Research Points to 'Smoking Gun' for PPI Risks By Brenda Goodman, MA WebMD Health News Reviewed by Michael W. Smith, MD

Brian King7/ 4/16

June 8, 2016 -- Recent research has tied certain kinds of acid-blocking heartburn drugs called proton pump inhibitors, or PPIs, to a host of scary health problems, including higher risks for dementia, kidney disease, and heart attacks.

What’s been less clear, though, is how these meds might be contributing to so many kinds of ills.

Now researchers working out of Stanford University and Houston Methodist Hospital in Texas think they may have found an important piece of the puzzle: The drugs don’t just turn off acid pumps in the stomach. Instead, the researchers say, PPIs also block the production of acid in every cell in our bodies, an effect that hampers the body’s ability to rid itself of damaged proteins -- the “garbage” that builds up as we age.

“I think we now have a smoking gun,” says John Cooke, MD, PhD, chair of Cardiovascular Disease Research at Houston Methodist Hospital.

New Risks Tied to PPIs
Proton pump inhibitors dramatically diminish the amount of acid made by glands that line the inside of the stomach. They can provide big relief for people who have heartburn, where stomach acid splashes into the esophagus, causing fiery pain.

Millions of Americans take them. According to IMS Health, proton pump inhibitors were the ninth most commonly prescribed kinds of drugs in 2015, ahead of thyroid medications.

Top sellers include Nexium, Prevacid, and Prilosec. They're available over the counter and by prescription. The maker of Nexium and Prilosec, AstraZeneca, says it stands behind the safety of its products.

But there’s a downside to getting rid of stomach acid, too. It’s important for the absorption of some vitamins and minerals and for killing some of the harmful bacteria that we may swallow.

The drugs already carry warnings for several known risks, including C. difficile infections, which can cause chronic diarrhea; pneumonia; low magnesium levels, which can cause muscle spasms; heart palpitations and convulsions; and fractures of the hip, wrist, or spine. Fracture risks are generally highest in people who've taken high doses of the drugs for more than one year.
They may reduce the effectiveness of clopidogrel (Plavix), a drug that prevents blood clots.

In addition to those risks, two recent studies have raised troubling new questions about the long-term use of these drugs.

The first study, published in February, found that PPI use was tied to a higher risk for chronic kidney disease, while the use of a different kind of acid-blocking drug, called an H2 blocker, was not.

The second study, published in April, found a higher risk for dementia in people who use PPIs compared to those who don’t.

The studies linking PPIs to long-term health problems have been high-quality, but observational, experts say. At best, they can only show when two trends travel in the same direction. They can’t prove one thing causes another.

Scott Gabbard, MD, a gastroenterologist at the Cleveland Clinic in Ohio, says so many of his patients have become frightened of PPIs that he’s had to do his homework so he can fully explain the risks.

Take, for instance, the recent study that linked PPIs to chronic kidney disease. The study, which included more than 250,000 people, found that taking a PPI hiked a person’s risk of kidney disease by about 50%. But in absolute terms, the increased risk was still relatively small. Over 10 years, people who took a PPI had an almost 12% risk of developing chronic kidney disease, while people who weren’t taking the drugs had an 8.5% risk of getting kidney disease -- a difference of about 3%.

The same goes for the recent study that tied PPIs to dementia. Gabbard says the absolute risk increase seen in the study was small. People who took these meds had a 13% risk of getting dementia over the 7 years of the study, while people who didn’t take them had about an 8% -- a difference of about 5%.

Older studies have raised other health concerns. A 2015 study linked PPIs to a higher risk for heart attacks.

Also, there’s an ongoing debate about whether taking a PPI may increase a person’s risk for cancers of the esophagus and stomach.

People who have chronic acid reflux are at higher risk for a condition called Barrett’s esophagus, which is thought to be a precursor to full-blown esophageal cancer. Some studies have suggested that because PPIs protect damaged tissue in the esophagus from repeated exposure to stomach acid, allowing it to heal, the drugs might lower a person’s risk for cancer.

At the same time, many doctors have noted that rates of esophageal cancers have continued to increase, even as PPI medications have become a standard treatment for Barrett’s esophagus.

A 2014 study of 10,000 people diagnosed with Barrett’s esophagus in Denmark found that people who took PPIs were actually more likely to get cancer. The risk was highest for “high-adherence” users -- those who took their pills most faithfully. The study was observational, though, and it couldn't show cause and effect.

