Dipeptidyl peptidase-4 inhibitor
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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 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.
Examples
Drugs belonging to this class are :
- Sitagliptin[5] (FDA approved 2006, marketed by Merck & Co. as Januvia),
- Vildagliptin[6] (EU approved 2007, marketed in the EU by Novartis as Galvus),
- Saxagliptin (FDA approved in 2009, marketed as Onglyza),
- Linagliptin (FDA approved in 2011, marketed as Tradjenta by Eli Lilly Co and Boehringer Ingelheim),[7]
- Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)[8]
- Teneligliptin (approved in Japan in 2012[9])
- Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company)
- Gemigliptin (being developed by LG Life Sciences)[10]
- Dutogliptin (being developed by Phenomix Corporation), Phase III[11]
Other chemicals which inhibit DDP4 include:
- Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.[12]
- Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.
Risks and side effects
Adverse effects, including nasopharyngitis, headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies.
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".[13] 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.[14] 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.[15]
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.[16][17]
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
- ↑ "FDA Approves New Treatment for Diabetes" (Press release). U.S. Food and Drug Administration. October 17, 2006. Retrieved 2006-10-17.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Banting and Best Diabetes Centre at UT sitagliptin
- ↑ Banting and Best Diabetes Centre at UT vildagliptin
- ↑ "FDA approves new treatment for Type 2 diabetes". Fda.gov. 2011-05-02. Retrieved 2013-04-15.
- ↑ http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf
- ↑ 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) - ↑ "LG Life Science". Lgls.com. Retrieved 2013-04-15.
- ↑ "Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM".
- ↑ "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.
- ↑ "IN RE: INCRETIN MIMETICS PRODUCTS LIABILITY LITIGATION" (PDF). USJP. United States Judicial Panel on Multidistric Litigation. August 26, 2013. Retrieved 2013-08-26.