Effective Acid Suppressors

Proton pump inhibitors (PPIs) are the most widely prescribed class of medications worldwide. Prescription PPIs, along with the availability of OTC PPIs, account for approximately $13 billion in global sales.¹ Due to their effective acid-suppressing effects, PPIs are approved for numerous indications, including short-term management of gastroesophageal reflux disease, erosive esophagitis, H pylori, and duodenal and gastric ulcers.² Long-term indications for PPIs include nonsteroidal anti-inflammatory drug–associated gastric ulcers, hypersecretory conditions, and maintenance of healing erosive esophagitis.² There are currently six prescription PPIs that vary in indication and four OTC PPI products indicated for the short-term management of heartburn experienced twice weekly. While this class of drug has a relatively favorable safety profile, recent observational studies have put the long-term use of PPIs into question.

PPIs Bind to Proton Pumps in the Stomach, Blocking Acid Production

PPIs work by irreversibly blocking the H+/K+ ATPase enzyme or the gastric proton pump, which is found within the parietal cells of the stomach and is the final step of acid production. The side-effect profile is mild, and the most common adverse reactions reported are headache, abdominal pain, nausea, diarrhea, vomiting, and flatulence.² Observational studies recently making headlines have questioned the long-term use of PPIs and their potential to cause a variety of serious adverse events. Some of these adverse events are already noted in the FDA-approved product information, such as Clostridium difficile–associated diarrhea (CDAD); increased risk of osteoporosis-related fractures of the hip, wrist, or spine; vitamin B₁₂ deficiency; hypomagnesemia; acute interstitial nephritis; and diminished antiplatelet activity of clopidogrel.² Additional proposed warnings that have come to light recently include dementia, cardiovascular events, and pneumonia. An increased gut pH level is one hypothesized mechanism for some of these adverse events. Decreasing gut acidity could potentially encourage the growth of other organisms, leading to infection, as in the case of CDAD and pneumonia, or reduce the absorption of certain nutrients.^3,4 It is proposed that vitamin B₁₂ deficiency may play a role in dementia-related effects, and calcium deficiency may be a cause for increased bone-fracture risk.⁴ While there are many drug interactions with this class of drug, inhibition of CYP2C19, specifically with antiplatelet drugs such as clopidogrel, is hypothesized to play a role in cardiac-related events.¹

Observational Studies and Risk of Long-Term Effects

While randomized, controlled studies are considered the gold standard study design and provide a cause-and-effect relationship, they are not always feasible or ethical. They also often exclude patients with comorbidities seen in clinical practice. An observational study is an epidemiological study that examines the causes, preventions, or treatments for a specific outcome. Although observational studies typically include patients representative of clinical practice, they can only establish or suggest associations to a specific outcome. Confounding factors or other causes for an outcome may show correlations where there are none. 

The literature recently making news headlines has focused on the use of PPIs and their link to dementia, kidney disease, and cardiac disease. Strengths and weaknesses have been identified in the recent literature, and only a potential association between PPIs and these adverse events has been concluded. Some of the concerns with these studies include the inability to control for all confounding factors, no dose-response relationship noted, only self-reported PPI use, and use of OTC PPIs. Observational studies, while beneficial, do not show causality, and even strong associations need to be further investigated before healthcare professionals change prescribing practices and alter instructions to patients.

Clinical Recommendations for Practitioners

The FDA has published a Drug Safety Communication document for three adverse events including CDAD, bone fractures, and hypomagnesemia.⁵ General recommendations from the FDA include prescribing the lowest PPI dose for the shortest duration of therapy, identifying those at higher risk for developing these adverse events, and reporting any adverse events to FDA MedWatch. The Beers Criteria were updated in 2015 to include PPIs and the potential risk of CDAD and bone fractures in the geriatric population. The American Gasteroenterologic Association recommends basing the decision to start maintenance PPI therapy on patients’ symptoms, quality of life, and risks versus benefits.⁶ Encourage lifestyle modifications that may reduce or eliminate the need for long-term PPI use. Based on the current literature, additional warnings to the current OTC PPI labeling are not warranted. With medical information being readily available to patients, it is important to educate them that further studies are required to examine the link between PPIs and adverse effects such as dementia, cardiac events, and kidney disease.

REFERENCES

1. Shah NH, et al. Proton pump inhibitor usage and the risk of myocardial infarction in the general population. PLoS ONE. 2015;10(6).
2. PPI product package inserts, various.
3. Johnson DA, Oldfield EC. Reported side effects and complications of long-term proton pump inhibitor use: dissecting the evidence. Clin Gastroenterol Hepatol. 2013;11(5):458-464.
4. Kerner DK, Wu Y. Adverse effects associated with long-term use of proton pump inhibitors. June 2016. https://spahp.creighton.edu/sites/spahp.creighton.edu/files/LTC Update June 2016.pdf.
5. FDA Drug Safety Communications. www.fda.gov/Drugs/DrugSafety/ucm199082.htm.
6. American Gastroenterological Association. www.gastro.org.

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