A fresh look at proton pump inhibitor (PPI)-associated adverse events through a CYP2C19 pharmacogenetic lens.

Since their introduction in 1980s, proton pump inhibitors (PPI) heralded a sweeping change in the management of acidrelated disorders. Their efficacy and ease to obtain have led to common use of PPIs. Perhaps a direct consequence of decreasing stomach acidity, appreciation of the wide-ranging physiologic functions of low stomach pH increased; functions such asfacilitation of vitamin and mineral absorption and suppression of enteric infections. Incidental and recurrent Clostridioides difficile infections cause significant morbidity, but pneumonia and exacerbation of hepatic encephalopathy have also been reported with both shortand long-term PPI use. With chronic use, unopposed hypergastrinemia, gastric atrophy, and bacterial overgrowth have been associated with an increased incidence of gastric cancer [1]. Additionally, idiosyncratic reactions unrelated to their pharmacotherapeutic profile have also been reported, notably interstitial nephritis (IN). Media attention and litigation followed hard to replicate and often conflicting PPI side effect evidence [2] in nested case–control studies, retrospective observational studies (including studies based on secondary use of administrative health databases), and their meta-analysis. These studies show a spectrum of risks associated with PPI use and are beset by limitations inherent to the study population. Long-term PPI use, for example, is more common among older individuals with multiple confounding comorbidities and polypharmacy (directly relevant to C. difficile and IN risk, respectively). Limitations also exist in the study methodology, including cohort definition [3] with respect to dose and duration of PPI use, compounded by difficulties in finding precisely matching controls not treated with PPIs. With the results of these pharmacoepidemiology studies conflicting, prescribers and patients are left with the same question: Are the results of big data analysis a true risk signal or noise? We do not advocate that PPIs be used without consideration of consequences, rather that further prospective studies are needed to measure risk and provide mechanistic insights for adverse effects (AE). Until then, a rational approach to begin is to stratify the available AE data by the patients’ phenotype for cytochrome P450 (CYP) 2C19, the hepatic enzyme responsible for PPI drug metabolism.