DPP-4 Inhibitors - Mechanism Of Action

DPP-4 is a serine protease that is widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T-lymphocytes, and in a circulating form. DPP-4 cleaves the two N-terminal amino acids from peptides with a proline or alanine in the second position.

Although there are many potential substrates for this enzyme, it seems to be especially critical for the inactivation of GLP-1 and GIP glucose-dependent insulinotropic polypeptide; gastric inhibitory peptide . DPP-4 inhibitors increase the AUC of GLP-1 and GIP when their secretion is by a meal.

Several agents provide nearly complete and long-lasting inhibition of DPP-4, thereby increasing the proportion of active GLP-1 from 10-20% of total circulating GLP-1 immunoreactivity to nearly 100%. Two of these, sitagliptin and saxagliptin are now available in the U.S.; a third, vildagliptin, is available in the E.U.; a fourth compound, alogliptin, is in advanced stages of clinical trials. Sitagliptin and alogliptin are competitive inhibitors
of DPP-4, whereas vildagliptin and saxagliptin bind the enzyme covalently. Despite these differences, all four drugs can be given in doses that lower measurable activity of DPP-4 by more than 95% for 12 hours. This causes a greater than 2-fold elevation of plasma concentrations of active GIP and GLP-1 and is associated with
increased insulin secretion, reduced glucagon levels, and improvements in both fasting and postprandial hyperglycemia. Inhibition of DPP-4 does not appear to have direct effects on insulin sensitivity, gastric motility, or satiety, nor does chronic treatment with DPP-4 inhibitors affect body weight. DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduced HbA1c levels by an average ∼0.8%. These compounds are also effective for chronic glucose control when
added to the treatment of diabetic patients receiving metformin, thiazolidinediones, sulfonylureas, and insulin. The effects of DPP-4 inhibitors in combination regimens appear to be additive. The recommended dose of sitagliptin is 100 mg once daily. The recommended dose of saxagliptin is 5 mg once daily.

Absorption, Distribution, Metabolism, and Excretion:
DPP-4 inhibitors are absorbed effectively from the small intestine. They circulate in primarily in unbound form and are excreted mostly unchanged in the urine. DPP-4 inhibitors do not bind to albumin, nor do they affect the hepatic cytochrome oxidase system. Both sitagliptin and saxagliptin are excreted renally, and lower doses should be used in patients with reduced renal function. Sitagliptin has minimal metabolism by hepatic microsomal enzymes. Saxagliptin is metabolized by CYP 3A4/5 to an active metabolite.

Adverse Effects and Drug Interactions. There are no consistent adverse effects that have been noted in clinical trials with any of the DPP-4 inhibitors. With
few exceptions the incidence of adverse effects in drug-treated and placebo-treated patients has been similar. DPP-4 is expressed on lymphocytes; in the immunology literature, the enzyme is referred to as CD26. Although there is some evidence of minor effects on in vitro lymphocyte function with DPP-4
inhibitors, there is no evidence from clinical studies of major adverse effects in humans. This area bears scrutiny as more patients are treated with these compounds.