View source for Dipeptidyl peptidase-4 inhibitor

{{Short description|Enzyme blocker and diabetes treatment drug}}
[[Image:Incretins and DPP 4 inhibitors.svg|thumb|300px|right|DPP-4 inhibitors and GLP-1]]
'''Inhibitors of dipeptidyl peptidase 4''' ('''DPP-4 inhibitors''' or '''gliptins''') are a class of [[oral hypoglycemic]]s that [[Enzyme inhibitors|block]] the [[enzyme]] [[dipeptidyl peptidase-4]] (DPP-4). They can be used to treat [[diabetes mellitus type 2]].
The first agent of the class – [[sitagliptin]] – was approved by the [[U.S. Food and Drug Administration|FDA]] in 2006.<ref name=FDAapproval>{{cite press release  | title = FDA Approves New Treatment for Diabetes  | publisher = U.S. Food and Drug Administration  | date = October 17, 2006  | url = https://www.fda.gov/bbs/topics/NEWS/2006/NEW01492.html  | access-date = 2006-10-17 }}</ref>
[[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 [[gastric inhibitory polypeptide|GIP]]),<ref name="pmid15780435">{{cite journal | vauthors = McIntosh CH, Demuth HU, Pospisilik JA, Pederson R | title = Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents? | journal = Regulatory Peptides | volume = 128 | issue = 2 | pages = 159–65 | date = June 2005 | pmid = 15780435 | doi = 10.1016/j.regpep.2004.06.001 | s2cid = 9151210 }}</ref><ref name="pmid12697069">{{cite journal | vauthors = Behme MT, Dupré J, McDonald TJ | title = Glucagon-like peptide 1 improved glycemic control in type 1 diabetes | journal = BMC Endocrine Disorders | volume = 3 | issue = 1 | pages = 3 | date = April 2003 | pmid = 12697069 | pmc = 154101 | doi = 10.1186/1472-6823-3-3 | doi-access = free }}</ref><ref name="pmid7789625">{{cite journal | vauthors = Dupre J, Behme MT, Hramiak IM, McFarlane P, Williamson MP, Zabel P, McDonald TJ | title = Glucagon-like peptide I reduces postprandial glycemic excursions in IDDM | journal = Diabetes | volume = 44 | issue = 6 | pages = 626–30 | date = June 1995 | pmid = 7789625 | doi = 10.2337/diabetes.44.6.626 }}</ref> 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]] in patients with type 2 diabetes.<ref>{{cite journal | vauthors = Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K | title = 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: A Systematic Review and Meta-analysis | journal = JAMA | volume = 319 | issue = 15 | pages = 1580–1591 | date = April 2018 | pmid = 29677303 | pmc = 5933330 | doi = 10.1001/jama.2018.3024 }}</ref>
==Examples==
Drugs belonging to this class are:
* [[Sitagliptin]]<ref>{{UTGlucagon|sitagliptin}}</ref> (FDA approved 2006, marketed by [[Merck & Co.]] as [[Januvia]])
* [[Vildagliptin]]<ref>{{UTGlucagon|vildagliptin}}</ref> (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]])<ref>{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm253501.htm |title=FDA approves new treatment for Type 2 diabetes |publisher=Fda.gov |date=2011-05-02 |access-date=2013-04-15}}</ref>
* [[Gemigliptin]] (approved in Korea in 2012, marketed by [[LG Chem|LG Life Sciences]])<ref>{{cite web |url=http://www.lgls.com/rd/pipeline.jsp |title=LG Life Science |publisher=Lgls.com |access-date=2013-04-15 |archive-url=https://web.archive.org/web/20130906063308/http://www.lgls.com/rd/pipeline.jsp |archive-date=2013-09-06 |url-status=dead }}</ref> Marketed as Zemiglo
* [[Anagliptin]] (approved in Japan as Suiny in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and [[Kowa (company)|Kowa Company, Ltd.]])<ref>{{cite web |url=http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf |title=New Drugs Approved in FY 2012  |access-date=2013-08-07 |url-status=dead |archive-url=https://web.archive.org/web/20130718002132/http://www.pmda.go.jp/english/service/pdf/list/NewdrugsFY2012.pdf |archive-date=2013-07-18 }}</ref>
* [[Teneligliptin]] (approved in Japan as Tenelia in 2012<ref>{{cite book | vauthors = Bronson J, Black A, Dhar TM, Ellsworth BA, Merritt JR | title = Teneligliptin (Antidiabetic). To Market, To Market | journal = Annual Reports in Medicinal Chemistry | volume = 48 | pages = 523–524  |year = 2012 | doi=10.1016/b978-0-12-417150-3.00028-4| isbn = 9780124171503 }}</ref>)
* [[Alogliptin]] (FDA approved 2013 as Nesina/ Vipidia, marketed by [[Takeda Pharmaceutical Company]])
* [[Trelagliptin]] (approved for use in Japan as Zafatek/ Wedica in 2015)
