PPI dangers
Proton Pump Inhibitors are amongst the most prescribed drugs in the world but how safe are they?
Controversy over long term medication
Over the years, many papers have been produced that appeared to show an association or correlation bewteen th euse of PPI medication and other serious maladies.
However, these have all been since rebuffed and the recent study linked below, published in Gastroenterology & Endoscopy News in July 2019, has eventually looked at the detail.
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.
The study also revealed Lawyers Behind Increased PPI Reports to FDA.
In October 2023 AstraZeneca agreed to pay $425 million over 11,000 claims the heartburn drugs Nexium and Prilosec caused chronic kidney disease. However it admits no wrongdoing and still believes the suits filed against it are “without merit.”
Since there is no evidence supporting the claim, AZ were correct but it was cheaper for them to settle than fight a protracted legal battle.
Correllation vs Causation: The umbrella conundrum.
When it rains, more umbrellas are seen, but they didn't cause the rain.
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 to manage their symptoms.
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.”
This 2019 study published in PLoS one, "Proton pump inhibitor use does not increase dementia and Alzheimer’s disease risk: An updated meta-analysis of published studies involving 642305 patients" concluded, "our current evidence indicates that PPI use does not increase dementia and AD risk".
A fresh study in 2023 "Association of Proton Pump Inhibitor use with Incident Dementia and Cognitve Decline in Older Adults" concluded, "In adults ≥ 65 years of age, PPI and H2RA use were not associated with incident dementia, CIND, or decline in cognition over time. These data provide reassurance about the safety of long-term use of PPIs among older adults."
Another paper (published in Neurology in 2023) "Cumulative Use of Proton Pump Inhibitors and Risk of Dementia: The Atherosclerosis Risk in Communities Study has gained publicity through the sensationalist media. Again it shows association rather than causation. In its discussion, the authors state, "Future studies are needed to understand possible pathways between cumulative PPI use and the development of dementia." and in it's conclusion it says, "This study provides Class III evidence that use of prescribed PPIs for > 4.4 years by individuals ages 45 years and older is associated with a higher incidence of newly diagnosed dementia."
Class III evidence is defined as "Moderately high risk. Study has flaws in design and/or execution that increase potential for bias that may invalidate study results."
This study (published in medRxiv in 2023) Association between dietary inflammatory index score and incident dementia suggests rather the association is with the inflammation the PPIs were taken to help. "Higher DII [Dietary Inflammatory Index] scores were associated with a higher risk of incident all-cause dementia and AD. Although these promising findings need to be replicated and further validated, our results suggest that diets which correlate with low DII scores may prevent late-life dementia."
A paper published in 2013 appeared to show PPIs could cause oesophageal cancer [a-xv] but this, too, quickly received rebuffs: [a-xvi.]
Continuing suggestions of a link between PPIs and gastric cancer prompted this review published in December 2022, Meta-analysis: Use of proton pump inhibitors and risk of gastric cancer in patients requiring gastric acid suppression which concluded, "We found no association between PPIs and gastric cancer in NRS having adequately controlled for confounding. Published studies may suffer residual confounding."
A paper published in Histopathology in 2020 looked at NeuroEndocrine Tumours (NETs) possibly caused by PPIs, "Gastric neuroendocrine tumours from long-term proton pump inhibitor users are indolent tumours with good prognosis".
It concluded "results show that gastric neuroendocrine tumours of long-term PPI users are probably less aggressive compared to Type III sporadic tumours and have an indolent disease course. Our findings support the classification of gastric neuroendocrine tumours in long-term PPI users as a separate subtype."
Another popular misconception is PPIs cause osteoporosis. Again this is correlation rather than causation.
As discussed in the chapter on oestrogen, one of the benefits bestowed by the female hormone is some protection against the pain of heartburn. On nearing the menopause, that protection disappears and women are more likely to start feeling heartburn and using PPIs. At the same time, reduction in oestrogen can be accompanied by genesis of osteoporosis, not caused by PPI usage but coinciding with its introduction.
The Korean Chonnam Medical Journal published this article in 2023 "Adverse Effects Associated with Long-Term Use of Proton Pump Inhibitors" which was a historic review of papers that had shown an association of epiphenomena rather than any causal links.
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]
This 2024 paper published in Neurology Clinical Practice, "Understanding the malignant potential of gastric metaplasia of the oesophagus and its relevance to Barrett’s oesophagus surveillance: individual-level data analysis " found an association between all acid suppressants and antacids with headaches and migraines.
