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Pramlintide in the Treatment of Diabetes Mellitus

Original Editor - Ashton Randolph

Top Contributors - Lucinda hampton, Stacy Lawrence, Ashton Randolph, Vidya Acharya, Breonna Tucker, Aminat Abolade and Mohamed A Hassanin  

Introduction

Pramlintide acetate is a synthetic amylinomimetic agent that replicates the physiological actions of human amylin, a 37-amino acid neuroendocrine hormone[1][2]. Amylin is normally co-secreted with insulin from pancreatic Beta cells (β-cells) in response to nutrient intake, but its secretion is deficient or absent in individuals with Diabetes. [3]

In patients with Type 1 Diabetes, amylin secretion is completely absent due to autoimmune destruction of β-cells, whilst in Type 2 Diabetes, amylin secretion is reduced proportionally to insulin secretion as β-cell function declines[2]. This deficiency contributes to postprandial hyperglycaemia, excessive glucagon secretion, and impaired satiety - factors that complicate glucose management despite insulin therapy optimisation[1][3].

Pramlintide was approved by US Food and Drug Administration (FDA) in 2005 for use as adjunctive therapy in adults with type 1 or type 2 diabetes who use mealtime insulin but fail to achieve adequate glycaemic control[4]. By addressing the pathophysiological consequences of amylin deficiency, pramlintide offers a complementary approach to insulin therapy, targeting postprandial glucose excursions, reducing insulin requirements, and promoting modest weight loss[5][6].

Pathophysiology: The Role of Amylin

Normal Amylin Physiology In healthy individuals, amylin is co-secreted with insulin from pancreatic β-cell in a 1:100 ratio (amylin:insulin) in response to nutrient ingestion[4][2]. Amylin exerts multiple glucoregulatory effects that complement insulin's actions:

1. Slowing Gastric Emptying: Amylin delays the rate at which nutrients, particularly carbohydrates, empty from the stomach into the small intestine.[2]. This modulates the nutrient absorption and blunts postprandial glucose excursions by preventing rapid increases in blood glucose following meals.
2. Suppressing Postprandial Glucagon Secretion: Amylin inhibits the inappropriate secretion of glucagon from pancreatic Alpha (α-cells) cells during the postprandial period[4][2]. Since glucagon stimulates hepatic glucose production, its suppression reduces hepatic glucose output when it is not needed[7].
3. Promoting Satiety: Amylin acts on the area postrema in the brainstem, a key satiety centre in the central nervous system, to reduce appetite and food intake[2]. This contributes to meal-related satiety and helps regulate energy balance[8].

Amylin Deficiency in Diabetes
Type 1 Diabetes: Complete absence of amylin secretion due to autoimmune β-cell destruction results in[1][3]:

  • Unregulated gastric emptying leading to erratic postprandial glucose levels
  • Excessive postprandial glucagon secretion despite hyperglycaemia
  • Impaired satiety signalling
  • Greater postprandial glucose excursions despite insulin therapy


Type 2 Diabetes: Progressive β-cell dysfunction leads to proportional reductions in both insulin and amylin secretion[2][9]:

  • Relative amylin deficiency worsens as the disease progresses
  • Contributes to inadequate postprandial glucose control
  • Impaired satiety may contribute to overeating and weight gain
  • Becomes more problematic as patients require exogenous insulin therapy

Clinical Pharmacology

Mechanism of Action

Pramlintide is an amylinomimetic agent that replicates the physiological actions of endogenous amylin by binding to and activating amylin receptors in the brain and gastrointestinal tract[1][2].
Primary Glucoregulatory Effects:
1. Slows gastric emptying[2]

  • Delays the rate at which nutrients enter the small intestine from the stomach
  • Reduces the postprandial glucose excursions by 30-40% compared to insulin alone
  • Slows absorption of carbohydrates, resulting in a more gradual blood glucose rise

2. Suppresses Postprandial Glucagon Secretion[1]

  • Prevents inappropriate glucagon release during and after meals
  • Reduces hepatic glucose output during the postprandial period by 20-30%
  • Particularly beneficial in type 1 diabetes, where glucagon regulation is severely impaired

3. Promotes Satiety [2]

  • Acts on the postrema area (brain satiety centre) to enhance fullness
  • May improve adherence to dietary recommendations by reducing hunger

Indications

Pramlintide is indicated as adjunctive therapy for adults using mealtime insulin therapy. Those with type 1 or 2 Diabetes with inadequate glycaemic control despite optimised insulin therapy[4].

