Risk of Proton Pump Inhibitor–Induced Mild Hyponatremia in Older Adults

Abstract

To the Editor: The incidence of hyponatremia, a side effect that can result from using proton pump inhibitors (PPIs), is unknown in elderly adults. A prospective clinical study of individuals with suspected drug-induced moderate hyponatremia was recently conducted; 47% of the population was being treated with PPIs, indicating that the risk of PPI-induced hyponatremia is significant in elderly adults (≥65).1 This was a retrospective study. The main objective was to determine the incidence of hyponatremia in the elderly population being treated with PPIs; other objectives were to determine the odds ratio of PPI inducing hyponatremia, the relationship between PPI dose and occurrence of hyponatremia, and risk of hyponatremia in association with other medications. The incidence of hyponatremia in individuals who had been taking PPIs for at least 1 year was compared with that in a control group of individuals who had not been exposed to PPIs. Hyponatremia risk factors, except drugs known to induce hyponatremia, were exclusion criteria. The study included individuals in a unit of a general hospital admitted during 2011. Of 302 individuals analyzed, 145 were included. Twenty-four (16.6%) had moderate hyponatremia, and 48 (33.1%) had been taking PPIs for longer than 1 year, 31.3% of whom (95% confidence interval (CI) = 18.7–46.3%) had moderate hyponatremia, versus 9.3% (95% CI = 14.3–16.9%) in the rest of the population (OR = 4.4, 95% CI = 1.8–11.1, P = .001). The relationship between dose and occurrence of hyponatremia was not significant (coefficient of determination = 0.05, P = .74). Individuals taking PPIs and tramadol had a significantly higher risk of having hyponatremia than those taking neither (OR = 7.7, 95% CI = 1.9–31.2). Table 1 describes the relationship between hyponatremia, medication use, and potentiation in association with PPIs. The results are expressed as incidence of hyponatremia and the number of affected subjects for each drug or each drug combined with PPIs. In the literature, cases of hyponatremia in conjunction with PPI use have been reported without reporting the incidence rate.2 Moreover, hyponatremia is described as a rare event in PPI product information (<0.1%).3 Between 18.7% and 46.3% of elderly PPI users had hyponatremia in the current study. This study demonstrates that the chronic use of PPIs increases the risk of hyponatremia in older adults. This could be a result of their antidiuretic activity or the potentiation of the reactive antidiuretic hormone secretion.2 The association between PPIs and tramadol also appears to potentiate the risk of hyponatremia. Risk of hyponatremia with tramadol has been described in the literature.4 This combination is frequently administered to elderly adults and requires further study. Drugs are an underestimated cause of hyponatremia in elderly adults.5 Moderate hyponatremia significantly increases morbidity, for example, by increasing the risk of falls and fractures, and increases the risk of osteoporosis. It is also a predictor of death, myocardial infarction, and longer duration of hospitalization in elderly adults.6, 7 The effectiveness of PPIs and their safety has led to their widespread use. The known potential consequences of chronic use of PPIs include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, which causes rebound acid hypersecretion. PPI use is also a risk factor for Clostridium difficile enteritis, pneumonia, nutritional deficiencies, and interactions with antiplatelet agents.8 Although PPI moderate hyponatremia is an unknown effect, more fractures are being reported. It may be that episodes of hyponatremia potentiate these events by causing attention deficits, with a higher incidence of falls causing fractures, which adds to the direct effect on bone remodeling.9, 10 Thus, the literature suggests a need for a benefit: risk balance assessment amended by the latest knowledge of pharmacovigilance, and the current study confirms the potential adverse effects of PPI use in the elderly population. PPIs are commonly administered to elderly adults: 33% in the current study. The extensive use of PPIs in elderly adults is often the result of a lack of therapeutic reevaluation or requests from the individual to avoid treatment interruption. PPIs must be discontinued when the risk-benefit balance becomes unfavorable. Reassessment of the prescription is useful, particularly because a recent study has shown that hyponatremia is reversible; the reduction of drugs that may induce hyponatremia was associated with significant clinical improvement.1 Future prospective studies that include follow-up laboratory results for comparisons of pre- and post-PPI therapy would be optimal and informative. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Buon, Peyro Saint Paul: acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript. Gaillard, Fedrizzi, Mosquet, Coquerel: analysis and interpretation of data, preparation of manuscript. Martin: acquisition of subjects, analysis and interpretation of data, and preparation of manuscript. Sponsor's Role: No sponsor.