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

Once-weekly cagrilintide-semaglutide (CagriSema) reduced HbA1c and body weight more than placebo in adults with early type 2 diabetes inadequately controlled by diet and exercise. Both dose combinations tested over 40 weeks were superior to placebo on these measures. Adverse events were mostly mild to moderate gastrointestinal effects.

Late-phase clinical trial — Randomised double-blind placebo-controlled phase 3a trial. Population: Adults aged 18 years or older with type 2 diabetes inadequately controlled with diet and exercise. Sample size: 189 people. Follow-up: 40 weeks. Interventions: cagrilintide 2.4 mg plus semaglutide 2.4 mg once weekly; cagrilintide 1.0 mg plus semaglutide 1.0 mg once weekly. Cited by 2 other papers.

The estimated mean change in HbA1c 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 the 1.0 mg dose, and -0.1 percentage points (0.2) with placebo. Corresponding treatment differences versus placebo were -1.7 percentage points (95% CI -2.0 to -1.3) and -1.3 percentage points (-1.8 to -0.9), both p<0.0001. Estimated mean relative change in bodyweight was -13.8% (SE 1.0) for the 2.4 mg dose, -11.8% (1.0) for the 1.0 mg dose, and -1.4% (0.7) for placebo, with treatment differences of -12.4 percentage points (95% CI -14.7 to -10.1) and -10.4 percentage points (-12.9 to -8.0), both p<0.0001. Most adverse events were mild or moderate and gastrointestinal related.

For researchers working on semaglutide or cagrilintide, this phase 3a trial provides pivotal efficacy and safety data for their fixed-dose combination, CagriSema, in early type 2 diabetes. It shows clinically meaningful HbA1c and bodyweight reductions but does not establish effects on cardiovascular outcomes, long-term safety, or comparisons with established GLP-1 receptor agonist treatments.

Key findings

Cagrilintide-semaglutide (2.4 mg each) reduced HbA1c by 1.8 percentage points versus 0.1 with placebo, a treatment difference of -1.7 percentage points (95% CI -2.0 to -1.3; p<0.0001).
Cagrilintide-semaglutide (1.0 mg each) reduced HbA1c by 1.5 percentage points versus 0.1 with placebo, a treatment difference of -1.3 percentage points (95% CI -1.8 to -0.9; p<0.0001).
Cagrilintide-semaglutide (2.4 mg each) led to a -13.8% change in bodyweight versus -1.4% with placebo, a treatment difference of -12.4 percentage points (95% CI -14.7 to -10.1; p<0.0001).
Cagrilintide-semaglutide (1.0 mg each) led to a -11.8% change in bodyweight versus -1.4% with placebo, a treatment difference of -10.4 percentage points (95% CI -12.9 to -8.0; p<0.0001).
Adverse events occurred in 49 (79%) of 62 participants on cagrilintide-semaglutide (2.4 mg each), 47 (75%) of 63 on the 1.0 mg dose, and 42 (66%) of 64 on placebo.

Limitations

No active comparator, so relative efficacy versus other diabetes treatments is not established.
Follow-up limited to 40 weeks; longer-term durability and safety are not addressed.
Predominantly White population (78%), limiting generalizability to other ethnic groups.
The trial was funded by the manufacturer.

The record

Journal: The lancet. Diabetes & endocrinology 14(8): 649-661
Published: 2026-06-07
PMID: 42251860 — DOI: 10.1016/s2213-8587(26)00126-9
MeSH terms: Humans, Diabetes Mellitus, Type 2, Blood Glucose, Hypoglycemic Agents, Treatment Outcome, Exercise, Drug Administration Schedule, Double-Blind Method, Adult, Aged, Middle Aged, Female, Male, Glucagon-Like Peptides, Islet Amyloid Polypeptide, Glycated Hemoglobin, Semaglutide
Funding: Novo Nordisk AS
Author countries: Belgium, Canada, Denmark, Italy, USA

Peptide profiles: Semaglutide, Cagrilintide.

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