Dipeptidyl peptidase-4 inhibitor



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 as Suiny in 2012, marketed by Sanwa Kagaku Kenkyusho Co., Ltd. and 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
 * Neogliptin
 * 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 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 (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 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 glucose production.