Issue: December 2017
December 18, 2017
15 min read

Evidence of PPI Risks Weak, But Overuse Remains a Problem

Issue: December 2017
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With an ever-growing laundry list of studies drawing associations between proton pump inhibitor use and sometimes alarming adverse effects — many of which have made national headlines — both providers and patients are facing new concerns about long-term use of these common reflux drugs.

Despite the daunting number of associations — including kidney disease, dementia, osteoporotic fracture, myocardial infarction, small intestinal bacterial overgrowth, Clostridium difficile infection, pneumonia, micronutrient deficiencies, gastrointestinal malignancies and even death — experts told Healio Gastroenterology and Liver Disease that overall the evidence for these is consistently weak, and that providers should reassure their concerned patients to avoid unnecessary PPI discontinuation.

David A. Leiman

“Many of the recent studies on the risks of PPI use are interesting and provocative, but I don’t know that the quality of the evidence is compelling enough to change practice, particularly in light of the fact that so much of the data in favor of using PPIs — in the appropriate condition — is based on high quality evidence from randomized controlled trials,” David A. Leiman, MD, MSHP, of the division of gastroenterology at Duke University School of Medicine, said in an interview.

Nonetheless, Leiman and others also emphasized that the widespread attention given these safety concerns provides a much-needed opportunity for providers to discuss limiting and tapering PPIs, not just due to the associated risks, but because many patients are taking them unnecessarily.

“When used in the right patient for the appropriate condition, PPIs are extremely valuable. But as with all medications, the overriding principle should be to use the lowest effective dose to mitigate risk that may or may not be ultimately born out with further research,” Leiman said.

Advocating for a common-sense approach to PPI prescribing, experts like Daniel E. Freedberg, MD, of the division of digestive and liver diseases at Columbia University Medical Center, echoed the recent best practice recommendations for long-term PPI use issued by the AGA, which suggested that the benefits of PPIs likely outweigh the risks as long as they are prescribed for appropriate indications — primarily appropriately selected GERD patients, Barrett’s esophagus, and NSAID bleeding prophylaxis in high-risk patients.

“When I talk to prescribers about PPIs, the point I try to emphasize is: don’t worry too much about the risks — worry about the indications,” Freedberg, who co-authored the AGA best practice recommendations, said in an interview. “If you’ve got a good reason for prescribing the PPI, you’re probably okay.”


Aiming to reassure providers and help them communicate with patients who are concerned about the risks of PPIs they have heard about in the news, Freedberg and others maintained that one should first look at the limited quality of evidence produced by these studies that continue to make headlines.

Weak Associations

Foremost, it is important for both patients and providers to know that the magnitude of the associations drawn in most of these studies has tended to be small, Freedberg said.

“If the studies are right — and by no means is that certain — even then the risks would be very low in absolute magnitude for the given patient,” he said.

For example, based on the available data, the absolute excess risk for chronic kidney disease among long-term PPI users ranges from 0.1% to 0.3% annually per patient, while the absolute excess risk for dementia ranges from 0.07% to 1.5%, according to a recent review article by Michael F. Vaezi, MD, PhD, professor of medicine in the division of gastroenterology and hepatology, and director of the Center for Swallowing and Esophageal Disorders at Vanderbilt University Medical Center, and colleagues.

Vaezi agreed with Freedberg that the emerging evidence underlying the associations tied to PPI use — beyond the established acute risks — is so far unconvincing. He and colleagues warned in their review that “such epidemiological studies may often trigger ‘false alarms.’”

“The main risks that are potentially justified are those that acutely cause issues,” Vaezi said in an interview. “We know a small subgroup of patients may have side effects when they take PPIs — for example, abdominal pain, diarrhea, loose stool, headache. The chronic risks are problematic in that the majority of these studies are large database case-control studies, and the magnitude of the association is really not that strong. The associations are weak at best, and I’m not convinced causal in most.”

After evaluating whether these associations may in fact be causal in their review, Vaezi and colleagues concluded that the evidence to draw such conclusions is insufficient, and credited much of the controversy about PPI safety to residual confounding related to study design.

Michael F. Vaezi

Inherent Study Limitations

Because most of these studies are retrospective, “it is exceedingly difficult to control for all elements,” Vaezi said. “If you don’t control or adjust for a variety of comorbidities, you will find an association with PPIs, and that applies no matter what association you’re talking about.”


Freedberg agreed that the low quality of evidence underlying these associations is due in part to the inherent limitations of the large epidemiological studies reporting them, and their inability to completely control for potential confounding factors.

