Cagrilintide

Cagrilintide is a long-acting synthetic analogue of human amylin (islet amyloid polypeptide) developed by Novo Nordisk. It is a 37-amino acid acylated peptide engineered for once-weekly subcutaneous administration, contrasting with the native amylin half-life of approximately 13 minutes. Cagrilintide is in Phase 3 clinical development both as a standalone obesity treatment and as a component of CagriSema, a fixed-ratio combination with semaglutide.

The combination approach (CagriSema) represents the most advanced amylin + GLP-1 RA strategy in clinical development. By targeting two complementary satiety pathways — amylin signaling through the area postrema and GLP-1 signaling through hypothalamic neurons — the combination has produced weight reductions exceeding 22% in Phase 3 trials, surpassing the efficacy of either component alone and approaching the range of metabolic surgery.

Cagrilintide activates amylin receptors, which are heteromeric complexes consisting of the calcitonin receptor (CTR) co-expressed with receptor activity-modifying proteins (RAMPs). The primary central target is the area postrema, a circumventricular organ in the brainstem that lacks a complete blood-brain barrier, allowing circulating cagrilintide to directly access CNS satiety circuits. Amylin receptor activation in the area postrema reduces meal size and promotes satiety through signals relayed to the nucleus of the solitary tract and lateral parabrachial nucleus.

The complementarity with GLP-1 agonism arises because amylin and GLP-1 reduce food intake through anatomically and neurochemically distinct pathways. GLP-1 acts primarily on hypothalamic circuits regulating homeostatic hunger, while amylin acts on hindbrain circuits that process satiation signals from meal ingestion. Additionally, cagrilintide slows gastric emptying (complementing GLP-1's similar effect through a different mechanism), suppresses postprandial glucagon secretion, and may improve glucose disposal independent of insulin. The acyl chain modification enables albumin binding, extending plasma half-life to support weekly dosing while preserving full amylin receptor agonist activity.