Amylin: the hormone that waited twenty years | Peptalis

The first amylin medicine was approved in 2005. Then the whole class went quiet for a long time. Only in recent years has amylin returned to research, now as a long-acting analogue paired with semaglutide. This is the story of pramlintide, cagrilintide, and the question of how a working mechanism could sit in the waiting room for twenty years.

Amylin: the hormone that waited twenty years

After a meal the beta cell of the pancreas releases not one hormone but two. Insulin is the familiar one. The second is called amylin, stored in the same granules and secreted together with insulin. Amylin acts to complement insulin: it slows gastric emptying, suppresses the release of glucagon after a meal, and sends a satiety signal through the brainstem. Where insulin moves glucose into the cell, amylin tempers the speed at which glucose appears in the blood at all.

Two hormones from one cell

On paper that makes amylin a natural partner to insulin. The practical route to it was harder than the mechanism suggested.

Why amylin was a difficult molecule

Human amylin has an awkward property. It aggregates into amyloid, the same kind of insoluble protein deposit found in the islets of Langerhans in type 2 diabetes. A molecule that clumps together in solution cannot be formulated as a medicine.

The solution was a targeted redesign. In pramlintide, three positions in the chain, residues 25, 28 and 29, are replaced by proline. Proline breaks the structure that drives aggregation. The result is a stable, soluble analogue that keeps amylin's action. Pramlintide engages the same amylin and calcitonin receptors and does in the body what amylin does: slow gastric emptying, suppress post-meal glucagon, reduce appetite.

One limitation remained, and it shapes the later story. Pramlintide is short-acting. It is injected at each meal, separately from insulin, as its own injection. That is pharmacologically clean and practically demanding.

What pramlintide showed in the clinic

Pramlintide did not stall in the laboratory. In March 2005 the US regulator, the FDA, approved pramlintide under the brand name Symlin as an adjunct to mealtime insulin in diabetes. That approval is a fact about the regulator, and it rests on a series of large, year-long, placebo-controlled studies.

In type 1 diabetes, a randomized study of 651 participants published by Ratner and colleagues in 2004 tested pramlintide added to insulin over 52 weeks. It reported an improvement in the long-term glucose measure HbA1c and in weight compared with placebo. A second type 1 diabetes study, by Whitehouse and colleagues in 2002, followed 480 participants with an open-label extension and confirmed the long-term picture. In type 2 diabetes, a study of 656 participants published by Hollander and colleagues in 2003 did the same: pramlintide added to insulin improved glucose and weight control over a year. Ryan and colleagues summarized the class picture in a 2009 review.

The studies also reported what went wrong. Nausea was common, especially during dose titration. In combination with insulin, an increased risk of low blood sugar was seen. These are observations from those trials, not a recommendation, and they belong to an honest account of what the agent did in people.

Twenty years of relative quiet

After 2005, little visible happened around amylin for a long time. There are sober reasons for that. Pramlintide asked for an extra injection at every meal, on top of the insulin a person already injected. The weight effect was real but modest. And the field's attention shifted to another gut-hormone route, that of GLP-1, where a single weekly injection gave a larger and broader effect. The incretins got the laboratory, the clinic and the headlines.

The amylin mechanism was not refuted by this. It was parked. The open question was whether the aggregation problem and the short-acting problem could be separated from the working core.

The revival: long-acting

The answer came with a new generation of molecules designed to last a week. Cagrilintide is one such long-acting amylin analogue. In a phase 1b study by Enebo and colleagues in 2021, a half-life of 159 to 195 hours was measured, comfortably enough for weekly dosing. That same design sharpens the comparison with pramlintide: the same route, a very different dosing rhythm.

As a stand-alone agent, cagrilintide showed what it can do on its own in a phase 2 dose-finding study by Lau and colleagues in 2021. In that study of 706 people with overweight or obesity, over 26 weeks, the highest dose of 4.5 mg gave a weight reduction of 10.8 percent, against 3.0 percent with placebo and 9.0 percent with the comparator GLP-1 analogue liraglutide.

The interesting step was the combination. Cagrilintide and semaglutide act on different routes, amylin and GLP-1, and their effects stack. In the phase 1b study by Enebo and colleagues, cagrilintide 2.4 mg together with semaglutide 2.4 mg gave a weight reduction of up to 17.1 percent over twenty weeks. The combination was named CagriSema. Frias and colleagues studied it in 2023 in a phase 2 trial of 92 people with type 2 diabetes, over 32 weeks. CagriSema gave a weight reduction of 15.6 percent and an HbA1c fall of 2.2 percentage points, against 5.1 percent and 1.8 percentage points with semaglutide alone.

Since 2026 the phase 3 results have arrived. In the REIMAGINE 1 study by Aroda and colleagues, in 189 people with type 2 diabetes on diet and exercise, CagriSema over 40 weeks gave a weight reduction of 13.8 percent and an HbA1c fall of 1.8 percentage points versus placebo. The larger REIMAGINE 2 study by Buse and colleagues, with 2713 participants over 68 weeks, was designed to test CagriSema directly against semaglutide on glucose control. CagriSema came out superior on HbA1c, with a fall of 1.91 percentage points against 1.75 percentage points for semaglutide alone. All of these outcomes are findings of the respective trials.

