Dipeptidyl peptidase-4 inhibitor

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DPP-4 inhibitors and GLP-1

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are anti-diabetic drugs and a class of oral hypoglycemics that block DPP-4. They can be used to treat diabetes mellitus type 2.

The first agent of the class - sitagliptin - was approved by the FDA in 2006.[1]

Glucagon increases blood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increase incretin levels (GLP-1 and GIP),[2][3][4] which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.

DPP-4 inhibitors may reduce mortality when used for treating diabetes mellitus type 2.[5]

Examples

Drugs belonging to this class are :

Other chemicals which inhibit DDP4 include:

Risks and side effects

Adverse effects, including nasopharyngitis, headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies.

Heart failure (possible association)

Dipeptidyl-Peptidase IV Inhibitors may[14][15][16][17][18][19][20] or may not[21][22][23][24] be associated with heart failure.

Pancreatic cancer (possible association)

A 2013 study of the DPP-4 inhibitor sitagliptin reported found "worrisome changes in the pancreases of the rats that could lead to pancreatic cancer".[25] A second paper by the same authors reported an increase in precancerous lesions in the pancreases of organ donors who had taken GLP-1 inhibitors.[26] In response to these reports, the United States FDA and the European Medicines Agency each undertook independent reviews of all clinical and preclinical data related to the possible association of DPP-IV inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicines, the agencies stated that "Both agencies agree that assertions concerning a causal association between incretin-based drugs and pancreatitis or pancreatic cancer, as expressed recently in the scientific literature and in the media, are inconsistent with the current data. The FDA and the EMA have not reached a final conclusion at this time regarding such a causal relationship. Although the totality of the data that have been reviewed provides reassurance, pancreatitis will continue to be considered a risk associated with these drugs until more data are available; both agencies continue to investigate this safety signal.[27]

Lawsuits have been filed in which plantiffs who developed pancreatic cancer claim that DPP-IV inhibitors or incretins had a causative role in the development of their cancers.[28][29]

Further reading

  • Herper, Matthew; Langreth, Robert (27 April 2006). "Diabetes Drugs to Watch". Forbes.com. Pharmaceuticals. Retrieved 26 April 2009.
    See pages of this article for Galvus aka LAF237 (Novartis) and Januvia aka MK-0431 (Merck)
  • Nielsen, L (2005). "Incretin mimetics and DPP-IV inhibitors for the treatment of type 2 diabetes". Drug Discovery Today. 10 (10): 703–10. doi:10.1016/S1359-6446(05)03460-4. PMID 15896683.
    Includes table describing an overview of type 2 diabetes drug therapies; 76 references.

