Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial

This phase 2 trial published in The Lancet evaluated the CagriSema combination — weekly co-administration of cagrilintide 2.4 mg (amylin analogue) with semaglutide 2.4 mg (GLP-1 agonist) — in patients with type 2 diabetes mellitus. The multicenter, randomized, double-blind study compared the combination with each component alone over 32 weeks.

The results demonstrated clear superiority of the combination: CagriSema produced a mean weight loss of 15.6%, significantly greater than semaglutide alone (5.1%) and cagrilintide alone (8.1%). The effect on glycemic control was equally impressive, with an HbA1c reduction of 2.2 percentage points with CagriSema, versus 1.8% with semaglutide and 0.9% with cagrilintide alone.

The rationale for the combination lies in the complementarity of their mechanisms of action: semaglutide acts on GLP-1 receptors (predominantly in the hypothalamus and pancreas), while cagrilintide activates amylin receptors (predominantly in the area postrema of the brainstem). These pathways converge on appetite and metabolism regulation through distinct neural circuits, producing a synergistic effect when combined.

The safety profile of the combination was consistent with the individual components, with gastrointestinal events as the main adverse effect. No unexpected safety signals were observed. CagriSema represents one of the most promising anti-obesity combinations in development, with the potential to achieve weight loss levels previously associated only with bariatric surgery, and is currently in phase 3 trials for type 2 diabetes and obesity.