Issue: February 2020
Disclosures: Howden reports consulting for Ironwood, Phathom and RedHill Biopharma. Chan and Pandolfino report no relevant financial disclosures.
February 27, 2020
8 min read

PPIs: Fears Persist Despite Little Evidence for Risks

Issue: February 2020
Disclosures: Howden reports consulting for Ironwood, Phathom and RedHill Biopharma. Chan and Pandolfino report no relevant financial disclosures.
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A number of high-profile, but ultimately weakly associated, risks have hounded proton pump inhibitors for years. The mainstream media caught on to research that linked the drugs to scary conditions such as dementia, myocardial infarction and even malignancies causing some patients to discontinue them entirely. However, new research over the last several years has either disproven those previous claims or found the associations to be extremely weak. How can the gastroenterology community rebuild the image of PPIs?

A possible link between PPI use and dementia received a great deal of media attention even although this was from a retrospective analysis from a database and reported hazard ratio of 1.34. This was reported on national TV as indicating that PPIs increased the risk for dementia by 34%. “The average NBC evening news viewer is not really in the position to assimilate that information properly, and a lot of them took away from it, ‘If I’m on a PPI, I’ve got a 34% chance of becoming demented or 34% of people who take PPIs are going to develop dementia,”’ Colin W. Howden, MD, FACG, Hyman Professor of Medicine and chief of the division of gastroenterology at the University of Tennessee Health Science Center, told Healio Gastroenterology and Liver Disease. “There were a lot of misperceptions about that and unfortunately when subsequent better quality studies reported little or no association, they did not attract any media attention.”

Howden said the general public may only think of PPIs as being for heartburn and may discontinue them to start something else. However, PPIs have broader indications than just reflux disease. Discontinuation of PPI therapy by patients taking them to reduce risk for ulcers and ulcer bleeding from NSAIDS could have serious consequences.

A survey conducted by researchers from the University of Michigan found that concern about PPIs was associated with attempts at discontinuation, often without a recommendation from a health care provider. Of 755 responding patients, only 24% had discussed PPI risks with their doctor, 39% had attempted to stop, and of those, 83% did so without the advice of a provider.

“Talk to your doctor and realize that your doctor doesn’t want you to be on medicine that you don’t need,” John E. Pandolfino, MD, said. “PPIs could be preventing you from getting a food impaction or a GI bleed, which are life threatening emergencies.”
“Talk to your doctor and realize that your doctor doesn’t want you to be on medicine that you don’t need,” John E. Pandolfino, MD, said. “PPIs could be preventing you from getting a food impaction or a GI bleed, which are life threatening emergencies.”
Photo source: American College of Gastroenterology.

“The fact that patients are so unnecessarily worried about PPI safety, and that many of them are stopping PPIs without even consulting their doctor, is concerning,” Howden said. “If someone has reflux disease and they decide, ‘I’m not going to take the risk of a PPI. I’ll stop it,’ then they’re going to get heartburn. There are worse things to live with than heartburn. However, elderly patients who are taking aspirin and/or non-steroidals may be on a PPI to reduce their risk of ulcer formation and ulcer bleeding. If they stop their PPI, they could get a life-threatening or life-ending GI bleed from an ulcer.”

Healio Gastroenterology and Liver Disease spoke with Howden and other experts about the supposed risks of PPIs and how GIs can address them to alleviate patient fears and provide the best care possible.

Safety Concerns Arise

As with many drugs, the beneficial impact of PPIs comes with a compensatory response. John E. Pandolfino, MD, chief of gastroenterology and hepatology at Northwestern Medicine, said the body tries to make things like stomach acid levels stay in balance, but PPIs prevent that natural balancing act from happening.

“If the acid levels are made low in the stomach, then that will trigger a negative feedback loop that is going to try to make things go back the way they were,” he said in an interview. “If the body can’t, because you’re blocking it, there is going to be some effects that might happen.”


Because the body produces stomach acid for a reason, there was some thought when PPIs were developed that they might have some negative impact on patients.

“By taking away that acid, there was always a thought that they will probably be a little bit more predisposed to specific infections, and how they process certain foods or minerals might be impacted,” Pandolfino said.

The major concerns arose when a number of studies came out that linked PPIs to serious conditions and side effects, like osteoporotic fracture, cardiovascular risks and dementia. However, Walter W. Chan, MD, MPH, director for the Center for Gastrointestinal Motility at Brigham and Women’s Hospital, Harvard Medical School, told Healio Gastroenterology and Liver Disease that many of these studies came with built-in limitations that meant they did not tell the whole story.

Walter W. Chan, MD, MPH
Walter W. Chan

“A lot of these studies may show an association between the PPI and different conditions, but that doesn’t necessarily mean that the PPI is causing these conditions,” Chan said. “Initially, researchers often do reviews of databases to look at if PPI use is higher in people with the condition than people without the condition. When other researchers start doing larger-scale and prospective studies that control for other factors, frequently they end up finding that the initial observation does not stand.”

In some cases, these studies may have been skewed because patients who take PPIs are generally sicker than individuals who do not, Pandolfino said.

