The Growing Dark Side of Proton Pump Inhibiting Drugs

There are other options!

The methods used to study and approve drugs often do not have the sensitivity to predict complications that may occur with the longer-term use of many drugs.  These complications will typically not become apparent for a decade or so.  As we get well out past a decade of use with the most common class of drugs to limit stomach acid production, proton pump inhibitors or PPIs, the list of complications continues to grow.

Prior to the last 2 years the established list of adverse events associated with long-term PPI use included:

·         IBS

·         Intestinal clostridia infection

·         Gut yeast infection

·         Pneumonia

·         Neuropathy

·         Magnesium deficiency

·         Osteopenia/osteoporosis

Over the past few years several potentially more serious adverse effects have been seen.   These more recently understood adverse effects are even more alarming given their strong potential impact of quality of life and mortality.  These newer associated effects include:

Stroke  -  Results of a new study were presented at the annual scientific meeting of the American Heart Association.  Higher dose PPI long-term use was associated with a 70% risk of ischemic stroke.  The researchers presenting this study data conclude that “Physicians should encourage more cautious use of PPIs”.  They extended these conclusions to a special concern about PPI use in the United States where several of the PPIs associated with the risk are available without a prescription over-the-counter (OTC).

These complications are thought to be the result of their reduction in nitric oxide synthase levels, an enzyme needed for healthy relaxation of blood vessel walls.  This opens the understanding of another recently associated adverse effect, cardiovascular events such as heart attack.

Cardiovascular events  -  A just published study in the journal Neurogastroenterology and Motility (2016) reviewed all of the data from the previous 17 research trials involving 1750 subjects.  The analysis found that patients using a PPI had a mean increase in cardiovascular events of 70%, strikingly similar to the increase in stroke risk.  Use of one particular PPI was associated with a 217% increased risk which is particularly of concern as it is perhaps the most commonly used OTC drug.  The longest users of any PPI were also at greater risk than the group as a whole with a 133% increased risk.

Chronic kidney disease  -  A study just published in JAMA Internal Medicine collected data from 2 large population studies involving over 250,000 adults looking at PPI use and the risk of chronic kidney disease.  Any use was associated with between 24% and 45% increased risk over the 12-year study period.  Higher use was associated with increased risk of 46% to 76%.

Dementia  -  A new study published in JAMA Neurology looked at the association between PPI use and subsequent dementia risk in a population of over 74,000 older adults.  Those using PPIs had a 44% increased risk of dementia.  Given this huge problem in aging populations the researchers concluded, “The avoidance of PPI medication may prevent the development of dementia.”  Part of the impetus for looking at this association was the observation in other research that the use of these drugs in laboratory animals was found to increase β-amyloid deposits in the brain.  β-amyloid is a toxic protein that is a major contributor to brain cell degeneration in Alzheimer’s and dementia.

The mechanisms by which PPIs increase this risk is not fully understood, but it is thought to be associated with:

·         PPIs are known to lower B12 and other B vitamin absorption.  These vitamins are needed for brain cell normal function.

·         PPIs enter the brain intact and have been shown to alter the function of the enzymes that are involved in β-amyloid production breakdown.

Other solutions

This growing and frightening list of concerns about PPI use should cause a paradigm shift – a new way of looking at the whole problem of dyspepsia or indigestion.  Perhaps the first area to look at is the overuse of these drugs.  Reflux, indigestion and related symptoms are often not coming from over-production of stomach acid.  There are several lines of research supporting this. They include:

·         40-50% of those taking the drugs do not have good symptom resolution.

·         Studies of prescribing find that 50% of patient’s receiving a PPI do not meet published guidelines for appropriate use.

·         There are several known triggers of reflux symptoms such as food sensitivities which can be resolved by eliminating the problem.

·         Finding a solution should begin with an accurate assessment of the problem.  Most PPIs are prescribed solely on the basis of symptoms.  Even when an endoscopic exam is done and found to be normal, the institution of PPI therapy is then just symptom based.

The Heidelberg GastricpH Test is ideally suited to truly evaluate upper digestive tract acidity.  The test uses a telemetry capsule to transmit pH signals to a receiver which is placed over the stomach. The capsule is swallowed with water, and once it reaches the stomach it sends pH readings to the receiver on the surface of the stomach.  The capsule is tethered to a piece of surgical thread to hold it in the stomach preventing it from quickly passing into the small intestine.  This allows stomach pH readings to be taken repeatedly over the 1-2 hours needed for the test.

A more in-depth description of the test can be found at the link above.  When this test is combined with a thorough history and evaluation, the source of reflux/indigestion can be found and targeted corrective therapy can be used.  The broad use of PPIs as is the norm now will continue to be looked at with greater caution as the research about the long-term effects evolves.  Quick relief today may come at a great cost down the road.