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PPI Side Effects Continue to Scare Us To Death

PPI side effects keep accumulating. The latest news relates to type 2 diabetes. Will the FDA pay attention to these serious complications?

Have you ever met people who have a hard time admitting they might have made a mistake? Such individuals defend their decisions and actions no matter what the consequences. It feels to us as if the Food and Drug Administration is a lot like that. The agency has a hard time reversing course. Once the FDA declares a class of drugs safe for over-the-counter use, it seemingly hates to admit there’s a problem. Such appears to be the case with serious PPI side effects. The latest worrisome complication appears to be type 2 diabetes (Gut, Sept. 28, 2020). 

New PPI Side Effects:

Proton Pump Inhibitors (PPIs) are among the most popular drugs in the drug store. You may not recognize generic names like dexlansoprazole, esomeprazole, lansoprazole, omeprazole, pantoprazole and rabeprazole. The brand names, however, are almost household words: Aciphex, Dexilant, Nexium, Prevacid, Prilosec and Protonix. Millions of people swallow such pills every day.

PPI Side Effects Keep Accumulating!

PPIs are widely used for a range of digestive disorders from stomach ulcers to heartburn. They were once perceived as extremely safe medications. So safe, in fact, that the FDA has permitted over-the-counter sales of drugs such as Nexium 24HR, Prilosec OTC and Prevacid 24HR.

There is now growing evidence that PPIs are associated with a number of serious side effects. The latest unexpected adverse reaction associated with proton pump inhibitors is type 2 diabetes (Gut, Sept. 28, 2020).

Researchers reviewed data from more than 200,000 participants in the Nurses Health Study, the Nurses Health Study II and the Health Professionals Follow-up Study. The authors introduce their research by nothing these serious PPI side effects:

“Proton pump inhibitors (PPIs) are among the top 10 most commonly used medications worldwide. PPIs are routinely recommended for acid-related disorders such as gastro-oesophageal reflux disease, peptic ulcer disease and non-ulcer dyspepsia. It is generally accepted that short-term use of PPIs for valid indications is safe. However, long-term use of PPIs has been linked to various adverse effects such as bone fractures, chronic kidney disease, enteric infections and gastric cancer. Recent studies have shown that PPIs can affect gut microbial communities by shifting the native gastrointestinal tract milieu.”

In this study, people who used proton pump inhibitors regularly were 24% more likely to develop type 2 diabetes over the decades. The absolute risk of developing this metabolic disorder was 7.4 per thousand person years among PPI users. That compares to 4.3 per thousand person years among the volunteers who did not take PPIs.

The conclusions of this research:

“Overall, this prospective analysis of over 0.2 million participants indicated that regular PPI use was likely to be associated with an increased risk of type 2 diabetes, particularly for those with prolonged use. Owing to its wide usage, the overall number of diabetes cases associated with PPI use could be considerable. Given the potential risk of diabetes and other adverse effects such as enteric infections, clinicians should carefully balance the benefits and harms in prescribing PPIs, particularly for long-term continuous use. For patients who have to receive long-term PPI treatment, screening for abnormal blood glucose and type 2 diabetes is recommended.”

In other words, people who have been taking such drugs for long periods of time should have their blood glucose levels monitored on a regular basis.

PPIs and Liver Disease:

A study utilizing a mouse model suggests that these powerful acid-suppressing drugs may increase liver inflammation and liver disease (Nature Communications, Oct. 10, 2017). This may be a particular problem for people who drink a lot of alcohol.

PPIs are very effective at blocking stomach acid secretion. As a result, the balance of microbes in the intestines changes, and that can affect liver health. With reduced stomach acid, bacteria in the Enterococcus genus flourish. They can migrate to the liver and cause inflammation and damage.

The researchers analyzed stool samples from human subjects. These were alcoholics who were at risk for liver damage. The individuals who were taking proton pump inhibitors had higher levels of Enterococcus in their stool samples. They also seemed to be more vulnerable to alcohol-induced liver disease.

Learn to Love Your Liver:

Americans pretty much take their livers for granted…until something goes wrong. The French, on the other hand, love their livers. They are quite concerned about maintaining healthy livers, even though they do drink a lot of wine.

Without a healthy liver you are in very big trouble. Sadly, liver disease is increasing at an alarming rate. Obesity plays a big role. Fatty liver disease is a serious problem that results from the obesity epidemic. Alcohol abuse leads to cirrhosis of the liver. It too is a killer.

The idea that changing the bacterial balance in the gut with PPIs might affect the liver worries us. The lead author of the research is Bernd Schnabl, MD. He told the University of California San Diego Health Communications Department:

“Our stomachs produce gastric acid to kill ingested microbes, and taking a medication to suppress gastric acid secretion can change the composition of the gut microbiome. Since we found previously that the gut microbiome — the communities of bacteria and other microbes living there — can influence liver disease risk, we wondered what effect gastric acid suppression might have on the progression of chronic liver disease. We found that the absence of gastric acid promotes growth of Enterococcus bacteria in the intestines and translocation to the liver, where they exacerbate inflammation and worsen chronic liver disease.”

