Amylin Is the New Frontier: Inside the Class That Took Over ADA 2026

For five years the metabolic peptide conversation has been a GLP-1 conversation — then a GLP-1/GIP conversation, then a triple-agonist conversation. At the American Diabetes Association's 86th Scientific Sessions in New Orleans this June, the center of gravity moved somewhere else entirely.

The story of ADA 2026 was amylin.

What Amylin Actually Is

Amylin is a hormone co-secreted with insulin by the pancreatic beta cells. It is not an incretin, and it does not work like one. Where GLP-1 agonists act largely through slowed gastric emptying and central appetite suppression, amylin signaling promotes satiation — the sense of having finished a meal — along with slowed gastric emptying and suppression of post-meal glucagon.

The practical difference is the entire reason this class is interesting: the amylin pathway appears to produce meaningful weight loss with substantially less gastrointestinal misery than the incretin pathway. If that holds up, it reframes what "tolerable" means in this category.

The Three Compounds That Made the Meeting

Petrelintide — the tolerability story

Petrelintide is a long-acting amylin analog from Zealand Pharma, partnered with Roche, designed for once-weekly dosing. Its phase 2 ZUPREME-1 trial enrolled 493 participants with a mean BMI of 37 across sites in the US, Poland and Romania.

The efficacy: up to 10.7% mean weight loss at week 42, against 1.7% on placebo.

That number is well short of what tirzepatide or retatrutide produce, and if you stop reading there you will miss the point. The headline finding was tolerability — at the maximally effective dose, the trial reported no cases of vomiting and no discontinuations due to gastrointestinal adverse events. Set that against retatrutide's 11.3% discontinuation rate at its top dose and you can see why this got the room's attention. Petrelintide has been designed for chemical and physical stability without fibrillation near neutral pH, which is what makes it co-formulable with other peptides — a deliberate choice that signals where this is heading. ZUPREME-2, in people with overweight or obesity and type 2 diabetes, reports in the second half of 2026.

Zenagamtide (amycretin) — one molecule, two receptors

If you have been following amycretin, note the name change: zenagamtide is the international nonproprietary name for the same Novo Nordisk molecule, and coverage now uses both interchangeably.

Zenagamtide is a unimolecular agonist of both the GLP-1 and amylin receptors — not two drugs combined, but a single peptide hitting both pathways. Its phase 2 trial in type 2 diabetes enrolled 262 adults across six weekly subcutaneous doses (0.4 mg to 40 mg) over 36 weeks, in people inadequately controlled on metformin.

At 40 mg: A1c fell 1.71 points from a 7.8% baseline (a 1.56-point treatment difference versus placebo, p<0.0001), with 89.1% reaching an A1c below 7%. Weight loss reached 14.6%, against 2.1% on placebo — in a diabetes population, where weight loss is typically harder to achieve. Novo plans to begin phase 3 in type 2 diabetes in the second half of 2026.

CagriSema — the combination approach

Where zenagamtide puts both mechanisms in one molecule, CagriSema combines two: cagrilintide, a long-acting amylin analog, with semaglutide.

The REIMAGINE program reported its first phase 3 data on June 7 across three trials — REIMAGINE-1 (189 drug-naïve participants), REIMAGINE-2 (2,728 participants on metformin over 68 weeks), and REIMAGINE-3 (274 participants adding to basal insulin). REIMAGINE-2 showed superiority over semaglutide monotherapy. In REIMAGINE-3, A1c fell from 8.8% to 6.5% with weight reduction up to 12%.

The consistent finding across all three: the combination beat either component alone, without a proportional increase in GI burden, and with no severe hypoglycemia reported.

Why This Matters Beyond the Trial Data

There is a second reason to pay attention. Cagrilintide is one of the fastest-growing compounds on the gray market, frequently stacked with semaglutide, tirzepatide or retatrutide as what sellers market as an "amylin supercharger."

It is worth being precise about what the trial data does and does not support. The REIMAGINE program studied a specific co-formulated product at controlled doses in monitored patients. It did not study a research-chemical vial of cagrilintide added to whatever someone is already injecting. Those are not the same intervention, and the favorable tolerability finding does not transfer.

Every compound in this article is investigational. Petrelintide is in phase 2. Zenagamtide has not begun phase 3. CagriSema has been submitted to the FDA for weight management but is not approved.

The Honest Caveat

Amylin's promise is a better ratio — respectable weight loss for far less GI cost — not a bigger number. Petrelintide's 10.7% will not compete with retatrutide's 28.3% on a chart. The bet the field is making is that a drug people can actually stay on for years beats a drug that produces spectacular results for the fraction of people who tolerate it.

That bet is reasonable, and it is still a bet. Phase 2 tolerability findings have a long history of looking less pristine at phase 3 scale.

The Takeaway

Amylin went from a footnote to the main event in a single conference cycle. Petrelintide is the tolerability proof-of-concept, zenagamtide is the elegant one-molecule approach with the strongest phase 2 numbers, and CagriSema is the furthest along regulatorily. Watch ZUPREME-2 in the back half of 2026 for the next real signal.

This article is for research and educational purposes only. It is not medical advice, and it does not endorse the purchase or use of any compound. All compounds discussed are investigational and not approved for human use.