References

  1. "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration. October 17, 2006. Retrieved 2006-10-17.
  2. McIntosh, C; Demuth, H; Pospisilik, J; Pederson, R (2005). "Dipeptidyl peptidase IV inhibitors: How do they work as new antidiabetic agents?". Regulatory Peptides. 128 (2): 159–65. doi:10.1016/j.regpep.2004.06.001. PMID 15780435.
  3. Behme, Margaret T; Dupré, John; McDonald, Thomas J (2003). "Glucagon-like peptide 1 improved glycemic control in type 1 diabetes". BMC Endocrine Disorders. 3 (1): 3. doi:10.1186/1472-6823-3-3. PMC 154101. PMID 12697069.
  4. Dupre, J.; Behme, M. T.; Hramiak, I. M.; McFarlane, P.; Williamson, M. P.; Zabel, P.; McDonald, T. J. (1995). "Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM". Diabetes. 44 (6): 626–30. doi:10.2337/diabetes.44.6.626. PMID 7789625.
  5. Ou SM, Shih CJ, Chao PW, Chu H, Kuo SC, Lee YJ; et al. (2015). "Effects on Clinical Outcomes of Adding Dipeptidyl Peptidase-4 Inhibitors Versus Sulfonylureas to Metformin Therapy in Patients With Type 2 Diabetes Mellitus". Ann Intern Med. 163 (9): 663–72. doi:10.7326/M15-0308. PMID 26457538.
  6. Banting and Best Diabetes Centre at UT sitagliptin
  7. Banting and Best Diabetes Centre at UT vildagliptin
  8. "FDA approves new treatment for Type 2 diabetes". Fda.gov. 2011-05-02. Retrieved 2013-04-15.
  9. http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf
  10. Joanne Bronson, Amelia Black, T. G. Murali Dhar, Bruce A. Ellsworth, and J. Robert Merritt. "Teneligliptin (Antidiabetic)". Annual Reports in Medicinal Chemistry. 48: 523–524. |chapter= ignored (help)
  11. "LG Life Science". Lgls.com. Retrieved 2013-04-15.
  12. "Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/
  13. Al-Masri, Ihab M.; Mohammad, Mohammad K.; Tahaa, Mutasem O. (2009). "Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine". Journal of Enzyme Inhibition and Medicinal Chemistry. 24 (5): 1061–6. doi:10.1080/14756360802610761. PMID 19640223.
  14. Li L, Li S, Deng K, Liu J, Vandvik PO, Zhao P; et al. (2016). "Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies". BMJ. 352: i610. doi:10.1136/bmj.i610. PMID 26888822.
  15. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P; et al. (2014). "Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial". Circulation. 130 (18): 1579–88. doi:10.1161/CIRCULATIONAHA.114.010389. PMID 25189213. Review in: Ann Intern Med. 2015 Apr 21;162(8):JC11
  16. Udell JA, Cavender MA, Bhatt DL, Chatterjee S, Farkouh ME, Scirica BM (2015) Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol 3 (5):356-66. DOI:10.1016/S2213-8587(15)00044-3 PMID: 25791290
  17. Clifton P (2014). "Do dipeptidyl peptidase IV (DPP-IV) inhibitors cause heart failure?". Clin Ther. 36 (12): 2072–9. doi:10.1016/j.clinthera.2014.10.009. PMID 25453730.
  18. Weir DL, McAlister FA, Senthilselvan A, Minhas-Sandhu JK, Eurich DT (2014). "Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study". JACC Heart Fail. 2 (6): 573–82. doi:10.1016/j.jchf.2014.04.005. PMID 24998080.
  19. Monami M, Dicembrini I, Mannucci E (2014). "Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials". Nutr Metab Cardiovasc Dis. 24 (7): 689–97. doi:10.1016/j.numecd.2014.01.017. PMID 24793580.
  20. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B; et al. (2013). "Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus". N Engl J Med. 369 (14): 1317–26. doi:10.1056/NEJMoa1307684. PMID 23992601. Review in: Ann Intern Med. 2014 Jan 21;160(2):JC8-9
  21. Toh S, Hampp C, Reichman ME, Graham DJ, Balakrishnan S, Pucino F; et al. (2016). "Risk for Hospitalized Heart Failure Among New Users of Saxagliptin, Sitagliptin, and Other Antihyperglycemic Drugs: A Retrospective Cohort Study". Ann Intern Med. doi:10.7326/M15-2568. PMID 27110660.
  22. Filion KB, Azoulay L, Platt RW, Dahl M, Dormuth CR, Clemens KK; et al. (2016). "A Multicenter Observational Study of Incretin-based Drugs and Heart Failure". N Engl J Med. 374 (12): 1145–1154. doi:10.1056/NEJMoa1506115. PMID 27007958.
  23. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT; et al. (2015). "Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial". Lancet. 385 (9982): 2067–76. doi:10.1016/S0140-6736(14)62225-X. PMID 25765696.
  24. Eurich DT, Weir DL, Simpson SH, Senthilselvan A, McAlister FA (2015). "Risk of new-onset heart failure in patients using sitagliptin: a population-based cohort study". Diabet Med. doi:10.1111/dme.12867. PMID 26206341.
  25. Matveyenko AV, Dry S, Cox HI; et al. (July 2009). "Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin". Diabetes. 58 (7): 1604–15. doi:10.2337/db09-0058. PMC 2699878. PMID 19403868.
  26. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC (July 2013). "Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors". Diabetes. 62 (7): 2595–604. doi:10.2337/db12-1686. PMID 23524641.
  27. "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM".
  28. "Latest Januvia Lawsuits Alleging Pancreatic Cancer Help: Resource4thePeople Reports Cases Continue To Be Filed in Federal Multidistrict Litigation". DG. DigitalJournal.com. October 14, 2013. Retrieved 2013-10-14.
  29. "IN RE: INCRETIN MIMETICS PRODUCTS LIABILITY LITIGATION" (PDF). USJP. United States Judicial Panel on Multidistric Litigation. August 26, 2013. Retrieved 2013-08-26.

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