Elsevier

Therapies

Volume 73, Issue 3, May–June 2018, Pages 273-281
Therapies

Pharmacovigilance
Chronic use of proton pump inhibitors, adverse events and potential biological mechanisms: A translational analysis

https://doi.org/10.1016/j.therap.2017.08.003Get rights and content

Summary

Proton pump inhibitors (PPIs) are among the most frequently prescribed drugs. Even if PPI are usually considered as safe, there is a growing concern for a range of adverse effects of chronic PPI therapy often in the absence of appropriate indications. We propose, after a summary of renal, cardiovascular and neurological complications (dementia, chronic kidney disease, myocardial infarction and stroke), an integrative overview of the potential biological mechanisms involved. Eleven positive pharmacoepidemiological studies, mainly based on health insurance database linkage to hospital database, reported an increased risk of complications associated to PPI use and often a graded association suggesting also a possible dose-response relationship. Several mechanisms have been suggested through in vitro studies (endothelial dysfunction, endothelial senescence, hypomagnesemia, increase of chromogranin A levels, decrease of nitric oxide in endothelial cells) leading to the impairment of vascular homesostasis, paving the way to these complications. Evidence that PPIs may have off-targets and pleiotropic effects are mounting and may impose a cautious attitude in the prescription of PPI's, especially in elderly and/or in the context of chronic use.

Section snippets

Abbreviations

    ADMA

    asymmetrical dimethylarginine

    ARIC

    atherosclerosis risk in communities

    CANTAB

    CAmbridge Neuropsychological Test Automated Battery

    CgA

    chromogranin-A

    CKD

    chronic kidney disease

    DDAH

    dimethylarginine dimethylaminohydrolase

    DMSO

    dimethyl sulphoxide

    eGFR

    estimated glomerular filtration rate

    eNOS

    endothelial nitric oxyde synthaseGHS Geisinger health system

    GHS

    Geisinger health system

    iNOS

    inducible nitric oxyde synthase

    NO

    nitric oxide

    NOS

    nitric oxide synthase

    PPIs

    proton pump inhibitors

    PS

    propensity score

Conclusion

Even though in vivo studies are still required to understand and clarify the underlying mechanisms of such effects, the available fundamental and clinical data regarding drug safety should be considered. Actions should be undertaken particularly because these drug safety issues meet a body of evidence around the misuse and overprescribing of PPIs worldwide. As written by Lanas, even if the most of these adverse events have been mainly detected in observational studies, these potential adverse

Disclosure of interest

The authors declare that they have no competing interest.

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