Pramlintide

A synthetic 37-amino-acid analog of human amylin, stabilized by three proline substitutions, approved in 2005 as a mealtime adjunct to insulin in type 1 and type 2 diabetes and discontinued by its manufacturer in 2025.

Also referenced as: Pramlintide acetate, Symlin, SymlinPen, AC137, AC 0137, Tripro-amylin

Also appears in: Metabolic

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What is Pramlintide?

Pramlintide is a synthetic 37-amino-acid analog of human amylin — the beta-cell hormone, also called islet amyloid polypeptide, that is stored in the same secretory granules as insulin and released alongside it after a meal. It differs from human amylin at exactly three positions, where proline replaces alanine at residue 25 and serine at residues 28 and 29; those substitutions were taken from rodent amylin, which does not form amyloid fibrils, and they are what make the molecule soluble and formulable where native human amylin aggregates. The peptide has a molecular weight of 3949.4; the marketed form was the acetate salt, with variable acetate content.

It reached the U.S. market as SYMLIN in 2005 and is the first-generation approved member of a class that has since become one of the most active areas in metabolic drug development: cagrilintide, petrelintide, and eloralintide are all long-acting descendants of the same idea. Pramlintide appears in the research-compound market partly on that lineage, partly on its own obesity trial data, and partly because the branded prescription product left the U.S. market in late 2025.

How it works

• Amylin receptor agonism. Amylin receptors are not standalone proteins: they are heterodimers of the calcitonin receptor with one of three receptor activity-modifying proteins (RAMP1, RAMP2, or RAMP3), giving the AMY1, AMY2, and AMY3 subtypes, and pramlintide acts as an agonist at these receptors much as native amylin does (Hay et al., Pharmacological Reviews, 2015;67(3):564–600). The behavioral arm of the effect is centrally mediated, with the area postrema of the hindbrain the best-characterized site of action.
• Delayed gastric emptying. An intravenous infusion of pramlintide slowed gastric emptying in men with insulin-dependent diabetes (Kong et al., Diabetologia, 1997;40(1):82–88), and a follow-up study reproduced the effect with single subcutaneous doses before a meal — though the slowing did not carry over to a second meal eaten four hours later, an early sign of how brief the drug’s action is (Kong et al., Diabetologia, 1998;41(5):577–583). This is the mechanism the approved label credits for the blunted postprandial glucose rise, and it is also the mechanism behind the drug’s most common side effect and its interaction warnings.
• Suppression of postprandial glucagon. In type 1 diabetes, the meal-related rise in plasma glucagon is not corrected by insulin alone; pramlintide reduced it, curbing hepatic glucose output after eating (Fineman et al., Metabolism, 2002;51(5):636–641).
• Reduced meal size and caloric intake. In a six-week translational study in obese subjects, pramlintide reduced 24-hour caloric intake and meal sizes and improved self-reported control of eating (Smith et al., American Journal of Physiology-Endocrinology and Metabolism, 2007;293(2):E620–E627). This satiation effect, not the glucose effect, is what carried the compound into obesity trials.

Research status

Pramlintide has a genuine randomized trial record spanning both types of diabetes, a real approval built on it, and a second life in obesity research that ended without a filing. The honest summary is that the effects were consistent and small.

Approval. FDA approved SYMLIN under NDA 021332 on March 16, 2005, sponsored by Amylin Pharmaceuticals. The indication has always been narrow: adjunctive treatment in patients with type 1 or type 2 diabetes who use mealtime insulin therapy and have failed to achieve desired glucose control despite optimal insulin therapy. It is not a monotherapy, and safety and effectiveness in pediatric patients were never established.

First human signal. Intravenous infusion of AC137 — the development code for pramlintide — reduced postprandial hyperglycemia in subjects with insulin-dependent diabetes (Kolterman et al., Diabetes Care, 1995;18(8):1179–1182), followed by a 14-day subcutaneous study in the same program (Kolterman et al., Diabetologia, 1996;39(4):492–499).

Type 1 diabetes. In a 52-week, double-blind, placebo-controlled trial in 480 patients, 30 mcg four times daily produced a 0.67% HbA1c reduction at week 13 against 0.16% on placebo, with the placebo-corrected difference sustained to week 52, weight loss rather than weight gain, and no increase in the overall severe hypoglycemia event rate (Whitehouse et al., Diabetes Care, 2002;25(4):724–730). A second 52-week trial in 651 patients was more modest: HbA1c fell 0.29% on 60 mcg three times daily and 0.34% on 60 mcg four times daily, against 0.04% on placebo, with a 0.4 kg weight reduction versus a 0.8 kg gain (Ratner et al., Diabetic Medicine, 2004;21(11):1204–1212).

