Drug-drug interactions of empagliflozin and dapagliflozin

Abstract Introduction The sodium glucose co-transporter2-inhibitors dapagliflozin (Dapa) and empagliflozin (Empa), initially developed as antihyperglycemic agents, are increasingly also prescribed for non-diabetic patients with heart failure (HF). Glucuronidation by uridine-diphosphate glucuronosyltransferase (UGT)1A9 is the main mechanism of metabolism of Dapa, whereas Empa is eliminated mainly by excretion. Both Dapa and Empa are substrates of P-glycoprotein. The risk for drug-drug interactions (DDI) of Empa and Dapa is assumed to be low. Aim of this study was to summarize reports of DDI of Empa and Dapa from the literature. Methods Search-terms in PubMed were "drug-drug interaction" and AND "sodium glucose co-transporter2-inhibitors" OR "SGLT2" OR "dapagliflozin" OR "empagliflozin". The drugs were classified according the Anatomical Therapeutic Chemical (ATC) system. Included were randomized trials, pharmacovigilance studies, case series, case reports, studies in healthy subjects and in vivo data. The funding of the study and the disclosures of the authors were registered. Results In 45 reports DDI of Empa and Dapa with 29 drugs were described (Table). According to the ATC system, these were drugs for the alimentary tract and metabolism (n=5), blood and blood forming organs (n=2), cardiovascular system (n=11), genitourinary system and sex hormones (n=2), antiinfectives (n=2), antineoplastic and immunomodulating agents (n=3), musculo-skeletal system (n=2) and nervous system (n=2). The reports comprised studies in healthy subjects (n=28), case reports (n=7), case series (n=6), pharmacovigilance studies (n=2), a subgroup analysis of a randomized trial (n=1) and in vivo data (n=1). Most of the reports found no clinically relevant DDI (n=32). Dapa and Empa both had a synergistic diuretic effect with bumetanide, and led to severe infections when combined with the interleukin-17-inhibitors secukinumab or ixekizumab. Empa administered with intravenous iron was reported to increase cell-iron availability, with lithium to reduce lithium exposure and with valproate to increase valproate exposure. Dapa administered with sacubitril-valsartan was reported to lead to severe hypotension, with linezolid to pancytopenia, with donafenib to an increased exposure to donafenib, with rifampicin to a reduction and mefenamic acid to an increase in Dapa exposure. Of the 45 reports, 33 were funded by a pharmaceutical company marketing Dapa or Empa and 33 had authors with conflicts of interest with pharmaceutical companies marketing Dapa or Empa. Conclusions Most data about DDI of Empa and Dapa derive from studies in healthy subjects and from the marketing companies. The clinical relevance DDI of Empa and Dapa in polymorbid patients with polymedication is largely unknown. There is an urgent need for independent studies on DDI of these drugs in diabetic and non-diabetic patients with HF.Table