Amylin (Pramlintide): Metabolic Peptide Profile

The race to unlock body weight control through peptide therapeutics has intensified dramatically. While GLP-1 agonists like semaglutide captured mainstream attention with 15-20% weight loss, the next frontier pairs them with a different hormone entirely—one that the pancreas has been secreting alongside insulin for millions of years.

Amylin, also known as islet amyloid polypeptide (IAPP), is a 37-amino-acid hormone co-secreted with insulin from pancreatic beta cells. Its synthetic analog pramlintide became the first peptide-based diabetes drug approved since insulin in 1921. Now, a next-generation amylin analog called cagrilintide is showing 22.7% weight loss when combined with semaglutide in the CagriSema formulation—numbers that surpass either drug alone.

This profile examines amylin's metabolic mechanisms, pramlintide's clinical track record in diabetes, and why cagrilintide represents one of the most promising additions to the obesity treatment pipeline.

Quick Facts
What Is Amylin?
How Amylin Works: Mechanisms of Action
Pramlintide (Symlin): First-Generation Amylin Analog
Cagrilintide: Next-Generation Amylin Therapy
Safety and Side Effects
Regulatory and Legal Status
FAQs
Bottom Line
References

Quick Facts

Property	Details
Full Name	Islet Amyloid Polypeptide (IAPP)
Type	Pancreatic beta cell hormone
Structure	37 amino acids with N-terminal disulfide bridge (Cys2-Cys7) and C-terminal amide
Co-secretion	Released with insulin at approximately 100:1 insulin:amylin ratio
Primary Receptors	AMY1 (CRLR + RAMP1), AMY2 (CRLR + RAMP2), AMY3 (CRLR + RAMP3)
First Analog	Pramlintide (Symlin)
FDA Approval	March 16, 2005 (pramlintide)
Manufacturer	AstraZeneca (pramlintide/Symlin); Novo Nordisk (cagrilintide)
Current Status	Symlin discontinued October 2025; CagriSema under FDA review (2026)

What Is Amylin?

Amylin is a 37-amino-acid peptide hormone synthesized by pancreatic beta cells and stored in insulin secretory granules. When you eat a meal, beta cells release both insulin and amylin into the bloodstream. While insulin moves glucose from blood into cells, amylin controls the rate at which glucose arrives in the blood in the first place.

Evolutionary Context

Amylin shows 46% amino acid sequence homology with calcitonin gene-related peptide (CGRP), another 37-amino-acid signaling molecule. Both share structural features including an N-terminal disulfide bridge and C-terminal amide that are highly conserved across species—markers of evolutionary importance.

Interestingly, rat amylin differs from human IAPP at only six positions, with three critical proline residues at positions 25, 28, and 29. These prolines prevent rat amylin from aggregating into the toxic amyloid deposits seen in human type 2 diabetes. This species difference became the blueprint for designing pramlintide.

The Amylin Paradox: Hormone and Pathogen

Human amylin has a dark side. In over 90% of patients with type 2 diabetes, IAPP misfolds and aggregates into amyloid fibrils that are toxic to beta cells. These deposits contribute to progressive beta cell loss, worsening the disease.

The aggregation appears to follow a prion-like mechanism. When researchers injected pancreatic tissue containing IAPP aggregates into transgenic mice expressing human IAPP, it dramatically accelerated amyloid formation, accompanied by hyperglycemia, impaired glucose tolerance, and reduced beta cell mass.

This dual nature—essential metabolic hormone and potential cellular toxin—explains both the therapeutic promise of amylin analogs and the need to engineer them to resist aggregation.

How Amylin Works: Mechanisms of Action

Amylin complements insulin through three primary mechanisms that together reduce the rate of glucose appearance in the bloodstream after meals:

1. Slowing Gastric Emptying

Amylin delays how quickly food moves from the stomach to the small intestine, an effect lasting approximately three hours after administration. This mechanism is centrally mediated through neurons in the area postrema—a brainstem region that lacks a blood-brain barrier—and requires an intact vagus nerve.

Direct microinjection of amylin into the area postrema causes dose-dependent decreases in food intake. The area postrema then transmits signals to the nucleus tractus solitarius (NTS), an integrative relay center for gut-brain communication.

Notably, insulin-induced hypoglycemia reverses amylin's gastric emptying inhibition—a glucose-sensitive "fail-safe" that safeguards against severe hypoglycemia.

2. Suppressing Glucagon Secretion

Glucagon is the counter-regulatory hormone that raises blood glucose by stimulating the liver to release stored glucose. After meals, when glucose is already elevated, continued glucagon secretion is counterproductive.

