DPP-IV is an enzyme

Dipeptidyl peptidase IV (abbreviated either as DPP-IV or DPP-4) is an enzyme. It selectively cleaves and thus inactivates hormones in the incretin class, including glucagon-like-peptide-1 (GLP-1) and GIP. By inactivating incretins, DPP-IV prevents the incretins from having significant effects on insulin secretion and blood glucose levels.

GLP-1 is an incretin

GLP-1 is a gut hormone, and is called an incretin. It has an important role in the regulation of blood glucose via several mechanisms, mainly by stimulation of insulin secretion, but also by inhibition of glucagon secretion. GLP-1, however, is rapidly inactivated by DPP-IV, and hence is of little significance in most people.

How do DPP-IV inhibitors work?

Since the incretin hormones are inactivated by the enzyme DPP-IV, it seemed reasonable to speculate that if a drug could be developed that would inhibit the inactivator, then the incretin itself would remain more available to produce its effects. This concept has proven to be workable, and has led to the development of the drugs we now call DPP-IV inhibitors.

It was found that using DPP-4 inhibition to minimize incretin destruction produces doubles the amount of circulating incretin hormones, and as a result, there is better control of blood glucose.

Available DPP-IV inhibitors

Several DPP-IV inhibitors have been developed (see below). They are synthetic, reversible, orally-active drugs that work to lower blood sugar by allowing an increase in incretin levels, especially GLP-1. The first DPP-IV inhibitor to be approved for sale was Januvia, in 2006.

As of late 2009, there are three DPP-IV inhibitors available: Januvia (sitagliptin, Merck) and Onglyza (saxagliptin, BMS) are approved for sale in the United States and Europe; Galvus (vildagliptin, Novartis) is approved in Europe but not in the United States. Many other DPP-IV inhibitors are under development, including alogliptin (Takeda), linagliptin (BI), denagliptan (GSK), as well as compounds from Lilly, Pfizer, Roche, and other companies.

Side effect profile

Side effects of the the DPP-IV inhibitors are generally benign.

• They are unlikely to cause hypoglycemia, unless given in combination with other diabetes drugs such as sulfonylureas.
• They are "weight-neutral," unlikely to cause weight gain or weight loss.
• Allergic reactions, including rash, hives, and swelling of the face, lips, and throat, have occurred, and could be life-threatening.
• Safety in pregnancy and in children with diabetes has not been established.

None of the available agents are recommended in combination with insulin therapy, as the manufacturers have not performed clinical trials of the DPP-IV inhibitors and insulin together.

DPP-IV inhibitors are not recommended for use in type 1 diabetes.

Conclusion

The safety profile and generally good tolerance of DPP-4 inhibitors along with the ease of administration (once or twice daily, orally) suggest that these agents will occupy an increasing role in the treatment of T2DM. Several versions of DPP-IV inhibitors are now available to help treat type 2 diabetes, and more may be available in the future.

Also see

Development of dipeptidyl peptidase-4 inhibitors
http://en.wikipedia.org/wiki/Development_of_dipeptidyl_peptidase-4_inhibitors
at Wikipedia

DPP IV Inhibitors - Current Evidence and Future Directions: DPP IV Inhibitors for the Treatment of Type 2 Diabetes Mellitus
http://www.medscape.com/viewarticle/557503_3
at Medscape Today (requires free signup)