Dipeptidyl Peptidase-4 Inhibitors

Clinical data and clinical implications

• DPP-4, dipeptidyl peptidase-4
• FDA, Food and Drug Administration
• GIP, glucose-dependent insulinotropic polypeptide
• GLP-1, glucagon-like peptide-1

The enzyme dipeptidyl peptidase-4 (DPP-4) prevents the inactivation of glucagon-like peptide-1 (GLP-1). Since GLP-1–based therapy is a promising novel treatment of type 2 diabetes, the strategy to inhibit the enzyme has been explored. Several DPP-4 inhibitors are in clinical development; these are orally active and increase levels of active GLP-1, which in turn increases insulin secretion and reduces glucagon secretion and thereby lowers glucose levels. Most experience exists for sitagliptin (Merck) and vildagliptin (Novartis), which both have a long duration of action, allowing once-daily administration. In drug-naïve subjects with type 2 diabetes, both sitagliptin and vildagliptin reduce A1C levels by ∼1% as monotherapy, as demonstrated in studies up to 52 weeks. Also in combination with metformin and thiazolidinediones, sitagliptin and vildagliptin improve glycemic control with reduction of A1C of ∼1%. Both sitagliptin and vildagliptin are safe and tolerable with low risk of hypoglycemia. They are both body weight neutral. The studies presented thus far therefore suggest that DPP-4 inhibition is an efficient treatment of type 2 diabetes, both as monotherapy and combination therapy. Because of its efficiency, safety, and tolerability in association with the oral mode of administration, it is expected that DPP-4 inhibition will be a first-line treatment of the early stage of type 2 diabetes, particularly in combination with metformin or thiazolidinediones.