Amylin suppresses postprandial glucagon release from pancreatic alpha cells, reducing hepatic glucose output when it's least needed. This glucagonostatic effect appears to be centrally mediated and extrinsic to the pancreas, possibly through vagal nerve signals.

Critically, amylin's glucagon suppression is selective for meal-related secretion. The hormone preserves the ability of glucagon to respond during hypoglycemia—another built-in safety mechanism.

3. Promoting Satiety

Amylin acts as a satiation signal in the central nervous system to reduce food intake and body weight. After activating neurons in the area postrema, signals reach the arcuate nucleus of the hypothalamus, where they stimulate anorexigenic (appetite-suppressing) POMC/CART neurons.

This isn't merely nausea-induced appetite loss. Studies show that weight reductions with pramlintide are independent of nausea, suggesting genuine changes in satiety signaling rather than food aversion.

Amylin Receptors: A GPCR Family

Amylin doesn't have its own unique receptor. Instead, it activates a family of G-protein-coupled receptors formed when the calcitonin receptor (CTR) combines with one of three receptor activity-modifying proteins (RAMPs):

AMY1 (CTR + RAMP1): Binds both amylin and CGRP with high affinity; considered a secondary CGRP receptor
AMY2 (CTR + RAMP2): Preferentially binds amylin and calcitonin over CGRP
AMY3 (CTR + RAMP3): Binds amylin with high affinity but CGRP weakly

Cagrilintide acts as a non-selective agonist across all three amylin receptor subtypes, which may contribute to its superior efficacy compared to earlier analogs.

Pramlintide (Symlin): First-Generation Amylin Analog

Design and Development

Pramlintide is a synthetic analog of human amylin, modified at three positions to prevent the aggregation that plagues native IAPP. Based on the observation that rat amylin doesn't aggregate due to proline residues at positions 25, 28, and 29, researchers incorporated these same three proline substitutions into the human sequence.

These modifications serve as "β-sheet breakers" that stabilize the α-helical conformation and prevent conversion to the aggregation-prone β-sheet structure. The result is a non-amyloidogenic analog that retains amylin's biological activity.

Clinical Efficacy in Diabetes

Pramlintide was approved by the FDA on March 16, 2005, as adjunctive therapy for patients with type 1 or type 2 diabetes using mealtime insulin who have not achieved adequate glucose control.

Type 1 Diabetes: Clinical trials lasting 4 to 52 weeks showed HbA1c reductions of 0.1% to 0.67% with pramlintide at doses of 120-270 mcg/day. The between-group difference versus placebo was 0.2-0.3 percentage points.

Type 2 Diabetes: In five studies spanning 4 to 52 weeks, pramlintide at 90-450 mcg/day reduced HbA1c by 0.3% to 0.62%. When added to insulin therapy, the between-group difference was approximately 0.4 percentage points versus placebo.

Beyond glucose control, pramlintide consistently delivered modest weight loss averaging 1-2 kg—a notable benefit in a drug class (insulin) typically associated with weight gain.

Dosing and Administration

Pramlintide was administered as a subcutaneous injection immediately before major meals (≥250 calories or ≥30 grams of carbohydrate).

Type 2 Diabetes:

Initial dose: 60 mcg before each major meal
Increase to 120 mcg after 3 days if no clinically significant nausea occurs
Reduce back to 60 mcg if nausea persists

Type 1 Diabetes:

Initial dose: 15 mcg before each major meal
Gradually titrate to 30-60 mcg based on tolerance

Critical Safety Requirement: To reduce hypoglycemia risk, mealtime insulin doses must be reduced by 50% when initiating pramlintide. The injection site should be at least 2 inches away from insulin injection sites, and the two drugs should never be mixed.

Market Withdrawal

Despite its approval, pramlintide never achieved widespread use. The need for multiple daily injections, high incidence of nausea, careful insulin dose titration, and hypoglycemia risk limited adoption. All formulations of Symlin were discontinued in October 2025, ending the commercial availability of the first amylin-based therapy.

Cagrilintide: Next-Generation Amylin Therapy

Design Improvements

Cagrilintide (AM833) is a long-acting acylated amylin analog developed by Novo Nordisk for obesity and diabetes. The acylation allows albumin binding, extending the drug's half-life to permit once-weekly subcutaneous dosing—a dramatic improvement over pramlintide's three-times-daily regimen.

The compound retains non-amyloidogenic properties while acting as a non-selective agonist at all three amylin receptor subtypes (AMY1, AMY2, AMY3).

Clinical Efficacy: REDEFINE and REIMAGINE Programs

REDEFINE 1 (Obesity, Monotherapy): This Phase 3 trial in adults with obesity or overweight (without diabetes) showed average weight reduction of 11.8% with cagrilintide versus 2.3% with placebo over 68 weeks. Notably, 31.6% of patients achieved greater than 15% weight loss, compared to just 4.7% with placebo.

