View source for Dipeptidyl peptidase-4 inhibitor/en

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{{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.

[[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]]), 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.

==Examples==
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 and Company]] and [[Boehringer Ingelheim]])
* [[Gemigliptin]] (approved in Korea in 2012, marketed by [[LG Chem|LG Life Sciences]]) Marketed as Zemiglo
* [[Anagliptin]] (approved in Japan as Suiny in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and [[Kowa (company)|Kowa Company, Ltd.]])
* [[Teneligliptin]] (approved in Japan as Tenelia in 2012)
* [[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, 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)
* [[Evogliptin]] (approved as Suganon/ Evodine for use in South Korea)
* [[Gosogliptin]] (approved as Saterex for use in Russia)
* [[Dutogliptin]] (PHX- 1149 free base, being developed by [[Phenomix Corporation]]), Phase III
* [[Retagliptin]] (SP-2086), approved in China.
*[[Denagliptin]]
* [[Cofrogliptin]] (HSK- 7653, compound 2)
* [[Fotagliptin]]
* [[Prusogliptin]]

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.

==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.

Adverse effects include 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. However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.

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.

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.

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.

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.

===Cancer===
In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin, 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.

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.

==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]].

== See also ==
* [[Development of dipeptidyl peptidase-4 inhibitors]]


{{Oral hypoglycemics}}
{{Enzyme inhibition}}

{{二次利用|date=1 February 2024}}
{{DEFAULTSORT:Dipeptidyl Peptidase-4 Inhibitor}}
[[Category:Dipeptidyl peptidase-4 inhibitors| ]]