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Sunday, February 15, 2009

new approach in type 2 diabetes pharmacotherapy

A relatively new approach in type 2 diabetes pharmacotherapy is the result of understanding incretin physiology. Briefly, after eating a meal, certain gut hormones are released that sensitize the beta cell to secrete more insulin. One of the most important gut hormones is glucagon-like peptide-1 (GLP-1), which goes into the circulation and stimulates insulin secretion in a glucose-dependent manner.

In addition, this pathway has the added benefit of suppressing glucagon secretion, which has a role in the pathophysiology of diabetes. GLP-1 is also involved in slowing gastric emptying and in working on the central nervous system causing early satiety, leading to some beneficial effects in glycemic control. The problem is that GLP-1 is very rapidly degraded through the very important enzyme, DPP-IV. This leads to rapid inactivation of GLP-1, making its use impractical in patients who have type 2 diabetes.

It is also interesting to note that in some animal models, and in in-vitro studies, there are some exciting observations that this pathway may also help beta-cell differentiation. This has been shown to increase beta-cell mass, and the formation of new beta cells, but is not yet proven in humans. It is an exciting new concept that is still being explored.

Coming back to this pathway of GLP-1 degradation through DPP-IV, one of the ways to use this physiologic knowledge is to develop a drug that might block DPP-IV activity, which has been done with the DPP-IV inhibitors. They sustain GLP-1 level in the circulation longer, which then stimulates pancreatic insulin secretion and suppresses glucagon secretion. Another strategy that one can employ is to develop a GLP-1-like substance synthetically that is not recognized by DPP-IV. That is the approach underlying the GLP-1 analogs that are not degraded through this pathway, and you can then use that substance in the treatment of type 2 diabetes.

These are the 2 concepts behind the development of the new drugs. Incretin mimetics, which are analogs of GLP-1, are synthetically produced. Exenatide is one of these drugs used to treat patients with type 2 diabetes. Because of the protein, you have to inject exenatide subcutaneously; you cannot give it orally. Another drug in this class, liraglutide, is under US Food and Drug Administration (FDA) review and might be approved in the near future.

The second way to use this physiology is to develop DPP-IV inhibitors. One such agent, sitagliptin, has been on the market for 2 years. There are several other drugs in this class undergoing clinical trials. This is an important area to pursue, and many of the pharmaceutical companies are trying to develop these agents that will be easy to use in the oral form to improve glycemic control.

exenatide, a twice-daily injection, you can lower A1C by about 0.8% to 1%. The main side effect is nausea, sometimes vomiting. There may be appreciable weight loss, which is a desirable side effect of this drug. We do not have another approved drug yet that improves glycemic control and results in weight loss at the same time. The only medication that came close to it was metformin, but metformin is relatively weight-neutral; it does not cause weight loss in most patients.

Sitagliptin has very similar effects on A1C reduction as exenatide, except it does not cause weight loss. This drug is weight-neutral, but at least it does not cause weight gain. Another advantage of these drugs is that they do not cause gastrointestinal side effects, such as nausea.

Both GLP-1 agonists and DPP-IV inhibitors are being utilized in the strategy of combination therapy to achieve better glycemic control.

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