“Most of the evidence for those risks is very low in quality, as it comes from big epidemiologic retrospective studies, in which small baseline differences between people who do and don’t use PPIs can often account for whatever association you’re observing rather than a real causal difference,” he said. “So, it’s not the PPI, it’s something intrinsic in the patient that came before the PPI. Perhaps the patients in some of these studies who use PPIs are sicker than the patients who don’t, and it’s hard to completely account for that.”

As an example of how a large retrospective study with potential confounding can nonetheless produce results that may alarm the public, Freedberg pointed to the high-profile study by Xie and colleagues recently published in BMJ Open, which reported that long-term PPI users showed an increased risk for all-cause mortality.

In their primary cohort of nearly 350,000 U.S. veterans, they reported a 25% increased risk for death among PPI vs. H2RA users after a median follow-up of 5.71 years (HR = 1.25; 95% CI; 1.23-1.28), corresponding to one excess death for every 500 PPI users per year. Additional cohorts of millions of veterans showed increased mortality risks linked to PPI use vs. no PPI use (HR = 1.15; 95% CI, 1.14-1.15), and to PPI use vs. no PPI and no H2RA use (HR = 1.23; 95% CI, 1.22-1.24).

“No matter how we sliced and diced the data from this large data set, we saw the same thing: There’s an increased risk of death among PPI users,” study investigator Ziyad Al-Aly, MD, assistant professor of medicine at Washington University School of Medicine in St. Louis, said in a press release at the time of publication in July 2017. The investigators’ conclusions were then widely reported by mainstream media outlets like CBS News, WebMD, CNN, Reuters and Time.

Although the study authors acknowledged that the PPI users in their cohort were older and sicker than controls, they noted that the higher mortality risk remained after controlling for age and illness. But despite being performed carefully, Freedberg said the study’s retrospective design, its large data set, weak associations and the absence of a clear mechanism to explain them, all make drawing firm conclusions from the data exceedingly difficult.


A notable limitation, according to Freedberg, is that health care exposure itself is a potential confounding variable.

“In the study by Xie and colleagues — and also in some of the other relatively recent retrospective studies like those about chronic kidney disease — an important variable that’s either not captured or not completely captured is health care system exposure,” he said. “I recall a colleague of mine once said that PPIs are like the flypaper of the health care system; the more doctors you see, the more likely you are eventually going to stick to a PPI, and unfortunately it’s true.”

It is not uncommon, he said, for a patient hospitalized in the ICU to be prescribed a PPI for stress ulcer prophylaxis, and then continue taking it after being sent to the medical floor and even after discharge weeks later, despite there being no long-term indication.

“In this scenario, the PPI marks not just a previous hospitalization, but a particularly severe kind of hospitalization,” he said. “Unless you’re able to capture the richness of that scenario, you’re losing important information, which is more likely to bias against PPIs, because the PPIs are marking this increased health care exposure, when in reality all those other things that come along with the health care exposure are the real risks. The single most important confounding variable to explain some of the differences observed between PPI users and nonusers is health care exposure or severity of hospitalizations.”

Inconsistent Data

Further calling into question the quality of evidence for the risks of PPIs are the inconsistent results produced by different studies.

For example, a prospective cohort study published in 2016 in JAMA Neurology found regular PPI use was associated with a significantly increased risk for dementia (HR = 1.44; 95% CI, 1.36-1.52), while two observational studies published more recently found no evidence of this association, which the AGA said, “puts these claims to rest.” Even more recently, a population-based cohort study published in November 2017 in the Journal of the American Geriatrics Society also found no evidence that PPIs cause dementia, even in patients with high cumulative exposure.

Similarly, a “data-mining study” published in PLoS One in 2015 showed a 1.16-fold increased risk for myocardial infarction among PPI users, while a new retrospective study just published in Gastroenterology in October 2017 showed no evidence of this risk vs. H2RAs.

Again, while a meta-analysis published in 2016 in Osteoporosis International found a moderate increase in the risk for hip fracture associated with PPI use, a more recent case-control study published in October 2017 in Alimentary Pharmacology & Therapeutics showed that patients with Barrett’s esophagus who took long-term, high-dose PPIs showed no increased risk for bone fractures, osteopenia or osteoporosis vs. the general population.


However, when considering the conflicting data, study design limitations and the low magnitude of the risks drawn, Freedberg noted that there are some exceptions to the poor quality of evidence supporting some of these risks. Such associations, like the effects of PPIs on the gut microbiota, are perhaps more convincing as there is a plausible biological mechanism that could explain them, he said.

Daniel E. Freedberg

Plausible Mechanisms, Gut Microbiota Alterations

The “questionable clinical relevance” of many proposed biological explanations for the prominent associated risks of PPIs are yet another limitation to the available evidence, Vaezi and colleagues wrote in their review. As an example, they noted that one explanation of the link between PPIs and osteoporosis is that dietary calcium absorption could be inhibited by reduced gastric acidity, but results from clinical studies do not support this mechanism, having shown that bone-mineral density values do not significantly differ between women who take long-term PPIs and those who do not.

