What is amylin? How amylin analogs differ from GLP-1 drugs

Amylin is a 37-amino-acid hormone that beta cells in the pancreas release together with insulin when you eat.[1][2] It slows how fast the stomach empties, damps the glucagon rise after a meal and signals the brain to stop eating.[2][6] GLP-1 is a different hormone, made by L-cells lining the gut, and its signature action is boosting insulin release in a glucose-dependent way.[8] The two overlap on appetite and digestion but act on different receptors, and drugmakers are now testing amylin analogs both on their own and paired with GLP-1 drugs.[6]

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What amylin does after a meal

Amylin and insulin are stored in the same secretory granules and leave the beta cell together in response to food, so in healthy adults their blood levels follow similar patterns.[2] Insulin increases glucose use in tissues around the body. Amylin works on how fast glucose arrives in the blood after a meal.[4][2]

It does that in three ways, mapped mostly in nonclinical studies. It slows gastric emptying without reducing how much of the meal is eventually absorbed. It suppresses glucagon, the hormone that tells the liver to release glucose, a signal that insulin alone does not normalize. And it reduces food intake through the brain.[2]

That appetite effect is centered in the brainstem. Amylin acts mainly in a group of brain regions called circumventricular organs, particularly the area postrema, and it also acts in the hypothalamus to help bring a meal to an end.[1][6]

Diabetes breaks this partnership. People with type 1 diabetes have an absolute deficiency of both insulin and amylin, and people with type 2 diabetes have a relative deficiency of both.[4] So the first amylin medicine was built as an add-on for people with either type who already use mealtime insulin.[2]

Why human amylin is hard to turn into a drug

Scientists found amylin through disease. In the late 1980s it was identified as a major component of the amyloid deposits inside the pancreatic islets of people with type 2 diabetes, which is why it is also called islet amyloid polypeptide, or IAPP.[4][5]

That habit of clumping is the first problem for drug developers. Aggregated human IAPP is toxic to cells and is believed to be critically important in the loss of beta cells in type 2 diabetes.[5] The second problem is speed: human studies put natural amylin's half-life at less than 20 minutes.[4]

Pramlintide was the first workaround. It keeps the human sequence but copies three prolines from rat amylin, at positions 25, 28 and 29, which makes it a non-aggregating analog.[2][4] The FDA approved it as Symlin in March 2005 for people with type 1 or type 2 diabetes who use mealtime insulin and have not reached their glucose targets.[3][2]

Pramlintide proved the concept but was limited by modest efficacy and a demanding routine, since it had to be taken with each meal, separately from insulin.[6][4] In the label's pooled placebo-controlled trials lasting 26 to 52 weeks in people with type 1 diabetes, nausea affected 48% of 716 people on pramlintide plus insulin, compared with 17% of 538 on placebo plus insulin. The label also carries a boxed warning that use with insulin raises the risk of severe hypoglycemia, particularly in type 1 diabetes.[2] The FDA's Drugs@FDA database now lists every Symlin product as discontinued.[3]

Amylin vs GLP-1: different receptors, overlapping effects

GLP-1 starts in a different organ. Enteroendocrine L-cells in the gut release it, and they are most concentrated in the ileum and colon.[8] GLP-1 increases insulin, inhibits glucagon, slows gastric emptying and reduces food intake.[7] Its insulin effect is glucose-dependent, the incretin action GLP-1 was first identified for.[8] Amylin is not an insulin booster, and inside the islets it may even inhibit insulin and glucagon secretion.[5] Its effect on blood glucose after meals comes through slower stomach emptying, lower glucagon and reduced food intake.[2]

The receptors differ even more than the effects. The GLP-1 receptor is one protein, a class B G protein-coupled receptor.[8] An amylin receptor is a pair: the calcitonin receptor combined with one of three receptor activity-modifying proteins, or RAMPs. The three pairings form subtypes called AMY1, AMY2 and AMY3, each with its own pharmacological profile.[4][1]

That two-part design splits the new drugs into two camps. Selective amylin receptor agonists aim only at amylin receptors, while dual amylin and calcitonin receptor agonists, known as DACRAs, also activate the calcitonin receptor. Cagrilintide is a DACRA.[6] Eloralintide was developed as a selective amylin receptor agonist.[16]

The two hormones also seem to reach the brain's appetite circuits by different routes. Most studies indicate that circulating amylin works through the area postrema, while GLP-1's effect on eating seems to run mainly through vagal nerve fibers projecting to the hindbrain.[9] Separate routes are one rationale for combining the two, but they do not show that a combination helps people. Turning promising animal results with amylin analogs into human results has proven difficult.[4]

What the amylin drugs in trials are testing

Every trial below was funded by the company developing the drug.[10][14][16][18] The REDEFINE 4 results and CagriSema's regulatory timeline come from Novo Nordisk's own announcements.[12][13]

The furthest along is CagriSema, a fixed combination of cagrilintide and the GLP-1 drug semaglutide.[13] In the phase 3 REDEFINE 1 trial, 3,417 adults without diabetes who had obesity, or overweight plus at least one related health problem, were randomized for 68 weeks. Body weight fell an estimated 20.4% with the combination versus 3.0% with placebo. Gastrointestinal side effects included nausea, vomiting, diarrhea, constipation and abdominal pain, and were mainly transient and mild to moderate.[10]

The design is what makes REDEFINE 1 useful for the amylin question. Alongside 2,108 people on the combination and 705 on placebo, it had a semaglutide-only arm and a cagrilintide-only arm of 302 people each.[10] A separate analysis estimated what would happen if everyone continued treatment without rescue medication: weight fell an estimated 22.7% with the combination, 16.1% with semaglutide alone and 11.8% with cagrilintide alone. This hypothetical treatment continuation assumption differs from the analysis behind the 20.4% figure above, which includes treatment discontinuation and rescue interventions.[10][11] Within one trial and one population, adding the amylin analog produced more weight loss than the GLP-1 drug by itself.[11]

