Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial

Published in The Lancet, this phase 2 clinical trial was the first randomized study to evaluate cagrilintide (AM833), a long-acting amylin analogue administered weekly, for body weight management. The multicenter, double-blind study included placebo and active-control (liraglutide 3.0 mg daily) arms, allowing direct comparison with an already approved anti-obesity therapy.

Participants were randomized to receive escalating doses of weekly subcutaneous cagrilintide (0.3 mg, 0.6 mg, 1.2 mg, 2.4 mg, or 4.5 mg), liraglutide 3.0 mg daily, or placebo for 26 weeks. Results showed dose-dependent weight reductions: the highest cagrilintide dose (4.5 mg) produced a mean loss of 10.8% of body weight, compared to 9.0% with liraglutide 3.0 mg and 3.0% with placebo.

Cagrilintide works by mimicking amylin, a hormone co-secreted with insulin by pancreatic beta cells. Amylin reduces appetite through central action in the brainstem and hypothalamus, delays gastric emptying, and suppresses postprandial glucagon secretion. The long-acting formulation enables weekly administration, a significant advantage in terms of treatment adherence.

The most common adverse events were gastrointestinal (nausea, vomiting, diarrhea), generally mild to moderate and transient. The tolerability profile was comparable to that of liraglutide. This study was particularly relevant for demonstrating that the amylin pathway can be as effective as the GLP-1 pathway for weight loss, and that combining both approaches (as in the CagriSema program) could produce additive effects.