In contrast, the association drawn between PPI use and changes to the gut microbiota is explained by a plausible mechanism of action and supported by clinical studies, according to Freedberg.

William D. Chey

“Many of the proposed PPI adverse effects are systemic, so they would require PPIs to be in the bloodstream, but while PPIs have a long effective half-life, they have a short serum half-life, so they’re not in the bloodstream for very long,” he said. “However, they are effective in the stomach for a long time, so it seems logical to me that they could have some adverse effects related to the change in gastric acidity, and there are some small but robustly designed and convincing crossover studies that very consistently show significant changes in the kinds of bacteria that live in the stomach or small bowel in patients who are on PPIs.”

In one such study, Freedberg and colleagues showed that when healthy volunteers took PPIs for 4 to 8 weeks, specific bacterial taxa associated with C. difficile infection, including Streptococcaceae and Enterococcaceae, were increased in their fecal samples. This, he said, could be the mechanism by which PPIs predispose individuals to this infection, which has been associated with PPI use in retrospective studies.

“The clinical consequences of those microbial changes are much less certain, but I think we can be pretty sure that PPIs do change our upper GI flora, and they probably change our colonic flora a little bit as well,” Freedberg said. “Nonetheless, the evidence showing there is a big clinical risk for C. difficile infection with PPIs is still lacking, but at least the mechanistic evidence for a reason why they could be a risk factor for C. diff is, unlike the other adverse effects, pretty good.”


PPI Overuse, Deprescribing

Despite such exceptions, the data overwhelmingly show that PPIs are safe and beneficial for many patients, but regardless, experts agreed that efforts to limit and taper unnecessary PPI prescriptions should be more of a priority. Recent estimates have shown that current PPI use among non-institutionalized adults has doubled from 3.9% in 1999 to 7.8% in 2012 in the U.S., and up to 30% of patients have ever been exposed to a PPI.

According to Freedberg, unnecessary PPI prescriptions should be reined in for several reasons.

“One reason is that the future is unknown,” he said. “We can only make recommendations for the evidence we have today, but who knows what evidence will come out in the future, and if future evidence shows that maybe there is some convincing harmful effect of PPIs, I would want to be someone who had prescribed them only for strong indications.”

Additionally, Freedberg added that polypharmacy, even of safe medications, is simply bad practice.

“Polypharmacy wastes money, and taking medicines that aren’t very helpful really devalues the ones that are,” he said. “With the risks for medication errors, especially in elderly patients who are taking 8 to 10 medicines a day, and the risk for drug interactions, avoiding polypharmacy is important.”

According to Leiman, the factors that motivate providers to recommend PPI discontinuation for certain patients are not always clear. A recently published study in Clinical Gastroenterology and Hepatology evaluating clinical case vignettes of patients on PPIs for different indications and risk profiles showed that many providers would discontinue treatment for patients who “were actually at highest risk, and most likely to benefit from PPIs,” he said. “So understanding why someone chooses to adjust or stop their medications is important, and better insight into this may help gastroenterologists facilitate evidence-based decisions around PPI risks and benefits.”

Vaezi recommended that providers attempt to taper PPIs in all patients without specific conditions that require chronic PPIs, such as Zollinger-Ellison syndrome, Barrett’s esophagus and severe esophagitis.

“A large population of patients are on an unnecessary PPI for vague symptoms, or they are unresponsive to PPIs, at which point we really should be looking for potential causes other than reflux,” he said. “Aside from those patients who really require the PPI dose chronically, we should attempt to taper everybody else to alternatives like H2RAs, alginates or to dietary therapy. In my practice I find that in 50% of patients, I might be able to taper them to alternative therapies, but 50% of patients have chronic reflux and require chronic therapy.”


Effective Alternatives

Aside from commonly prescribed H2RAs, there are several other effective alternative therapies providers can consider if PPI tapering is appropriate in their patients.

Non-prescription alginate therapies — typically sold under the brand name Gaviscon (GlaxoSmithKline) in the U.S. — are effective alternatives for managing GERD symptoms, especially in patients with mild or intermittent symptoms, Leiman and colleagues reported last year in a meta-analysis published in Diseases of the Esophagus. They showed alginates increased GERD symptom resolution vs. placebo or antacids (OR = 4.42; 95% CI, 2.45-7.97), and though they were less effective than PPIs and H2RAs, this did not reach statistical significance (OR = 0.58; 95% CI, 0.27-1.22), and there was a high degree of heterogeneity between studies (P < .001).