Beating its own components is not the same as beating every rival. Novo Nordisk announced in February 2026 that in REDEFINE 4, an open-label trial of 809 people with obesity and at least one related condition, CagriSema missed its primary goal of showing it was not inferior to tirzepatide after 84 weeks. Weight fell 20.2% versus 23.6% in the treatment-regimen analysis, and 23.0% versus 25.5% if everyone had adhered to treatment.[12] The company says it submitted a New Drug Application for CagriSema in December 2025 and expects an FDA decision in the fourth quarter of 2026.[13]

Novo is also putting both signals into one molecule. Zenagamtide, formerly called amycretin, activates GLP-1, amylin and calcitonin receptors.[14] In a 36-week phase 2 trial of 262 adults with type 2 diabetes, HbA1c (glycated hemoglobin, a measure of average blood sugar over recent months) started at an average of 7.8%. It fell by 0.9 percentage points in the lowest-dose group and 1.7 in the highest, which was 0.77 and 1.56 points more than placebo. Most side effects were gastrointestinal and mild to moderate.[14] A phase 3 trial comparing it with semaglutide in obesity is recruiting.[15]

Lilly's eloralintide tests amylin activity without a GLP-1 partner. In a 48-week phase 2 trial of 263 adults with obesity, or overweight plus a weight-related condition, and no type 2 diabetes, mean weight fell 9% to 20% across eloralintide groups, compared with 0.4% on placebo. Nausea and fatigue were the most common side effects.[16] A phase 3 trial in 1,980 adults without type 2 diabetes is recruiting.[17]

Petrelintide, a long-acting amylin analog from Zealand Pharma, was tested in ZUPREME 1, a phase 2 trial of 493 adults with obesity, or overweight plus high blood pressure or abnormal blood lipids, and no type 2 diabetes. The trial involved 42 weeks of treatment, but its primary weight endpoint was at 28 weeks. In the analysis of 485 participants who received at least one dose, estimated weight loss at that endpoint ranged from 7.9% to 9.8% across treatment groups versus 1.7% with placebo. Nausea was the most common side effect with petrelintide, predominantly mild and occurring during dose escalation.[18] Roche is now the registered sponsor of a phase 3 trial against placebo with a target of 3,900 participants, listed as recruiting on 8 October 2026, and of a phase 2 trial pairing petrelintide with Roche's enicepatide.[19][22]

Zealand reported a separate result on 7 October in people with overweight or obesity and type 2 diabetes. Its phase 2 ZUPREME 2 trial was randomized, double-blind and placebo-controlled. The company describes 220 participants, 28 weeks of treatment and follow-up through week 38. At the primary endpoint of 28 weeks, mean weight loss was 7.4% to 9.2% across petrelintide groups versus 2.0% with placebo using the efficacy estimand, Zealand said.[24]

Those are company topline results, with full findings still awaiting presentation at a scientific conference. Zealand said the most frequently reported adverse events were gastrointestinal, the vast majority mild and occurring during dose escalation.[24] These figures come from different populations, durations and comparators, so they cannot be lined up to rank the drugs.

What is still unknown?

The biggest gap is outcomes. REDEFINE 3 is testing whether CagriSema reduces cardiovascular deaths, heart attacks and strokes in 7,101 adults with established cardiovascular disease, and its primary completion is estimated for September 2027.[20]

A second trial will test whether metabolic changes translate into fewer serious cardiovascular events. Novo Nordisk's AMBIENCE trial, first posted on ClinicalTrials.gov on 6 October 2026, plans to compare zenagamtide with placebo in an estimated 8,500 adults with overweight or obesity and established atherosclerotic cardiovascular disease, meaning artery disease caused by plaque. Its main measure combines cardiovascular death, nonfatal heart attack, nonfatal stroke and hospitalization or an urgent visit for heart failure. The phase 3 study was not yet recruiting when checked on 8 October, with primary completion estimated for September 2030.[23]

Tolerability is the second open question. Amylin drugs are often discussed as a route to better-tolerated weight-loss treatment.[21] Yet nausea and fatigue were the most common side effects of eloralintide in its phase 2 trial, while nausea was the most common with petrelintide.[16][18] Researchers are still working out how calcitonin receptor activity, drug exposure and the brain circuits involved decide whether eating less reflects normal fullness or an unpleasant, aversive signal.[21]

The next answers will come from specific documents. First is the FDA's decision on CagriSema, which Novo expects in the fourth quarter of 2026. After that come REDEFINE 3 and the phase 3 trials of eloralintide and petrelintide, whose primary completion dates the registry estimates for 2028.[13][17][19] AMBIENCE extends the cardiovascular outcomes timeline to an estimated September 2030 primary completion; that is a study milestone, not a promised publication date.[23] For now the firm finding is narrow: in one large trial, adding an amylin analog to semaglutide increased weight loss, and most other claims made for the class are still being tested.[11]

Frequently asked questions

Is amylin the same as amyloid?

No. Amylin is the hormone, and amyloid describes protein that has aggregated into fibril deposits. Human amylin can form those deposits in the pancreas, especially in type 2 diabetes, which is how it got the name islet amyloid polypeptide. Pramlintide was designed as a non-aggregating version.

[5] [4]

Is pramlintide (Symlin) still available?

The FDA approved pramlintide, sold as Symlin, in March 2005 as an add-on to mealtime insulin, and its label carries a boxed warning about severe hypoglycemia. When we checked the FDA's drug-approval data through openFDA on 8 October 2026, every Symlin product was listed as discontinued.

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