Treatment of type 2 diabetes mellitus continues to evolve with the recent addition of dipeptidyl peptide-4 (DPP-4) inhibitors to the armamentarium for the treatment of type 2 diabetes mellitus. The mechanism of action of this novel class of drugs is based on their inhibitory effect of the enzyme DPP-4, which catabolizes the incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). These incretins are secreted locally from the gastrointestinal tract in response to food intake. GLP-1 is secreted from L cells present in the mucosa of the distal small intestine and colon, whereas GIP is secreted from K cells of the jejunum. GLP-1 and GIP are fairly potent glucose-lowering agents, especially interfering with postprandial hyperglycemia, which has been associated with cardiovascular complications. After a meal these incretins regulate blood glucose levels by stimulating insulin release from b cells of the pancreas, increasing insulin sensitivity, delaying gastrointestinal emptying, and decreasing glucagon release from the liver. However, their action is short-lived (2 to 3 minutes) because they are rapidly catabolized by the enzyme DPP-4. Administration of DPP-4 inhibitors prevents the catabolism of GLP-1 and GIP, increases their blood levels, prolongs the duration of their action, and improves blood glucose control.

Recent studies in nonhumans and humans have shown a pleiotropic effect of these agents in addition to their antidiabetic action with respect to prevention of atherosclerosis, improvement of endothelial dysfunction, lowering blood pressure (BP), and preventing myocardial injury. The blood glucose-lowering effect of DPP-4 inhibitors is moderate, but it can be significantly increased by their combination with other antidiabetic drugs and especially metformin. In this concise review, the pleiotropic actions of DPP-4 inhibitors are discussed in the context of recent experimental and clinical evidence.

DPP-4 Inhibitors and Their Mechanism of Action

There are several DPP-4 inhibitors for the treatment of type 2 diabetes mellitus, some approved by the Food and Drug Administration and others still in development ( Table 1 ). Although they have different chemical structures, all successfully inhibit the DPP-4 enzyme and prevent the catabolism of GLP-1 and GIP. Of the 2 incretins, most of the action (80%) is mediated though GLP-1. The action of GLP-1 can be increased by the prevention of its catabolism by GLP-1 receptor stimulators such as exenatide and liraglutide, but these drugs have to be given by injection and are clinically impractical. Therefore, DPP-4 inhibitors given orally are preferable. Their mechanism of action is depicted graphically in Figure 1 . Glucoregulatory actions of GLP-1 in addition to those presented in Figure 1 include activation of insulin biosynthesis for subsequent use, b-cell proliferation and preservation, inhibition of apoptosis, delay of gastrointestinal emptying, and, of course, decreased appetite and weight loss in the long term.

Table 1

Dipeptidyl peptide inhibitors and their current status

Drug	Status	Chemistry
Alogliptin	Pending FDA approval	Xanthine compound
Demogliptin	In development	Cyanopyrolidine compound
Linagliptin	FDA approved	Xanthine compound
Saxagliptin	FDA approved	Cyanopyrolidine compound
Sitagliptin	FDA approved	Azetidine compound
Vildagliptin	FDA approved	Cyanopyrolidine compound

 

FDA = Food and Drug Administration.

Dipeptidyl peptidase-4 inhibitors block the action of the dipeptidyl peptidase-4 enzyme and thus increase the action of the incretin glucagon-like peptide-1 in controlling diabetes mellitus.