CagriSema (Combination Therapy): The real excitement centers on CagriSema—a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg administered once weekly.

In a Phase 3 trial, patients with mean baseline body weight of 106.9 kg achieved 22.7% weight loss with CagriSema after 68 weeks, compared to:

11.8% with cagrilintide 2.4 mg alone
16.1% with semaglutide 2.4 mg alone

This represents a synergistic effect beyond either drug individually, likely reflecting complementary mechanisms—semaglutide enhancing insulin secretion and cagrilintide controlling glucose appearance and satiety through distinct pathways.

REIMAGINE 2 (Type 2 Diabetes): Results announced in February 2026 showed CagriSema 2.4/2.4 mg achieved superior HbA1c reduction of 1.91 percentage points after 68 weeks compared to 1.76 points with semaglutide 2.4 mg, plus superior weight loss of 14.2% versus 10.2%.

Regulatory Status

Novo Nordisk filed for FDA approval of CagriSema in December 2025, with review expected in 2026. If approved, it would become the first injectable combination of a GLP-1 receptor agonist and amylin analog for weight management.

Additional Phase 3 trials include REDEFINE 3 (cardiovascular outcomes) and multiple studies in the REIMAGINE program for type 2 diabetes.

Safety and Side Effects

Common Adverse Events

Nausea: The most frequent side effect across all amylin analogs is transient nausea, occurring in up to 48% of patients taking pramlintide. Gradual dose titration reduces severity. With cagrilintide, nausea is typically mild to moderate.

Other GI Effects: Vomiting (up to 11%), diarrhea, constipation, and decreased appetite are reported but generally less common than nausea.

Injection Site Reactions: Redness, swelling, bruising, or itching at injection sites may occur.

Hypoglycemia Risk

Amylin analogs don't directly cause hypoglycemia—they lack any glucose-lowering mechanism when blood sugar is normal. However, when combined with insulin, severe insulin-induced hypoglycemia can occur, particularly in the first 3 hours after injection.

The risk is highest in type 1 diabetes. Reducing mealtime insulin by 50% when starting pramlintide and careful glucose monitoring are essential mitigation strategies.

Importantly, amylin's glucose-sensitive mechanisms (reversing gastric slowing during hypoglycemia, preserving glucagon responses) provide physiologic safeguards that limit but don't eliminate risk.

Contraindications

Confirmed diagnosis of gastroparesis (delayed gastric emptying)
Hypoglycemia unawareness
Allergy to pramlintide or cagrilintide
Pediatric use (safety not established)

Pregnancy and Lactation

Pramlintide is FDA Pregnancy Category C. Animal studies showed no teratogenic effects, but human data are limited. Use during pregnancy only if potential benefit justifies potential risk. It's unknown whether pramlintide or cagrilintide passes into breast milk.

Regulatory and Legal Status

United States

Pramlintide (Symlin):

FDA approved: March 16, 2005
Indication: Adjunctive therapy in type 1 and type 2 diabetes using mealtime insulin
Status: All formulations discontinued October 2025
Prescription only

Cagrilintide/CagriSema:

Status: Investigational; FDA filing submitted December 2025
Expected review: 2026
Not yet approved for any indication

International

Pramlintide received limited approval in other jurisdictions but never achieved broad international distribution. CagriSema is under regulatory review in multiple regions following completion of Phase 3 trials.

Research and Experimental Use

Amylin analogs including cagrilintide are available for legitimate research purposes through approved clinical trials. Neither pramlintide nor cagrilintide is available for "research use only" sale outside of clinical trials or approved medical use.

FAQs

What is the difference between amylin and insulin?

Both are hormones co-secreted by pancreatic beta cells in response to meals, but they have complementary functions. Insulin increases the rate of glucose disappearance from blood (Rd) by promoting cellular glucose uptake. Amylin decreases the rate of glucose appearance (Ra) in blood by slowing gastric emptying, suppressing glucagon, and promoting satiety. Together, they coordinate postprandial glucose control.

Why was pramlintide discontinued?

Despite FDA approval in 2005, pramlintide never gained widespread adoption. Barriers included the need for three daily injections before meals, high rates of nausea (up to 48%), complex insulin dose adjustments, hypoglycemia risk, and cost. Newer therapies like GLP-1 agonists offered better convenience (weekly dosing), superior weight loss, and cardiovascular benefits. AstraZeneca discontinued all Symlin formulations in October 2025.

How does cagrilintide differ from pramlintide?