“It seems to me, at the very least, we can say the drugs do not protect against cancer,” says Frederik Hvid-Jensen, MD, PhD, a surgeon and researcher at Arhus University in Aarhus, Denmark.

A Surprise Finding Points to Unintended Effects
Researcher Cooke doesn’t think PPIs should be available over the counter. “They should be pulled off the shelves. They should be by prescription and they should be medically monitored because of the risks,” he says.

AstraZeneca, meanwhile, says patient safety is an important priority, and “we believe all of our PPI medicines are generally safe and effective when used in accordance with the label. This has been established through human data studies and more than a decade of real world clinical use.”

Cooke is a cardiologist who studies the endothelium, the layer of cells that lines blood vessels.

Healthy young endothelium, he says, is “like the Teflon coating of the blood vessels. It prevents things from sticking.”

But as we age and our endothelium becomes damaged, it behaves more like Velcro, and things start to stick. That’s how blood clots can begin to form and cause problems like heart attacks and strokes.

When Cooke was at Stanford, he decided to put his lab to work searching that university’s vast drug library to see if he could find any compounds that might protect the endothelium from age-related damage. Unfortunately, they didn’t find any.

But they did find two drugs in the library that dramatically worsened how well endothelium works -- they were both proton pump inhibitors. His findings were published in 2013.

To Cooke, the implications of what they’d found were enormous.

He reasoned that if the drugs could truly harm blood vessel function, he should be able to find evidence of that in a large group of people. He and a colleague named Nigam Shah, PhD, used data-mining techniques to plumb a database of over 2 million patients to see if those taking proton pump inhibitors were more likely to have heart problems.

Out of about 70,000 people diagnosed with gastroesophageal reflux disease (GERD), roughly 45% were taking a PPI, and PPI users were 16% more likely than those who weren’t to have a heart attack. The risk of a heart attack increased by 25% for people taking a PPI before the age of 55. Cooke didn't find the same risks for people taking a different kind of medication to control their heartburn called an H2 blocker (examples of those meds include Pepcid, Tagamet, and Zantac.) Those study results were published in 2015.

Drugs’ Effects May Go Beyond the Stomach
Just how could PPIs be causing the damage?

In studies of mice and human cells in test tubes, PPIs have been shown to shut off acid pumps in tiny cell parts called lysosomes.

“A lysosome is like a little bag of acid in the cell,” Cooke explains. Certain enzymes in the lysosome only work under acidic conditions. Those enzymes break down proteins that have become damaged. “It’s kind of like a little garbage disposal that requires acid to work.”

When the lysosomes don’t work properly in cells, waste builds up and cells age more quickly than normal.

Experts say Cooke’s research could explain why PPIs might lead to damage in many different organs at the same time.

“In my mind, we’ve got the biologic mechanism by which the PPIs are harmful to some of these patients,” says Jonathan Lipham, MD, chief of the division of GI and general surgery at the University of Southern California’s Keck School of Medicine in Los Angeles.

Both Lipham and Cooke are quick to say that people who really need PPIs shouldn’t be afraid to take them if that’s what their doctor advises.

Cooke has applied for NIH funding to do a larger, longer-term clinical trial to more decisively test his theory.

In the meantime, he says, if the benefits of the drugs outweigh the risks for someone, they should keep taking their PPI under medical supervision.

But he points out that these drugs are often prescribed when people have no medical reason to be on them. One recent study of long-term care facilities in the Midwest found that 65% of people taking a PPI didn’t have any diagnosis that might explain why the drug was prescribed. And PPIs can be tough to quit. Stopping the meds often leads to a phenomenon called PPI rebound, which causes people to make even more stomach acid than they were before. That leads many to stay on them for years, though the drugs’ labels say patients should only take them for 4 to 8 weeks to help heal ulcers or control heartburn.

“There are people that need PPIs long-term. But they should know what the risks are long-term, and they should be made aware of other options. There are surgical options to treat reflux,” Cooke says.

Since his study, Hvid-Jensen says he has changed the way he treats patients with PPIs.

“I tell my patients, if they have Barrett’s esophagus, I tell them only to use PPIs if they have symptoms and if PPIs help their symptoms,” he says.

Gabbard takes a similar tack with his patients. He tells them if they’re able to use less of the medicines, they should.

Some important things Gabbard tells his patients to do to relieve acid reflux:

Lose weight. “Losing as little as 10 to 15% of your weight can reduce reflux,” he says.
Quit smoking.
Elevate the head of the bed.
All, he says, are proven, drug-free ways to get relief.

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