Pramlintide/Symlin (Islet Cell amyloid polypeptide analogues or amylin analogue)

Over the past decade there has been a plethora of new medications and class of pharmaceuticals developed to treat both Type 1 and Type 2 Diabetes Mellitus. One of the newer classes of pharmaceuticals is an analogue of islet cell polypeptide, Pramlitide or Symlin. This therapy is available at present in the United States. Symlin has multiple effects and may be useful in treatment of both Type 1 and Type 2 DM patients.

Background and History

Opie in 1900 described a "hyaline" appearance within the islets of Langerhans of individuals with diabetes mellitus.[1] The hyaline material was eventually identified to be amyloid. This was accomplished via histology and various staining methods.[2][3] In 1987, several investigators reported the sequence of a 37 amino acid peptide extracted from amyloid containing pancreatic material in patients with Type 2 diabetes mellitus. The was initially called IAP or "islet amyloid polypeptide, DAP or "diabetes associated peptide". This was changed in 1988 to amylin to indicate the origin of the peptide and the fact that its presence was not restricted to individuals with type 2 diabetes mellitus. [4][5][6] The analog of human amylin was given the name pramlintide and proprietary name Symlin.

Physiology and Metabolism

Human amylin and Pramlitide
Human amylin and Pramlitide
[7]

The molecular structure of amylin and Pramlintide is indicated above. Pramlintide is a water-soluble salt with a pH of 4.0. This leads to an issue with combination with other injectible anti-hyperglycemic agents. 7,[8]

Pramilintide reduces post prandial glucose levels. Several studies demonstrated sustained effects on post prandial glucoses in both Type 1 and Type 2 individuals. Doses of 100 mcg prevented increases in post prandial levels following ~ 14 days of administration. [9] Additional studies indicate a delay in gastric emptying in both Type 1 and Type 2 individuals with 30 or 60 mcg pramlintide.[10] Multiple other effects from cardiovascular, renal, bone and effects on glucagon and weight have been studied or proposed.[11]

The medication has also been studied with patients utilizing CSII (insulin pump) therapy. 2 studies of 29 weeks each were analyzed and indicated that pramlintide added to CSII therapy reduced overall A1C levels, improved post prandial glucoses compared to placebo and reduced blood glucose variability. Insulin doses were reduced by ~ 9%, mealtime insulin was also reduced. Weight reduction was noted to be 2.2 kg in the trial.[12]

Dose, Administration and Side Effects

Pramlintide is presently available only in a pen system. There are 2 different pens available: 60 mcg pen generally utilized for Type 1 DM individuals and 120 mcg pen utilized for Type 2 DM individuals. Both pens have various increments with the 60 mcg pen allowing for an initial starting dose of 15 mcg and increasing in 15 mcg increments to 60 mcg. The 120 mcg pen allows for 60 mcg and 120 mcg doses.

It is generally administered in divided doses prior to each meal subcutaneously. It is approved in the US to be used with individuals, both Type 1 and Type 2 DM who are utilizing insulin therapy. It is not approved at the present time to be utilized with other agents such as GLP-1 agonists and other oral agents.

The most common side effect of pramlintide have been nausea, vomiting, anorexia or decrease in appetite. Hypoglycemia can be an issue also, particularly if intake is diminished.[13] Weight loss was noted in individuals and several studies indicated that nausea was not responsible.[14]

Future Directions

The use of pramlintide has been limited by several factors. It is only available in a pen which does not allow at present combination with insulin or other agents. It is only available in the United States which limits the ability to find additional or novel uses. It is presently limited as a maximum dose of 120 mcg TID with meals.

However there have been several recent studies which may indicate additional and novel uses for the medication. A recently completed study indicated efficacy with increased escalation of doses to 360 mcg TID with meals.[15] Another study involved the use of 2 separate pumps, one utilizing insulin and the other pramlintide. Initial results published indicated improvement in A1C levels, decrease in insulin requirements and significant weight reduction. Additional studies were recommended to further delineate these effects.[16]

The role of pramlintide in the treatment of diabetes mellitus has yet to be fully determined. Additional clinical studies will be necessary and hopefully the medication will eventually be available worldwide to allow its role in the treatment of patients with diabetes mellitus to be fully defined.

