Proton pump inhibitors (PPI) are very widely used in society. Moreover, their use is often prolonged, lasting years if not decades. These agents have an important effect upon a fundamental biological mechanism: the transport of positively-charged ions across cell membranes. It is therefore a matter of great importance to investigate the potential risks of widespread and prolonged use of an agent with such a profound effect on the body’s metabolism.
It is already known, or at least frequent investigations have found, that, in addition to an increased risk of diarrhoea, there is an association between PPI use and all-cause mortality. A recent paper in the BMJ has investigated this matter further.[1] The study was based on a cohort of US Veterans. The investigators compared all-cause and specific-cause mortality in patients taking PPIs with those who were not, and also examined the strength of any association by duration of use. They also examined for possible reverse causality by looking at outcomes only after a considerable duration from the start of therapy. They examined for selection bias by comparing outcomes among people taking PPIs with those taking other medicines for upper abdominal symptoms.
The study replicated the findings of previous studies, confirming an association between PPI use and all-cause mortality. In fact there was an extra 45 deaths per thousand people taking PPIs (95% confidence interval 28.20–61.40). Kidney disease and cancer of the upper gastrointestinal tract were significantly increased. Risks increased in proportion to duration of use.
Of course, such an observational study cannot prove causality beyond all reasonable doubt. However, the finding that the results were not consistent with reverse causality and that they were unlikely to be due to selection bias, makes a causal explanation highly plausible. The increasing association of deaths with duration of use is of particular practical importance. Since the burden of evidence favours a causal explanation between increasing duration of use and risk of premature death, people taking these medicines should be weaned off them as soon as possible.
— Richard Lilford, CLAHRC WM Director
Reference:
- Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019; 365: l1580.