Pramlintide

Pramlintide ( Symlin ® ) is a synthetic analog of human amylin, a naturally occurring neuroendocrine hormone synthesized from pancreatic beta cells that contributes to glucose control during the postprandial period. Pramlintide, similar to insulin, is absent or deficient in patients with diabetes. When used with insulin, Pramlintide can help patients achieve improved glycemic control with additional benefits that cannot be realized with insulin alone.

Pramlintide is used with mealtime insulin to control blood sugar levels in people who have diabetes. Pramlintide is only used to treat patients whose blood sugar could not be controlled by insulin or insulin and an oral medication for diabetes. Pramlintide is in a class of medications called antihyperglycemics. It works by slowing the movement of food through the stomach. This prevents blood sugar from rising too high after a meal, and may decrease appetite and cause weight loss.


History of Invention

Amylin was described in 1987 by two independent groups of investigators, who discovered this 37 amino acid polypeptide while working with AE amyloid in patients with type 2 diabetes. Amylin is co-synthesized, co-packaged, and co-secreted with insulin by the beta cells' secretory granule. It may be referred to as insulin's "fraternal twin." In type 2 diabetes, amylin values are elevated, as are insulin values. The elevated levels of amylin result in the continued laying down of the IAPP deposits within the perivascular regions and interstitium of the islet.

In March 2005, the FDA approved Pramlintide acetate, an injectable medicine to control blood sugar for adults with type 1 and type 2 diabetes. Pramlintide is the only therapy for treating type 1 diabetes other than insulin. People with type 2 diabetes already have several other types of oral therapies available. Pramlintide is to be used only in combination with insulin to help lower blood sugar during the three hours after meals. It is meant for patients who cannot achieve adequate blood sugar control on intensive insulin therapy alone. So-called "tight" control of blood sugar is desirable in all patients with diabetes to reduce the risk of blindness, kidney disease, vascular disease, and other long-term problems that diabetes can cause.

The safety and effectiveness of Pramlintide were studied in about 5,000 people. Side effects include nausea, vomiting, abdominal pain, headache, fatigue, and dizziness. Because of three areas of concern, there will be a medication guide and a risk minimization action plan for the use of Pramlintide. First, the principal risk is hypoglycemia, an abnormally low concentration of sugar in the blood. This risk is greatest in people with type 1 diabetes and people with slow stomach emptying (gastroparesis), a long-term complication of diabetes. Second, there is a potential for medication errors, specifically, mixing Pramlintide with insulin in the same syringe, which can alter the activity of the insulin. Finally, the potential for off-label use in people where the benefit-risk profile has not been characterized or demonstrated is also of concern and will be monitored by the sponsor.

Pramlintide has not been evaluated in children. The therapy should not be used if people cannot tell when their blood sugar is low, have gastroparesis, or are allergic to pramlintide acetate, metacresol, D-mannitol, acetic acid, or sodium acetate.


Action

Glucagon-like peptide 1 agonist, Hypoglycemic agent and Amylin agonist prevents blood sugar from rising too high after a meal, decrease appetite and cause weight, loss lowers blood sugar and used together with insulin.

Pramlintide stimulates three key glucose-regulating effects deficient or absent in type 2 and type 1 diabetes

• Pramlintide slows gastric emptying

• Pramlintide suppresses postprandial glucagon secretion leading to suppression of endogenous glucose output from the liver

• Pramlintide modulates appetite by enhancing satiety. This effect is independent of nausea and may lead to weight loss


Status

Launched in the US in May 2005 for patients with type 1 or 2 diabetes treated with insulin




Chemistry

Pramlintide (25,28,29-pro-h-amylin) is the synthetic analog of human amylin, which is a 37 amino acid peptide related to calcitonin gene related peptide (CGRP) and calcitonin, and is co-secreted with insulin from pancreatic beta cells.

For: both Type 1 and Type 2 diabetes and for obesity under Phase II clinical studies


Adverse Effects:

Most adverse events were gastrointestinal in nature (nausea and vomiting). The incidence of nausea was higher at the beginning of Pramlintide treatment and decreased with time in most patients.

Severe Hypoglycemia. Pramlintide alone (without the concomitant administration of insulin) does not cause hypoglycemia. However, Pramlintide is indicated as an adjunct treatment in patients who use mealtime insulin therapy and co-administration of Pramlintide with insulin can increase the risk of insulin-induced hypoglycemia, particularly in patients with type 1 diabetes.



References

1. Kruger DF, Gatcomb PM, Owen SK. Clinical implications of amylin and amylin deficiency. Diabetes Educ. 1999;25(3):389-397.

2. Data on file, Amylin Pharmaceuticals, Inc.

3. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care. 2003;26(3):881-885.

4. SYMLIN® (pramlintide acetate) injection [Prescribing Information]. San Diego (CA): Amylin Pharmaceuticals, Inc. 2005.

5. Maggs DG, Fineman M, Kornstein J, et al. Pramlintide reduces postprandial excursions when added to insulin lispro in subjects with type 2 diabetes: a dose-timing study. Diabetes Metab Res. 2004;20:55-60.

6. Weyer C, Gottlieb A, Kim DD, et al. Pramlintide reduces postprandial glucose excursions when added to regular insulin or insulin lispro in subjects with type 1 diabetes: a dose-timing study. Diabetes Care. 2003;26(11):3074-3079.

7. Amiel SA, Heller SR, Macdonald IA, Schwartz SL, Klaff LJ, Ruggles JA, Weyer C, Kolterman OG, Maggs DG. The effect of pramlintide on hormonal, metabolic or symptomatic responses to insulin-induced hypoglycaemia in patients with type 1 diabetes. Diabetes, Obesity & Metabolism 2005 Sep;7(5):504-16

8. Ratner R, Whitehouse F, Fineman MS, Strobel S, Shen L, Maggs DG, Kolterman OG, Weyer C. Adjunctive therapy with pramlintide lowers HbA1c without concomitant weight gain and increased risk of severe hypoglycemia in patients with type 1 diabetes approaching glycemic targets. Experimental Clinical Endocrinological Diabetes 2005 Apr;113(4):199-204

9. Ceriello A, Piconi L, Quagliaro L, Wang Y, Schnabel CA, Ruggles JA, Gloster MA, Maggs DG, Weyer C. Effects of pramlintide on postprandial glucose excursions and measures of oxidative stress in patients with type 1 diabetes. Diabetes Care 2005 Mar;28(3):632-7

10. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, Weyer C, Kolterman OG. 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. Diabetic Medicine 2004 Nov;21(11):1204-12.