Tejas P. Desai, MD

Gerry Gajadharsingh writes:

“Proton pump inhibitors (PPIs) are a very commonly prescribed drug (also available over the counter), for symptoms such as Gastro Oesophageal Reflux Disease (GORD). Used, in the short term, they can certainly give symptom relief in many patients. I read an article several years ago, after they first appeared, suggesting that they should not really be used long term. Obviously, this was not read by patients nor some of their prescribers, as many patients seem to have taken them long term. Like many drugs taken long term, there will be a consequence, some of the adverse effects from PPI’s are now being realised. Many clinicians also notice an adverse effect on magnesium levels, an important mineral that the body needs for many of its systems to work properly.

 I suppose the elephant in the room is why not give patients appropriate nutritional advice, so that they don’t need to take them in the first place? This depends on the nutritional advice that is given! The main food group that I have found to be implicated with reflux in patients is wheat and wheat-based products. Please note this is not the same as Gluten. Too many people are currently avoiding gluten, unnecessarily.

 Also remember that the gastro-oesophageal valve (part of the thoracic diaphragm) is the junction that closes off the stomach from the oesophagus. When our diaphragm doesn’t work properly, this can allow this valve not to work properly, allowing leaking of stomach acid into the oesophagus, hence the classic symptoms of retrosternal pain.

 Which is why learning good breathing behaviour and avoid wheat-based products can often help.

 The research below focused on US veterans, in a 2-year period 215,000 were prescribed a PPI or a H2-receptor antagonists (H2RAs). That’s a lot of veterans, I wonder what they were eating?

 Further analyses revealed that three specific aetiologias were associated with mortality in the setting of chronic PPI use: cardiovascular disease, upper gastrointestinal cancers, and…wait for it….. Chronic kidney disease.

They were followed up for 10 years, it’s not clear if they continued with the PPI’s or H2RA’s and it was an observational study, not the gold standard randomised control studies that medicine is so fond of. So, the advice is to continue monitoring their use.”


 Proton pump inhibitors (PPIs) are ubiquitous in-patient medication lists, whether prescribed alone or as part of a cocktail to treat many upper gastrointestinal disorders. A variety of adverse renal effects have been associated with chronic PPI use, and these drugs have been blamed for episodes of acute kidney injury and progression of chronic kidney disease. It is no surprise then that some researchers have pondered whether chronic PPI use can contribute to the ultimate adverse effect in medicine: death.

PPIs Versus H2RAs and Mortality

Using the Department of Veterans Affairs national healthcare database of military veterans, Al-Aly and colleagues analysed the use of PPI’s and their counterparts, H2-receptor antagonists (H2RAs), to see whether there was any association with increased mortality. Their retrospective database study, however, is different from most, in that they incorporated several adjustments articulated by Hernan and Robins by which large observational studies can emulate (not replace) a large randomized trial.

From 2002 to 2004, nearly 215,000 veterans were prescribed either a PPI or an H2RA in a ratio of about 3:1, respectively. Researchers followed their course for 10 years and identified their cause of death in one of nine organ-specific categories. Using a variety of statistical models, the researchers measured the association of PPI and H2RA use with each cause of death. Once a statistically significant finding was identified, they delved further to identify aetiologies.

Their analyses show a slightly higher mortality rate of almost 38% in the group prescribed a PPI, compared with 37% for the entire cohort and just under 36% for H2RA users. Four causes of mortality were associated with PPI use: circulatory system, genitourinary system, and oncologic and infectious diseases. Further analyses revealed that three specific aetiologias were associated with mortality in the setting of chronic PPI use: cardiovascular disease, upper gastrointestinal cancers, and…wait for if. Chronic kidney disease.

Is the PPI to Blame?

How do we interpret these results? I would caution against any rash decision-making based on an observational study. Despite using sophisticated techniques to emulate a large clinical trial, database studies remain hypothesis-generating, in my opinion. We live in a time where big data sets are plentiful and ripe for a variety of analyses. Still, they cannot replace a slowly and rigorously conducted randomized trial.

For now, this study as well as others emphasize the need for continued re-evaluation of PPI use. Not all patients require chronic PPI therapy. As adverse renal effects continue to be reported, de-escalation measures should be implemented whenever possible.