Review: Inhibition of dipeptidyl peptidase-4 with vildagliptin: a potential new treatment for type 2 diabetes

Abstract

Type 2 diabetes mellitus is a growing problem in most parts of the world. There is now good evidence that controlling hyperglycaemia can help prevent many of the serious complications associated with the disease. Despite this evidence and the availability of several classes of oral antidiabetic agents and insulin, many people with diabetes do not achieve adequate glycaemic control (i.e. HbA_1C < 6.5 or 7.0%). Thus, there is an urgent unmet medical need to develop new and better treatments for type 2 diabetes. Among the most promising new classes of drugs for type 2 diabetes are those that leverage the incretin hormone glucagon-like peptide-1 (GLP-1). Vildagliptin, an orally available, potent and specific inhibitor of dipeptidyl peptidase-4 (DPP-4), the enzyme that rapidly inactivates GLP-1, augments endogenous active GLP-1 and gastric inhibitory polypeptide/glucose-dependent insulinotropic polypeptide (GIP) and reduces hyperglycaemia in patients with type 2 diabetes. Studies to date in patients exposed for up to one year indicate that vildagliptin produces clinically significant reductions in HbA_1C when used as monotherapy and in combination with metformin, glimepiride, or insulin. In general, the drug has proved to be well tolerated with low rates of hypoglycaemia and gastrointestinal side effects (including nausea) and no weight gain or oedema.

Keywords

GLP-1 GIP incretin hormone incretin enhancer DPP-4 diabetes.

Get full access to this article

View all access options for this article.

References

Wild S. , Roglic C. , Green A. et al. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes 2004;27:1047-53.

Diabetes Control and Complications Trial (DCCT) Research Group . N Engl J Med 1993;329:977-86.

Turner RC The UK Prospective Diabetes Study: A review. Diabetes Care 1998;21(suppl 3):C35-C38.

Ohkubo Y. , Kishikawa H. , Araki E. et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103-17.

Koro CE , Bowlin SJ , Bourgeois N. , Fedder DO. Glycemic control from 1988 to 2000 among U.S. adults diagnosed with type 2 diabetes: a preliminary report. Diabetes Care 2004;27:17-20.

Inzucchi SE Oral antihyperglycemia therapy for type 2 diabetes: scientific review. J Am Med Assoc 2002;287:360-72.

UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:85465.

Leahy JL Pathogenesis of type 2 diabetes mellitus. Arch Med Res 2005; 36:197-209.

Pratley RE , Weyer C. , Bogardus C. Metabolic abnormalities in the development of type 2 diabetes mellitus. In: Diabetes Mellitus: A Fundamental and Clinical Text, 2nd edition. LeRoith D , Taylor SI , Olefsky JM , editors; Lippincott Williams & Wilkins: Philadelphia; 1999, pp 548-557.

10.

Weyer C. , Bogardus C. , Mott DM , Pratley RE The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999;104:787-94.

11.

Pratley RE , Weyer C. The role of impaired early insulin secretion in the pathogenesis of type 2 diabetes mellitus. Diabetologia 2001;44:929-45

12.

Dunning BE , Foley JE , Ahren B. Alpha cell function in health and disease: influence of glucagon-like peptide-1 . Diabetologia 2005;48:1700-13.

13.

Butler AE , Janson J. , Bonner-Weir S. et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 2003;52: 102-10.

14.

Rachman J. , Barrow BA , Levy JC , Turner RC Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997;40: 205-11.

15.

Nauck MA , Meier JJ Glucagon-like peptide 1 (GLP-1) and its derivatives in the treatment of diabetes . Regul Pept 2005;124(suppl):135-48.

16.

Drucker DJ Enhancing Incretin Action for the Treatment of Type 2 Diabetes. Diabetes Care 2003;26:2929-40.

17.

Vilsbøll T. , Krarup T. , Deacon CF et al. Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients . Diabetes 2001;50:609-13.

18.

Toft-Nielsen MB , Damholt MB , Madsbad S. et al. Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 2001;86:3717-23.

19.

Nauck MA , Heimesaat MM , rskov C. et al. 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. J Clin Invest 1993;91:301-07.

20.

Kjems LL , Holst JJ , Volund A. , Madsbad S. The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 2003;52:380-6.

21.

Meier JJ , Gallwitz B. , Kask B. et al. Stimulation of insulin secretion by intravenous bolus injection and continuous infusion of gastric inhibitory polypeptide in patients with type 2 diabetes and healthy control subjects. Diabetes 2004;53(suppl 3):S220-4.

22.

Irwin N. , O'Harte FP , Gault VA et al. GIP(Lys16PAL) and GIP(Lys37PAL): novel long-acting acylated analogues of glucose-dependent insulinotropic polypeptide with improved antidiabetic potential. J Med Chem 2006;49:1047-54.

