Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.
The REIMAGINE 2 trial was a phase 3, double-blind, randomised, placebo- and active-controlled study evaluating the fixed-dose combination of cagrilintide (an amylin receptor agonist) and semaglutide (a GLP-1 receptor agonist), known as CagriSema, in 2,713 adults with inadequately controlled type 2 diabetes and overweight or obesity across 30 countries. Participants were on background metformin with or without an SGLT2 inhibitor and were followed for 68 weeks. The primary endpoint was change in HbA1c from baseline. The study found that the higher-dose CagriSema combination produced a statistically significantly greater reduction in HbA1c compared with semaglutide alone (-1.91 vs. -1.75 percentage points; treatment difference -0.16 percentage points; p=0.0035). Adverse events were more frequent in the combination group (86.9%) than in the semaglutide monotherapy group (81.2%), with gastrointestinal disorders being the most common across active treatment arms. Limitations include the relatively modest absolute difference in HbA1c reduction, a predominantly White study population, and industry funding by Novo Nordisk, which may introduce sponsorship bias.
Why this grade: This is a large (n=2,713), phase 3, double-blind, multi-national RCT with an active comparator, directly measuring a clinically validated endpoint (HbA1c) in humans with type 2 diabetes over 68 weeks.
Background The amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide have complementary effects on glycaemic control and bodyweight. We aimed to investigate the efficacy and safety of a fixed-dose combination of cagrilintide and semaglutide (cagrilintide-semaglutide; known as CagriSema) versus semaglutide or cagrilintide for glycaemic control in people with type 2 diabetes and overweight or obesity. Methods REIMAGINE 2 was a randomised, double-blind, placebo-controlled and active-controlled, parallel-group study conducted in 30 countries (trial sites included university hospitals, health-care centres, research centres, and other centres). Participants aged 18 years or older with inadequately controlled type 2 diabetes (HbA 1c 7·0-10·5% [53-91 mmol/mol]) receiving metformin with or without an SGLT2 inhibitor, and a BMI of 25 kg/m 2 or more, were randomly assigned (8:8:2:8:8:1:1) to receive once-weekly subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (hereafter cagrilintide-semaglutide [2·4 mg each]), semaglutide 2·4 mg, cagrilintide 2·4 mg, cagrilintide 1·0 mg plus semaglutide 1·0 mg (hereafter cagrilintide-semaglutide [1·0 mg each]), semaglutide 1·0 mg, or corresponding placebo for 68 weeks. Randomisation was done using a web-based system with blocked randomisation (block size 36) and stratification according to inclusion in the continuous glucose monitoring subgroup, HbA 1c less than 8·5% at screening (yes or no), and country of participation (Japan; yes or no). The study participants, investigators, and study sponsor staff were masked to treatment allocation within dose level throughout the study. The primary endpoint was change in HbA 1c from baseline to week 68 with cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg in the full analysis set; safety was assessed in all participants who received at least one dose of study product. This study is registered with ClinicalTrials.gov (NCT06065540) and is complete. Findings From Oct 10, 2023, to July 29, 2024, 3593 people were screened for eligibility, 2713 of whom were randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=603), semaglutide 2·4 mg (n=605), cagrilintide 2·4 mg (n=152), cagrilintide-semaglutide (1·0 mg each; n=595), semaglutide 1·0 mg (n=609), or placebo (pooled 2·4 mg and 1·0 mg; n=149). 1164 (42·9%) of 2713 were female, 1549 (57·1%) were male, and 2207 (81·3%) were White. Of the randomly assigned participants, 2595 (95·7%) completed the study and 2376 (87·6%) were on treatment at week 68. Mean baseline HbA 1c was 8·2% (SD 0·9). For the primary endpoint using the efficacy estimand, mean HbA 1c change was significantly greater with cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg (-1·91 percentage points [SE 0·04] vs -1·75 percentage points [0·04]; estimated treatment difference -0·16 percentage points [95% CI -0·27 to -0·05]; p=0·0035). Adverse events were reported in 524 (86·9%) of 603 participants in the cagrilintide-semaglutide (2·4 mg each) group, 491 (81·2%) of 605 in the semaglutide 2·4 mg group, 125 (82·2%) of 152 in the cagrilintide 2·4 mg group, 485 (81·6%) of 594 in the cagrilintide-semaglutide (1·0 mg each) group, 477 (78·5%) of 608 in the semaglutide 1·0 mg group, and 105 (70·5%) of 149 in the placebo group. The most common adverse events in the active treatment groups were gastrointestinal disorders. Interpretation Cagrilintide-semaglutide (2·4 mg each) was superior to semaglutide 2·4 mg in reducing HbA 1c in participants with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor. The safety profile of cagrilintide-semaglutide was consistent with the GLP-1 receptor agonist class and previous safety data for cagrilintide. These findings support the added benefit of cagrilintide-semaglutide (2·4 mg each) versus semaglutide 2·4 mg for glycaemic control. Funding Novo Nordisk.
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