PPI dangers

Proton Pump Inhibitors are amongst the most prescribed drugs in the world but how safe are they?

Controversy over long term medication

The efficacy of long term use of acid suppressant medication (particularly PPIs) has been questioned with some claiming they cause oesteoporosis, hypermagnesaemia, and even cancer. Whereas these claims are not entirely unfounded, the evidence is disputed. (See "hypochlorhydria").

PPIs have been linked to Myocardial Infarction [a-ix]. That those with heart conditions may be greater amongst those taking PPIs is not surprising since the symptoms of heart attack and indigestion can be so similar. The "evidence" shows a correlation not a causation.

Causation or Correlation?A more recent study [a-x] followed 54,422 GERD patients in Taiwan compared with 269,572 randomly selected age-, gender-, comorbidity- matched subjects, finding, amongst other things, "patients who were prescribed PPIs for more than one year had slightly decreased the risk of developing Acute Myocardial Infarction" and this paper, “Systematic review with meta-analysis: risk of adverse cardiovascular events with proton pump inhibitors independent of clopidogrel”, [p-iv] concluded, "There is no clear evidence of an association between PPI monotherapy and increased cardiovascular risk."

Similarly PPIs have been associated with Chronic Kidney Disease [a-xi]. Again this showed a correlation: those with kidney problems are more likely to be users of PPIs.

The authors of this paper, “Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease” [p-v] suggested, "I don't think the renal issue is a significant one when co-adjusted for all of the multiple risks".

This more recent paper, “Proton Pump Inhibitors and Risk of HepatoCellular Carcinoma in Patients” [p-vi]concluded,

"Based on a retrospective, nationwide population-based cohort study in Taiwan, where the prescription of PPI is tightly regulated, PPI use is not associated with the risk of developing HCC among patients."

Another study looking at the medicines used by patients over 75 with dementia, found a higher proportion of them used PPIs than amongst the general population. [a-xii] Another case of correlation rather than causation and some doctors were led to speak out about misinterpreting the data. [a-xiii.]

It led to a number of further studies disagreeing with the original premise, including these: “Proton Pump Inhibitor Use and Risk of Developing Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis”. [p-vii] finding "In this large, case-control analysis, we did not find any evidence for an increased risk of either AD or VaD related to PPI or H2RA use." and a paper published in Gastroenterology in June 2017 [a-xiv], also finding “no association between the use of proton pump inhibitors and the risk for mild cognitive impairment, dementia and Alzheimer’s disease.”

A paper published in 2013 appeared to show PPIs could cause oesophageal cancer [a-xv] but this, too, quickly received rebuffs: [a-xvi.]

The popular media loves scare stories like these and, never letting the facts get in the way of a good story, can exaggerate them causing real fear amongst some PPI users who often try turning to unproven "natural" remedies for their condition that may do more harm than good.

Why it's not safe to trust sensationalist press.

Let's try a thought experiment.

We manage to recruit 20 thousand people in a clinical trial looking at mortality from disease X with and without PPI medication.

We divide them into 2 equal cohorts of 10,000 in each. One cohort receives PPI medication and one cohort doesn't.

In the cohort not receiving PPIs. 3 people die (absolute risk is 0.03%). In the cohort receiving medication, 4 people die (absolute risk is 0.04%).

Our conclusion, based on our observation is those on PPIs may have had death risk increased by 33%.

Sensationalist journalist sees that and interprets it as 33% die of disease X due to PPI medication and headlines read, "Popular antacid drugs kill one in 3 people."

The graphic below shows how nonsensical that is. There are 20,000 boxes in two cohorts. The left one shows 3 dots, the right one 4: the patients in our hypothetical trial.

Always look at the research rather than misleading interpretations of it.

It is only right that such commonly prescribed drugs should be the subject of rigorous scientific scrutiny. Links to many other research papers regarding risks of PPIs may be found in the PPI references.

An article entitled, “Adverse Effects of Proton Pump Inhibitors: Fact or Fake News?” published in Current Opinions in Gastroenterology in 2018, summarises: “Most of the recent highly publicized serious adverse effects ascribed to proton pump inhibitors are not based on demonstrable evidence.” [p-viii]

Can PPIs protect against Cancer?

A Danish study in 2014 had concluded: "No cancer-protective effects from PPI's were seen. In fact, high-adherence and long-term use of PPI were associated with a significantly increased risk of adenocarcinoma or high-grade dysplasia." [a-xvii] in contradiction of a 2013 study which concluded: "The use of PPIs is associated with a decreased risk of OAC and/or BO-HGD in patients with BO. None of the studies showed an increased risk of OAC." [a-xviii] and an article published in 2014 which claimed a protective effect for PPIs. [a-xix]

There has been research however that shows PPIs most probably do have a chemo-protective effect helping reduce incidences of oesophageal cancer as published in a 2014 meta-analysis [a-xx] finding "PPI use was associated with a 71% reduction in risk of OAC and/or BO-HGD in patients with BO."

Subsequent research has also supported the possibility of a chemo-protective effect.

A November 2016 paper “showed that esomeprazole, especially at high concentrations (50, 100, and 200 μM) increased apoptosis of EAC cells.“ “In conclusion, the present study demonstrates that PPI exerts antineoplastic effects on EAC in vitro.“ [p-ix]

A study of US male veterans published in June 2018 found, “PPI use to be associated with 41% lower risk, and H2RA use with 30% lower risk of Barrett's oesophagus progression to OAC after adjusting for multiple confounders." [p-x]

Also in June 2018, Cancer Research UK released findings from the AspECT trial (Aspirin + Esomeprazole Cancer protection Trial) . Following 2,500 Barrett’s Oesophagus patients for an average of 9 years each, it found, "people who took this combination for at least seven years were 20% less likely to develop oesophageal cancer than if they had been untreated." [p-xi]

Published in May 2018, the paper, “The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses” also looked at the possible mechanism for chemo-protection. [p-xii]

New Evidence

Since the publication of the latest edition of this book, this research has been published:

Large Randomized Trial Supports Safety of PPIs,

Previous analyses tended to be association studies with the disclaimer that prospective, randomized data are needed to confirm their findings. The new trial, with more than 17,000 randomized patients, provides that evidence.

With more than 53,000 years of patient follow-up, use of PPIs was not associated with any of the events so far described with the possible exception of enteric infection.

Published in Gut 1 July 2021: Proton pump inhibitors and risk of colorectal cancer found, "the use of PPIs was not associated with an overall increased risk of colorectal cancer "

Do Proton Pump Inhibitors prevent Barrett's Esophagus progression to High Grade Dysplasia and Esophageal AdenoCarcinoma? An updated meta-analysis


PPI use is associated with a decreased risk of HGD/EAC in patients with BE. For further investigation, that more well-designed studies are still needed to elucidate the protective effect of PPI usage on BE patients to prevent HGD/EAC.