“If you took 100 people who are not on a PPI and 100 people who are on a PPI, those people on the PPI are just going to be sicker,” he said. “They’re going to have more bone disease. They’re going to have more kidney disease. They may have slightly more dementia. They’re going to have more peripheral vascular disease. So, it’s really hard to get rid of a lot of the confounding factors that are there. Even if you control for certain risk factors, it’s still very difficult.”

Colin W. Howden, MD, FACG
Colin W. Howden

Even with these limitations, these studies attracted a lot of media attention. Although he never gave much credence to associated PPI risks like dementia, Howden said he can understand why they got a lot of attention.

“Because so many people are taking PPIs, rightly or wrongly, if the increased risk for something as serious as dementia comes up, then that’s newsworthy,” he said.

Current Risk Landscape

There has been a steady stream of new studies that have looked at the risks associated with PPIs and many have returned with much more favorable results than the initial studies that first brought attention to the drug’s safety.

In a meta-analysis published in Alimentary Pharmacology & Therapeutics, researchers found no solid evidence of an association between PPI monotherapy and cardiovascular risk. Their analysis included data from eight randomized controlled trials and determined that there was no increased risk (RR = 0.89; 95% CI, 0.34–2.33).


In another study comprising data from more than 4,000 patients with Alzheimer’s, researchers found that long-term PPI use did not increase the risk for hip fracture.

Howden was a lead investigator on a recent study that explored the link between PPIs and dementia. In their analysis, researchers found no clinically meaningful association between short-term PPI use and increased risk for dementia.

Chan acknowledged that gastroenterologists could do a better job relaying this important research to the public and patients who have concerns about PPIs. That means providing guidance about these newer, better-designed studies and emphasizing their findings to dispel fears that came about because of the limited studies of the past.

“As gastroenterologists, [we] need to do a better job in explaining these findings not just among ourselves or other GI caregivers, but also to primary care providers, other specialists and the lay public,” he said. “I don’t think, currently, we’re doing enough of that. It’s easy for nice, big, catchy headlines of some of these initial association studies to get a lot of people to worry. When these types of studies come out and when we get a chance to talk about them with the press, with the public, or with other non-GI physicians, we should really emphasize the limitations and point out the fact that just because something is associated with something else doesn’t mean it’s causing it.”

Talking With Patients

Because so many patients have fears about taking PPIs, it is critical to have a plan to talk with them. For Howden, that means trying to provide a better understanding for what the reported risks would mean even if they were true.

“Even if you accept that the alleged association is true — and for many of them I don’t accept that it’s true — you have to try to put it in perspective,” he said. “Even if it is true, the level of risk is very, very small, and you have to weigh that with the benefits that these drugs are providing.”

Pandolfino said when the risks are laid out with real numbers, the actual impact can become clearer. “When someone says your risk is one out of a million, and if do something to increase the risk, now it’s two out of a million, that’s a doubling of your risk, a 100% increase,” he said. “That’s a pretty low relative risk, and a low likelihood that you’re going to get that complication. Instead of being one out of a million now and one out of 500,000, and that’s still an extremely low likelihood that you’re going to get that.”

Experts agreed that doctors should tailor their message to each patient based on their level of understanding. However, they all made it clear that the low-evidence risks associated with PPIs are not strong enough on their own to outweigh the benefits that go beyond heartburn relief.

PPIs have indications in GI bleeding, eosinophilic esophagitis and other conditions that need long-term management, Chan said.

“There’s actually a lot of good indications for this drug, other than just the treating of some heartburn alone,” he said. “I think we really need to think about the quality of those risk association data, judge them against the well-established benefits of PPI, and balance them before we decide to take a patient off the drug.”


Moving Forward

While overuse is still a concern, Pandolfino said that patients should understand that doctors do not take prescribing PPIs or any other medicine lightly.

“Talk to your doctor and realize that your doctor doesn’t want you to be on medicine that you don’t need,” he said. “PPIs could be preventing you from getting a food impaction or a GI bleed, which are life threatening emergencies.”

Better research has provided reassurance to physicians and patients about the safety of PPIs. However, Howden said he still sees a bias against them in the literature.

“I’m an editor of a journal, and I get lots of papers across my desk talking about PPI safety and looking at PPI safety, and they virtually all end up with, ‘PPIs should only be given in the lowest-effective dose for people who have valid indications,’” Howden said. “However, the same is true for every single drug in the pharmacopoeia. All drugs should be given in the lowest-effective dose and only for appropriate indications. There’s nothing magical about the PPIs in that regard.”

Patients who are on PPIs — particularly older patients — are often taking other medications that come with bigger risks than those associated with PPIs.

“Things like sedatives, diuretics and anticoagulants,” he said. “Patients may be on them for very good reasons, or sometimes not but they carry many more substantial risks than PPIs. So, it’s a question of perspective.” – by Alex Young

Disclosures: Howden reports consulting for Ironwood, Phathom and RedHill Biopharma. Chan and Pandolfino report no relevant financial disclosures.