Cagrilintide is a long-acting acylated amylin analog with albumin-binding properties that extend its half-life, allowing once-weekly subcutaneous dosing instead of three times daily. It shows greater efficacy for weight loss (11.8% as monotherapy versus 1-2 kg with pramlintide) and appears better tolerated. The extended pharmacokinetics also make it practical to combine with weekly GLP-1 agonists in formulations like CagriSema.

Can amylin analogs be used without insulin?

Pramlintide was approved only as adjunctive therapy with insulin in diabetes patients. However, cagrilintide is being studied as monotherapy for obesity in patients without diabetes. The REDEFINE 1 trial demonstrated 11.8% weight loss with cagrilintide alone in adults with overweight or obesity. CagriSema combines cagrilintide with semaglutide (not insulin) for weight management.

What is CagriSema and when will it be available?

CagriSema is a fixed-dose combination of cagrilintide 2.4 mg and semaglutide 2.4 mg in a once-weekly subcutaneous injection. Phase 3 trials showed 22.7% weight loss over 68 weeks—superior to either drug alone. Novo Nordisk submitted the FDA application in December 2025, with regulatory review expected in 2026. If approved, it could launch in late 2026 or 2027.

Does amylin cause beta cell damage in type 2 diabetes?

Native human amylin has a dual nature. While it serves essential metabolic functions, it also misfolds and aggregates into toxic amyloid deposits in over 90% of type 2 diabetes patients, contributing to progressive beta cell loss. Pramlintide and cagrilintide were specifically engineered to resist aggregation through structural modifications (proline substitutions in pramlintide, acylation in cagrilintide) while retaining biological activity. These analogs do not form amyloid deposits.

Can you take amylin analogs with GLP-1 drugs like semaglutide or tirzepatide?

CagriSema is explicitly designed as a combination of cagrilintide and semaglutide in a single injection, leveraging complementary mechanisms for superior weight loss. However, combining pramlintide with GLP-1 agonists wasn't extensively studied, as pramlintide was approved before the GLP-1 era. Tirzepatide already combines GLP-1 and GIP agonism in one molecule. Using cagrilintide monotherapy alongside other incretin drugs outside of approved combinations would be off-label and should only occur under medical supervision in research settings.

What role does amylin play in healthy metabolism?

In healthy individuals, amylin acts as a synergistic partner to insulin. After meals, beta cells release both hormones at a roughly 100:1 insulin:amylin ratio. Amylin prevents glucose overshooting by slowing gastric emptying (controlling glucose delivery), suppressing glucagon (preventing unnecessary hepatic glucose output), and promoting satiety (controlling energy intake). Patients with type 1 diabetes lack amylin secretion entirely, contributing to postprandial glucose excursions and weight gain from insulin therapy. Type 2 diabetes patients have diminished amylin responses related to beta cell impairment.

Bottom Line

Amylin represents a metabolic control system that has been hiding in plain sight since the discovery of insulin over a century ago. While researchers focused on insulin's role in glucose disposal, amylin quietly controlled glucose appearance—slowing gastric emptying, suppressing glucagon, and regulating appetite through central and peripheral mechanisms.

Pramlintide proved the concept but struggled with practicality: three daily injections, frequent nausea, hypoglycemia risk, and modest benefits limited adoption. Its discontinuation in 2025 closed a chapter on first-generation amylin therapy.

Cagrilintide opens a new one. With once-weekly dosing, 11.8% weight loss as monotherapy, and 22.7% weight loss when combined with semaglutide in CagriSema, next-generation amylin analogs are finally delivering on the hormone's therapeutic promise. The synergy with GLP-1 agonists makes mechanistic sense: semaglutide enhances insulin secretion and reduces appetite through incretin pathways, while cagrilintide independently slows nutrient delivery and suppresses glucagon through amylin pathways.

If FDA approval comes through in 2026 as expected, CagriSema could establish a new ceiling for pharmaceutical weight loss—one that pairs two naturally co-evolved hormonal systems (GLP-1 and amylin) that evolution designed to work together in the first place.

For patients with diabetes, obesity, or both, the question isn't whether amylin-based therapy works—it's whether the medical system will learn from pramlintide's failure to make the next generation accessible and practical for the millions who could benefit.

Disclaimer

This article is for educational and informational purposes only. It does not constitute medical advice. Pramlintide is currently unavailable following discontinuation in 2025. Cagrilintide and CagriSema are investigational drugs not approved by the FDA for any indication. Do not attempt to obtain or use investigational peptides outside of approved clinical trials. Amylin analogs carry risks including severe hypoglycemia when used with insulin, nausea, vomiting, and other adverse effects. Only use approved medications under the direct supervision of a qualified healthcare provider. Always consult your physician before starting, stopping, or modifying any medication or treatment regimen.

References

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