Proton Pump Inhibitors: How Safe Are They?

Proton pump inhibitors (also called PPIs) debuted in the 1990s and have since become one of the most commonly prescribed medicines, with about 113 million prescriptions filled each year worldwide.

In the United States alone, where they are the third top-selling medication, more than 20 million people use proton pump inhibitors, and the number of proton pump inhibitors prescribed annually has increased dramatically in the past couple of decades, especially among older people.

The demand for proton pump inhibitors is driven mostly by the need to control symptoms in the growing population of people with gastroesophageal reflux disease (GERD). The drugs’ ongoing popularity may also stem from the prevailing belief that proton pump inhibitors have few side effects.

However, increasing evidence suggests proton pump inhibitors may not be as benign as people think, over time. Associations have been found between proton pump inhibitors use and a number of medical problems, such as low bone density and an increased risk of fracture in the wrist, hip, and spine; reduced levels of the crucial minerals magnesium and calcium; and an increased risk for Clostridium difficile infection, which can cause diarrhea and illness severe enough to require hospitalization.

Adding to the evidence, a few recently published studies have found associations between proton pump inhibitor use and the risk of kidney disease, dementia, and heart attack.

It's important to note, however, that while each of the studies found an association between proton pump inhibitor use and an increased risk of the disease or condition examined, none were able to show that proton pump inhibitors actually cause the conditions.

What the science says

• Kidney disease. In a study published in JAMA Internal Medicine in February 2016, researchers from a number of U.S. centers analyzed data on 10,482 adults, ages 45 to 64. Their aim was to identify risk factors for chronic kidney disease, or CKD, with an eye on overused medications in particular.

They hypothesized that proton pump inhibitor use would be a risk factor for chronic kidney disease. They also hypothesized that taking another type of GERD medication called a histamine H2-receptor antagonist (H2 blocker), such as Pepcid AC or Zantac, would not increase the risk for chronic kidney disease.

The researchers collected information on age, weight, race, socioeconomic status, tobacco use, blood pressure, diabetes, hypertension, cardiovascular disease, and other characteristics. In addition to considering proton pump inhibitor and H2 blocker use, they took into account other medications people might be taking, such as statins, aspirin, and antihypertension drugs.

The study, which reviewed records from 1996 to 2011, found that of 322 people who used proton pump inhibitors from the beginning, 56 experienced a chronic kidney disease event (about 17 percent) compared with 1,224 of the 9,204 non-proton pump inhibitor users (about 13 percent). The researchers determined that the chronic kidney disease risk was 1.45 times higher in proton pump inhibitor users, and concluded that proton pump inhibitor use was associated with a 20 to 50 percent higher risk of chronic kidney disease than found in the average population.

They found a comparable association in a validation cohort—a group of similar, but separate individuals—of nearly 250,000 people. H2 blocker use, however, was not associated with an increased risk of chronic kidney disease in either group. The researchers concluded that proton pump inhibitor use itself may be a risk factor for kidney disease.

• Dementia. Past research has suggested that proton pump inhibitors may affect cognition, possibly by causing a B12 deficiency, which has been linked with cognitive decline; by crossing the blood-brain barrier to have some effect on the brain; and by affecting certain enzymes that influence cognitive function.

In a study published in JAMA in April 2016, researchers in Germany analyzed data on 73,679 people age 75 or older in an endeavor to investigate the effect of proton pump inhibitor use on cognition. All participants were free of dementia at the onset of the study, which ran from 2004 to 2011.

Subjects were considered proton pump inhibitor users if they had at least one prescription written per quarter for a proton pump inhibitor—but not if they took this type of drug only occasionally. During the study period, 29,510 patients were diagnosed with some form of dementia including Alzheimer’s disease or vascular dementia; about 31 percent were diagnosed with unspecified dementia.

The researchers observed consistent proton pump inhibitor use in 2,950 subjects. They estimated the risk of dementia to be 1.44 times higher in proton pump inhibitor users than in nonusers, and noted that the correlation was more pronounced in men.

Interestingly, although the incidence of dementia generally increases with age, the risk of proton pump inhibitor-associated dementia in this study was highest in people 75 to 79 years old, and decreased with age.

The researchers acknowledged that it is not yet clear why proton pump inhibitors would play a role in the development of dementia, and that their study points only to an association, not a direct cause. Nonetheless, they suggest that avoiding PPIs might help prevent dementia.

• Heart attack. People who take blood thinners after coronary procedures are often prescribed proton pump inhibitors to reduce the risk of gastrointestinal bleeding. This practice prevents bleeding but may reduce the effects of antiplatelet medications, specifically in people who take clopidogrel (Plavix), and according to some small studies, contributed to an increased risk for cardiovascular events.

Some studies have found an association between proton pump inhibitor use and cardiovascular problems in people at high risk for adverse cardiovascular events who do not take clopidogrel, and at least one prior study found that this risk extends to people with no history of cardiovascular problems.

In a study published in PLOS ONE in June 2015, researchers used multiple data sources to review information on 2.9 million people to investigate the hypothesis that proton pump inhibitors might increase the risk of adverse cardiovascular events in the general population. They examined proton pump inhibitor use and H2 blocker use, and found that only the former was associated with any heart-related harm.

However, all these studies only show associations and cannot determine whether some other contributing factor is the true cause.

What to do

Understandably, associations with kidney disease, cardiovascular disease, and dementia sound frightening, but the risk is just slightly higher than average in all the studies.

As the American Gastroenterological Association noted in an online discussion, people who require proton pump inhibitors to control GERD might also have other characteristics or behaviors, such as obesity or smoking, which could increase their risk for illness in general.

The best advice is to take your prescribed proton pump inhibitor and have a discussion every year with your physician about how much you need to take. It’s been estimated that as many as 70 percent of the proton pump inhibitor prescriptions in the United States may be written for inappropriate reasons.

Also, studies suggest that about 25 percent of longtime proton pump inhibitor users could stop using the medications and not experience a return of their symptoms.

Under the right circumstances, proton pump inhibitors generally do more good than harm. Talk with your doctor about the risks and benefits of taking a proton pump inhibitor. Also discuss alternatives, such as H2 blockers, which could help alleviate your symptoms and are likely to have fewer risks overall.

Consider adjusting your lifestyle by following a healthy diet, losing weight if you need to, eating smaller meals, quitting smoking, and exercising. That’s a much better path to freedom from symptoms.

Read more about medication versus surgery for improving GERD symptoms.