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DPP-4 Inhibitors

A novel class of drugs for treating Type 2 diabetes that may actually slow or halt the diabetes disease process. DPP-4 inhibitors prevent the breakdown of incretins, the hormones that stimulate insulin secretion in response to meals.

The two predominant incretin hormones are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). GLP-1, made in the intestine, is released in response to meals. It stimulates insulin secretion in a glucose-dependent manner—that is, insulin is secreted only when glucose is present in the bloodstream. GLP-1 also appears to delay stomach emptying, which blunts high blood glucose after meals, curbs appetite, appears to promote regeneration of the pancreatic beta cells (the cells that secrete insulin), and improves survival of the beta cells.

GIP is made by cells called K cells, which line the stomach and upper intestinal walls, and is carried through the intestinal wall and transported via the bloodstream to the pancreatic beta cells, where it stimulates insulin secretion. Like GLP-1, GIP appears to promote beta-cell proliferation and beta-cell survival.

A drug called exenatide (brand name Byetta), which mimics the action of GLP-1 and must be taken by injection, is currently used to treat Type 2 diabetes. DPP-4 inhibitors increase the levels of GLP-1 and GIP by working against the action of dipeptidyl peptidase IV (or DPP-4), an enzyme that normally breaks down these hormones. A number of pharmaceutical companies have been developing DPP-4 inhibitors, hoping that these orally administered drugs may provide at least some of the same benefits as exenatide. The most thoroughly tested DPP-4 inhibitors are vildagliptin (Galvus—not yet on the market) and sitagliptin (Januvia).

Early clinical studies with vildagliptin and sitagliptin suggest that they are well tolerated and that they effectively lower blood glucose levels, both when used alone and when combined with other drugs. Sitagliptin was approved by the U.S. Food and Drug Administration (FDA) for treating adults with Type 2 diabetes in October 2006. The FDA granted similar approval in March 2007 for a combination of sitagliptin and metformin called Janumet. While the DPP-4 inhibitors appear safe and effective over the short term, it is not yet known how safe and effective they will be over the long term. Their exact role in the treatment of Type 2 diabetes remains to be determined.

 

 

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