“Alginic acid derivatives have been around for decades, and there are compelling data to support their use in some populations, but further studies are needed to figure out who the optimal patient is, and whether this should be an adjunct for patients who are already on PPIs but are suboptimally controlled, or perhaps ideal for the patient with mild or intermittent symptoms who prefers not to be on a PPI,” Leiman said.

William D. Chey

Additionally, several lifestyle and dietary interventions, both traditional and emerging, may be considered as alternatives for patients in whom PPI taper should be attempted, according to William D. Chey, MD, Nostrant Professor of gastroenterology and nutrition sciences at Michigan Medicine, Ann Arbor.

“For many years we’ve recommended common-sense strategies like reducing fatty or greasy foods in meals, because these can have effects on gastric emptying, or effects on the lower esophageal sphincter (LES) that could aggravate problems with reflux,” he said in an interview. “Similarly, we’ve recommended that people eat smaller, more frequent meals, based on the idea that larger meals that distend the stomach to a greater degree will increase the rate of transient LES relaxations, so eating smaller meals would tend to aggravate that reflux relaxation of the LES to a lesser degree, and in that way reduce reflux events. Another thing that helps a lot of patients is trying not to eat too close to bedtime if they have nocturnal reflux-related complaints.”

However, Chey said the data supporting diet and lifestyle interventions to alleviate GERD symptoms have evolved over time, and in recent years, the role of weight loss and more intensive dietary interventions has become more apparent.

“It turns out weight loss is key,” Chey said. “There’s no question we have a huge problem with obesity in the U.S., and in fact, over 60% of the U.S. adult population is now overweight, or obese, which is astounding, but true. What’s also been shown very convincingly is that weight loss by any of a number of different means — diet, medication, surgical approaches — can significantly reduce reflux events and also reflux symptoms. So, weight loss is an evidence-based approach to managing patients with GERD, and dietary modification with the intention of reducing caloric intake, along with exercise in hopes of achieving weight loss, should be part of the prescription for every patient with GERD in which those types of interventions are appropriate.”


More recently, provocative data have emerged that suggest that more drastic dietary interventions, such as a very low carbohydrate diet, can benefit reflux symptoms, Chey said.

For instance, a study published in Alimentary Pharmacology and Therapeutics in 2016 showed that a high-fat/low-carbohydrate diet resolved GERD symptoms in 41 obese women after 10 weeks.

“Organized dietary strategies like a very low carbohydrate diet might be of benefit, although currently, interventions like these should still be viewed as experimental and require further study and validation before they’re routinely recommended for clinical practice,” Chey said.

Traditional and emerging surgical approaches may also be alternatives for certain patients, Leiman noted.

“Nissen fundoplication may be appropriate for the right type of patient, particularly those with volume regurgitation who have already demonstrated benefit from PPI use, but for intolerance or other reasons may want to minimize — at least for a period of time — their use of PPIs,” he said. “Magnetic sphincter augmentation may be another option, and there are increasing data to support this surgical alternative. This is a relatively new intervention, and I think recent data are promising, but we don’t have enough data yet to completely change practice.”

Weighing the Risks and Benefits

As the potential risks of PPIs continue to generate media attention, experts agreed with the AGA recommendations that physicians should ensure they adequately understand the emerging science to appropriately advise their patients who may be, quite justifiably, concerned.

According to Chey, providers must make sure they are keeping up with the emerging data to effectively counsel patients about these risks. “Providers need to be aware of these potential risks, and be able to discuss those issues in detail with their patients, because increasingly patients are reading about this on the internet, hearing about it in the lay press, and coming to their physicians and allied health professionals with lots of questions and concerns about PPIs,” he said. “So, it behooves providers to be up-to-date on the information on the potential risks of PPI therapy to be able to provide perspective for patients, so that they’re not overly concerned about certain things, or conversely, unconcerned about things they maybe should be concerned about.”

Being open and honest with patients about the research on PPIs is essential, Chey said, and until stronger evidence of these risks becomes available, physicians should adhere to best practices by exercising prudence in prescribing long-term PPIs, and weighing the risks and benefits of treatment in every patient.


“There certainly is a lot of smoke swirling around PPIs at the current time, particularly as it pertains to risks associated with long-term use of high dose PPI therapy — it doesn’t seem that a week goes by that we don’t hear about a new article drawing some association between long-term PPI use and some catastrophic illness,” he said. “It’s hard to separate what’s smoke and what’s fire at this point, but I think it’s fair to say that people should be thoughtful about the patients in which they recommend long-term PPI therapy, and there clearly needs to be a risk-benefit assessment in every patient to determine whether the benefits outweigh the potential risks.” – by Adam Leitenberger

Disclosures: Freedberg reports he has consulted for Pfizer. Chey, Leiman and Vaezi report no relevant financial disclosures.