Dipeptidyl peptidase-4 inhibitor

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DPP-4 inhibitors and GLP-1

Inhibitors of dipeptidyl peptidase 4, also DPP-4 inhibitors or gliptins, are a class of oral hypoglycemics that block DPP-4 (DPP-IV). 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.

A 2018 meta analysis found no favorable effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality, myocardial infarction or stroke[5].

Examples[edit]

Drugs belonging to this class are:

Other chemicals which may inhibit DPP-4 include:

  • Berberine, an alkaloid found in plants of the genus Berberis, inhibits dipeptidyl peptidase-4 which may at least partly explains its antihyperglycemic activity.[17]

Adverse effects[edit]

In those taking sulphonylureas there is an increased risk of low blood sugar.[18]

Adverse effects, A7a including nasopharyngitis, headache, nausea, heart failure, hypersensitivity and skin reactions.

The U.S. Food and Drug Administration (FDA) is warning that the type 2 diabetes medicines like sitagliptin, saxagliptin, linagliptin, and alogliptin may cause joint pain that can be severe and disabling. FDA has added a new Warning and Precaution about this risk to the labels of all medicines in this drug class, called dipeptidyl peptidase-4 (DPP-4) inhibitors. [19] However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.[20]

A 2014 review found increased risk of heart failure with saxagliptin and alogliptin, prompting the FDA in 2016 to add warnings to the relevant drug labels.[21]

A 2018 meta analysis showed that use of DPP-4 inhibitors was associated with a 58% increased risk of developing acute pancreatitis compared with placebo or no treatment[22].

A 2018 observational study suggested an elevated risk of developing inflammatory bowel disease (specifically, ulcerative colitis), reaching a peak after three to four years of use and decreasing after more than four years of use.[23]

Cancer[edit]

In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin,[24][25] 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-4 inhibitors with pancreatic cancer. In a joint letter to the New England Journal of Medicine, the agencies stated that they had not yet reached a final conclusion regarding a possible causative relationship.[26]

A 2014 meta-analysis found no evidence for increased pancreatic cancer risk in people treated with DPP-4 inhibitors, but owing to the modest amount of data available, was not able to completely exclude possible risk.[27]

Combination drugs[edit]

Some of the DPP-4 inhibitor drugs have gotten approval from the FDA to be used with metformin concomitantly with additive effect to increase glucagon-like peptide 1 (GLP-1) which also decrease hepatic glucose production.[28]

See also[edit]

References[edit]

  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 154101Freely accessible. 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. ^ Zheng, Sean L.; Roddick, Alistair J.; Aghar-Jaffar, Rochan; Shun-Shin, Matthew J.; Francis, Darrel; Oliver, Nick; Meeran, Karim (17 April 2018). "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes". JAMA. 319 (15): 1580. doi:10.1001/jama.2018.3024. 
  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. ^ "LG Life Science". Lgls.com. Retrieved 2013-04-15. 
  10. ^ "Archived copy" (PDF). Archived from the original (PDF) on 2013-07-18. Retrieved 2013-08-07. 
  11. ^ Joanne Bronson; Amelia Black, T. G.; Murali Dhar; Bruce A. Ellsworth; J. Robert Merritt (2012). "Teneligliptin (Antidiabetic). To Market, To Market". Annual Reports in Medicinal Chemistry. 48: 523–524. doi:10.1016/b978-0-12-417150-3.00028-4. 
  12. ^ "Merck MARIZEV Once-Weekly DPP-4 Inhibitor For Type2 Diabetes Approved In Japan". NASDAQ. 28 September 2015. Retrieved 29 September 2015. 
  13. ^ "Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes". Retrieved 18 September 2015. 
  14. ^ "Dong-A ST's DPP4 inhibitor, SUGANON, got approved for type 2 diabetes in Korea". pipelinereview.com. October 2, 2015. 
  15. ^ "SatRx LLC Announces First Registration in Russia of SatRx (gosogliptin), an Innovative Drug for Treatment of Type 2 Diabetes" (Press release). SatRx LLC. 
  16. ^ "Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/
  17. ^ 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. 
  18. ^ Salvo, Francesco; Moore, Nicholas; Arnaud, Mickael; Robinson, Philip; Raschi, Emanuel; De Ponti, Fabrizio; Bégaud, Bernard; Pariente, Antoine (3 May 2016). "Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis". BMJ. 353: i2231. doi:10.1136/bmj.i2231. PMC 4854021Freely accessible. PMID 27142267. 
  19. ^ "DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain". FDA. 2015-08-28. Retrieved 1 September 2015. 
  20. ^ Kathe, Niranjan; Shah, Anuj; Said, Qayyim; Painter, Jacob T. (2018-02-01). "DPP-4 Inhibitor-Induced Rheumatoid Arthritis Among Diabetics: A Nested Case–Control Study". Diabetes Therapy. 9 (1): 141–151. doi:10.1007/s13300-017-0353-5. ISSN 1869-6953. 
  21. ^ Diabetes Meds Containing Saxagliptin and Alogliptin Linked to Increased HF. April 2016
  22. ^ Zheng, Sean L.; Roddick, Alistair J.; Aghar-Jaffar, Rochan; Shun-Shin, Matthew J.; Francis, Darrel; Oliver, Nick; Meeran, Karim (17 April 2018). "Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes". JAMA. 319 (15): 1580. doi:10.1001/jama.2018.3024. 
  23. ^ Abrahami, Devin; Douros, Antonios; Yin, Hui; Yu, Oriana Hoi Yun; Renoux, Christel; Bitton, Alain; Azoulay, Laurent (2018-03-21). "Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study". BMJ. 360: k872. doi:10.1136/bmj.k872. ISSN 0959-8138. PMID 29563098. 
  24. ^ 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 2699878Freely accessible. PMID 19403868. 
  25. ^ Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC (July 2013). "Marked expansion of exocrine 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. PMC 3712065Freely accessible. PMID 23524641. 
  26. ^ "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM". 
  27. ^ Monami M, Dicembrini I, Mannucci E (January 2014). "Dipeptidyl peptidase-4 inhibitors pancreatitis risk: a meta-analysis of randomized clinical trials". Diabetes Obes Metab. 16 (1): 48–56. doi:10.1111/dom.12176. PMID 23837679. 
  28. ^ Tatjana Ábel. "A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors" (PDF). Retrieved November 23, 2015.