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

A fixed-dose combination of cagrilintide and semaglutide (CagriSema, 2.4 mg each) lowered HbA1c significantly more than semaglutide 2.4 mg alone in adults with type 2 diabetes and overweight or obesity after 68 weeks. The between-group difference was small, and the safety profile was consistent with this drug class, with gastrointestinal side effects most common.

Late-phase clinical trial — Double-blind, randomised, placebo- and active-controlled phase 3 trial. Population: Adults with inadequately controlled type 2 diabetes and BMI ≥25 kg/m², receiving metformin with or without an SGLT2 inhibitor, at sites in 30 countries. Sample size: 2713 participants. Follow-up: 68 weeks. Interventions: cagrilintide-semaglutide (CagriSema) 2.4 mg each once weekly; cagrilintide-semaglutide (CagriSema) 1.0 mg each once weekly. Cited by 4 other papers.

The primary endpoint was met: cagrilintide-semaglutide (2.4 mg each) reduced HbA1c by -1.91 percentage points (SE 0.04) versus -1.75 percentage points (SE 0.04) with semaglutide 2.4 mg (difference -0.16, 95% CI -0.27 to -0.05; p=0.0035). Mean baseline HbA1c was 8.2% (SD 0.9). Adverse events were reported in 86.9% of the cagrilintide-semaglutide (2.4 mg each) group and 81.2% of the semaglutide 2.4 mg group, with gastrointestinal disorders the most common in active treatment groups. 95.7% of randomised participants completed the study, and 87.6% were still on treatment at week 68.

This paper directly informs researchers working on cagrilintide and semaglutide combinations, showing an additive but small glycaemic benefit of CagriSema 2.4 mg over semaglutide 2.4 mg in people with type 2 diabetes. It does not establish effects on bodyweight, long-term safety, or clinical outcomes such as cardiovascular events.

Key findings

• Cagrilintide-semaglutide (2.4 mg each) reduced HbA1c by 1.91 percentage points vs 1.75 percentage points with semaglutide 2.4 mg (estimated treatment difference -0.16 percentage points; 95% CI -0.27 to -0.05; p=0.0035).
• Mean baseline HbA1c was 8.2% (SD 0.9) among 2713 randomly assigned participants.
• Adverse events were reported in 86.9% (524/603) of the cagrilintide-semaglutide (2.4 mg each) group vs 81.2% (491/605) of the semaglutide 2.4 mg group; gastrointestinal disorders were most common.
• Of 2713 randomised participants, 2595 (95.7%) completed the study and 2376 (87.6%) were on treatment at week 68.

Limitations

• The 68-week follow-up does not cover longer-term efficacy or safety.
• The population was predominantly White (81.3%), so generalisability to other groups may be limited.
• The primary comparison was against semaglutide 2.4 mg, and placebo-controlled results for the primary endpoint are not reported in the abstract.
• The abstract does not report bodyweight outcomes despite bodyweight being a stated study aim.

The record

• Journal: The lancet. Diabetes & endocrinology 14(8): 662-677
• Published: 2026-06-07
• PMID: 42251859 — DOI: 10.1016/s2213-8587(26)00125-7
• MeSH terms: Humans, Diabetes Mellitus, Type 2, Blood Glucose, Drug Combinations, Hypoglycemic Agents, Double-Blind Method, Adult, Aged, Middle Aged, Female, Male, Glucagon-Like Peptides, Islet Amyloid Polypeptide, Glycated Hemoglobin, Semaglutide
• Funding: Novo Nordisk A/S
• Author countries: Canada, Czech Republic, Denmark, USA

Peptide profiles: Cagrilintide, Semaglutide.

All indexed evidence: Cagrilintide trials & papers, Semaglutide trials & papers.

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