Amylin analogues as a novel perspective in anti‐obesity therapy

Public health systems face a major challenge because of the worldwide obesity epidemic. The number of obese individuals has increased dramatically and, even in Switzerland which may be considered a relatively "lean" country, the numbers are alarmingly high and have reached almost 50% of the adult population. There is an urgent need for effective, safe and widely-available therapeutic interventions worldwide. The development of analogues of physiological gut hormones has led to highly effective treatment options based on two incretins: glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Analogues of the pancreatic hormone amylin, next to the above incretins and glucagon, have yielded more promising body weight-lowering effects in preclinical and clinical studies, and several new amylin analogues are under development. Despite progress in anti-obesity pharmacotherapy, major challenges remain. Here, I discuss recent findings in the amylin field, including amylin's potential role in improving memory, and the characterisation of specific neurons and circuits involved in amylin signalling in the caudal hindbrain. This is followed by a more in-depth discussion of challenges linked to amylin pharmacotherapy, or anti-obesity pharmacotherapy in general. Three of these challenges are addressed, specifically: (1) What are the potential mechanisms of the muscle sparing effect of amylin-based weight loss drugs? (2) Is there improved weight loss effectiveness of amylin-based anti-obesity therapy in type 2 diabetes mellitus (T2D) patients compared with incretin-based approaches? (3) Can amylin analogues improve maintenance of reduced body weight after the weight loss phase because of their role as leptin sensitiser?