Amylin and Incretin Enhancers for Diabetes Type 2
Article Outline
While there are many options for treating type 2 diabetes, almost half of the treated diabetic patients have hemoglobin A1c levels above 7%.1 Clearly, new treatment options are needed.
Traditional medications for treating diabetes include sulfonylureas, glinides, thiazolidinediones, and insulin. They all act to stimulate beta-cells to release insulin, or they are insulin sensitizers, augmenting insulin action in the liver and the periphery. These drugs are known to cause weight gain and hypoglycemia. All these agents have declining efficacy with the progression of diabetes.
Pathophysiology
Type 2 diabetes is characterized as pancreatic islet dysfunction with a failure of beta-cells to secrete an adequate quantity of insulin and inappropriate production of glucagon from the alpha-cells. It is a progressive metabolic disorder with insulin resistance and increasing beta-cell failure, resulting in insulin deficiency.
Currently, the roles of amylin and incretin hormones have been shown to be important in the control of glucose. Amylin is a beta-cell hormone that is secreted in the gut in response to nutrient intake, which suppresses glucagon secretion. Amylin also regulates gastric emptying, which influences the rate of glucose entering into the circulation.
There are two incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), and both are produced in the gut. GLP-1 is considered more important in humans. GLP-1 has many functions: it enhances insulin secretion in response to glucose, suppresses postprandial glucagon secretion from the alpha-cells, and slows gastric emptying, which may help reduce food intake and body weight. It may preserve or even enhance beta-cell mass, although this has not been clearly proven. It also reduces blood pressure and triglyceride levels and may have a protective effect on the vasculature and kidneys. In diabetes there is a decreased secretion of GLP-1.2
Mechanism of Action
GLP-1 agonists have the same action as native GLP-1 but have longer half-lives. The limiting factor in using native GLP-1 is its very short half-life. The enzyme that breaks down GLP-1 is called dipeptidyl peptidase (DPP-4). DPP-4 inhibitors slow the breakdown of endogenous GLP-1, prolonging its action. DPP-4 is expressed in many tissues, including lymphocytes.3
Practical Considerations
There are a number of incretin and amylin enhancers on the market (Table 1). All of these drugs are useful in the control of postprandial glucose—and all are expensive.
Table 1. Amylin and Incretin Enhancers
| Medication (Trade name) | Administration |
|---|---|
| Amylin Enhancer | |
| Pramlintide (Symlin) | Subcutaneous with meals |
| Incretin Enhancers | |
| Glucagon Like Peptide-1 Receptor Agonists | |
| Exenatide (Byetta) | Subcutaneous twice a day or once a week |
| Liraglutide (Victoza) | Subcutaneous daily |
| Dipeptidyl Peptidase | |
| 4 Inhibitors | |
| Sitagliptin (Januvia) | Oral |
| Saxagliptin (Onglyza) | Oral |
Pramlintide, a synthetic variant of the hormone amylin that has a potentiating insulin action, requires gradual dosage titration. It can cause nausea and vomiting and weight loss, an action distinct from the nausea. Pramlintide can cause severe hypoglycemia; therefore, mealtime insulin should be decreased by 30% to 50% when pramlintide is added.
The major drawback to the GLP-1 analogs is that they must be administered subcutaneously. The exenatide dose must be titrated. Their most common adverse reaction is nausea, which is frequently reported, along with diarrhea. Hypoglycemia is generally not a problem unless the drugs are used with a sulfonylurea. The dosage of the sulfonylurea must be decreased when exenatide is added; this drug is excreted by the kidneys and contraindicated in patients with severe renal impairment.1
Exenatide and liraglutide are very similar. Liraglutide causes a lower incidence of nausea and may be more effective. Liraglutide may also cause less weight loss.3
DPP-4 inhibitors are not as effective as incretin enhancers in decreasing A1c, but they can be given orally. They have a lower incidence of nausea, seldom cause hypoglycemia, and are weight neutral. They are associated with an increased risk of upper respiratory infection and urinary tract infection. Headache may occur. Sitagliptin is eliminated unchanged in the urine, so decreased dosage is required in patients with renal disease. Hypersensitivity has been noted.4
Patients with diabetes have an increased risk of pancreatitis. Acute pancreatitis has been observed with use of both exenatide and sitagliptin, although it has not been determined that these drugs increase the incidence of pancreatitis.
Incretin-based therapies may be particularly useful for patients at increased risk for hypoglycemia, with progressive weight gain and with elevated postprandial glucose elevations. DPP-4 inhibitors work best early in the course of diabetes, because they depend on endogenously produced GLP-1.3
GLP-1 agonists are generally given in combination with oral agents. They are particularly beneficial in obese patients and those patients with other cardiovascular risk factors because of the blood pressure- and lipid-lowering effects.3
The possibility that these drugs may halt or reverse the progression of diabetes is very exciting. While these drugs have been on the market for several years, their place in diabetes treatment remains to be fully elucidated.
References
- . Clinical application of incretin-based therapy: therapeutic potential, patient selection and clinical use . Am J Med . 2009;122:S37–S50
- . Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes. Medscape 2008 . Available at www.medscape.com/viewarticle/578051_print Accessed March 7, 2010.
- . Differentiating incretin therapies based on structure, activity, and metabolism: Focus on liraglutide . Pharmacotherapy . 2009;29(12):25S–32S
- . Efficacy and safety of incretin-based therapies in patients with type 2 diabetes mellitus . Am J Med . 2009;122:S11–S24
Suggestions for topics are welcome.
PII: S1555-4155(10)00289-8
doi:10.1016/j.nurpra.2010.05.008
© 2010 American College of Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