“Our findings indicate that the recent rise in use of gastric acid-suppressing medications might have contributed to the increased incidence of chronic liver disease. Although obesity and alcohol use predispose a person to acid reflux requiring antacid medication, many patients with chronic liver disease take gastric acid suppressive medications without appropriate indication. We believe clinicians should consider withholding medications that suppress gastric acid unless there is a strong medical indication.”

Other PPI Side Effects:

Changing the Gut Microbiome:

Dr. Schnabl is not the only researcher to discover that PPI side effects include changing the bacterial balance in the intestinal tract. Dutch investigators reported the following (Gut, May, 2016) :

“The differences between PPI users and non-users observed in this study are consistently associated with changes towards a less healthy gut microbiome. These differences are in line with known changes that predispose to C. difficile infections and can potentially explain the increased risk of enteric infections in PPI users. On a population level, the effects of PPI are more prominent than the effects of antibiotics or other commonly used drugs.”

Learn more about the disrupted microbiome at this link:

“Do Heartburn Drugs Disturb Bacterial Balance in the GI Tract?”

Kidney Disease:

All this bad news comes on top of prior research suggesting that proton pump inhibitors may increase the risk for kidney disease. Here is an article on this topic:

“Can PPI Heartburn Drugs Harm Kidneys Without Early Symptoms?”

More PPI Side Effects:

As if kidney and liver disease were not enough, here is a list of other potential PPI complications:

Scary PPI Side Effects:

• Infections (pneumonia, Clostridium difficile, aka C. diff)

• Heart attacks and vascular calcification

• Dementia, Alzheimer’s disease

• Malabsorption of nutrients (calcium, magnesium, zinc, vitamin B12)

• Weakened bones, osteopenia, osteoporosis, fractures

• Blood disorder (thrombocytopenia, anemia, iron deficiency)

PPI Side Effects and Early Death:

As scary as the PPI side effects listed above may be, the ultimate adverse reaction is death. An epidemiological study published in BMJ (July 4, 2017) was titled:

“Risk of Death Among Users of Proton Pump Inhibitors:

A Longitudinal Observational Cohort Study of United States Veterans.”

The investigators conclude:

“This study provides insights into the excess risk of death associated with PPI use. In a large primary cohort of new users of acid suppression therapy followed for a median of 5.71 years, we show a significant association between PPI use and risk of all-cause mortality. Risk was increased among those with no documented medical indications for PPI use and with prolonged duration of use…

“PPI are widely used by millions of people for indications and durations that were never tested or approved; they are available over the counter (without prescription) in several countries and generally perceived as safe class of therapeutics. They are often overprescribed, rarely deprescribed and frequently started inappropriately during a hospital stay, and their use extended for long-term duration without appropriate medical indication.

“…we consistently found a significant association between PPI use and increased risk of death. The consistency of study findings in our report and the growing body of evidence in the literature showing a host of adverse events associated with PPI use are compelling, and because of the high prevalence of PPI use, it may have public health implications. Exercising pharmacovigilance and limiting PPI use to instances and durations where it is medically indicated may be warranted.”

The investigators who carried out the liver studies also recommend that clinicians reserve PPI-type drugs for people who absolutely must suppress stomach acid.
[Nature Communications, Oct. 10, 2017]


Despite all the worrisome PPI side effects described above, never stop a PPI without medical supervision. And never stop a PPI suddenly. Rebound hyperacidity can be horrific. You can learn about horrible heartburn from PPI withdrawal at this link.

Where’s the FDA?

Imagine the FDA’s outrage if a dietary supplement or herb were linked to heart attacks, strokes, kidney or liver disease. There almost assuredly would be immediate regulatory action. Go back and read the list of PPI side effects. These are not trivial complications. Some are life threatening. And yet the FDA seems uninterested in alerting the public to such adverse reactions. Remember, PPIs are 1) readily available in pharmacies, supermarkets, gas stations, quickie marts and other convenience stores and 2) it is not easy to stop PPIs after you have taken them for several weeks.

Do you think the FDA should do anything about the growing list of serious PPI side effects? We would love to get your feedback in the comment section below.

Want to learn more about effective ways to deal with indigestion or other gastrointestinal complications such as constipation or diarrhea? Our newly revised eGuide to Overcoming Digestive Disorders. It is available in our Health eGuides section. Please share this article with friends and family by scrolling to the top of this article and clicking on one of the icons for email, Facebook or Twitter.

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About the Author
Joe Graedon is a pharmacologist who has dedicated his career to making drug information understandable to consumers. His best-selling book, The People’s Pharmacy, was published in 1976 and led to a syndicated newspaper column, syndicated public radio show and web site. In 2006, Long Island University awarded him an honorary doctorate as “one of the country's leading drug experts for the consumer.”.
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  • Yuan, J., et al, "Regular use of proton pump inhibitors and risk of type 2 diabetes: results from three prospective cohort studies," Gut, Sept. 28, 2020, http://dx.doi.org/10.1136/gutjnl-2020-322557
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