USE OF PRAMLITIDE FOR TYPPE 2

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Pramlintide Therapy, Chapter 11 - Part 1

Diagnosis_and_Management_of_Type_2_DiabetesSteve V. Edelman, MD

R. Henry, MD

The discovery of insulin over 80 years ago is one of the great success

stories in the history of modern medicine. Although insulin remains the

mainstay of therapy for many patients with diabetes, the greatest deterrents

to the use of intensive insulin regimens are hypoglycemia, the fear of

hypoglycemia, and the need for...

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frequent fine-tuning of insulin doses on a day-to-day basis. Particularly

in patients with Type 2 diabetes, who are often overweight, the weight gain

associated with intensive insulin therapy is also a significant concern.

Additionally, current insulin formulations and methods of delivery fail to

duplicate insulin action of healthy individuals, especially during the

postprandial period when normally there is a rapid surge of insulin into the

portal vein.

Given these concerns, the quest for more physiologic, and thus more

effective, approaches to treatment has prompted investigation of other

glucoregulatory hormones. These include the beta-cell hormone amylin, the

alpha-cell hormone glucagon, and numerous gut-derived hormones, such as the

potent incretins glucagon-like polypeptide-1 (GLP-1) and gastric inhibitory

peptide (GIP). Because the effects of some, if not all, of these hormones

are dysregulated to some extent in people with diabetes, many researchers

now believe that replicating glucose homeostasis requires a multipronged

effort involving more than replacement of insulin and/or enhancement of

peripheral glucose uptake. Along these lines, replacing the function of both

pancreatic beta-cell hormones, amylin and insulin, may afford more complete

restoration of the physiology of glucose control.

The synthetic human amylin analog, pramlintide acetate (Symlin) injection,

which retains the desired biologic activities of human amylin but has

superior stability and solubility, was FDA approved as an adjunct treatment

for patients with Type 2 diabetes who have failed to achieve desired glucose

control despite optimal insulin therapy, with or without a concurrent SFU

agent and/or MET, and also for patients with Type 1 diabetes who use

mealtime insulin therapy and have failed to achieve desired glucose control

despite optimal insulin therapy.

A New Paradigm: Regulating Glucose Appearance and Disappearance

Given the physiology of glycemic regulation, management of patients with

diabetes requires interventions aimed at reestablishing and maintaining

glycemic homeostasis by regulating glucose appearance and disappearance.

Type 2 diabetes is a progressive disease characterized by ongoing beta-cell

failure. The current management paradigm for patients with Type 2 diabetes

starts with diet and exercise, followed as needed with sequential oral

antidiabetic agents. Ultimately, because of progressive beta-cell failure,

these initial steps are not sufficient to maintain adequate glycemic

control, and the patient will require insulin.

Insulin controls PPG by two major mechanisms. First, it promotes the uptake

of glucose into insulin-sensitive peripheral tissues. Second, it inhibits

hepatic glucose output by exerting direct and indirect effects on the liver,

including suppression of glucagon secretion. Amylin is packaged together

with insulin in the beta-cell granules and is co-secreted with insulin. In

healthy individuals, amylin secretion follows the same pattern as insulin,

whereby it surges into the bloodstream in response to nutrient uptake

(Figure 11.1-A). Like insulin, amylin secretion is abnormal in patients with

Type 2 diabetes and is deficient in patients with Type 1 diabetes (Figure

11.1-.

Whereas insulin primarily stimulates the disappearance of glucose from

plasma, amylin inhibits its appearance through three different mechanisms of

action, all of which are thought to be mediated via the central nervous

system (Figure 11.2):

.. Pramlintide slows gastric emptying, i.e., the rate at which food is

released from the stomach to the small intestine.

.. Pramlintide suppresses glucagon secretion, which leads to suppression of

endogenous glucose output from the liver.

.. Pramlintide regulates food intake due to centrally mediated modulation of

appetite.

Edelman11-1

FIGURE 11.2 - Proposed Model of Amylin and Insulin Action in Postprandial

Glucose Homeostasis

Edelman11-2

Insulin is the major hormonal regulator of glucose disposal. Preclinical and

clinical studies indicate that amylin complements the effects of insulin by

regulating the rate of glucose inflow to the bloodstream.

* Reported in rodents.

Edelman SV, Weyer C. Diabetes Technol Ther. 2002;4:180.

Thus amylin is a neuroendocrine hormone that regulates glucose appearance

and works in concert with insulin, which primarily promotes glucose

disappearance. In patients with diabetes, glucose regulation is disrupted.

With the development of pramlintide, a more comprehensive approach to

glucose homeostasis is possible.

Next Week, Part 2: Mechanisms of Action of Pramlintide

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