Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus.
As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged-the dipeptidyl peptidase IV (DPP-IV) inhibitors. Unlike conventional oral antidiabetic agents, these agents promote glucose homeostasis through inhibition of DPP-IV, the enzyme responsible for degradation of two key glucoregulatory hormones: glucagon-like peptide-1 (GLP-1), which extends the action of insulin while also suppressing the release of glucagon, and glucose-dependent insulinotropic peptide (GIP). Other proposed mechanisms of action of GLP-1 and thus DPP-IV inhibitors include satiety, increased beta-cell production, and inhibition of apoptosis of beta cells. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying, and stimulate insulin release. The DPP-IV inhibitors appear to have excellent therapeutic potential in the management of type 2 diabetes as monotherapy or in combination with existing agents, such as metformin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with sustainable reductions in glycosylated hemoglobin levels and relatively few adverse effects. Their distinctive mechanism of action and adverse-event profiles may offer advantages over existing therapies, including low risk for hypoglycemia and possible augmentation of pancreatic beta-cell regeneration.
Langley
Alissa K
AK
Department of Pharmacy Services, Saint Joseph HealthCare, Lexington, Kentucky 40504, USA.
Suffoletta
Terri J
TJ
Jennings
Heath R
HR
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D058892:Adenosine Deaminase Inhibitors; D000284:Administration, Oral; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4; D054873:Dipeptidyl-Peptidase IV Inhibitors; D016503:Drug Delivery Systems; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D006023:Glycoproteins / Q000037:antagonists & inhibitors*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000077597:Vildagliptin
D058892:Adenosine Deaminase Inhibitors; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006023:Glycoproteins; D007004:Hypoglycemic Agents; D009570:Nitriles; D011719:Pyrazines; D011759:Pyrrolidines; D014230:Triazoles; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D000077597:Vildagliptin; D000218:Adamantane; D000068900:Sitagliptin Phosphate