Amylin Analogues: Pramlintide and Cagrilintide Reviewed

Amylin is the second peptide hormone of the pancreatic beta cell, released alongside insulin after meals. For two decades its main research application was a single approved analogue, pramlintide. That changed with long-acting analogues such as cagrilintide, and amylin-pathway agonism is now one of the most active areas in metabolic peptide research. This review traces the path from the native hormone to modern analogues, explains why amylin is chemically difficult, and summarises the clinical evidence.

Origin and discovery

Amylin, also called islet amyloid polypeptide (IAPP), was identified in 1987 as the main protein component of the amyloid deposits found in pancreatic islets of people with type 2 diabetes. Two groups published its isolation and sequence that year (Cooper et al., 1987; Westermark et al., 1987). Subsequent work showed that amylin is co-packaged with insulin in beta-cell secretory granules and released in parallel with it.

Physiologically, amylin complements insulin. It reduces meal size, slows gastric emptying and suppresses postprandial glucagon secretion. People with type 1 diabetes lack both insulin and amylin, which provided the rationale for developing an amylin replacement.

Structure and chemistry

Human amylin is a 37-residue peptide with a disulfide bridge between cysteines 2 and 7 and an amidated C-terminus. It is closely related to calcitonin and calcitonin gene-related peptide (CGRP), which share the N-terminal ring and C-terminal amide.

The central problem is aggregation. Human amylin readily forms β-sheet-rich fibrils, the same process that produces islet amyloid. The region around residues 20–29 is particularly amyloidogenic. Rat amylin, by contrast, does not form fibrils, largely because it contains proline residues in that region.

Pramlintide was designed by Amylin Pharmaceuticals by replacing human residues at positions 25, 28 and 29 with proline, mirroring the rat sequence. The resulting peptide is soluble and non-fibrillating while retaining receptor activity. Its half-life is short, on the order of minutes to an hour.

Cagrilintide was developed by Novo Nordisk as a long-acting, non-fibrillating analogue (Kruse et al., 2021). Its design combines amino-acid substitutions that reduce aggregation with N-terminal acylation by a fatty diacid that binds albumin, giving a half-life of about a week in clinical pharmacology studies.

For laboratories, amylin-family peptides require attention to aggregation: solution history, pH, ionic strength and surfaces can all influence fibril formation, which in turn affects assay results.

Receptor pharmacology and mechanism studied

Amylin receptors are a textbook example of receptor heterodimerisation. The calcitonin receptor (CTR), a class B GPCR, pairs with one of three receptor activity-modifying proteins (RAMP1, RAMP2 or RAMP3) to form amylin receptors AMY1, AMY2 and AMY3. Without a RAMP, the calcitonin receptor responds preferentially to calcitonin (Hay et al., 2015).

Key mechanistic findings include:

• Hindbrain signalling. The area postrema and nucleus of the solitary tract express amylin receptors. Activation here reduces meal size and promotes satiety, and the area postrema lies outside the blood–brain barrier, giving circulating peptides access.
• Gastric emptying and glucagon. Amylin slows gastric emptying and suppresses glucagon secretion after meals.
• Leptin interaction. Rodent studies have reported that amylin can restore leptin responsiveness in diet-induced obesity, an observation that motivated amylin–leptin combination research.
• Calcitonin receptor activity. Cagrilintide activates both amylin receptors and the calcitonin receptor. Whether this dual profile adds to or detracts from its effects relative to a selective amylin agonist is still under study.

Research and clinical-trial landscape

Pramlintide was evaluated in randomised trials as an adjunct to mealtime insulin in type 1 and type 2 diabetes, including the studies summarised by Ratner et al. (2004), with glycaemic and body-weight endpoints. It was approved by the FDA in 2005.

Cagrilintide alone was evaluated in a phase 2 trial in adults with overweight or obesity without diabetes, which compared several exposure levels with placebo and liraglutide and evaluated body-weight endpoints (Lau et al., 2021).

CagriSema, the fixed combination of cagrilintide and semaglutide, has been studied in:

• a phase 1b trial in adults with overweight or obesity (Enebo et al., 2021);
• a phase 2 trial in type 2 diabetes evaluating glycaemic and body-weight endpoints (Frias et al., 2023);
• the phase 3 REDEFINE programme, including REDEFINE 1 in obesity and REDEFINE 2 in obesity with type 2 diabetes (Garvey et al., 2025; Davies et al., 2025).

