Beyond GLP-1: Amylin-based pharmacotherapy and the search for better-tolerated weight-loss drugs.

Amylin-based pharmacotherapy has re-emerged as a promising strategy for the treatment of obesity and metabolic disease with pharmacological and neural mechanisms distinct from incretin-based therapies. Amylin is a pancreatic β-cell hormone co-secreted with insulin that contributes to postprandial glucose regulation, slows gastric emptying, suppresses glucagon secretion, and promotes satiation through actions in the central nervous system. Recent advances in peptide engineering, lipidation, and reversible albumin binding have enabled the development of long-acting amylin-based agents, including cagrilintide, eloralintide, petrelintide and NN1213. These therapies differ in their pharmacokinetic properties and receptor selectivity, ranging from more selective amylin receptor agonists to dual amylin/calcitonin receptor agonists. This distinction may be critical for understanding both efficacy and tolerability, as calcitonin receptor engagement, exposure kinetics, and downstream neural circuit recruitment may influence whether reduced food intake reflects physiological satiation or aversive signaling. In this review, we summarize the biology of amylin signaling, the historical development of amylin-based therapeutics, and the emerging clinical landscape of long-acting amylin analogs. We place particular emphasis on the tolerability profile of this drug class and discuss how receptor pharmacology, hindbrain and parabrachial circuitry, species differences, and pharmacokinetic exposure may shape nausea, malaise, and emesis. Understanding how amylin-based therapies dissociate weight-loss efficacy from gastrointestinal intolerance may guide the rational design of next-generation anti-obesity drugs with improved clinical utility.