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Inhibition of dipeptidyl peptidase-4: The mechanisms of action and clinical use of vildagliptin for the management of type 2 diabetes

By Galina Smushkin and Adrian Vella

Abstract

Postprandial hyperglycemia in type 2 diabetes is characterized by impaired insulin secretion and action, decreased glucose effectiveness and defective suppression of glucagon secretion. Newly available therapies for type 2 diabetes target the pathway of the incretin hormone glucagon-like peptide-1 (GLP-1). Oral inhibitors of dipeptidyl peptidase-4 (DPP-4) raise the level of endogenous GLP-1 by inhibiting its clearance thereby lowering fasting and postprandial glucose concentrations. Unlike compounds which act as agonists of the GLP-1 receptor, DPP-4 inhibitors are not associated with significant effects on gastrointestinal motility, which led to a controversy around the mechanisms responsible for their glucose-lowering effects. Here we review the evidence in regards to the mechanisms whereby DPP-4 inhibitors lower glucose concentrations. Their effects are most likely mediated by an increase in endogenous GLP-1, although additional mechanisms may be involved. The pharmacology, efficacy and safety of vildagliptin, a novel DPP-4 inhibitor, are also discussed

Topics: Review
Publisher: Dove Medical Press
OAI identifier: oai:pubmedcentral.nih.gov:3048000
Provided by: PubMed Central

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Citations

  1. a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects.
  2. (2006). Absolute bioavailability of vildagliptin in healthy subjects. Clin Pharmacol Ther.
  3. (2009). Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab Dispos.
  4. Addition of vildagliptin to insulin improves glycæmic control in type 2 diabetes.
  5. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects.
  6. Chronic inhibition of circulating dipeptidyl peptidase IV by FE 999011 delays the occurrence of diabetes in male Zucker diabetic fatty rats.
  7. Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of Type 2 diabetes.
  8. (2008). Comparison of vildagliptin and acarbose monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med.
  9. (2007). Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care.
  10. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen.
  11. Degradation of endogenous and exogenous gastric inhibitory polypeptide in healthy and in type 2 diabetic subjects as revealed using a new assay for the intact peptide.
  12. (1995). Degradation of glucosedependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV.
  13. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients.
  14. Dipeptidyl peptidase IV inhibitor treatment stimulates beta-cell survival and islet neogenesis in streptozotocin-induced diabetic rats.
  15. (2009). Dipeptidyl peptidase-4 inhibition by vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 diabetes. Diabetes Care.
  16. (1999). Dipeptidyl-peptidase IV (CD26) – role in the inactivation of regulatory peptides. Regul Pept.
  17. Dose proportionality and the effect of food on vildagliptin, a novel dipeptidyl peptidase IV inhibitor, in healthy volunteers.
  18. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors.
  19. Effect of glucagon-like peptide 1(7–36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.
  20. Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes.
  21. Effects of glucagon-like peptide-1 (7–36) amide on motility and sensation of the proximal stomach in humans.
  22. (2008). Effects of the dipeptidyl peptidase IV inhibitor vildagliptin on incretin hormones, islet function, and postprandial glycemia in subjects with impaired glucose tolerance. Diabetes Care.
  23. (2008). Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab.
  24. Efficacy and safety of incretin therapy in type 2 diabetes.
  25. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab.
  26. Efficacy and tolerability of vildagliptin in drug-naïve patients with type 2 diabetes and mild hyperglycæmia. Diabetes Obes Metab.
  27. (1995). Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes.
  28. (2008). Evidence that vildagliptin attenuates deterioration of glycæmic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycæmia. Diabetes Obes Metab.
  29. (2009). Fifty-two-week efficacy and safety of vildagliptin vs glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin monotherapy. Diabetes Obes Metab.
  30. (1998). Improved glucose tolerance in Zucker fatty rats by oral administration of the dipeptidyl peptidase IV inhibitor Ile-thiazolidede.
  31. Incretin secretion in relation to meal size and body weight in healthy subjects and people with type 1 and type 2 diabetes mellitus.
  32. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes.
  33. Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study.
  34. Long-term treatment with the dipeptidyl peptidase IV inhibitor improves hepatic and peripheral insulin sensitivity in the VDF Zuker rat: a euglycemic-hyperinsulinemic clamp study.
  35. Long-term treatment with the dipeptidyl peptidase IV inhibitor P32/98 causes sustained improvements in glucose tolerance, insulin sensitivity, hyperinsulinemia, and beta-cell glucose responsiveness in VDF (fa/fa) Zucker rats.
  36. (2007). Management of type 2 diabetes in treatment-naïve elderly patients. Diabetes Care.
  37. Measurement of islet function and glucose metabolism with the dipeptidyl peptidase 4 inhibitor vildagliptin in patients with type 2 diabetes.
  38. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance.
  39. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes.
  40. (1996). On the effects of glucagon-like peptide-1 on blood glucose regulation in normal and diabetic subjects.
  41. (2007). Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus. Clin Pharmakinet.
  42. Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance.
  43. (1993). Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type 2 diabetes mellitus.
  44. (1993). Preserved incretin activity of glucagon-like peptide 1 [7–36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus.
  45. (1995). Proline motifs in peptides and their biological processing.
  46. (2004). Receptor gene expression of glucagon-like peptide-1, but not glucose dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci.
  47. Reduced postprandial concentrations of intact biologically active glucagon-like peptide in patients with type 2 diabetic patients.
  48. Secretion of incretin hormones and the insulinotropic effect of gastric inhibitory polypeptide in women with a history of gestational diabetes.
  49. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic subjects.
  50. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect.
  51. (2006). The classic incretin receptors for GLP-1 and GIP are essential for the sustained glucoregulatory actions of vildagliptin in mice. Diabetologia.
  52. The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients.
  53. (2008). The effect of dipeptidyl peptidase 4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double blind, placebo-controlled crossover study. Clin Endocrinol (Oxf).
  54. (2008). The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study. Clin Endocrinol.
  55. (1996). The hepatic vagal nerve is receptive to incretin hormone glucagon-like peptide-1, but not to glucose dependent peptide-1, but not to glucosedependent insulinotropic polypeptide, in the portal vein.
  56. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects.
  57. (1994). The insulinotropic actions of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (7–37) in normal and diabetic subjects. Regul Pept.
  58. The therapeutic actions of DPP-IV inhibition are not mediated by glucagon-like peptide 1.
  59. Vildagliptin enhances islet responsiveness to both hyper- and hypoglycemia in patients with type 2 diabetes.
  60. (2007). Vildagliptin in combination with pioglitazone improves glycæmic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab.
  61. (2007). Vildagliptin in drug-naïve patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple dose study. Horm Metab Res.