Table 2 Concerns about long-term therapy with proton pump inhibitors (PPIs): Extra-digestive effects

Infectious consequences of long-term PPI-induced hypochlorhydria

• More and higher quality studies are needed to confirm or refute any causal link with community-acquired pneumonia, especially in long-term users [471, 472]

Bone consequences of long-term PPI therapy

• PPI use is not associated with accelerated bone mineral density loss or osteoporosis [473], which are thought to be the underlying biological explanation for the modest increase in the risk of bone fracture [474–476]

Dementia and Alzheimer’s disease

• Although, in a mouse model, very high-dose PPI use increased the level of β-amyloid in the brain [477], human data linking these drugs to development of dementia are conflicting [478, 479]

• The risk of development of Alzheimer’s disease in PPI users appears comparable to that of any incident dementia [480]

Delirium

• PPIs were found to be an independent factor associated with development of delirium in geriatric inpatients [481], likely reflecting poly-pharmacy and drug-to-drug interactions (DDIs)

Acute myocardial infarction (AMI)

• Since PPIs do not impair endothelial function [482], more and higher quality studies, which have to be free from confounders [483], are needed to confirm [484, 485] or refute [277, 278, 408] any causal link with AMI

Idiosyncratic reactions to PPIs

• PPIs appear to be the most common cause of drug-induced acute interstitial nephritis (AIN). After PPI withdrawal and corticosteroid therapy, almost all patients recovered a normal renal function [486, 487]

• There is a small but definite increase in risk of chronic kidney disease in long-term PPI users, likely resulting from undiagnosed or residual PPI-induced AIN [487]

• Polymyositis and other myopathies, including the life-threatening condition of rhabdomyolysis, have been described with all PPIs [488, 489]

• Immediate and delayed hypersensitivity to PPIs, with cross reactivity amongst the members of the class, has been described [490]

PPI-drug interactions

• Acid suppression reduces absorption of levothyroxine, ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, and dipyridamole while increasing that of nifedipine, digoxin, and alendronate [400]

• Concomitant use of some PPIs with clopidogrel attenuates the antiplatelet effect of clopidogrel, but may not be clinically relevant since there are no clinical differences in the risk for major adverse CV events [401–403]

• Only a few drug interactions (e.g., with diazepam, warfarin, phenytoin, and methotrexate) involving PPIs (mainly omeprazole and lansoprazole) are of clinical significance [401, 403]

• DDIs may be more frequent in some patient populations (e.g., AIDS or cancer) [403]

• The degree of DDIs associated with PPIs and the respective clinical outcomes depend on different factors such as genotype status of CYP enzymes, ethnicity, and drug regimen [403–405]