Type 2 diabetes. A 52-week trial in 656 insulin-treated patients found sustained HbA1c reductions of 0.68% at week 26 and 0.62% at week 52 on 120 mcg twice daily (Hollander et al., Diabetes Care, 2003;26(3):784–790). Added to titrated insulin glargine in 212 patients over 16 weeks, pramlintide produced a 0.70% A1C reduction against 0.36% on placebo, with weight falling 1.6 kg while placebo patients gained 0.7 kg (Riddle et al., Diabetes Care, 2007;30(11):2794–2799). A 24-week open-label comparison in 113 patients is the most informative of the set: mealtime pramlintide matched titrated rapid-acting insulin analogs on A1C (7.2% versus 7.0%) while avoiding their 4.7 kg weight gain and causing less mild-to-moderate hypoglycemia, but produced nausea in 21% of patients versus none on insulin (Riddle et al., Diabetes Care, 2009;32(9):1577–1582).

The critical read. An independent systematic review found the trial data too heterogeneous to pool. Its conclusion: between-group HbA1c differences of roughly 0.2–0.3% in type 1 diabetes on conventional insulin, roughly 0.4% in type 2 diabetes, no advantage over placebo in one trial of intensively treated type 1 patients, no trial longer than 52 weeks, none in children, and more frequent nausea and severe hypoglycemia than placebo (Lee et al., Annals of Family Medicine, 2010;8(6):542–549). Durability beyond a year, and effects on morbidity or mortality, were never established.

Obesity — studied, never approved. In a 16-week Phase 2 study in 204 obese subjects with no accompanying lifestyle program, pramlintide at up to 240 mcg three times daily produced placebo-corrected weight loss of 3.7% (3.6 kg), with 31% of treated subjects losing at least 5% of body weight versus 2% on placebo (Aronne et al., Journal of Clinical Endocrinology & Metabolism, 2007;92(8):2977–2983). A 4-month dose-ranging study in 411 obese subjects with a structured lifestyle intervention, extended to 12 months, reported placebo-corrected weight loss of about 6–7 kg at month 12 — but among only 146 subjects evaluable at that point, after substantial attrition (Smith et al., Diabetes Care, 2008;31(9):1816–1823). The most cited result came from combination: pramlintide plus the leptin analog metreleptin produced 12.7% weight loss at week 20 versus 8.4% for pramlintide alone and 8.2% for metreleptin alone, in 93 evaluable subjects (Ravussin et al., Obesity, 2009;17(9):1736–1743). Pramlintide was also tested alongside sibutramine or phentermine (Aronne et al., Obesity, 2010;18(9):1739–1746).

Why the obesity program stopped. In March 2011 Amylin Pharmaceuticals and Takeda voluntarily suspended the Phase 2 pramlintide/metreleptin obesity study after an antibody-related laboratory finding with metreleptin in two patients from a previously completed study. In August 2011 the partners discontinued the combination program outright, citing a commercial reassessment. The trigger was a finding about the leptin analog, not about pramlintide — but no obesity indication was ever filed for pramlintide, alone or in combination.

Discontinuation of the marketed product. On October 27, 2025, FDA’s drug-shortage database recorded SymlinPen 60 and SymlinPen 120 as to-be-discontinued, with cessation of manufacture given as the reason. Drugs@FDA now lists all three products under NDA 021332 as discontinued, and no generic pramlintide has ever been approved. The approval itself was not withdrawn for safety or efficacy reasons; the manufacturer stopped making it.

