Cagrilintide-semaglutide (CagriSema) as an add-on to basal insulin in adults with type 2 diabetes (REIMAGINE 3): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study.
The REIMAGINE 3 trial investigated the combination of cagrilintide and semaglutide (CagriSema) as a weekly add-on to daily basal insulin in adults with type 2 diabetes and suboptimal glycaemic control (HbA1c 7.0–10.5%). In this 40-week, double-blind, placebo-controlled phase 3 study conducted across 46 centres in six countries, 274 participants were randomised to one of two active dose combinations (2.4 mg each or 1.0 mg each) or pooled placebo. The primary endpoint—change in HbA1c from baseline to week 40—was significantly greater with both CagriSema doses (–2.33% and –2.10%, respectively) compared with placebo (–0.66%). Both active groups also achieved substantial bodyweight reductions versus placebo, and no additional hypoglycaemia risk was observed. The safety profile was consistent with the GLP-1 receptor agonist class. Limitations include a relatively short 40-week duration, a moderately sized sample, and industry funding by Novo Nordisk. The study authors conclude that CagriSema meaningfully improved glycaemic control when added to basal insulin, without increasing hypoglycaemia risk.
Why this grade: This is a double-blind, placebo-controlled, multicentre phase 3 RCT in a well-defined human population (n=274) with pre-specified primary and secondary endpoints, providing strong direct evidence in humans, though a 40-week duration and industry sponsorship are noted limitations.
Background Basal insulin treatment for type 2 diabetes often results in inadequate glycaemic control and is associated with weight gain and increased risk of hypoglycaemia. We aimed to compare the efficacy and safety of a once per week combination of cagrilintide with semaglutide (CagriSema) versus placebo as an add-on to basal insulin in individuals with type 2 diabetes. Methods This double-blind, parallel-group, randomised, controlled, phase 3a study (REIMAGINE 3) was done at 46 centres (university hospitals, health-care centres, research centres, and other clinical trial sites) in six countries (the USA, China, Japan, Serbia, Slovakia, and South Africa). Adults with type 2 diabetes (glycated haemoglobin [HbA 1c ] 7·0-10·5%) receiving stable once per day basal insulin with or without metformin were randomly assigned (2:2:1:1) to once per week subcutaneous cagrilintide 2·4 mg plus semaglutide 2·4 mg (hereafter cagrilintide-semaglutide [2·4 mg each]) or cagrilintide 1·0 mg plus semaglutide 1·0 mg (hereafter cagrilintide-semaglutide [1·0 mg each]) or dose-matched placebo (2·4 mg plus 2·4 mg or 1·0 mg plus 1·0 mg) for 40 weeks. Randomisation was stratified by HbA 1c of less than 8·5% at screening (yes or no) and country (Japan; yes or no). Participants, care providers, investigators, and outcome assessors were masked within each dose level to treatment allocation, with active treatments visually identical to placebo. The primary endpoint was mean HbA 1c change (percentage points) from baseline to week 40 in all participants randomly assigned to treatment; secondary endpoints included change in bodyweight and safety, including hypoglycaemia. This trial was registered with ClinicalTrials.gov (NCT06323161) and is complete. Findings Between March 26 and Nov 29, 2024, we screened 340 individuals and 274 were included and randomly assigned to cagrilintide-semaglutide (2·4 mg each; n=90), cagrilintide-semaglutide (1·0 mg each; n=93), or placebo (pooled; n=91). Mean baseline HbA 1c was 8·8% (SD 1·0), 159 (58%) participants were male, and 115 (42%) were female. Mean HbA 1c reductions were significantly greater with cagrilintide-semaglutide (2·4 mg each -2·33% [SE 0·08] and 1·0 mg each -2·10% [0·08]) versus placebo (-0·66% [0·11]) at week 40, using the efficacy estimand (estimated treatment difference for cagrilintide-semaglutide [2·4 mg each] vs placebo -1·68 percentage points [95% CI -1·95 to -1·41], p Interpretation Cagrilintide-semaglutide at doses of 2·4 mg each and 1·0 mg each met the primary endpoint, with statistically significant and clinically relevant HbA 1c reductions versus placebo when added to basal insulin-treated type 2 diabetes. These reductions were accompanied by robust bodyweight reduction and no additional risk of hypoglycaemia. The safety profile was consistent with that of the GLP-1 receptor agonist class and previous safety data for cagrilintide. Findings support the use of cagrilintide-semaglutide as an add-on to once per day basal insulin to significantly improve glycaemic control. Funding Novo Nordisk.
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