Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes.
This review examines the development and clinical progress of long-acting amylin-related peptides as treatments for obesity and type 2 diabetes. It traces the field from the first-generation amylin receptor (AMYR) agonist pramlintide—which acts centrally to induce satiety, suppress glucagon, and reduce post-meal hyperglycemia but had limited use as an insulin adjunct—to a new generation of non-aggregating, long-acting analogues. The authors describe advances in understanding the heterodimeric structure of amylin-calcitonin receptor complexes that have guided the rational design of these newer agents. Highlighted compounds include the dual AMYR/calcitonin-receptor agonist cagrilintide, the combination product CagriSema (cagrilintide plus semaglutide), and the unimolecular tri-agonist amycretin. Several monotherapy candidates (eloralintide, petrelintide, Met-233, AZD6234) are also discussed. The review notes that gastrointestinal side effects—chiefly nausea—are common during initiation but typically resolve with continued use, and highlights emerging preclinical and early clinical signals for potential benefits in fatty liver disease, diabetic kidney disease, and resistant hypertension. As a narrative review, it synthesizes heterogeneous sources and does not itself generate new primary data.
Why this grade: This is a narrative review article that synthesizes existing preclinical and clinical literature rather than presenting original primary data, so it is graded as a review rather than an independent level of clinical evidence.
The first therapeutically useful amylin receptor (AMYR) agonist, pramlintide was based upon the structure of non-aggregating rat amylin and found limited application as an adjunct to insulin therapy. It acts centrally to induce satiety, promote weight loss, suppress prandial glucagon release and reduce prandial hyperglycaemia. Recent understanding of the heterodimeric structure of amylin-calcitonin receptor complexes and of amylin structure-function properties has assisted the design of a second generation of non-aggregating, long-acting amylin analogues. These are now advancing in clinical development and promise to provide an effective additional resource for the management of obesity and type 2 diabetes. Amongst these agents is the dual AMYR/ calcitonin-receptor (CTR) agonist, cagrilintide that has also been co-formulated into a once weekly subcutaneous injection with the long-acting glucagon-like peptide-1receptor (GLP-1R) agonist, semaglutide (CagriSema). In clinical trials, CagriSema has achieved greater effects than either component alone. A unimolecular AMYR/CTR/GLP-1R multi-agonist peptide, amycretin has been developed for weekly injection and as a once-daily tablet. Several recently developed long-acting amylin analogues have shown strong efficacy as monotherapy in clinical trials: these include eloralintide, petrelintide, Met-233 and AZD6234. Other analogues with marked efficacy in preclinical studies, including non-peptide AMYR agonists are under development. Gastrointestinal side effects, especially nausea, similar to those reported for GLP-1R agonists are commonplace during initiation and up-titration of amylin analogues but mostly resolve during continued use. Evidence is emerging that long-acting AMYR agonists may show potential therapeutic benefits in treatment of patients with fatty liver disease, diabetes-associated kidney complications and resistant hypertension.
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