its individual components [semaglutide and cagrilintide] or with placebo,” said study author Dr Akshay Jain from the University of British Columbia, Canada. “Overall, CagriSema provided additional benefits over its monocomponents in adults with [T2D] inadequately controlled on metformin and SGLT2 inhibitors.”
Patients in the REIMAGINE 2 trial (n=2,728) had T2D with overweight or obesity and inadequately controlled blood glucose on metformin, with or without an SGLT2 inhibitor. Mean baseline HbA1c was 8.2 percent, and mean BMI was 35.1 kg/m². Thirty-nine percent were on SGLT2 inhibitors; 98 percent were on metformin. [Lancet Diabetes Endocrinol 2026;S2213-8587(26)00125-7]
Patients were randomly assigned to receive 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 68 weeks.
REIMAGINE 3: CagriSema as an add-on to insulin
When tested as an add-on to basal insulin treatment in the REIMAGINE 3 trial, CagriSema met the primary endpoint, with statistically significant and clinically relevant reductions in HbA1c vs placebo.
At week 40 after CagriSema treatment, patients with T2D inadequately controlled on basal insulin, with or without metformin, had HbA1c reductions of 2.33 and 2.10 percentage points with CagriSema 2.4 mg and 1.0 mg, respectively vs 0.66 percentage points with placebo (p<0.0001). [Lancet 2026;408:38-51]
“This benefit was accompanied by robust weight loss and no additional risk of hypoglycaemia,” reported Dr Julio Rosenstock of the University of Texas Southwestern Medical Center in Dallas, Texas, US at ADA 2026.
The study included 274 patients with a diabetes duration of 15 years. Their mean age was 59 years, and nearly 60 percent were male. Mean baseline HbA1c was 8.8 percent, and mean BMI was 31.6 kg/m².
“As we seek more robust options for T2D beyond insulin-based therapies, it is important to note that the safety and tolerability profile of CagriSema was consistent with that observed in previous GLP-1 RA trials,” Rosenstock said. “CagriSema may become a solid option to basal insulin in inadequately controlled T2D, with potentially greater HbA1c reductions and weight loss than previously shown with a GLP-1 RA.”
In a related editorial, Dr Daniël van Raalte of Amsterdam University Medical Centers, Amsterdam, and Dr Marcel Muskiet of Leiden University Medical Center, Leiden, both in the Netherlands, commented that if substantiated, REIMAGINE 3 might ultimately be remembered “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.” [Lancet 2026;408:3-5]