Suspected Adverse Drug Reactions of the Type 2 Antidiabetic Drug Class Dipeptidyl-Peptidase IV inhibitors (DPP4i): Can polypharmacology help explain?

Abstract

To interpret the relationship between the polypharmacology of dipeptidyl-peptidase IV inhibitors (DPP4i) and their suspected adverse drug reaction (ADR) profiles using a national registry. A retrospective investigation into the suspected ADR profile of four licensed DPP4i in the United Kingdom using the National MHRA Yellow Card Scheme and OpenPrescribing databases. Experimental data from the ChEMBL database alongside physiochemical (PC) and pharmacokinetic (PK) profiles were extracted and interpreted. DPP4i show limited polypharmacology alongside low suspected ADR rates. We found minimal statistical difference between the unique ADR profiles ascribed to the DPP4i except for total ADRs (χ2; p <.05). Alogliptin consistently showed the highest suspected ADR rate per 1,000,000 items prescribed. Saxagliptin showed the lowest suspected ADR rate across all organ classes but did not reach statistical difference (χ2; p >.05). We also confirmed the Phase III clinical trial data that showed gastrointestinal and skin reactions are the most reported ADR across the class and postulated underlying mechanisms for this based on possible drug interactions. We have proposed underlying mechanisms behind the reported suspected ADRs and their polypharmacology. The main pharmacological mechanism behind the ADRs is attributed to interactions with DPP4 activity and/or structure homologue (DASH) proteins which augment the immune-inflammatory modulation of DPP4.