* [[Omarigliptin]] (MK-3102) (approved as Marizev in Japan in 2015,<ref>{{cite web|url=http://www.nasdaq.com/article/merck-marizevonceweekly-dpp4-inhibitor-for-type2-diabetes-approved-in-japan-20150928-00333|title=Merck MARIZEV Once-Weekly DPP-4 Inhibitor For Type2 Diabetes Approved In Japan|date=28 September 2015|publisher = NASDAQ|access-date=29 September 2015}}</ref> 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<ref name="omarigliptin_research">{{cite journal | vauthors = Sheu WH, Gantz I, Chen M, Suryawanshi S, Mirza A, Goldstein BJ, Kaufman KD, Engel SS | display-authors = 6 | title = Safety and Efficacy of Omarigliptin (MK-3102), a Novel Once-Weekly DPP-4 Inhibitor for the Treatment of Patients With Type 2 Diabetes | journal = Diabetes Care | volume = 38 | issue = 11 | pages = 2106–14 | date = November 2015 | pmid = 26310692 | doi = 10.2337/dc15-0109 | doi-access = free }}</ref>)
* [[Evogliptin]] (approved as Suganon/ Evodine for use in South Korea<ref>{{Cite news | title = Dong-A ST's DPP4 inhibitor, SUGANON, got approved for type 2 diabetes in Korea | date = October 2, 2015 | url = https://www.pipelinereview.com/index.php/2015100259148/Small-Molecules/Dong-A-STs-DPP4-inhibitor-SUGANON-got-approved-for-type-2-diabetes-in-Korea.html | publisher = pipelinereview.com}}</ref>)
* [[Gosogliptin]] (approved as Saterex for use in Russia<ref>{{cite press release | url = https://www.prnewswire.com/news-releases/satrx-llc-announces-first-registration-in-russia-of-satrx-gosogliptin-an-innovative-drug-for-treatment-of-type-2-diabetes-300281578.html | title = SatRx LLC Announces First Registration in Russia of SatRx (gosogliptin), an Innovative Drug for Treatment of Type 2 Diabetes | publisher = SatRx LLC}}</ref>)
* [[Dutogliptin]] (PHX- 1149 free base, being developed by [[Phenomix Corporation]]), Phase III<ref>"Forest Splits With Phenomix", San Diego Business Journal, Tuesday, April 20, 2010 http://www.sdbj.com/news/2010/apr/20/forest-splits-phenomix/</ref>
* [[Neogliptin]]<ref>{{cite journal | vauthors = Maslov IO, Zinevich TV, Kirichenko OG, Trukhan MV, Shorshnev SV, Tuaeva NO, Gureev MA, Dahlén AD, Porozov YB, Schiöth HB, Trukhan VM | title = Design, Synthesis and Biological Evaluation of Neogliptin, a Novel 2-Azabicyclo[2.2.1]heptane-Based Inhibitor of Dipeptidyl Peptidase-4 (DPP-4) | journal = Pharmaceuticals | volume = 15 | issue = 3 | pages = 273 | date = February 2022 | pmid = 35337071 | doi = 10.3390/ph15030273 | doi-access = free | pmc = 8949241 }}</ref>
* [[Retagliptin]] (SP-2086), approved in China.
* [[Denagliptin]]
* [[Cofrogliptin]] (HSK- 7653, compound 2)
* [[Fotagliptin]]
* [[Prusogliptin]]
* [[Cetagliptin]]/[[CGT 8012]]
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.<ref>{{cite journal | vauthors = Al-masri IM, Mohammad MK, Tahaa MO | title = Inhibition of dipeptidyl peptidase IV (DPP IV) is one of the mechanisms explaining the hypoglycemic effect of berberine | journal = Journal of Enzyme Inhibition and Medicinal Chemistry | volume = 24 | issue = 5 | pages = 1061–6 | date = October 2009 | pmid = 19640223 | doi = 10.1080/14756360802610761 | s2cid = 25517996 | doi-access = free }}</ref>
==Adverse effects==
In those already taking [[sulphonylurea]]s, there is an increased risk of [[hypoglycemia|low blood sugar]] when taking a medicine in the DPP-4 drug class.<ref>{{cite journal | vauthors = Salvo F, Moore N, Arnaud M, Robinson P, Raschi E, De Ponti F, Bégaud B, Pariente A | display-authors = 6 | title = Addition of dipeptidyl peptidase-4 inhibitors to sulphonylureas and risk of hypoglycaemia: systematic review and meta-analysis | journal = BMJ | volume = 353 | pages = i2231 | date = May 2016 | pmid = 27142267 | pmc = 4854021 | doi = 10.1136/bmj.i2231 }}</ref>
Adverse effects include nasopharyngitis, [[headache]], [[nausea]], [[heart failure]], hypersensitivity and skin reactions. {{cn|date=January 2025}}