Here too the studies report the downside. Gastrointestinal complaints were the most reported adverse event across all active groups, mostly mild to moderate. That is the through-line of the whole class and the hinge for what is now being developed.

The next generation: selectivity

Amylin acts through more than one receptor. Part of the nausea appears to track with which receptors are engaged. The newest design step tries to steer that. Eloralintide, a selective agonist of the amylin 1 receptor, was described by Briere and colleagues in 2025, from preclinical work to a first phase 1 study in 48 healthy participants. In rats, eloralintide produced less conditioned taste avoidance than cagrilintide, a behavioural measure linked to nausea. In the phase 1 study, the 12 mg dose gave a weight reduction of 4.4 percent after four weeks versus placebo. This is early work, in a small cohort, but it shows the question now driving the class: can an amylin molecule stay effective and at the same time be better tolerated by engaging more selectively?

What pramlintide and cagrilintide show together

Two molecules on one route say more together than either does alone. Pramlintide is the clinically travelled, approved anchor of the amylin axis: short-acting, at the meal, in use since 2005. Cagrilintide is the long-acting revival: weekly, and in combination with semaglutide part of the most studied metabolic programme of the moment. The axis between them is the same. The difference lies in the dosing rhythm and in twenty years of design.

What is still open matters as much as what is shown. There is little direct comparative evidence yet between the short-acting and the long-acting amylin approach. The durability of the effect over several years is still being gathered. And the core question of the class, whether more selective receptor agonists genuinely reduce gastrointestinal complaints without losing the effect, has not been answered. For laboratories dissecting amylin receptor pharmacology in vitro, that is a clear and current field of work. At Peptalis, pramlintide and cagrilintide are available strictly for research use only, for in-vitro laboratory research, not for human or animal use.

Registered nurse with eleven years in psychiatry and founder of Peptalis. Writes the platform's knowledge layer: compound profiles, evidence reviews and the quality methodology. Works from primary literature (PubChem for chemistry, PubMed for studies) and states where evidence is absent.

Sources checked via PubMed · 10 references

• Two hormones from one cell
• Why amylin was a difficult molecule
• What pramlintide showed in the clinic
• Twenty years of relative quiet
• The revival: long-acting
• The next generation: selectivity
• What pramlintide and cagrilintide show together

• Ryan et al. 2009 ↗
• Ratner et al. 2004 ↗
• Lau et al. 2021 ↗
• Frias et al. 2023 ↗
• Briere et al. 2025 ↗

• DEEP DIVEThe GLP class: from one receptor to three
• DEEP DIVECagrilintide: the amylin track beside GLP-1

Compounds in this article

• Pramlintide · Not in catalogue · Research profile
• Cagrilintide · Not in catalogue · Research profile

For laboratory research use only. Not for human use.

SCIENTIFIC REFERENCES

These references are provided for informational and research purposes only. They do not constitute medical advice.

1. 01ReviewReview of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes.Ryan G, et al. Drug Des Devel Ther. 2009.DOI →
2. 02Human RCTAmylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: a 1-year, randomized controlled trial.Ratner RE, et al. Diabet Med. 2004.DOI →
3. 03Human RCTPramlintide as an adjunct to insulin therapy improves long-term glycemic and weight control in patients with type 2 diabetes: a 1-year randomized controlled trial.Hollander PA, et al. Diabetes Care. 2003.DOI →
4. 04Human RCTA randomized study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct to insulin therapy in type 1 diabetes.Whitehouse F, et al. Diabetes Care. 2002.DOI →
5. 05Human RCT · phase 2Once-weekly cagrilintide for weight management in people with overweight and obesity: a dose-finding phase 2 trial.Lau DCW, et al. Lancet. 2021.DOI →
6. 06Human RCT · phase 1bSafety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a phase 1b trial.Enebo LB, et al. Lancet. 2021.DOI →
7. 07Human RCT · phase 2Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a phase 2 trial.Frias JP, et al. Lancet. 2023.DOI →
8. 08Human RCT · phase 3aEfficacy and safety of once-weekly cagrilintide-semaglutide (CagriSema) in adults with type 2 diabetes inadequately controlled on diet and exercise (REIMAGINE 1): a phase 3a study.Aroda VR, et al. Lancet Diabetes Endocrinol. 2026.DOI →
9. 09Human RCT · phase 3Cagrilintide-semaglutide (CagriSema) versus semaglutide or cagrilintide in people with type 2 diabetes (REIMAGINE 2): a phase 3 study.Buse JB, et al. Lancet Diabetes Endocrinol. 2026.DOI →
10. 10Preclinical + human phase 1Eloralintide (LY3841136), a novel amylin receptor agonist for the treatment of obesity: from discovery to clinical proof of concept.Briere DA, et al. Mol Metab. 2025.DOI →