Where the research is now. ClinicalTrials.gov lists roughly 64 studies naming pramlintide as an intervention (August 2026), most completed and a decade or more old. Recent work is largely mechanistic rather than therapeutic. A pilot outpatient study of a fully closed-loop insulin-plus-pramlintide system in 12 adults with type 1 diabetes found time in range comparable to carbohydrate-counted control, with none of the differences reaching statistical significance (Odabassian et al., Journal of Diabetes Science and Technology, 2025;19(6):1457–1463). Separately, pramlintide is being used as a challenge agent rather than a treatment in an Alzheimer’s blood-test program, where a single 60 mcg subcutaneous injection produced a surge in plasma amyloid-beta and a fall in total tau in subjects with Alzheimer’s disease but not in controls (Zhu et al., Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 2017;3(1):33–43; NCT03560960). Academic groups also use it as a human probe of amylin physiology — for instance to provoke migraine-like attacks under controlled conditions in patients with migraine without aura (Ghanizada et al., Annals of Neurology, 2021;89(6):1157–1171), work that continues in registered headache and satiety studies.

Common dosage forms

• Prescription pen-injectors — SymlinPen 60 and SymlinPen 120, disposable multidose pens containing 1000 mcg/mL of pramlintide in 1.5 mL and 2.7 mL presentations, formulated with metacresol as preservative, D-mannitol as tonicity modifier, and acetate buffer at approximately pH 4.0. Both are now discontinued.
• Original prescription vials — the 2005 launch presentation was a 5 mL vial at 0.6 mg/mL, drawn with a U-100 insulin syringe. It preceded the pens and is long gone.
• Research-market lyophilized vials — powder for reconstitution, commonly labeled in milligrams (5 mg is a typical presentation). This is a different basis of measurement from the licensed product, which was always a ready-to-use acidic solution dosed in micrograms per meal, and the conversion between them is not obvious from the label.
• Multi-peptide vials — pramlintide combined with GLP-1-class compounds in a single blended vial, where the amount of each component is often not stated separately.
• No non-injectable form — pramlintide was only ever marketed as a subcutaneous injection, and no oral, inhaled, or transdermal version has been approved.

This section describes formats only and is not dosing guidance.

Key considerations

• Approved, but no longer manufactured. The status here is unusual and easy to misread in either direction. Pramlintide holds a real FDA approval that has never been withdrawn, so “FDA approved” is accurate; it is also the case that both pen presentations were posted for discontinuation in October 2025 on grounds of ceasing manufacture, that Drugs@FDA lists every SYMLIN product as discontinued, and that no generic has ever been approved. Copy that treats the approval as evidence of current availability, or treats the discontinuation as a safety verdict, is wrong on both counts.
• The boxed warning is about the combination, not the molecule. Pramlintide alone does not cause hypoglycemia. The boxed warning covers severe hypoglycemia when it is coadministered with mealtime insulin — seen within 3 hours of injection when it occurs — and the label requires cutting the mealtime insulin dose by 50% at initiation. In six-month type 1 trials run without that dose reduction, patient-ascertained severe hypoglycemia occurred in 16.8% of pramlintide patients versus 10.8% on placebo over the first three months. Labeled contraindications are hypoglycemia unawareness, confirmed gastroparesis, and prior serious hypersensitivity, and the label advises against pediatric use.
• A short half-life is the defining limitation, and the reason the class moved on. Pramlintide’s plasma half-life is approximately 48 minutes with subcutaneous bioavailability of 30–40%, which is why it required an injection before every major meal. The modern amylin analogs exist to solve exactly that: cagrilintide was developed as a lipidated, long-acting analog explicitly because pramlintide’s short half-life forced three injections a day (Kruse et al., Journal of Medicinal Chemistry, 2021;64(15):11183–11194).
• Slowed gastric emptying has consequences beyond nausea. In the label’s pooled placebo-controlled trials, nausea was reported by 48% of type 1 patients against 17% on placebo, and by 28% of type 2 patients against 12%; it is dose-dependent and generally fades with gradual titration. Because the drug delays gastric emptying, the label directs that oral medications requiring rapid onset be taken at least one hour before or two hours after a dose, and it prohibits mixing pramlintide with insulin in the same syringe, since mixing alters the pharmacokinetics of both.
• Naming confusions are frequent. Pramlintide is not amylin: native human amylin, or IAPP, is the amyloidogenic hormone pramlintide was engineered to replace. AC137 and AC 0137 are its development codes, tripro-amylin an early descriptive name, and SYMLIN and SymlinPen its brands. It is routinely grouped with cagrilintide, petrelintide, and eloralintide, and with the CagriSema combination — but those are weekly-dosed molecules with their own receptor selectivity profiles and their own trial records, and results do not transfer in either direction. Finally, pramlintide is not pralmorelin, which is the international nonproprietary name for the unrelated growth hormone secretagogue GHRP-2.