Novo Nordisk posted Phase III data showing that its next pipeline obesity hope CagriSema, a fixed-dose injectable of the amylin receptor agonist cagrilintide and the GLP-1 receptor agonist semaglutide, out-performed semaglutide alone in the Phase III REIMAGINE 2 trial. The focus of the study was adults with type 2 diabetes inadequately controlled on metformin with or without an SGLT2 inhibitor, with CagriSema producing superior reduction in glycosylated hemoglobin (HbA1c) and body weight, specifically an incremental HbA1c reduction of up to 1.91%-points and weight loss of up to 14.2% at week 68 versus the semaglutide comparator.

Novo Nordisk is assessing CagriSema as a once-weekly subcutaneous injectable treatment for obesity/overweight in the REDEFINE program, and for type 2 diabetes in the REIMAGINE series of trials. The molecule is on course to be the first amylin-based combination therapy on the market, having been filed for approval in obesity/overweight in December 2025.

Trial specifics

The REIMAGINE 2 study was a 68-week, multicenter, randomized, double-blind Phase III trial enrolling 2,728 adults with type 2 diabetes, with baseline HbA1c of around 8.2% and mean body weight of approximately 101 kg. Participants were randomized to once-weekly subcutaneous CagriSema at two fixed doses, corresponding doses of semaglutide, cagrilintide monotherapy, or placebo, with changes in HbA1c and body weight from baseline to week 68 as the primary endpoints.

At the higher CagriSema dose, mean HbA1c reduction reached 1.91%-points versus 1.76%-points with semaglutide 2.4 mg, while mean weight loss was 14.2% compared with 10.2%. A meaningful proportion of patients achieved at least 15% and 20% weight loss, and across estimand analyses accounting for treatment adherence, the combination consistently outperformed semaglutide alone on both glycemic and weight measures. The safety profile was consistent with incretin and amylin receptor agonists, with mostly mild to moderate gastrointestinal adverse events.

Research context

Cagrilintide mimics endogenous amylin, a peptide hormone co-secreted with insulin from pancreatic beta cells. Amylin acts centrally (in the brain) to promote satiety, delays gastric emptying, and suppresses postprandial glucagon secretion, thereby reducing food intake and improving glycemic control. Semaglutide enhances insulin secretion and also promotes satiety via GLP-1 receptor activation. The combination is designed for synergistic effects on weight loss and glycemic control.

Amylin analogues historically predate many modern incretins, with Amylin Pharmaceuticals’ pramlintide (Symlin) approved in 2005 as an adjunct in diabetes, but they have not, until now, been developed as long-acting agents or co-formulated therapies.

CagriSema is ahead of alternative amylin-centric candidates in the clinic, with the competitive landscape including several direct competitors in development, including both selective amylin receptor agonists and dual agonists targeting amylin and other metabolic pathways. Key competitors include:

• Eli Lilly’s eloralintide, a selective amylin receptor agonist that is being readied for Phase III development as a monotherapy for obesity and in combinations with other metabolic targets such as GLP-1 or GIP receptor agonists.
• Novo Nordisk’s amycretin, a dual agonist targeting both GLP-1 and amylin pathways in an oral formulation that has produced promising Phase Ib/IIa data in weight loss and is on course for Phase III study.
• Zealand Pharma/Roche’s petrelintide, Phase II initiated in 2025.
• AstraZeneca’s AZD6234, Phase II stage.