Efficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a randomised, double-blind, placebo-controlled, phase 3a study.
REIMAGINE 1 was a randomised, double-blind, placebo-controlled phase 3a trial evaluating once-weekly subcutaneous cagrilintide-semaglutide (CagriSema) — a combination of an amylin receptor agonist (cagrilintide) and a GLP-1 receptor agonist (semaglutide) — in 189 adults with type 2 diabetes inadequately controlled by diet and exercise alone. Conducted across 42 sites in six countries over 40 weeks, participants were assigned to one of two active dose levels or matched placebo. The primary endpoint was change in HbA1c from baseline to week 40. The study found that both active dose levels produced statistically significant and clinically meaningful reductions in HbA1c compared to placebo (estimated treatment differences of −1.7 and −1.4 percentage points for the higher and lower doses, respectively; p<0.0001 for both). Body weight reduction was a notable secondary finding. The safety profile was described as consistent with the GLP-1 receptor agonist class. Key limitations include the relatively small sample size (n=189), short 40-week duration, an early-stage diabetes population not on background glucose-lowering medications, and industry funding from Novo Nordisk, which may introduce bias. These results suggest CagriSema may be a promising therapeutic option for early-stage type 2 diabetes.
Why this grade: This is a randomised, double-blind, placebo-controlled phase 3a trial in humans with a relevant clinical endpoint, but the relatively small sample size (n=189) and single 40-week trial duration limit the strength of evidence to moderate rather than strong.
Background Cagrilintide-semaglutide (CagriSema) is a novel, once-weekly combination of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide. We aimed to assess the efficacy and safety of cagrilintide-semaglutide for people with type 2 diabetes inadequately controlled with diet and exercise. Methods REIMAGINE 1 was a randomised, double-blind, parallel-group, phase 3a study carried out at 42 sites (study sites included university hospitals, health-care centres, research centres, and other centres) in six countries. Adults aged 18 years or older with type 2 diabetes inadequately controlled with diet and exercise were randomly assigned (2:1:2:1) to receive once-weekly subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (cagrilintide-semaglutide [2·4 mg each]), placebo 2·4 mg plus 2·4 mg, cagrilintide 1·0 mg plus semaglutide 1·0 mg (cagrilintide-semaglutide [1·0 mg each]), or placebo 1·0 mg plus 1·0 mg for 40 weeks. Randomisation was done using a web-based system with a block size of six and stratified according to HbA 1c less than 8·5% at screening and participation in the MRI substudy. Participants, care providers, investigators, and outcome assessors were masked within dose level and all participants received visually identical injections to maintain masking throughout the study. The primary endpoint was change in HbA 1c from baseline to week 40 in the full analysis set; safety was assessed in all participants who received at least one dose of the trial product. Change in bodyweight from baseline to week 40 was a prespecified secondary endpoint. This study is registered with ClinicalTrials.gov, NCT06323174, and is complete. Findings Between March 19 and Dec 5, 2024, 294 people were screened for eligibility, 189 of whom were enrolled and randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=62), cagrilintide-semaglutide (1·0 mg each; n=63), or placebo (n=64). 103 (54%) of 189 were male, 86 (46%) were female, 147 (78%) were White, and 26 (14%) were Asian. Baseline mean HbA 1c was 7·8% (SD 0·7) and BMI was 35·2 kg/m 2 (7·4). Using the efficacy estimand, the estimated mean change in HbA 1c after 40 weeks was -1·8 percentage points (SE 0·1) with cagrilintide-semaglutide (2·4 mg each), -1·5 percentage points (0·1) with cagrilintide-semaglutide (1·0 mg each), and -0·1 percentage points (0·2) with placebo. This corresponded to an estimated treatment difference of -1·7 percentage points (95% CI -2·0 to -1·3; p Interpretation In a population of people with early-stage type 2 diabetes inadequately controlled with diet and exercise, cagrilintide-semaglutide (2·4 mg each and 1·0 mg each) was superior to placebo in reducing HbA 1c . The safety profile was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide. These findings support cagrilintide-semaglutide as a potential novel and effective therapeutic intervention for people with early-stage type 2 diabetes. Funding Novo Nordisk.
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