Other amylin-pathway candidates in clinical development include further long-acting amylin analogues and unimolecular GLP-1/amylin agonists, such as amycretin. Their public data are still early.

Across the class, the most common adverse events reported were gastrointestinal, particularly nausea.

Evidence quality and open questions

• Pramlintide. Well characterised in randomised trials, but its short half-life limited its use and research interest moved to longer-acting analogues.
• Cagrilintide alone. Evidence for cagrilintide as a single agent rests mainly on phase 2 data; its development has focused on combination with semaglutide.
• Contribution of each component. In CagriSema trials, monotherapy arms help separate the amylin and GLP-1 contributions, but how the two pathways interact mechanistically in the hindbrain is not fully mapped.
• Receptor selectivity. The relative importance of AMY receptors versus the calcitonin receptor, and the long-term significance of calcitonin receptor activation, are unresolved.
• Body composition. Some researchers have proposed that amylin agonism may differ from GLP-1 agonism in its effect on lean tissue; this requires dedicated studies.

Regulatory and anti-doping status

Amylin itself is an endogenous hormone. Pramlintide is an approved prescription medicine in the United States (Symlin) for type 1 and type 2 diabetes in people using mealtime insulin; a European marketing application was withdrawn. Cagrilintide and CagriSema are investigational and not approved by the FDA or EMA at the time of writing.

None of these compounds is named on the WADA Prohibited List at the time of writing. Non-approved substances may fall under the S0 category, so researchers working with athletes should consult the current list.

Summary table

	Amylin (human)	Pramlintide	Cagrilintide
Nature	Endogenous hormone	Synthetic analogue	Synthetic acylated analogue
Length	37 residues	37 residues	Amylin-based, modified
Key feature	Disulfide 2–7, C-terminal amide	Pro25, Pro28, Pro29	Non-fibrillating substitutions; fatty diacid
Aggregation	Highly amyloidogenic	Non-fibrillating	Non-fibrillating
Half-life	Minutes	Short	About one week
Receptors	AMY1–3 (CTR + RAMP)	AMY1–3	AMY1–3 and CTR
Status	Endogenous	Approved Rx (US)	Investigational

References

• Cooper GJ, Willis AC, Clark A, et al. Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients. Proc Natl Acad Sci USA. 1987;84(23):8628–8632.
• Westermark P, Wernstedt C, Wilander E, et al. Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells. Proc Natl Acad Sci USA. 1987;84(11):3881–3885.
• Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev. 2011;91(3):795–826.
• Hay DL, Chen S, Lutz TA, Parkes DG, Roth JD. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev. 2015;67(3):564–600.
• Ratner RE, Dickey R, Fineman M, et al. Amylin 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. Diabet Med. 2004;21(11):1204–1212.
• Kruse T, Hansen JL, Dahl K, et al. Development of cagrilintide, a long-acting amylin analogue. J Med Chem. 2021;64(15):11183–11194.
• Lau DCW, Erichsen L, Francisco AM, et al. Once-weekly cagrilintide for weight management in people with overweight and obesity: a multicentre, randomised, double-blind, placebo-controlled and active-controlled, dose-finding phase 2 trial. Lancet. 2021;398:2160–2172.
• Enebo LB, Berthelsen KK, Kankam M, et al. Safety, tolerability, pharmacokinetics, and pharmacodynamics of concomitant administration of multiple doses of cagrilintide with semaglutide 2.4 mg for weight management: a randomised, controlled, phase 1b trial. Lancet. 2021;397:1736–1748.
• Frias JP, Deenadayalan S, Erichsen L, et al. Efficacy and safety of co-administered once-weekly cagrilintide 2.4 mg with once-weekly semaglutide 2.4 mg in type 2 diabetes: a multicentre, randomised, double-blind, active-controlled, phase 2 trial. Lancet. 2023;402:720–730.
• Garvey WT, Blüher M, Osorto Contreras CK, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. N Engl J Med. 2025.
• Davies MJ, Bajaj HS, Broholm C, et al. Cagrilintide–semaglutide in adults with overweight or obesity and type 2 diabetes. N Engl J Med. 2025.