23.

Egan JM , Meneilly GS , Habener JF , Elahi D. Glucagon-like peptide-1 augments insulin-mediated glucose uptake in the obese state. J Clin Endocrinol Metab 2002;87:3768-73.

24.

Nauck MA , Niedereichholz U. , Ettler R. et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol (Endocrinol Metab) 1997;273:E981-8.

25.

Perfetti R. , Hui H. The role of GLP-1 in the life and death of pancreatic beta cells. Horm Metab Res 2004 ;36:804-10.

26.

Trumper A. , Trumper K. , Trusheim H. , Arnold R. , Goke B. , Horsch D. Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. Mol Endocrinol 2001;15:1559-70.

27.

Deacon CF , Nauck MA , Toft-Nielsen M-B et al. Both subcutaneously and intravenously administered glucagon-like peptide-1 are rapidly degraded from the amino-acid terminus in type 2 diabetic patients and in healthy subjects. Diabetes 1995;44:1126-31.

28.

Mentlein R. Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept 1999;85:9-24.

29.

Ahrén B. : Exenatide: a novel treatment of type 2 diabetes. Therapy 2005; 2:207-22.

30.

Buse JB , Henry RR , Han J. et al. Effects of Exenatide (Exendin-4) on Glycemic Control Over 30 Weeks in Sulfonylurea-Treated Patients With Type 2 Diabetes. Diabetes Care 2004;27:2628-35.

31.

Marguet D. , Baggio L. , Kobayashi T. et al. Enhanced secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 2000;97:6874-9.

32.

Nagakura T. , Yasuda N. , Yamazaki K. et al. Improved glucose tolerance via enhanced glucose-dependent insulin secretion in dipeptidyl peptidase IVdeficient Fischer rats. Biochem Biophys Res Commun 2001;284:501-06.

33.

Villhauer EB , Brinkman JA , Naderi GB et al. 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem 2003;46:2774-89.

34.

Lankas GR , Leiting B. , Roy RS et al. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005;54:2988-94.

35.

Ahren B. Vildagliptin: an inhibitor of dipeptidyl peptidase-4 with antidiabetic properties . Expert Opin Investig Drugs 2006;15:431-42.

36.

Tran P. , Yin H. , Smith T. , Fischer F. : Disposition of (14C)LAF237 in rats and humans. Drug Metab Rev 2002;34:293.

37.

He Y-L. , Sabo R. , Wang Y. et al. The Influence of Hepatic Impairment on the Pharmacokinetics of Vildagliptin. Diabetes 2006;55(suppl 1):A469.

38.

Ahren B. , Landin-Olsson M. , Jansson P-A et al. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004;89: 2078-84.

39.

Ristic S. , Byiers S. , Foley J. , Holmes D. Improved glycaemic control with dipeptidyl peptidase-4 inhibition in patients with type 2 diabetes: vildagliptin (LAF237) dose response. Diabetes Obes Metab 2005;7:692-8.

40.

Pratley R. , Jauffret-Kamel S. Galbreath, E. Holmes D. Twelve-week monotherapy with the DPP-4 inhibitor LAF237 improves glycemic control in patients with type 2 diabetes (T2DM). In Press: Hormone and Metabolic Research 2006.

41.

Dejager S. , Lebeaut A. , Couturier A. , Schweizer A. Sustained Reduction in HbA1c during One-Year Treatment With Vildagliptin in Patients with Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl 1):A29.

42.

Rosenstock J. , Baron MA , Schweizer A. et al. Vildagliptin Is As Effective As Rosiglitazone In Lowering HbA1C but Without Weight Gain In Drug-Naive Patients With Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl 1): A133.

43.

Ahren B. , Gomis R. , Standl E. et al. Twelve- and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. Diabetes Care 2004;27:2874-80.

44.

Garber A. , Camisasca RP , Ehrsam E. et al. Vildagliptin Added to Metformin Improves Glycemic Control and May Mitigate Metformin-Induced GI Side Effects in Patients with Type 2 Diabetes (T2DM) Diabetes 2006;55(suppl 1):A29.

45.

Fonseca V. , Dejager S. , Albrecht S. et al. Vildagliptin as Add-On to Insulin in Patients with Type 2 Diabetes (T2DM). Diabetes 2006;55(suppl 1):A111.

46.

Nathwani A. , Lebeaut A. , Byiers S. et al. Reduction In Blood Pressure In Patients Treated With Vildagliptin As Monotherapy or in Combination with Metformin for Type 2 Diabetes. Diabetes 2006;55(suppl 1):A113.

47.

Matikainen N. , Manttari S. , Schweizer A. et al. Vildagliptin Decreases Postprandial Chylomicron Triglycerides (TGs) in Drug-Naive Patients with Type 2 Diabetes (T2DM) Diabetes 2006;55(suppl 1):A125.