The first agent of the class –
sitagliptin – was approved by the
FDA in 2006.[1]
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),[2][3][4] 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.[5]
Trelagliptin (approved for use in Japan as Zafatek/ Wedica in 2015)
Omarigliptin (MK-3102) (approved as Marizev in Japan in 2015,[12] 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[13])
Evogliptin (approved as Suganon/ Evodine for use in South Korea[14])
Berberine, an
alkaloid found in plants of the genus Berberis, inhibits dipeptidyl peptidase-4 which may at least partly explains its antihyperglycemic activity.[18]
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.[19]
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.[20] However, studies assessing risk of rheumatoid arthritis among DPP-4 inhibitor users have been inconclusive.[21]
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.[22]
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.[23]
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.[24]
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.[25]
Cancer
In response to a report of precancerous changes in the pancreases of rats and organ donors treated with the DPP-4 inhibitor sitagliptin,[26][27] 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.[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, was not able to completely exclude possible risk.[29]
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
hepaticglucose 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.