Amylin

Amylin

Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino-acid peptide hormone co-secreted with insulin by pancreatic beta cells in response to nutrient intake. Its physiological actions are complementary to insulin’s: amylin slows gastric emptying, suppresses post-meal glucagon secretion, and produces centrally mediated appetite suppression by acting on receptors in the area postrema, the nucleus of the solitary tract, and other hypothalamic regions.

Amylin signaling is reduced in type 2 diabetes (in parallel with insulin deficiency) and is partly absent in type 1 diabetes. Pramlintide, the first amylin analogue developed, was approved by the FDA in 2005 for both type 1 and type 2 diabetes but achieved limited clinical adoption due to short half-life, mealtime injection requirement, and tolerability issues.

The mechanistic interest in amylin has been revived by long-acting amylin analogues designed for once-weekly dosing in obesity. Cagrilintide is the leading example, currently formulated with semaglutide as CagriSema (Novo Nordisk). The therapeutic rationale is that amylin and GLP-1 activate complementary, independent appetite-suppression pathways in the brain — combining them produces greater reduction in caloric intake than either alone. CagriSema reported -22.7% mean weight loss at 68 weeks in the REDEFINE-1 Phase 3 trial (published in NEJM) and an FDA New Drug Application was filed in December 2025.

Retatrutide, by contrast, does not engage the amylin receptor; its triple-agonist mechanism combines GLP-1, GIP, and glucagon receptor activation to act on both energy intake and energy expenditure. The retatrutide-versus-CagriSema comparison illuminates a strategic choice in next-generation obesity drugs: dual-pathway appetite suppression versus combined appetite suppression plus energy expenditure augmentation.