CONICET | Buscador de Institutos y Recursos Humanos

Sitagliptin is a highly selective oral dipeptidyl peptidase-4 (DPP-4) inhibitor, that effectively inhibits the enzyme activity for 24 hours in a dose dependent fashion. Through this mechanism, this drug increases the plasma concentration of active glucagon like peptide-1 (GLP-1) and Glucose-dependent insulinotropic peptide (GIP). These two hormones then simulate the secretion of insulin in a glucose dependent manner and inhibit glucagon secretion,,thus reducing circulating glucose levels; GLP-1 also reduces the â-cell stress evidenced as a decrease in the proinsulin:insulin ratio. In animal models, GLP-1 increases â-cell mass by a combined effect: decreases apoptosis and increases â-cell replication and differentiation from duct cells. In human beings sitagliptin administration reduces fasting and postprandial glucose and A1c levels, being as effective as glipizide but having less frequency of hypoglycemic events than other oral insulin secretagogues. Since metformin reduces hepatic glucose production and it also increases GLP-1 release, combined therapy with sitagliptin becomes complementary and it has thus been specifically studied showing important additive effects. The safety profile of this combination is similar to that of metformin employed alone. Combination with pioglitazone resulted in improved metabolic control when compared with pioglitazone plus placebo, without changes neither the incidence of oedema nor the liver enzymes profile. Add-on combination with sulfonylurea was recently approved by FDA. Combined administration with insulin requires further studies. The weight neutral effect of sitagliptin, its glucose dependent action (lower risk of hypoglycemia), the benefitial effects upon â-cell function and its eventual protective action upon â-cell mass, makes sitagliptin an excellent option either for monotherapy or combined with metformin, glitazones or even sulfonylurea.