Proton-pump inhibitors (PPIs) seem benign enough—they’ve been available over-the-counter for years for treating heartburn and gastric acid reflux—but emerging evidence indicates that these popular drugs may harbour untoward effects. 

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First approved in 1989, PPIs work by decreasing the production of gastric acid via irreversibly binding the hydrogen/potassium ATPase found on the surface of gastric parietal cells. Currently, they are one of the most popularly prescribed drug classes. PPIs are generally considered safe when taken as directed, which is typically once daily for 14 days, with no more than three such courses of treatment per year. The problem is that many consumers take them indefinitely, either unaware or indifferent to the adverse effects of these drugs used long term. 

The following are some evidence-based links between PPI use and pathology. These associations are a mix of causative and possibly causative.

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Vitamin B12 deficiency

In a large case-control study published in JAMA, Kaiser Permanente researchers found that patients who took PPIs for 2 or more years were more likely to experience vitamin B12 deficiency, and doses of more than 1.5 pills per day were more strongly linked with the condition than doses of less than 0.75 pills per day. Untreated vitamin B12 deficiency can lead to dementia, neurologic damage, anemia, and other complications.

Gastric acid is needed to release vitamin B12 from dietary proteins for terminal-ileum absorption. However, vitamin B12 levels are not routinely monitored in people taking PPIs.

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Hypomagnesemia

Low magnesium levels can lead to muscle spasm, arrhythmias, and convulsions. Treatment for hypomagnesemia involves magnesium supplements. But these don’t always reverse hypomagnesemia in patients who continue long-term use of PPIs. 

The threat of hypomagnesemia in those taking PPIs prompted the FDA to issue a warning in 2011.

“Proton pump inhibitor (PPI) drugs may cause low serum magnesium levels (hypomagnesemia) if taken for prolonged periods of time (in most cases, longer than one year),” the FDA wrote. “In approximately one-quarter of the cases reviewed, magnesium supplementation alone did not improve low serum magnesium levels and the PPI had to be discontinued.”

Importantly, because over-the-counter PPIs are formulated at lower doses, the risk of hypomagnesemia for a 14-day course up to three times a year is likely low, according to the FDA. However, prescription PPIs, which can be taken for 180 days at a higher dose, can lead to magnesium deficits.

The FDA warned,

“Healthcare professionals should consider obtaining serum magnesium levels prior to initiation of prescription PPI treatment in patients expected to be on these drugs for long periods of time, as well as patients who take PPIs with medications such as digoxin, diuretics or drugs that may cause hypomagnesemia. For patients taking digoxin...this is especially important because low magnesium can increase the likelihood of serious side effects. Healthcare professionals should consider obtaining magnesium levels periodically in these patients.”

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Bone fractures

Although the underpinnings remain to be elucidated, several studies have demonstrated a correlation between high-dose/long-term PPI use and fracture risk.

In a large retrospective cohort study published in Nature, Taiwanese researchers found that patients with type 2 diabetes who used PPIs long-term, regardless of dose, exhibited a 40% greater risk of hip fracture compared with non-users with type 2 diabetes.

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Deadly diarrhea

PPIs may be linked to an increased risk of Clostridium difficile infection, which has high morbidity and mortality. Consider a diagnosis of C. diff in patients taking PPIs who develop diarrhea that fails to resolve, along with symptoms of abdominal pain and fever, the FDA stressed, adding that PPIs should be discontinued posthaste.

The FDA also recommended that the lowest dose and shortest duration of PPI therapy be used, and adverse events involving PPIs should be reported to the FDA MedWatch program.

The link between C. diff infection and acid-reducing PPIs could be due to the possibility of a vegetative form of C. diff that survives the resulting alkaline environment. In addition, 1 to 2 months of PPI therapy may alter the gut microbiome enough to predispose patients to develop C. difficile infection. 

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Kidney disease

Research has linked PPIs to chronic kidney disease (CKD) and acute kidney injury (AKI). Authors of a review article published in Mayo Clinic Proceedings cited various disconcerting findings from different studies. For instance, after adjusting for covariates, PPI users had a 50% greater risk of developing CKD than non-users, with a 3.3% increase in absolute risk during a 10-year period. Similarly, PPI users also had a 64% increase in AKI risk. Other research has indicated that the risk is higher in those taking PPIs twice a day compared with those taking the drugs once a day.

“Based on the results of these studies, initiation and cumulative use of PPIs have been associated with risk for kidney disease,” the authors wrote. “No recommendations have been proposed for monitoring kidney function in patients receiving long-term PPI therapy, irrespective of dose. We believe that until this association is better clarified, it is reasonable to monitor estimated glomerular filtration rate annually, based on CKD guidelines for monitoring patients taking potentially nephrotoxic medications.”

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Bottom line

PPI use has been linked to increased risk of various conditions based mostly on retrospective observational studies. Granted, many of these studies are limited by covariates, bias, and lack of causality. Moreover, most relative risks are only mild to moderate—ranging from 1 to 2—and absolute risks are low. Nevertheless, physicians should approach the long-term or frequent use of these drugs with care.

The authors of the review put it best:

“Based on current recommendations, the American Gastroenterological Association does not recommend routine laboratory monitoring or use of supplemental calcium, vitamin B12, and magnesium in patients taking PPIs daily. However, as this story evolves, our current practice is to check creatinine levels yearly, complete blood cell counts every other year, and vitamin B12 levels every 5 years in patients receiving long-term PPI therapy.” 

They concluded that,

“The best strategy is to prescribe PPIs at the lowest dose on a short-term basis when appropriately indicated so that the potential benefits outweigh any adverse effects associated with the use of PPIs.”

This story is contributed by Naveed Saleh and is a part of our Global Content Initiative, where we feature selected stories from our Global network which we believe would be most useful and informative to our doctor members.