Perils and Pitfalls of Long-term Effects of Proton Pump Inhibitors

Expert Commentary

There is widespread use of PPIs for a number of indications both in the inpatient and outpatient settings. While PPIs are generally considered safe and well tolerated, more serious adverse events have been reported. The risk of pneumonia was increased 27–39% in short-term use of PPIs in three meta-analyses. The use of PPIs is associated with CDI and appears to be dose related. Fractures and the impaired magnesium absorption associated with the use of PPIs have led the FDA to issue a warning regarding their use. Thrombocytopenia, iron deficiency, vitamin B12 deficiency, rhabdomyolysis and AIN have also been reported with the use of PPIs.

There are some limitations to the data in this review. Many of the adverse effects are relatively rare and are reported as cases and case series. In other literature, adverse effects are reported in cohort and case–control studies based on retrospective databases. Some of the studies adjusted for potential confounding factors are known to increase the risk of a particular adverse effect, while others do not. For example, in the studies assessing the risk of pneumonia, many trials adjust for risk factors of pneumonia such as alcohol use, underlying GERD and chronic obstructive pulmonary disease; however, the risk factors used varied from study to study. In addition, the risk of developing pneumonia with short-term PPI use may be attributed to a protopathic bias, wherein early signs of pneumonia may have been mistreated as GERD with PPIs. In the case of hip fracture risk, study results are conflicting. This may be secondary to the retrospective nature of the studies and using information from databases which may result in missing or incorrectly coded data. Missing data may not allow for adjustment for other confounding risk factors for fractures such as smoking history, alcohol intake, age, family history, height and weight, history of immobility, dizziness or falls and timing of PPI use in relation to worsening osteoporosis. The nature of the data used also makes it difficult to assess adherence to PPI therapy. Several reports discuss laboratory-based adverse effects (i.e., magnesium level, platelet count, B12 concentration) but do not relate these to clinical manifestations, which makes it difficult to determine the clinical significance of these effects. The published meta-analyses are based on small or retrospective studies and include heterogeneous patient populations with varied indications, duration and doses of PPIs. Most trials combined the different PPIs to assess adverse effects. Based on the available data, it is difficult to determine whether these adverse effects are due to a class effect of all PPIs or are specific to a particular PPI.

Although PPIs are most commonly associated with minor adverse effects such as headache, nausea, abdominal pain, flatulence and diarrhea, there is mounting evidence that they are associated with more serious adverse events. Practitioners need to be vigilant about such adverse effects and counsel patients accordingly and use PPIs only when indicated.