Dipeptidyl peptidase-4 inhibitor
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), which inhibit glucagon release, which in turn increases insulin secretion, decreases gastric emptying, and decreases blood glucose levels.
Drugs belonging to this class are :
- Sitagliptin (FDA approved 2006, marketed by Merck & Co. as Januvia),
- Vildagliptin (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),
- Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)
- Teneligliptin (approved in Japan in 2012)
- Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company)
- Gemigliptin (being developed by LG Life Sciences)
- Dutogliptin (being developed by Phenomix Corporation), Phase III
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.
- Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.
Risks and side effects
Long-term effects of DPP-4 inhibitors on mortality and morbidity are so far inconclusive, although adverse effects, including nasopharyngitis, headache, nausea, hypersensitivity and skin reactions, have been observed in clinical studies. Consistent with this FDA approval of Novartis' DPP-4 inhibitor vildagliptin (Galvus®) was delayed because of skin lesions with blistering observed in nonhuman primate toxicology studies; One year later, Novartis CEO Dan Vasella remained uncertain as to their ability to ever file to market the drug in the United States. Other possible adverse effects, including hypersensitivity reactions and pancreatitis, have been reported. These effects may relate to DPP-4's function in restricting the inflammatory actions of the chemokine CCL11/eotaxin, so that inhibiting DPP-4 might unleash the recruitment of inflammatory cells.
An in vitro study found that DPP-4 inhibitors, together with GLP-2, increased proliferation and migration of colon cancer cells, which might encourage cancer cells to metastasize,
Dr. Peter C. Butler, Chief of Endocrinology at UCLA and former editor of Diabetes, the flagship journal of the American Diabetes Association, studied the DPP-4 inhibitor "Januvia" and "found worrisome changes in the pancreases of the rats that could lead to pancreatic cancer". His follow-up studies now threaten the future of not only Januvia but all the drugs in its class (DPP-4 inhibitors). There are currently more than 100 lawsuits representing 575 plaintiffs around the country are claiming injury from the GLP-1 agonist, Byetta, according to the latest quarterly regulatory filing from Bristol-Myers. Forty-three suits claim that another DPP-4 inhibitor, Januvia, caused pancreatic cancer, according to Merck. Dr. Butler and colleagues found far more cases of pancreatitis and pancreatic cancer reported for the [DPP-4 inhibitor] drugs than for Avandia. In Dr. Butler’s study of human pancreases obtained from 34 organ donors who had died for reasons unrelated to pancreatic disease, seven of the donors happened to have taken Januvia and one had taken Byetta. the pancreases of those eight people tended to have more precancerous lesions than the organs of the diabetics who had not taken those drugs, or those of the nondiabetics. There was also one case of a neuroendocrine tumor, a type of pancreatic cancer. Also, the pancreases of the incretin drug users were heavier, with faster growth of certain cells. “There were strange growths” that “you’d never see in a normal human pancreas,” Dr. Alexandra Butler said.
A 2013 study showed roughly a doubling of the risk of acute pancreatitis among a group of users of the DPP-4 inhibitor sitagliptin and GLP-1 agonist exenatide. A recent study however concluded that the benefits of GLP-1 based therapy far outweigh the risks.
In March 2013, the FDA issued a Drug Safety Communication announcing investigations into DDP-4 inhibitors due to findings by academic researchers that could lead to new warnings and possible removal from the market if the findings are confirmed. A few weeks later, the European Medicines Agency launched a similar investigation into GLP-1 agonists and DPP-4 inhibitors that could lead to similar warnings, restrictions or removals from market.
In August 2013, a federal judiciary panel approved the consolidation of dozens of lawsuits against manufacturers of DPP-4 inhibitors before a judge in U.S. District Court in San Diego. Claims involving allegations of pancreatitis, pancreatic cancer and other side effects attributed to the use of Januvia, Janumet, Byetta and Victoza will continue to be eligible for review. The U.S. Judicial Panel on Multidistrict Litigation in its order described the common allegations: “Plaintiffs in all actions allege that the use of one or more of four anti-diabetic incretin based medications – Janumet (sitagliptin combined with metformin), Januvia (sitagliptin), Byetta (exenatide) and Victoza (liraglutide) – caused them or their decedent to develop pancreatic cancer,” the panel said. The order referenced the March 2013 FDA study announcement that included the drugs exenatide (Byetta, Bydureon), liraglutide (Victoza), sitagliptin (Januvia, Janumet, Janumet XR, Juvisync), saxagliptin (Onglyza, Kombiglyze XR), alogliptin (Nesina, Kazano, Oseni), and linagliptin (Tradjenta, Jentadueto).
- 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.
- "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.
- Joanne Bronson, Amelia Black, T. G. Murali Dhar, Bruce A. Ellsworth, and J. Robert Merritt. To Market, To Market - 2012. "Teneligliptin (Antidiabetic)". Annual Reports in Medicinal Chemistry 48: 523–524.
- "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.
- "The FDA's Decision on Galvus". Seeking Alpha. February 28, 2007. Retrieved 2011-09-19.
- Goldstein, Jacob (January 17, 2008). "Novartis Diabetes Drug May Never Be Sold in U.S.". Wall Street Journal Health Blog. Wall Street Journal. Retrieved 2011-09-19. "“It’s on the cards, that we won’t refile, but it’s also on the cards that we will,” [Novartis CEO Dan Vasella] said, according to Dow Jones Newswires. “But what is certainly clear, is that refiling without new data makes no sense.""
- "Dipeptidyl peptidase-4 inhibitors (‘gliptins’) for type 2 diabetes mellitus". NPS RADAR. August 1, 2010. Retrieved August 6, 2010.
- Forssmann, Ulf; Stoetzer, Carsten; Stephan, Michael; Kruschinski, Carsten; Skripuletz, Thomas; Schade, Jutta; Schmiedl, Andreas; Pabst, Reinhard et al. (2008). "Inhibition of CD26/Dipeptidyl Peptidase IV Enhances CCL11/Eotaxin-Mediated Recruitment of Eosinophils In Vivo". Journal of Immunology 181 (2): 1120–7. PMID 18606664.
- Masur, K; Schwartz, F; Entschladen, F; Niggemann, B; Zaenker, K (2006). "DPPIV inhibitors extend GLP-2 mediated tumour promoting effects on intestinal cancer cells". Regulatory Peptides 137 (3): 147–55. doi:10.1016/j.regpep.2006.07.003. PMID 16908079.
- Pollack, Andrew (May 30, 2013). "A Lone Voice Raises Alarms on Lucrative Diabetes Drugs". New York Times Business Day. The New York Times Company. Retrieved 2013-05-30.
- Singh, Sonal (February 25, 2013). "Glucagonlike Peptide 1–Based Therapies and Risk of Hospitalization for Acute Pancreatitis in Type 2 Diabetes Mellitus". JAMA Internal Medicine. American Medical Association. Retrieved 2013-02-25.
- "FDA investigating reports of possible increased risk of pancreatitis and pre-cancerous findings of the pancreas from incretin mimetic drugs for type 2 diabetes". FDA. U.S. Food and Drug Administration. March 3, 2013. Retrieved 2013-03-14.
- "European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes". EMA. European Medicines Agency Sciences Medicines Health. March 26, 2013. Retrieved 2013-03-26.
- "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". USJP. United States Judicial Panel on Multidistric Litigation. August 26, 2013. Retrieved 2013-08-26.