While most patients don’t experience safety issues, studies over the years have raised questions about a number of serious and potentially life-threatening side effects. Among other things, these pills have been tied to an increased risk of premature death, heart disease, certain cancers, dementia, lung disorders, fractures, kidney damage, pneumonia, and bacterial infections. Here’s what you need to know to decide if these drugs are right for you, and whether you need to see a doctor before you try over-the-counter PPIs.
What Is Heartburn and How Can PPIs Help?
Heartburn happens to lots of us when we have an especially spicy, fatty, or heavy meal. It develops when stomach acid flows up into the esophagus, or food pipe, causing a burning sensation in the chest, often accompanied by a bitter or sour taste in the mouth and throat. Symptoms are especially common among the elderly, pregnant women, smokers, and people who are overweight or obese. More than 60 million Americans experience heartburn at least once a month, and more than 15 million people suffer daily symptoms, according to the American College of Gastroenterology. Sometimes heartburn eases with lifestyle changes, like eating smaller meals and eating more slowly. Avoiding tobacco, alcohol, and caffeine can also help. Over-the-counter antacids, like Alka-Seltzer, Mylanta, and Tums, can help ease occasional pain and discomfort caused by heartburn or acid reflux. But these drugs don’t actually stop acid production. That’s where PPIs come in. Sold under brand names like Prilosec (omeprazole) and Nexium (esomeprazole), PPIs work by curbing production of stomach acid. Doctors prescribe these drugs to treat GERD, a condition that develops when stomach acid backs up into the esophagus. PPIs also treat Helicobacter pylori, a bacteria that can cause ulcers in the stomach and small intestine. And, the drugs can also halt the production of stomach acid that causes ulcers with long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin and ibuprofen (Advil or Motrin). When doctors prescribe PPIs, benefits like reducing hospitalizations for GERD generally outweigh the risk of rare side effects associated with the drugs, says Joel Rubenstein, MD, an associate professor of gastroenterology at the University of Michigan Medical School in Ann Arbor. But the picture is different for many people who buy PPIs without ever seeing a doctor, he adds.
`Zero Benefit’
“Many millions of patients with symptoms thought to be due to GERD are taking a PPI,” but don’t actually have GERD or need these drugs, Dr. Rubenstein says. “In these patients, the tiny risks of PPI and substantial financial cost are not worth the zero benefit.” People who take over-the-counter PPIs shouldn’t stay on these drugs for more than two weeks or turn to these drugs more than once every four months without seeing a doctor, according to warning labels on the medicines. “The side effects are rare only if the course is a short-term one; less than two or a maximum of three weeks,” says Ruben Abagyan, PhD, a professor at the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California in San Diego. “The side effects look almost inevitable if the drugs are taken for a long period of time,” Dr. Abagyan says. And there’s research to support that. First off, there’s the potential for PPIs to lead to an early grave. One observational study published in July 2017 in the journal BMJ followed almost 350,000 U.S. veterans for a median of 5.7 years and found patients who got new PPI prescriptions were 23 percent more likely to die during follow-up than people who didn’t take acid-suppression drugs. The same research team published a longer study in May 2019 in BMJ that followed almost 215,000 veterans. This time, they found the drugs associated with a 10-year mortality risk of 45 excess deaths for every 1,000 patients. “The absolute risk is small, but given the millions of people on PPIs, the overall population level risk is substantial,” says senior author of both studies Ziyad Al-Aly, MD, director of the clinical epidemiology center and chief of research and education service at Veterans Affairs St. Louis Health Care System in Missouri. Generally, the risk of side effects is higher in people who don’t need PPIs but take them anyway, Dr. Al-Aly says. He, too, cautioned against using the OTC drugs for more than two weeks without seeing a doctor. Most of the studies that have found safety issues with PPIs weren’t clinical trials designed to prove whether or how these drugs might directly cause certain side effects. Instead, they were observational studies that simply looked at data on large groups of people to compare health outcomes for patients who took PPIs and patients who didn’t.