References

  1. ^ Opie, E.L. The relation of diabetes mellitus to lesions of the Hyaline degeneration of the islands of Langerhans; Journal of Experimental M397; 1900

  2. ^ Ahronheim, JH; The nature of the hyaline material in the pancreatic island in diabetes mellitus; American Journal of Pathology; 19: 873; 1943

  3. ^ Ehrlich, JC and Ratner, IM; Amyloidosis of the islets of Langerhans; American Journal of Pathology 38: 49; 1961

  4. ^ Cooper, GJS, Willis, AC, Clark, A, Turner, RC, Sim, RB and Reid, KB; Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients; Proceedings National Academy Science, USA 84: 8628; 1987

  5. ^ Cooper, GJS, Leighton, B, Dimitriadis, GD, Parry-Billings, M, Kowalchuk, JM, Howland, K, Rothbard, JB, Willis, AC and Reid, KB; Amylin found in amyloid deposits in hyman type 2 diabetes mellitus may be a hormone that regulates glycogen metabolism in skeletal muscle; Proceedings National Academy Science USA 85: 7763, 1988

  6. ^ Cooper, GJS, Day, AJ, Willis, AC, Roberts, AN, Reid, KB and Leighton, B; Amylin and the amylin Structure, function and relationship to the iselt amyloid and to diabetes mellitus; Biochim. Biophys. A1014; 247; 1989

  7. ^ Gunberger, G.; Novel therapies for the management of type 2 diabetes mellitus: Part 1. Pramlitide and bromocriptine-QR Journal of Diabetes: 5: 110; 2013

  8. ^ Younk, LM, Mikeladze, M. and Davis, SN; Pramlintide and the treatment of diabetes: a review of the data since its introduction: Expert Opinion Pharmacotherapeutics 12: 1439; 2011

  9. ^ Kolterman, OG, Schwartz, S, Corder, C. Effect of 14 days subcutaneous administration of human amylin analogue, pramlitidie on an intravenous challenge and response to a standard liquid meal in patients with IDDM; Diabetologia 39: 492, 1996

  10. ^ Kong M-G, King P, McDonald, IA; Infusion of pramilitide, a human amylin analogue, delays gastric emptying in men with IDDM; Diabetalogia 40: 82, 1997

  11. ^ Young, A; Amylin: Physiology and Pharmacology; Advances in Pharmacology: Volume 52, 2005

  12. ^ Hermann K, Frias JP, Edelman, SV, Lutz K, Shan K, Chen S, Maggs D and Kolterman, OG; Pramilintide Improved Measures of Gluycemic Control and Body Weight in Patients With Type 1 Diabetes Mellitus Undergoing Continuous Subcutaneous Insulin Infusion Therapy; Post Graduate Medicine 125: 136 2013

  13. ^ Edelman S, Garg S, Frias J, Maggs D, Wang Y, Zhang B, Strobel S, Lutza K and Kolterman O; A Double Blind Placebo Controlled Trial Assessing Pramlintide Treatmenet in the Setting of Intensive Insulin Therapy in Type 1 Diabetes; Diabetes Care 29: 2189 2006

  14. ^ Riddle M, Pencek R, Charenkavanich S, Lutz K, Wilhelm K and Porter L; Randomized Comparison of Pramlintide or Mealtime Insulin Added to Basal Insulin Treatment for Patients with Type 2 Diabetes; Diabetes Care 32: 1577 2009

  15. ^ Rosenfeld C; ClinicalTrials.gov Identifier: NCT01137695

  16. ^ Schorr A and Ofran R; Simultaneous Use of Two External Subcutaneous Pumps Delivering Insulin and Symlin: Use of a Double Pump System; Journal of Diabetes Science and Technology 6: 1507 2012

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