REIMAGINE-2: how effective is combination therapy for type 2 diabetes?

Cagrilintide is a long-acting amylin receptor agonist. It helps to improve insulin sensitivity and aids in weight loss.

Previous trial papers showed that semaglutide and cagrilintide have different but complementary effects on blood sugar control and weight management.

REIMAGINE-2¹ combines them. This phase 3 trial compared the efficacy and safety of treatment of cagrilintide-semaglutide (CagriSema) treatment in participants whose type 2 diabetes is inadequately controlled with metformin.

Note: CagriSema is investigational and not licensed for use in the UK, so it is not currently a prescribing option.

TRIAL DESIGN:

• The phase 3 trial randomised 2,713 adults with type 2 diabetes

• Participants had a baseline HbA1c between 7.0% and 10.5% and a body mass index of at least 25 kg/m². Mean baseline HbA1c was 8.2%

• All participants were already receiving metformin with or without an SGLT2 inhibitor

• Participants were assigned one of six treatments: CagriSema 2.4 mg each, CagriSema 1.0 mg each, semaglutide 2.4 mg, semaglutide 1.0 mg, cagrilintide 2.4 mg, or placebo.

RESULTS:

HBA1c

• The primary endpoint was the change in HbA1c after 68 weeks, comparing CagriSema (2.4 mg each) to semaglutide (2.4 mg)

• CagriSema (2.4 mg) significantly reduced HbA1c by 1.91%, vs. a 1.75% reduction under semaglutide (2.4 mg) (p=0·0035); meeting the primary endpoint

• The 1.0 mg combination also proved superior to semaglutide 1.0 mg in reducing HbA1c (p < 0·0001), which the authors suggest is the result of an add-on benefit from cagrilintide

• On safety, nausea was reported substantially more often with CagriSema than with semaglutide alone, but this did not lead to higher rates of vomiting or treatment discontinuation. Nausea, diarrhoea and vomiting were highest during dose escalation and settled afterwards.

WEIGHT LOSS

• Secondary endpoints compared the effects on bodyweight reductions

• CagriSema showed superior weight loss profiles at all dose levels in patients with type 2 diabetes, with a mean weight loss of 14.2% versus 20.2% using 2.4 mg of semaglutide (p <0·0001)

• A significantly higher proportion of participants on CagriSema (2.4 mg each) reached clinical weight loss targets of 10%, 15% and 20% compared with those on semaglutide treatment (2.4 mg):

10% weight loss: 66.0% vs 47.4% (p < 0.0001)

15% weight loss: 42.8% vs 25.7% (p < 0.0001)

20% weight loss: 23.7% vs 9.9% (p < 0.0001)

• These proportions were lower than those CagriSema reached in its obesity trials in people without type 2 diabetes, which is expected, as weight loss is harder to achieve in type 2 diabetes^2,3

THE MECHANISM:

CagriSema works through two pathways. GLP-1 increases insulin secretion, slows gastric emptying and reduces appetite. Amylin is a neuroendocrine peptide hormone, often co-secreted with insulin, that adds a separate satiety signal, reduces postprandial glucagon, and may improve insulin sensitivity.

WHAT THIS MEANS FOR PRIMARY CARE:

REIMAGINE-2 is among the few trial papers that directly compares CagriSema with semaglutide. Adding cagrilintide to semaglutide has a potential additive effect on weight loss in people who are overweight and living with type 2 diabetes. A bodyweight reduction of 10% or more is associated with better glycaemia and with improvement in obesity-related conditions, and CagriSema seemed to move more people past that threshold than semaglutide alone.

CagriSema is currently under review by the FDA, expected to reach a decision in 2026. However, the results support its use in adults with type 2 diabetes who are overweight or obese, so it’s expected to get approved by late 2026 or early 2027.

References

1. Buse JB, Bajaj HS, Dalskov S-M, et al. Cagrilintide–semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a double-blind, randomised, controlled, phase 3 study. Lancet Diabetes Endocrinol. Published online June 7, 2026. doi:10.1016/S2213-8587(26)00125-7

2. Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide–semaglutide in adults with overweight or obesity and type 2 diabetes. N Engl J Med. 2025;393:648-59. doi:10.1056/NEJMoa2502082

3. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021;397:971-84. doi:10.1016/S0140-6736(21)00213-0

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