Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study.

Abstract

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/m² 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.