DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20184872

Role of DPP-4 inhibitors in the management of type 2 diabetes

Ramesh ., D. D. Gupta

Abstract


Among various insulinotropic agents used in treatment of Type 2 DM, inclusion of DPP4 inhibitors are considered as major breakthrough as far as new drug development is concerned. In this review article we have discussed in detail about the pathogenesis of diabetes mellitus especially the role of incretin, DPP4 enzyme and implication of its inhibitors in treatment of DM. Also, various clinical studies regarding use of DPP4 inhibitors as monotherapy and as combination therapy with other antidiabetic agents were discussed. DPP-4 inhibitors control glucose in fasting as well as in postprandial state both in monotherapy and in combination with other oral antidiabetic agents. Significant reduction in HbA1c observed with DPP4 inhibitors as monotherapy. On combining DPP 4 inhibitor as add-on therapy to metformin, glitazone or sulphonylurea therapy in patients with type 2 diabetes not reaching therapeutic goals, DPP-4 inhibitors reduce HbA1c, fasting plasma glucose and 2-h postprandial plasma glucose up to the desired level. Various DPP-4 inhibitors have been proven to be as safe and tolerable both as monotherapy and combination with other antidiabetic agents. Inhibition of DPP-4 enzyme has been proven as a promising aspect in the treatment of type 2 diabetes and various drugs inhibiting DPP4 enzymes have been developed now. They are highly recommended in the treatment of Type 2 DM both as monotherapy as well as combination therapy.


Keywords


Diabetes mellitus, DPP4 inhibitors, Incretin

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References


Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectrum. 2004;17:183-90.

Gallwitz B. New therapeutic strategies for the treatment of type 2 diabetes mellitus based on incretins. Rev Diabet Stud. 2005;2(2):61-9.

Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705.

Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003 Dec 1;144(12):5149-58.

Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132:2131-57.

Boyle PJ, Freeman JS. Application of incretin mimetics and dipeptidyl peptidase IV inhibitors in managing type 2 diabetes mellitus. J Am Osteopath Assoc. 2007;107(suppl 3):S10-S16.

Vaag AA, Holst JJ, Vølund A, Beck-Nielsen HB. Gut incretin hormones in identical twins discordant for non-insulin-dependent diabetes mellitus (NIDDM)-evidence for decreased glucagon-like peptide-1 secretion during oral glucose ingestion in NIDDM twins. Eur J Endocrinol. 1996;135:425-32.27.

Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF. Insulinotropic action of glucagonlike peptide-I-(7-37) in diabetic and nondiabetic subjects. Diabetes Care. 1992;15:270-6.

Lynn FC, Thompson SA, Pospisilik JA, Ehses JA, Hinke SA, Pamir N, et al. A novel pathway for regulation of glucose-dependent insulinotropic polypeptide (GIP) receptor expression in β cells. The FASEB J. 2003 Jan;17(1):91-3.

Lambeir AM, Durinx C, Scharpe S, De Meester I. Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV. Crit Rev Clin Lab Sci. 2003;40:209-4.

Miller S, St. Sitagliptin OEL. a dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother. 2006;40:1336-43.

Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010;38:667-78.

European Medicines Agency (EMEA). Galvus (vildagliptin)- European public assessment report (EPAR)- scientific discussion. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/galvus/H- 771-en6.pdf. Accessed 5 July 2010.

European Medicines Agency (EMEA). Onglyza (saxagliptin)- European public assessment report (EPAR)- CHMP Assessment Report. Available at: http://www.emea.europa.eu/humandocs/PDFs/EPAR/onglyza/H-1039-en6.pdf. Accessed 5 July 2010.

Feng J, Zhang Z, Wallace MB, Stafford JA, Kaldor SW, Kassel DB, et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem. 2007;50:2297-300.

Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, et al. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3, 7-dihydropurine-2, 6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J Med Chem. 2007;50:6450-3.

Kim YB, Kopcho LM, Kirby MS, Hamann LG, Weigelt CA, Metzler WJ, et al. Mechanism of Gly-Pro-pNA cleavage catalyzed by dipeptidyl peptidase-IV and its inhibition by saxagliptin (BMS-477118). Arch Biochem Biophys. 2006;445:9-18.

Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc. 2009;49(Suppl. 1):S16-29.

Bristol-Myers Squibb. Onglyza (saxagliptin) 5 mg filmcoated tablets. Summary of Product Characteristics. Last date of revision: 09 October 2009. Available at: http://emc.medicines.org.uk/medicine/22315/SPC/Onglyza+5mg+film-coated+tablets [accessed 06.10].

Thomas L, Eckhardt M, Langkopf E, Tadayyon M, Himmelsbach F, Mark M. (R)-8-(3-amino-piperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydro-purine-2,6-dione (BI 1356), a novel xanthinebaseddipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther. 2008;325:175-82.

Thomas L, Tadayyon M, Mark M. Chronic treatment with the dipeptidyl peptidase-4 inhibitor BI 1356 [(R)-8-(3-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methylquinazolin- 2-ylmethyl)-3,7-dihydro-purine-2,6-dione] increases basal glucagon-like peptide-1 and improves glycemic control in diabetic rodent models. J Pharmacol Exp Ther. 2009;328:556-63.

Deacon CF, Ahren B, Holst JJ. Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes? Expert Opin Investig Drugs. 2004;13:1091-102.

Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonist and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705.

Gallwitz B. Sitagliptin: profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. Drugs Today (Barc). 2007;43:13-25.

Ristic S, Bates PC. Vildagliptin: a novel DPP-4 inhibitor with pancreatic islet enhancement activity for treatment of patients with type 2 diabetes. Drugs Today (Barc). 2006;42:519-31.

Raz I, Chen Y, Wu M, Hussain S, Kaufman KD, Amatruda JM, et al. Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008 Feb 1;24(2):537-50.

Nauck M, Meininger G, Sheng DO, Terranella L, Stein PP. Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double‐blind, non‐inferiority trial. Diabetes, Diabetes Obes Metab. 2007;9:194-205.

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 Nov;7(6):692-8.

Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes research and clinical practice. 2007 Apr 1;76(1):132-8.

Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP. Sitagliptin Study 014 Investigators. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Current medical research and opinion. 2007 Jun 1;23(6):1329-39.

Pratley RE, Rosenstock J, Pi-Sunyer FX, Banerji MA, Schweizer A, Couturier A, et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy. Diabetes Care. 2007;30:3017-22.

Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes care. 2007 Feb 1;30(2):217-23.

Schweizer A, Couturier A, Foley JE, Dejager S. Comparison between vildagliptin and metformin to sustain reductions in HbA1c over 1 year in drug‐naïve patients with Type 2 diabetes. Diabetic Medicine. 2007 Sep;24(9):955-61.

Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes care. 2007 Feb 2.

Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes care. 2006 Dec 1;29(12):2638-43.

Scott R, Loeys T, Davies MJ, Engel SS. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008 Oct 1;10(10):959-69.

Garber AJ, Schweizer A, Baron MA, Rochotte E, Dejager S. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo‐controlled study. Diabetes Obes Metab. 2007 Mar;9(2):166-74.

Garber AJ, Foley JE, Banerji MA, Ebeling P, Gudbjörnsdottir S, Camisasca RP, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008 Nov;10(11):1047-56.

Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733-45.

Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007 Jun 1;50(6):1148-55.

Burkey BF, Hoffmann PK, Hassiepen U, Trappe J, Juedes M, Foley JE. Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes Metab. 2008 Nov 1;10(11):1057-61.

Piteau S, Olver A, Kim SJ, Winter K, Pospisilik JA, Lynn F, et al. Reversal of islet GIP receptor down-regulation and resistance to GIP by reducing hyperglycemia in the Zucker rat. Biochemical and biophysical research communications. 2007 Nov 3;362(4):1007-12.

Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, et al. Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. Proceedings of the National Academy of Sciences. 2003 May 27;100(11):6825-30.

Alvin C. Powers and David D’Alessio. Endocine Pancreas and Pharmacotherapy of Diabetes Mellitus and Hypoglycemia. In: Goodman and Gilman’s The Pharmacological Basis of Therapeutics,13th ed. McGraw Hill Medical, New York; 2017:863-886.