However, we know acid relfuxers are more prone to headaches and migraines so this is likely to be another Umbrella conundrum: those with headaches and migraines identified in the study were most likely suffering from acid reflux which is why they were taking the medication, which would also explain why it was associated with simple antacids as well as acid blockers.
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
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]
A paper published in Clinical Oncolgy in February 2021, Do Proton Pump Inhibitors prevent Barrett's Esophagus progression to High Grade Dysplasia and Esophageal AdenoCarcinoma? An updated meta-analysis.cConcluded:
"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."
PPIs have also been found to have a possible chemo-protective effect on some other cancers.
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 "
Another paper from November 2021 published in World Journal of Gastroenterology, "Proton pump inhibitors and colorectal cancer: a systematic review", found "Of the six basic research studies on PPI-induced hypergastrinemia, four demonstrated that PPI did not influence CRC growth and progression, whereas two suggested that PPI may even have a protective effect against CRC"
A 2022 paper ublished in Cancer (Basel), "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9776228/Association between Proton Pump Inhibitor Use and the Risk of Female Cancers: A Nested Case-Control Study of 23 Million Individuals" found "The use of PPIs was significantly associated with reduced risk of breast cancer and ovarian cancer" and "PPI exposure was associated with a significant decrease in cervical and endometrial cancer risks"
The 2022 AGA Clinical Practice Update on De-Prescribing of Proton Pump Inhibitors provided Best Practice Advice for de-prescribing of PPIs when their use was not warrented. However they did provide this guidance for when PPIs ere deemed necessary:
Best Practice Advice 5
Patients with known Barrett’s esophagus, eosinophilic esophagitis, or idiopathic pulmonary fibrosis should generally not be considered for a trial of de-prescribing.
Best Practice Advice 6
PPI users should be assessed for upper gastrointestinal bleeding risk using an evidence-based strategy before de-prescribing.
Best Practice Advice 7
Patients at high risk for upper gastrointestinal bleeding should not be considered for PPI de-prescribing.
Best Practice Advice 10
The decision to discontinue PPIs should be based solely on the lack of an indication for PPI use, and not because of concern for PAAEs [PPI associated adverse event]. The presence of a PAAE or a history of a PAAE in a current PPI user is not an independent indication for PPI withdrawal. Similarly, the presence of underlying risk factors for the development of an adverse event associated with PPI use should also not be an independent indication for PPI withdrawal.
Does Ranitidine cause cancer?
In 2019 the US Food and Drug Adinistration (FDA) found higher than expected levels of NDMA (N-Nitrosodimethylamine) in some batches of Ranitidine that were tested,
NDMA is thought may contribute to caner. Although the levels found were similar to those that can be sometimes found on grilled meat, the drug was immediately withdrawn and, similar to that reported regarding PPIs above, lawyers immediately sensing an opportunity sought to bring lega actions against the drugs companies. In one case, the manufacturer made an out of court settlement rather than waste money on a protracted trial.
In December 2022 a paper was published of the findings of extensive research undertaken in SOuth Korea to determine the risks. The Association between ranitidine use with potential NDMA impurities and risk of cancer in Korea published in Nature Scientific Reports concluded, "In summary, no association was found between ranitidine with potential NDMA impurities and the risk of overall cancer and major individual malignancies. Our study supported the findings of other investigations after rigorous controlling for confounding variables to ensure comparability in the population where ranitidine use was highly prevalent."
This article in The Statesman, "No link between use of ranitidine and risk of cancer" on 12 April 2023 gave a comprehensive review of the paper adding, "The Florida court dismissed almost 2,500 lawsuits alleging links between heartburn medication Zantac (Ranitidine) and cancer.
The judge had said that almost 2,500 lawsuits filed in federal court by plaintiffs were based on flawed science and that the only reliable testing of the blockbuster drug undertaken showed an ‘unprovable risk of cancer.’"
This study "Large Study Eases Fears Over Zantac-Cancer Link" published in JAMA 19 September 2023, "including 1 183 999 individuals from 11 large databases across Europe, North America, and Asia, risk of cancer among ranitidine users did not differ from users of other H2RAs. Ranitidine use was not associated with an increased risk of esophageal, stomach, or colorectal cancer, or 13 other subtypes of cancer. "
Page updated 7 January 2024