Glucagon increasesblood glucose levels, and DPP-4 inhibitors reduce glucagon and blood glucose levels. The mechanism of DPP-4 inhibitors is to increaseincretin levels (GLP-1 andGIP),[2][3][4] which inhibitglucagon release, which in turn increasesinsulin secretion, decreases gastric emptying, and decreasesblood glucose levels.
A 2018meta-analysis found no favorable effect of DPP-4 inhibitors on all-cause mortality, cardiovascular mortality,myocardial infarction orstroke in patients with type 2 diabetes.[5]
Trelagliptin (approved for use in Japan as Zafatek/Wedica in 2015)
Omarigliptin (MK-3102; approved as Marizev in Japan in 2015,[12] having been developed byMerck & Co. In November 2015, Sheu and colleagues[13] showed that omarigliptin could be used once-weekly and was generally well tolerated throughout the base and extension studies)
Evogliptin (approved as Suganon/Evodine for use in South Korea)[14]
Berberine, analkaloid found in plants of the genusBerberis (the "barberry"), inhibits DPP-4, which may at least partly explains the chemical's antihyperglycemic activity.[18]
In individuals already takingsulphonylureas, use of DPP-4-class medications concurrently increases their risk for low blood sugar events relative to those on sulphonylureas alone.[19]
In late August 2015, the US FDA issued a warning that drugs likesitagliptin,saxagliptin,linagliptin,alogliptin, and other DPP-4 inhibitors could cause joint pain that can be severe and disabling.[20] However, studies assessing risk ofrheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.[21] A 2014 review found that the use of saxagliptin and alogliptin increased individuals' risk of developingheart failure, leading the FDA to add warnings to the labels of these drugs in 2016.[22] A 2018meta-analysis indicated that the use of DPP-4 inhibitors was associated with a 58% increased risk of developingacute pancreatitis compared to placebo or no treatment.[23] Additionally, a 2018observational study suggested an elevated risk of developinginflammatory bowel disease, specificallyulcerative colitis, which peaked after three to four years of use and decreased after more than four years.[24] Finally, a 2020Cochrane systematic review found insufficient evidence to suggest thatmetformin monotherapy reduced all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal myocardial infarction, non-fatal stroke, or end-stage renal disease when compared to DPP-4 inhibitors for the treatment of type 2 diabetes.[25]
In response to a report ofprecancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin,[26][27] the US 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 withpancreatic cancer. In a joint letter to theNew England Journal of Medicine, the agencies stated that they had not yet reached a final conclusion regarding a possible causative relationship.[28] 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, the authors were unable to completely exclude possibly increased risk.[29]
Some DPP-4 inhibitor drugs have received approval from the FDA to be used withmetformin concomitantly with additive effect to increase the level of glucagon-like peptide 1 (GLP-1) which also decreaseshepaticglucose production.[citation needed]
^McIntosh CH, Demuth HU, Pospisilik JA, Pederson R (June 2005). "Dipeptidyl peptidase IV inhibitors: how do they work as new antidiabetic agents?".Regulatory Peptides.128 (2):159–65.doi:10.1016/j.regpep.2004.06.001.PMID15780435.S2CID9151210.
^Monami M, Dicembrini I, Mannucci E (January 2014). "Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials".Diabetes, Obesity & Metabolism.16 (1):48–56.doi:10.1111/dom.12176.PMID23837679.S2CID7642027.