Contraindications

Absolute[4]:

  1. Confirmed diagnosis of gastroparesis could lead to unpredictable glucose control and medication absorption. Pramlintide could further delay gastric emptying
  2. Hypersensitivity to Pramlintide or components such as metacresol (preservative)
  3. Hypoglycaemia unawareness - inability to recognize hypoglycaemia symptoms


Relative[4]:

  1. Paediatric patients (<18years) limited safety and efficacy data in children and adolescents
  2. Pregnancy and breastfeeding
  3. Severe renal impairment

Administration

Pramlintide is administered subcutaneously (0-15 minutes) before meals. For patients with type 2 diabetes, the dose starts at 60 mcg. This can be increased up to 120 mcg after 3-7 days if tolerated. Lowering the starting dose to 30mcg if the patient is nausea-prone. For patients with type 1 diabetes, the dose starts at 15 mcg and can be increased by 15 mcg every 3-7 days up to 60 mcg[10].

Physiotherapy Management

Physical therapists play an essential role in the comprehensive management of patients using pramlintide therapy[11][12]. The role encompasses:
* Education: Recognising hypoglycaemia symptoms during [Exercise and Diabetes|exercise]]. Impact of exercise and medication timing[10].
* Exercise prescription: Developing individualised programmes accounting for medication timing. Exercise 1-2 hours after meals when glucose is elevated, but medication effects are waning[12].
* Monitoring: Blood glucose assessment before and after treatment sessions
* Interprofessional collaboration: Coordinating with the diabetes care team regarding medication adjustments.
* Patient safety: Educating patients in injection site consideration and avoiding physical modalities near injection sites. Avoid deep tissue massage over injection sites, as this may alter drug absorption and increase local adverse reactions (erythema, swelling, pain)[11][10].

Back to Pharmacological Management of Diabetes Mellitus

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 Ryan GJ, Jobe LJ, Martin R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin Ther. 2005;27(10):1500-12.
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 Edelman S, Maier H, Wilhelm K. Pramlintide in the Treatment of Diabetes Mellitus. BioDrugs. 2008;22(6):375–86.
  3. ↑ 3.0 3.1 3.2 Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, et al. A Double-Blind, Placebo-Controlled Trial Assessing Pramlintide Treatment in the Setting of Intensive Insulin Therapy in Type 1 Diabetes. Diabetes Care. 2006 Sep 26;29(10):2189–95.
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 Ryan G, Jobe L, Briscoe T. Review of pramlintide as adjunctive therapy in treatment of type 1 and type 2 diabetes. Drug Design, Development and Therapy. 2008 Oct;203.
  5. ↑ Arechavaleta R, Seck T, Chen Y, Krobot KJ, O’Neill EA, Duran L, et al. Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial. Diabetes, Obesity and Metabolism. 2010 Dec 27;13(2):160–8.
  6. ↑ Hollander PA, Levy P, Fineman MS, Maggs DG, Shen LZ, Strobel SA, et al. Pramlintide 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. Diabetes Care. 2003 Mar 1;26(3):784–90.
  7. ↑ Levetan C, Want LL, Weyer C, Strobel SA, Crean J, Wang Y, et al. Impact of Pramlintide on Glucose Fluctuations and Postprandial Glucose, Glucagon, and Triglyceride Excursions Among Patients With Type 1 Diabetes Intensively Treated With Insulin Pumps. Diabetes Care. 2003 Jan 1;26(1):1–8.
  8. ↑ Lutz TA. Amylinergic control of food intake. Physiology & Behaviour. 2006 Nov;89(4):465–71.
  9. ↑ Koda JoyE, Fineman M, Rink TimothyJ, Dailey GeorgeE, Muchmore DouglasB, Linarelli LouieG. Amylin concentrations and glucose control. The Lancet. 1992 May;339(8802):1179–80.
  10. ↑ 10.0 10.1 10.2 HIGHLIGHTS OF PRESCRIBING INFORMATION [Internet]‌
  11. ↑ 11.0 11.1 American Diabetes Association. Diabetes Care [Internet]. American Diabetes Association. 2024. Available from: https://diabetesjournals.org/care/issue/47/Supplement_1
  12. ↑ 12.0 12.1 Colberg SR, Sigal RJ, Yardley JE, Riddell MC, Dunstan DW, Dempsey PC, et al. Physical activity/exercise and diabetes: a Position Statement of the American Diabetes Association. Diabetes Care [Internet]. 2016;39(11):2065–79.
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