In the market for obesity care, all the noise is all about GLP-1s. Wegovy tablets, orforglipron tablets (coming soon), high dose semaglutide, and the battle for dominance between semaglutide and tirzepatide. But research on amylin receptors is suggesting that a different neuropeptide pathway might be the next big thing. Perhaps soon, amylin will be garnering more attention than GLP-1.

Will amylin actually break through the GLP-1 chatter? Let’s take a closer look.

Advancing Long-Acting Amylin Agonists

A new review in the journal Peptides describes the past, present, and future of research on amylin agonists. All of this started with pramlintide in the 1990s. Though the target seemed to  have great promise, pramlintide was a commercial disappointment after its U.S. approval in 2005. The science was great, but it presented some practical issues for patients.

Now, 20 years later, many new drugs targeting the amylin receptor are progressing for obesity, diabetes, and related indications. In that Peptides article, Clifford Bailey, Peter Flatt, and J. Michael Conlon describe the scope of it:

“In clinical trials, CagriSema has achieved greater effects than either component [cagrilintide or semaglutide] 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.”

Promising Candidates in Development

At this point, it is hard to say which, if any, of these candidates will turn out to deliver important clinical advantages. Bailey et al offer a snapshot of weight outcomes seen to date. Their visual (on the right, click for a larger view) leaves us intrigued about results to come from further research.

A new paper in the journal Metabolism gives a detailed review of one of the more intriguing of these drugs, amycretin. Linghua Fu and colleagues write that:

“Amycretin represents a pivotal advancement in the metabolic pharmacopeia as a next-generation unimolecular co-agonist. By synergistically integrating GLP-1, amylin, and calcitonin receptor signaling, it effectively overcomes the efficacy ceilings of current monotherapies, offering profound weight reduction and glycemic control comparable to surgical interventions.”

For now, we must wait and see. What is clear enough, though, is that amylin agonists may soon be shaking up the order of things with GLP-1s.

Click here for the new paper in Peptides and here for the paper in Metabolism. For further perspective, click here.

Graphical abstract from “Long-acting amylin-related peptides as therapies for obesity and type 2 diabetes,” by Bailey, Flatt, and Conlon, licensed under CC BY 4.0