Absolute Risk for Serious Side Effects Is Low
For many other serious side effects associated with PPIs, the absolute risk is low and the evidence isn’t definitive, says Dhyanesh Patel, MD, an assistant professor of medicine at the Center for Swallowing and Esophageal Disorders at Vanderbilt University Medical Center in Nashville, Tennessee. One study examining the link between PPIs and kidney disease found the drugs associated with up to a 0.3 percent greater risk of kidney disease per patient for each year on the drugs. Another study found the medicines associated with up to a 1.5 percent greater risk of dementia per elderly patient per year. And, each year on PPIs was associated with up to a 0.5 percent higher risk of hip fractures for older adults taking the drugs in a different observational study. These links — and connections to several other side effects — aren’t strong enough at this point for patients to steer clear of PPIs just because they have other risk factors, several doctors said. Elderly patients, for example, might be more prone to side effects associated with PPIs because of multiple chronic health problems that are unrelated to the PPIs and might be tied to their use of other medication, Dr. Patel says. “PPI therapy might be entirely appropriate, but yet may be blamed for any subsequent adverse event,” Patel says.
Infections Are Clearest Risk
The clearest exception may be infections, which have been consistently linked to PPIs in several large, observational studies over the years. One three-year study, published in May 2019 in the journal Gastroenterology, randomly assigned more than 17,000 patients to take a PPI or placebo in combination with blood-thinners, and found PPI users were 33 percent more likely to develop enteric infections. These infections develop in the small intestine and are caused by a type of bacteria known as campylobacter. Enteric infections are a leading cause of diarrhea. More than 900 people would need to take PPIs for over a year for one patient to develop an enteric infection that wouldn’t have otherwise occurred, says Paul Moayyedi, PhD, lead author of the study and assistant dean of research at McMaster University in Hamilton, Ontario, Canada. Patients on PPIs in this study were also more than twice as likely to develop Clostridium difficile infections, but there were only 13 cases and this made it impossible to rule out the possibility that the connection might be due to chance. So-called C. diff infections can cause symptoms ranging from diarrhea to life-threatening inflammation in the colon. Of all the potential safety concerns with PPIs, the risk of infections is one that doctors most consistently say changes how they prescribe the drugs. “I try to get patients off PPIs or minimize the dose if they have had C. diff,” says Rubenstein. “And I recommend that patients who have household contacts with enteric infections hold the PPI for a week to 10 days to reduce the risk of contracting the infection.”
Study Leaves More Questions Than Answers
Beyond the elevated infection risk, this study didn’t find a connection between PPIs and several other safety issues it examined that have been identified by earlier research. PPIs didn’t appear to cause fractures, kidney disease, dementia, cancer, heart disease, chronic obstructive pulmonary disease (COPD), hospitalizations, or premature death. “It is very reassuring that our trial was negative and suggests the risks of PPIs have at the very least been overstated,” Dr. Moayyedi says. Even though this study was the gold standard for drug safety research — randomly assigning some patients to take a medicine and others to take a placebo — the goal of the study was to test PPI safety only in people with damaged arteries who were prescribed aspirin or the blood-thinner Xarelto (rivaroxaban). It’s possible results would be different in other groups of people. Some side effects might also surface in a larger, longer study that didn’t appear in this trial. “We still can’t exclude a very small risk of harms,” Moayyedi says. For now, safety concerns shouldn’t deter doctors from prescribing PPIs to patients who need them, says Vandana Nehra, MD, associate professor of medicine at the Mayo Clinic in Rochester, Minnesota. That’s because most of the problems identified so far have been found in observational studies that can’t prove PPIs directly caused specific side effects, and because the association usually wasn’t a strong one, Dr. Nehra says. But patients should still exercise caution and common sense. Left to their own devices, many patients may take PPIs for conditions that the drugs are designed to treat, then take a higher than recommended dose for longer than they should when the drugs fail to work, Nehra says. “It’s important to use PPIs under the supervision of a clinician at the lowest effective dose for the shortest period of time,” Nehra advised.
