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.
Cagrilintide-semaglutide showed significant reductions in HbA1c and body weight compared to placebo in adults with type 2 diabetes inadequately controlled by diet and exercise.
Where it sits
this study against the rest of the cagrilintide (am833) corpusSummary and findings
This study assessed the efficacy and safety of cagrilintide-semaglutide in adults with type 2 diabetes inadequately controlled on diet and exercise. Participants received either cagrilintide-semaglutide (2.4 mg each), cagrilintide-semaglutide (1.0 mg each), or placebo for 40 weeks. The findings indicated a reduction in HbA1c levels and body weight compared to placebo.
Abstract
<h4>Background</h4>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.<h4>Methods</h4>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<sub>1c</sub> 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<sub>1c</sub> 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.<h4>Findings</h4>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<sub>1c</sub> was 7·8% (SD 0·7) and BMI was 35·2 kg/m<sup>2</sup> (7·4). Using the efficacy estimand, the estimated mean change in HbA<sub>1c</sub> 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<0·0001) for cagrilintide-semaglutide (2·4 mg each) versus placebo and -1·3 percentage points (-1·8 to -0·9; p<0·0001) for cagrilintide-semaglutide (1·0 mg each) versus placebo. Cagrilintide-semaglutide was superior to placebo with respect to estimated mean relative change in bodyweight from baseline to week 40 for cagrilintide-semaglutide (2·4 mg each; -13·8% [SE 1·0]) versus placebo (-1·4% [0·7]; estimated treatment difference -12·4 percentage points [95% CI -14·7 to -10·1]; p<0·0001) and cagrilintide-semaglutide (1·0 mg each; -11·8% [1·0]) versus placebo (-1·4% [0·7]; estimated treatment difference -10·4 percentage points [-12·9 to -8·0]; p<0·0001). Adverse events were reported by 49 (79%) of 62 participants in the cagrilintide-semaglutide (2·4 mg each) group, 47 (75%) of 63 in the cagrilintide-semaglutide (1·0 mg each) group, and 42 (66%) of 64 in the placebo group. Most adverse events were mild or moderate and gastrointestinal related.<h4>Interpretation</h4>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<sub>1c</sub>. 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.<h4>Funding</h4>Novo Nordisk.
Background
This study investigates the efficacy and safety of cagrilintide-semaglutide, a combination of an amylin receptor agonist and a GLP-1 receptor agonist, in adults with type 2 diabetes who are inadequately controlled by diet and exercise. Prior research has established the roles of GLP-1 receptor agonists in managing diabetes, but the combination with cagrilintide is novel. Understanding the effects of this combination therapy is crucial for developing new treatment options.
Methods
REIMAGINE 1 was a randomised, double-blind, parallel-group, phase 3a study involving 189 adults with type 2 diabetes. Participants were assigned to receive either cagrilintide-semaglutide (2.4 mg each), cagrilintide-semaglutide (1.0 mg each), or placebo for 40 weeks. The primary outcome was the change in HbA1c from baseline to week 40, with body weight as a secondary endpoint.
Results
The estimated mean change in HbA1c after 40 weeks was -1.8 percentage points (SE 0.1) for cagrilintide-semaglutide (2.4 mg each) and -1.5 percentage points (0.1) for cagrilintide-semaglutide (1.0 mg each), compared to -0.1 percentage points (0.2) for placebo. The estimated treatment difference for cagrilintide-semaglutide (2.4 mg each) versus placebo was -1.7 percentage points (95% CI -2.0 to -1.3; p<0.0001). For body weight, the relative change was -13.8% (SE 1.0) for cagrilintide-semaglutide (2.4 mg each) versus -1.4% (0.7) for placebo.
Interpretation
The findings suggest that cagrilintide-semaglutide significantly reduces HbA1c levels compared to placebo, with a treatment difference that is statistically significant. However, the clinical significance of the HbA1c reduction may be modest, and the safety profile aligns with existing GLP-1 receptor agonist data. Limitations include potential bias due to industry funding and the relatively short follow-up period, which may not capture long-term effects.
Key findings
- -1.8 percentage points change in HbA1c with cagrilintide-semaglutide (2.4 mg each) vs placebo at 40 weeks, p<0.0001.
- -1.5 percentage points change in HbA1c with cagrilintide-semaglutide (1.0 mg each) vs placebo at 40 weeks, p<0.0001.
- -13.8% relative change in body weight with cagrilintide-semaglutide (2.4 mg each) vs placebo at 40 weeks, p<0.0001.
- -11.8% relative change in body weight with cagrilintide-semaglutide (1.0 mg each) vs placebo at 40 weeks, p<0.0001.
- 49 (79%) of participants reported adverse events in the cagrilintide-semaglutide (2.4 mg each) group.
Limitations
- funded by Novo Nordisk, potential for bias
- 40-week follow-up may not capture long-term effects
- single-site study across six countries, may limit generalizability
- small sample size (n=189) for a phase 3 study