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To review recent clinical trials of oral dipeptidyl peptidase-4 inhibitors and examine their role in managing type 2 diabetes mellitus.Oral dipeptidyl peptidase-4 inhibitors improve islet function by increasing α-cell and β-cell responsiveness to glucose, resulting in improved glucose-dependent insulin secretion and reduced inappropriate glucagon secretion. These agents appear to have physiologically based antihyperglycemic effects and may modify the progressive nature of type 2 diabetes mellitus. In clinical trials sitagliptin and vildagliptin have modest demonstrated effectiveness, with clinically meaningful reductions of glycated hemoglobin when used as monotherapy. They appear promising in combination or added to ongoing therapy with other antidiabetic drugs (e.g. metformin, thiazolidinediones, or insulin). Dipetidyl peptidase-4 inhibitors themselves are not associated with hypoglycemia or weight gain and appear to have a benign safety profile.Oral dipeptidyl peptidase-4 inhibitors may prove valuable in the treatment of diabetes, given their effectiveness in reducing glycated hemoglobin with neutral weight effects and without the adverse events associated with other agents. Dipeptidyl peptidase-4 inhibitors appear to improve islet function and may modify the course of diabetes; this, however, must be confirmed with long-term controlled studies to demonstrate sustained glycemic control that translates into β-cell preservation.