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.<ref>{{cite web|title=DPP-4 Inhibitors for Type 2 Diabetes: Drug Safety Communication - May Cause Severe Joint Pain|url=https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm460238.htm|website=FDA|access-date=1 September 2015|date=2015-08-28}}</ref> However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.<ref>{{cite journal | vauthors = Kathe N, Shah A, Said Q, Painter JT | title = DPP-4 Inhibitor-Induced Rheumatoid Arthritis Among Diabetics: A Nested Case-Control Study | journal = Diabetes Therapy | volume = 9 | issue = 1 | pages = 141–151 | date = February 2018 | pmid = 29236221 | pmc = 5801239 | doi = 10.1007/s13300-017-0353-5 }}</ref>
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.<ref>{{cite web | url = http://www.pharmacypracticenews.com/Policy/Article/04-16/Diabetes-Meds-Containing-Saxagliptin-and-Alogliptin-Linked-to-Increased-HF/35964/ses=ogst | title = Diabetes Meds Containing Saxagliptin and Alogliptin Linked to Increased HF | date = April 2016 | work = Pharmacy Practice News }}</ref>
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.<ref>{{cite journal | vauthors = Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K | title = 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: A Systematic Review and Meta-analysis | journal = JAMA | volume = 319 | issue = 15 | pages = 1580–1591 | date = April 2018 | pmid = 29677303 | pmc = 5933330 | doi = 10.1001/jama.2018.3024 }}</ref>
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.<ref>{{cite journal | vauthors = Abrahami D, Douros A, Yin H, Yu OH, Renoux C, Bitton A, Azoulay L | title = Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study | journal = BMJ | volume = 360 | pages = k872 | date = March 2018 | pmid = 29563098 | pmc = 5861502 | doi = 10.1136/bmj.k872 }}</ref>
A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal [[myocardial infarction]], non-fatal [[stroke]] or [[Chronic kidney disease|end-stage renal disease]] when comparing [[metformin]] monotherapy to dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.<ref>{{cite journal | vauthors = Gnesin F, Thuesen AC, Kähler LK, Madsbad S, Hemmingsen B | title = Metformin monotherapy for adults with type 2 diabetes mellitus | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 6 | pages = CD012906 | date = June 2020 | pmid = 32501595 | pmc = 7386876 | doi = 10.1002/14651858.CD012906.pub2 | collaboration = Cochrane Metabolic and Endocrine Disorders Group }}</ref>
===Cancer===
In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin,<ref>{{cite journal | vauthors = Matveyenko AV, Dry S, Cox HI, Moshtaghian A, Gurlo T, Galasso R, Butler AE, Butler PC | display-authors = 6 | title = Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin | journal = Diabetes | volume = 58 | issue = 7 | pages = 1604–15 | date = July 2009 | pmid = 19403868 | pmc = 2699878 | doi = 10.2337/db09-0058 }}</ref><ref>{{cite journal | vauthors = Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC | title = 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 | journal = Diabetes | volume = 62 | issue = 7 | pages = 2595–604 | date = July 2013 | pmid = 23524641 | pmc = 3712065 | doi = 10.2337/db12-1686 }}</ref> 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.<ref>{{cite journal | vauthors = Egan AG, Blind E, Dunder K, de Graeff PA, Hummer BT, Bourcier T, Rosebraugh C | title = Pancreatic safety of incretin-based drugs--FDA and EMA assessment | journal = The New England Journal of Medicine | volume = 370 | issue = 9 | pages = 794–7 | date = February 2014 | pmid = 24571751 | doi = 10.1056/NEJMp1314078 | doi-access = free }}</ref>
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.<ref>{{cite journal | vauthors = Monami M, Dicembrini I, Mannucci E | title = Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials | journal = Diabetes, Obesity & Metabolism | volume = 16 | issue = 1 | pages = 48–56 | date = January 2014 | pmid = 23837679 | doi = 10.1111/dom.12176 | s2cid = 7642027 }}</ref>
==Combination drugs==
Some DPP-4 inhibitor drugs have received approval from the FDA to be used with [[metformin]] concomitantly with additive effect to increase the level of glucagon-like peptide 1 (GLP-1) which also decreases [[hepatic]] [[gluconeogenesis|glucose production]].{{citation needed|date=November 2019}}
== See also ==
* [[Development of dipeptidyl peptidase-4 inhibitors]]
== References ==
{{Reflist|32em}}
{{Oral hypoglycemics}}
{{Enzyme inhibition}}
{{DEFAULTSORT:Dipeptidyl Peptidase-4 Inhibitor}}
[[Category:Dipeptidyl peptidase-4 inhibitors| ]]