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 antidiabetic drugs 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.

Medical uses[edit]

In patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c, in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight and minimal hypoglycaemic risk.

Increased unit cost, which largely exceeds that of the older drugs, and uncertainty about their long term safety, however, should also be considered.[5]

A recent meta analysis found no favorable or harmful effect of DPPIV inhibitors on all-cause mortality, cardiovascular mortality, or stroke, but a marginally statistically significant increase in heart failure.[6]

Risks and side effects[edit]

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

The risk of hypoglycaemia was low with DPP-4 inhibitor treatment compared to placebo and compared to sulphonylureas in the absence of sulphonylurea or insulin co-therapy, but as part of a combination therapy with a sulphonylurea or insulin, the risk of hypoglycaemia is elevated with sitagliptin or linagliptin.[7]

Treatment with DPP-4 inhibitors was associated with a small but significant increase in nervous system disorders compared to placebo (mainly headache and dizziness). There was also a 1.5-fold risk of asthenia associated with vildagliptin or linagliptin treatment.[7]

Heart failure[edit]

A tendency for increased risk of cardiac and vascular disorders was detected when comparing certain gliptin treatments to placebo, but statistical significance was marginal. The long-term safety is still a subject of debate.[7] The trial SAVOR-TIMI 53 trial saxagliptin versus placebo found no significant difference in the composite endpoint of cardiovascular death, MI, or ischemic stroke. However, there was a significant excess in hospitalization for heart failure in the saxagliptin group. A similar signal, albeit not significant and in a sicker patient population, was found in the EXAMINE trial with alogliptin. A 2014 meta analysis found a marginally statistically significant increase in heart failure.[8]The FDA is conducting an investigation of this possible risk.[9]

Pancreatitis and pancreas cancer risk[edit]

There was an increased relative risk reported to the FDA with sitagliptin versus other comparators, but reporting bias could not be excluded. In rather short-term clinical trials with well-selected diabetic patients, no increased risk of acute pancreatitis has been observed with any of the five commercialized DPP-4 inhibitors.[10] 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".[11] A report of 8 human pancreases obtained post-mortem showed considerable pancreatic enlargement in some instances, with a 40% increase overall, most with use of sitagliptin.[12] Other experts conclude animal and human studies indicate that there could be a connection between incretin-based therapies and pancreatitis, pancreatic cancer, thyroid cancer and other neoplasms. Therefore whenever such therapy is started it would be wise to proceed with caution, especially if personal history of neoplasms is present.[13]

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-4 inhibitors and GLP1 agonists 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 (DPP4) 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."[14]

A systematic review found data from randomised controlled trials were not adequate to assess the risk of pancreatitis from incretins, but several large observational studies, with methodological limitations, provided relatively precise estimates. Among five observational studies, only one case-control study suggested an increased risk of admissions for acute pancreatitis. The available evidence suggested that the incidence of pancreatitis in patients with type 2 diabetes taking incretins was low and that incretins did not increase risk of pancreatitis. They stated also the current body evidence, however, was not definitive and more carefully designed and conducted observational studies were needed.[15]

Products[edit]

Drugs belonging to this class are :

Other chemicals which inhibit DDP4 include:

See also[edit]

Further reading[edit]

  • 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[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 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. ^ Karagiannis, T.; Paschos, P.; Paletas, K.; Matthews, D. R.; Tsapas, A. (12 March 2012). "Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis". BMJ 344 (mar12 1): e1369–e1369. doi:10.1136/bmj.e1369. 
  6. ^ Wu S, Hopper I, Skiba M, Krum H (April 2014). "Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: Meta-analysis of randomized clinical trials with 55,141 participants". Cardiovasc Ther. doi:10.1111/1755-5922.12075. PMID 24750644. 
  7. ^ a b c Gooßen, K.; Gräber, S. (May 2012). "Longer term safety of dipeptidyl peptidase-4 inhibitors in patients with type 2 diabetes mellitus: systematic review and meta-analysis". Diabetes, Obesity and Metabolism: no–no. doi:10.1111/j.1463-1326.2012.01610.x. 
  8. ^ Wu S, Hopper I, Skiba M, Krum H (April 2014). "Dipeptidyl peptidase-4 inhibitors and cardiovascular outcomes: Meta-analysis of randomized clinical trials with 55,141 participants". Cardiovasc Ther. doi:10.1111/1755-5922.12075. PMID 24750644. 
  9. ^ Lusten, Harry. "FDA Investigating Heart Failure Risk Linked To Onglyza". Forbes. Retrieved 9 April 2014. 
  10. ^ Scheen, Andre (July 2013). "Gliptins (dipeptidyl peptidase-4 inhibitors) and risk of acute pancreatitis". Expert Opinion on Drug Safety 12 (4): 545–557. doi:10.1517/14740338.2013.793671. 
  11. ^ 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. 
  12. ^ Butler, AE; Campbell-Thompson, M; Gurlo, T; Dawson, DW; Atkinson, M; Butler, PC (Jul 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/db13-0996. PMID 23524641. 
  13. ^ Labuzek, K; Kozłowski, M; Szkudłapski, D; Sikorska, P; Kozłowska, M; Okopień, B (Apr 2013). "Incretin-based therapies in the treatment of type 2 diabetes--more than meets the eye?". European journal of internal medicine 24 (3): 207–12. doi:10.1016/j.ejim.2013.01.009. PMID 23375875. 
  14. ^ Egan, Amy G.; Blind, Eberhard; Dunder, Kristina; de Graeff, Pieter A.; Hummer, B. Timothy; Bourcier, Todd; Rosebraugh, Curtis (27 February 2014). "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment". New England Journal of Medicine 370 (9): 794–797. doi:10.1056/NEJMp1314078. 
  15. ^ Li, L.; Shen, J.; Bala, M. M.; Busse, J. W.; Ebrahim, S.; Vandvik, P. O.; Rios, L. P.; Malaga, G.; Wong, E.; Sohani, Z.; Guyatt, G. H.; Sun, X. (15 April 2014). "Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies". BMJ 348 (apr15 2): g2366–g2366. doi:10.1136/bmj.g2366. 
  16. ^ Banting and Best Diabetes Centre at UT sitagliptin
  17. ^ Banting and Best Diabetes Centre at UT vildagliptin
  18. ^ "FDA approves new treatment for Type 2 diabetes". Fda.gov. 2011-05-02. Retrieved 2013-04-15. 
  19. ^ http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf
  20. ^ 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. doi:10.1016/b978-0-12-417150-3.00028-4. 
  21. ^ "LG Life Science". Lgls.com. Retrieved 2013-04-15. 
  22. ^ "Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/
  23. ^ >Tesfaye Biftu, Ranabir Sinha-Roy, Ping Chen, Xiaoxia Qian, Dennis Feng, Jeffrey T. Kuethe, Giovanna Scapin, Ying Duo Gao, Youwei Yan, Davida Krueger, Annette Bak, George Eiermann, Jiafang He, Jason Cox, Jacqueline Hicks, Kathy Lyons, Huaibing He, Gino Salituro, Sharon Tong,Sangita Patel, George Doss, Aleksandr Petrov, Joseph Wu, Shiyao Sherrie Xu, Charles Sewall, Xiaoping Zhang, Bei Zhang, Nancy A. Thornberry, and Ann E. Weber (2014). "Omarigliptin (MK-3102): A Novel Long-Acting DPP‑4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes". Journal of Medicinal Chemistry 57: 3205−3212. doi:10.1021/jm401992e. 
  24. ^ 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.