The Incretin Pathway: A New Area of Treatment for Type 2 Diabetes
Last updated: 11/30/2006
In 2005, 20.8 million people in the United States had diabetes. In the year 2050, that number is expected to double. It is well known that having diabetes increases your risk for heart disease, stroke and death, and most diabetics have other comorbid disease states such as hypertension and obesity.
The progression of type 2 diabetes starts with insulin resistance as a result of diet, sedentary lifestyle, and genetic factors. Compensation of this insulin resistance occurs early on in type 2 diabetes and results in hypersecretion of insulin by the beta cells of the pancreas. As insulin sensitivity continues to deteriorate, type 2 diabetics have worsening beta cell function with resulting fasting hyperglycemia. As the progression continues, chronic hyperglycemia and insulin resistance lead to a decrease in beta cell mass and an increase in beta cell death, which leads to a further decrease in insulin secretion.
Good glycemic control is critical to minimize microvascular and macrovascular complications of diabetes, but it is often elusive. Factors that challenge the achievement of this goal are the progressive loss of beta cell function, lack of diet and exercise, and poor adherence to prescribed therapy. Approximately two of three adults with type 2 diabetes do not achieve the hemoglobin A1C goal of less than 7.0%.
The current treatment of type 2 diabetes includes sulfonylureas, thiazolidinediones, metformin, metig-linides and alpha-glucosidase inhibitors. These drugs initially work well at controlling hyperglycemia in many patients. However, with time, their effects are minimized and patients often need exogenous insulin replacement. Additionally, none of these agents influence the natural course of the disease.
There is now a new approach for the treatment of type 2 diabetes. Years ago, a simple glucose administration test was performed and highlighted this new drug target. Glucose doses calculated to give identical serum glucose elevations were given orally and intravenously to a group of patients. The insulin response was measured, and it was found that the oral glucose evoked a greater insulin re-sponse than the intravenous glucose. This occurs because gastrointestinal hormones in the gut stim-ulate insulin release after a meal. The difference in this insulin response was known as the ?incretin effect? and these gastrointestinal hormones were known as the "incretins."
The two most important incretin hormones in humans are glucose-dependent insulinotropic pep-tide (GIP), and glucagon-like peptide (GLP-1). Type 2 diabetic patients generally lack the glucose-lowering response to GIP; however, the response to GLP-1 is intact but the circulating levels are diminished. The antidiabetogenic effects of GLP-1 in the body include stimulation of insulin secretion, inhibition of glucagon secretion from alpha cells, delay of gastric emptying, increase in insulin sensitivity, suppression of appetite, and an actual increase in beta cell mass. More effects are shown in the figure below. GLP-1 has a half-life of less than two minutes following exogenous administra-tion, mostly because it is metabolized rapidly by the enzyme dipeptidyl peptidase-4 (DPP-4).
Right now, there are two approaches for enhancing GLP-1 action in vivo. These are the incretin mimetics [Byetta® (exenatide)] and DPP-4 inhibitors [Januvia® (sitagliptin]). Neither of these agents is currently on the Cabell Huntington Hospital formulary. Other drugs utilizing these pathways are soon to be here but are still seeking FDA approval.
Byetta® is the first incretin mimetic available in the United States for type 2 diabetics not optimally controlled with sulfonylureas or metformin, or the combination of both. It was approved in 2005, and is a synthetic form of the naturally occurring peptide exendin-4. This peptide was discovered in the salivary glands of the Gila monster and has an amino acid sequence similar to GLP-1; however, is not degraded by DPP-4. Byetta® is given twice daily as a subcutaneous injection one hour before morn-ing and evening meals. The most common side effect associated with Byetta® is nausea, with an incidence as high as 40% in some literature. Other side effects include hypoglycemia, especially when combined with a sulfonylurea, vomiting, diarrhea, headache, nervousness, and decreased appetite. Clinical trials have shown that this drug, in com-bination with other agents, could lower hemoglobin A1C levels up to 1% and cause weight loss. The drug has only been studied for a limited amount of time, however, and whether these clinical effects will persist with continued use remains to be seen.
DPP-4 inhibitors inhibit GLP-1 degradation by the DPP-4 enzyme, and thereby extend the life of circulating GLP-1. Januvia®, approved late in 2006, is the only drug thus far in this class. Januvia® is indicated for treatment of type 2 diabetes as either monotherapy or in combination with metformin or thiazolidinediones. It is dosed at 100mg by mouth every day, although adjustments are needed for patients with renal insufficiency. It may be taken with or without food. It has few side effects reported in clinical trials, but those noted include upper res-piratory infection, nasopharyngitis, headache, diarrhea, and abdominal pain. Theoretically, ad-ditional drug side effects may occur as DPP-4 also inhibits the degradation of numerous other pep-tides, and their respective increases may result in unwanted effects including hypertension. Addition-ally, DPP-4 is also known as CD26, which plays an important role in T cell activation and could affect immune function. While there was no indication that these theoretical adverse reactions occurred in clinical trials, the long-term safety of sitagliptin is unknown. Clinical trials have proved that Januvia® can decrease hemoglobin A1C values up to 0.8%. Unlike exenatide, there appears to be no benefit of weight loss with sitagliptin.
The prevalence of type 2 diabetes is steadily growing. Over half of diabetic patients are not reaching their A1C goal and their current treatment has no effect on the improvement of beta cell function. The drug targets within the incretin pathway offer a new frontier for treating more than just the blood sugars in patients with diabetes.
References
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Drucker D, et al. "The biology of incretin hormones." Cell Metab. 2006; 3:153-165.
Dungan K, et al. "Amylin and GLP-1 based therapies for treatment of diabetes." www.uptodate.com. November 10 2006
"FDA Approvals: Januvia" Accessed online at www.medscape.com on November 10 2006.
Gallwitz B, et al. "Beta-cell defects in type 2 diabetes and the possibility of treatment options with GLP-1 based therapies." European Endocrine Disease. 2006; 21:43-46.
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"Januvia package insert." Accessed online at www.merck.com on November 10 2006.