Inhibitors of dipeptidyl peptidase 4 (DPP-4 inhibitors or gliptins) are a class of oral hypoglycemics that 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 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 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 Life Sciences) Marketed as Zemiglo Anagliptin (approved in Japan in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and Kowa Company, Ltd.) Teneligliptin (approved in Japan in 2012) Alogliptin (FDA approved 2013, marketed by Takeda Pharmaceutical Company) Trelagliptin (approved for use in Japan in 2015) Omarigliptin (MK-3102) (approved 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 for use in South Korea) Gosogliptin (approved for use in Russia) Dutogliptin (being developed by Phenomix Corporation), Phase III 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 sulphonylureas, there is an increased risk of 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