Dipeptidyl peptidase-4 inhibitor

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 2014 meta analysis found no favorable or harmful effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality, or stroke, but a marginally statistically significant increase in heart failure.^[5]

Examples

Drugs belonging to this class are:

• Sitagliptin^[6] (FDA approved 2006, marketed by Merck & Co. as Januvia)
• Vildagliptin^[7] (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 and Company and Boehringer Ingelheim)^[8]
• Gemigliptin (approved in Korea in 2012, marketed by LG Life Sciences)^[9]
• Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.)^[10]
• Teneligliptin (approved in Japan in 2012^[11])
• Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company)
• Trelagliptin (approved for use in Japan in 2015)
• Dutogliptin (being developed by Phenomix Corporation), Phase III^[12]
• Omarigliptin (MK-3102) (approved in Japan in 2015,^[13] developed by Merck & Co.; research showed that omarigliptin can be used as once-weekly treatment and generally well-tolerated throughout the base and extension studies^[14])

Other chemicals which inhibit DPP-4 include:

• Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.^[15]
• Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.

Adverse effects

Adverse effects, including nasopharyngitis, headache, nausea, heart failure, hypersensitivity and skin reactions. They may cause severe joint pain.^[16] In those taking sulphonylureas there is an increased risk of low blood sugar.^[17]

Cancer

In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin,^[18][19] 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.^[20]

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.^[21]

Other

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.^[22]

Combination drugs

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.^[23]

See also

• Development of dipeptidyl peptidase-4 inhibitors

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. 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. 32: 147–58. doi:10.1111/1755-5922.12075. PMID 24750644.
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. http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf
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. "Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/
13. "Merck MARIZEV Once-Weekly DPP-4 Inhibitor For Type2 Diabetes Approved In Japan". NASDAQ. 28 September 2015. Retrieved 29 September 2015.
14. "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.
15. 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.
16. "DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain". FDA. 2015-08-28. Retrieved 1 September 2015.
17. 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 4854021. PMID 27142267.
18. 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.
19. 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 3712065. PMID 23524641.
20. "Pancreatic Safety of Incretin-Based Drugs — FDA and EMA Assessment — NEJM".
21. 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.
22. Diabetes Meds Containing Saxagliptin and Alogliptin Linked to Increased HF. April 2016
23. Tatjana Ábel. "A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors" (PDF). Retrieved November 23, 2015.