Amylin's second act: what the petrelintide phase 2 trials tell us

For most of the past decade, the story of peptide drugs for weight was a GLP-1 story. A second gut-and-pancreas hormone, amylin, is now drawing serious attention, and two phase 2 readouts this year for an experimental amylin analog called petrelintide give researchers a clearer picture of what this class might offer. The trial results below come from studies in people, but petrelintide itself is still investigational and not approved anywhere ³.

A hormone that travels with insulin

Amylin is a 37-amino-acid peptide made by the beta cells of the pancreas ⁴. It is packed into the same storage granules as insulin and released alongside it after a meal ¹. Its job, broadly, is to help the body handle food: it slows how fast the stomach empties, damps down the rise in glucagon after eating, and acts in the brain to reduce how much people eat ¹.

The catch is that human amylin is notoriously sticky. It tends to misfold and clump into amyloid fibrils, and these deposits are found in the pancreatic islets of most people with type 2 diabetes ⁴. That made the natural hormone a poor drug. Chemists worked around it by swapping three amino acids for prolines, borrowing a trick from rat amylin; the result, pramlintide, does not form fibrils ⁴. The FDA approved pramlintide (Symlin) in March 2005 ², and it is used as an add-on for adults with type 1 or type 2 diabetes who take mealtime insulin ¹. It is injected at mealtimes ¹, so a newer goal has been a long-acting amylin analog stable enough for weekly use ³.

What petrelintide is designed to do

Petrelintide, developed by Zealand Pharma with Roche, is a long-acting amylin analog designed for once-weekly injection ³. Its developer says it was engineered to stay chemically and physically stable and to resist fibril formation near neutral pH, which is what would let it be mixed with other peptides in one product ³. The company's hypothesis is that amylin drugs mainly increase fullness, while GLP-1 drugs mainly reduce appetite, and that this could translate into weight loss with better tolerability and possibly more preserved lean muscle ³. That last point is a hypothesis to be tested, not a finding.

ZUPREME-1: people without diabetes

The first phase 2 trial, ZUPREME-1, enrolled 493 adults with overweight or obesity and ran for 42 weeks, randomised, double-blind and placebo-controlled ⁵. Participants on petrelintide lost up to 10.7% of body weight on average by week 42, compared with 1.7% on placebo ⁵.

The companies highlighted the tolerability results. Stomach-related side effects were mostly mild; vomiting was less common than with placebo across the petrelintide groups, and diarrhoea and constipation were in the single digits and similar to placebo ⁵. In the most effective group, 4.8% stopped because of side effects, against 4.9% on placebo ⁵.

ZUPREME-2: people with type 2 diabetes

The second trial, reported on 7 October 2026, enrolled 220 adults with overweight or obesity and type 2 diabetes who were already taking metformin, with or without an SGLT2 inhibitor ⁶. At 28 weeks, mean weight loss was up to 9.2% with petrelintide versus 2.0% with placebo, and HbA1c, a long-term blood sugar measure, fell by between 0.61 and 0.88 percentage points more than with placebo ⁶. Gastrointestinal side effects were mostly mild and occurred mainly while doses were being increased, and stopping because of them was rare and similar between groups (1.9% vs 1.7%) ⁶.

Keeping the numbers in perspective

These are mid-stage results, reported so far largely by the companies, and the trials were designed to compare petrelintide with placebo, not with GLP-1 drugs. The weight loss is smaller than the 20.1% reported at 48 weeks for Lilly's amylin agonist eloralintide in its own phase 2 trial ⁷, but trials differ in length, populations and design, so cross-trial comparisons are rough at best. As of the 7 October announcement, full ZUPREME-2 results were expected at an upcoming scientific conference ⁶.

A crowded and hopeful field

Petrelintide is not alone. Lilly says eloralintide is now in phase 3 trials for obesity and related conditions ⁸. In June 2025, Novo Nordisk said it planned to take amycretin, a single molecule that activates both GLP-1 and amylin receptors, into phase 3 for weight management ⁹. For a hormone whose natural form clumps too readily to work as a drug, that is a notable shift, though none of these newer amylin drugs is approved yet.

What to watch

• Phase 3 results. Zealand and Roche have started three phase 3 trials planned to include about 7,000 people, covering people with overweight or obesity with and without type 2 diabetes, and people with established cardiovascular disease ⁶.
• Combinations. A phase 2 trial pairing petrelintide with Roche's GLP-1-based candidate CT-388 (enicepatide) is planned ⁶.
• Body composition. Whether amylin drugs really preserve more lean mass than other weight-loss medicines, as the developer suggests ³, is an open question that larger trials should help answer.

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