Novo Nordisk's CagriSema Beats Tirzepatide for Weight Loss in Phase 3 Trial

Novo Nordisk announced topline results from the phase 3 REIMAGINE 5 and REDEFINE 9 trials of once-weekly cagrilintide and semaglutide (CagriSema) in adults with type 2 diabetes and in adults with overweight or obesity, respectively, highlighted at the company's Capital Markets Day investor briefing on September 21, 2026.¹

In REIMAGINE 5, CagriSema 1.0 mg/1.0 mg achieved superior weight loss of 12.4% compared with 9.1% for tirzepatide 5 mg, with non-inferior HbA1c reduction, in adults with type 2 diabetes. In REDEFINE 9, CagriSema 1.0 mg/1.0 mg produced 21.0% weight loss compared with 2.0% for placebo in adults with overweight or obesity, meeting its primary superiority endpoint.¹

"The results from CagriSema are very encouraging, demonstrating the strong potency of the combination of semaglutide and cagrilintide," said Martin Holst Lange, MD, PhD, executive vice president of R&D and chief scientific officer at Novo Nordisk, in a company press release.¹ "With only 1.0 mg/1.0 mg, CagriSema shows superior weight loss versus tirzepatide 5 mg as well as strong results across obesity and type 2 diabetes."

What did the REIMAGINE 5 trial show?

REIMAGINE 5 evaluated once-weekly CagriSema 1.0 mg/1.0 mg against tirzepatide 5 mg in adults with type 2 diabetes inadequately controlled on metformin, a sodium-glucose cotransporter 2 inhibitor, or both. The dual primary endpoints were change in hemoglobin A1c (HbA1c) and relative change in body weight from baseline to week 60.¹ In the trial, CagriSema achieved superior weight loss of 12.4% compared with 9.1% for tirzepatide and a non-inferior HbA1c reduction of 1.71% compared with 1.67% for tirzepatide.¹

What did the REDEFINE 9 trial show?

REDEFINE 9 evaluated once-weekly CagriSema 1.7 mg/1.7 mg and 1.0 mg/1.0 mg against placebo, as an adjunct to a reduced-calorie diet and increased physical activity, in adults with overweight or obesity. The primary endpoints were relative change in body weight and the proportion of patients achieving at least 5% weight reduction from baseline to week 68.¹ CagriSema 1.0 mg/1.0 mg produced weight reduction of 21.0% compared with 2.0% for placebo, meeting its primary superiority endpoint. Greater improvements than placebo were seen across supportive endpoints, including systolic blood pressure, waist-to-height ratio, and fasting lipid profile.¹ In both trials, CagriSema was well tolerated, with a safety profile consistent with previous studies.¹

How does CagriSema work, and what has earlier data shown?

CagriSema is a fixed-dose combination of cagrilintide, a long-acting amylin receptor agonist, and semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, administered by weekly subcutaneous injection. Amylin, co-released with insulin from pancreatic beta cells, induces satiety through both homeostatic and hedonic regions of the brain, a mechanism distinct from and complementary to GLP-1 receptor agonism.²

In the earlier phase 3 REDEFINE 1 trial, CagriSema 2.4 mg/2.4 mg produced a mean weight reduction of 20.4% compared with 3.0% for placebo over 68 weeks in adults with overweight or obesity, with 60% of participants achieving at least 20% weight loss.³ Novo filed a new drug application with FDA in December 2025 for CagriSema for weight management, with a decision expected in the fourth quarter of 2026.¹

Separately, Novo presented preliminary data on painful diabetic neuropathy in type 2 diabetes for the first time during Capital Markets Day, with the company saying more details will be shared at a later date.¹

What are the limitations?

These are topline results presented at an investor briefing, and detailed statistical and safety data from REIMAGINE 5 and REDEFINE 9 have not yet been published in a peer-reviewed journal. CagriSema remains investigational and has not been approved by any regulatory authority for either indication.

References

1. Novo Nordisk. Novo's CagriSema delivers superior weight loss versus tirzepatide in REIMAGINE 5 trial. Press release. Published September 21, 2026. Accessed September 22, 2026. https://www.novonordisk.com/content/nncorp/global/en/news-and-media/news-and-ir-materials/news-details.html?id=916774
2. D'Ascanio AM, Mullally JA, Frishman WH. Cagrilintide: a long-acting amylin analog for the treatment of obesity. Cardiol Rev. 2024;32(1):83-90. doi:10.1097/CRD.0000000000000513
3. Garvey WT, Blüher M, Osorto Contreras CK, et al; REDEFINE 1 Study Group. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med. 2025;393(7):635-647. doi:10.1056/NEJMoa2502081