Dipeptidyl peptidase-4 inhibitor
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 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.
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 inhibit DPP-4 include:
- Berberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its antihyperglycemic activity.
- Lupeol, found in mango, red alder (Alnus rubra), and dandelion coffee.
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. 
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.
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.
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