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GERD Drugs (PPI) Cause Esophageal Cancer - The Very Disease They Should Prevent

haidut

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Forum users who follow my posts have probably noticed the number of threads I have posted exposing the fraud and ineffectiveness of the PPI drugs commonly prescribed for GERD. Another user who likely shares my passion against the PPI is @aguilaroja who will likely find the study sadly unsurprising.
PPI drugs are probably the most prescribed class of drugs in the US and they are approved for pretty much any age group. I know of both month-old toddlers and 90+ year old adults who take them on a regular basis. This mass prescription materialized despite serious concerns surrounding the animal studies with PPI, showing increased incidence of gastric cancer, osteoporosis, neurodegenerative disease and mental health issues. The main reason cited by the FDA for approving the PPI in the 1990s was the rapidly rising incidence of esophageal cancer (EC) - one of the deadliest and most difficult to treat cancers. After the PPI approval, subsequent studies over the years found that GERD is not really an acid- but an inflammatory-driven condition for which PPI drugs do absolutely nothing.
GERD (acid Reflux) Is Caused By Inflammation, Not Stomach Acid
Of course, this new insight did nothing to curtail the prescription of PPI drugs around the world. Now, this new study found what many forum users have suspected for years about so many drugs prescribed like candy - i.e. the drugs prescribed for a condition are not only ineffective as treatment but often cause/contribute to that very condition they are supposed to treat. This exactly what the study below found. Namely, not only are PPI drugs ineffective in curtailing the rise in EC rates but people using them have dramatically higher chance of developing EC. And of course, as we have discussed many times on this forum, the study also found that the older GERD drugs known as H2 antagonists (famotidine anyone?) did not lead to increased risk of EC. There is really no other way to describe this finding except as an absolute disgrace for both the pharma industry and the medical profession which enables this massive fraud to occur every day.

Maintenance proton pump inhibition therapy and risk of oesophageal cancer - ScienceDirect
Medscape: Medscape Access

"...Long-term maintenance therapy with proton-pump inhibitors (PPIs) was shown to be associated with an increased risk for esophageal cancer, even in patients taking PPIs for indications not previously associated with this cancer risk, according to results from a new study from Sweden. The authors call for "a more restrictive attitude towards maintenance use of PPIs."

"...To evaluate confounding by indication, stratified analyses were performed for each indication not associated with an increased risk for EAC. This separate analysis was one of the study's chief strengths because it minimized the risk for confounding by indication that has limited previous research, Brusselaers and colleagues say. However, they were unable to identify the indication for PPI therapy in 25% of the cohort...A comparative analysis in 20,177 patients taking only histamine-2 receptor (H2) antagonists (such as ranitidine) found no increased risk for EAC (SIR, 0.39) or SCC (SIR, 0.50). This finding "lends support to the hypothesis that this association may be due to PPI medication per se, and not related to other factors that predispose to using anti-acidic medications," the study authors say...Since the introduction of PPIs, the incidence of SCC of the esophagus has increased dramatically, Johnson acknowledged. The incidence of EAC in industrialized countries has also increased."
 
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aguilaroja

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...PPI drugs are probably the most prescribed class of drugs in the US and they are approved for pretty much any age group. I know of both month-old toddlers and 90+ year old adults who take them on a regular basis.
...After the PPI approval, subsequent studies over the years found that GERD is not really an acid- but an inflammatory-driven condition for which PPI drugs do absolutely nothing.
GERD (acid Reflux) Is Caused By Inflammation, Not Stomach Acid
... the study also found that the older GERD drugs known as H2 antagonists (famotidine anyone?) did not lead to increased risk of EC. There is really no other way to describe this finding except as an absolute disgraceful fiasco for both the pharma industry and the medical profession which enabled this massive fraud to occur every day.

Maintenance proton pump inhibition therapy and risk of oesophageal cancer - ScienceDirect
Medscape: Medscape Access
...This finding "lends support to the hypothesis that this association may be due to PPI medication per se, and not related to other factors that predispose to using anti-acidic medications," the study authors say...Since the introduction of PPIs, the incidence of SCC of the esophagus has increased dramatically, Johnson acknowledged. The incidence of EAC in industrialized countries has also increased."

PPI’s are also associated with a THREE-fold risk of stomach cancer. Again, famotidine and its cousins did NOT have this risk. For PPI users younger than 40 years old, the association with stomach cancer apparently rises more than TWENTY TWO times. (The risk for younger users appears so high I would appreciate if other readers double check my understanding.)

Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden
“Among 797 067 individuals on maintenance PPI therapy, the SIR[Standardised incidence ratios] of gastric cancer was over threefold increased (SIR=3.38…). Increased SIRs were found in both sexes and all age groups, but were especially increased among PPI users younger than 40 years (SIR=22.76…)
“…Long-term users of histamine 2 receptor antagonists, which have the same indications as PPIs, were not at any increased risk.”

Every major pharma category deserves scrutiny, because of numbers of people. The PPI problems, or “risks” and “adverse effects” list is ridiculously large. Imagine the outrage if these problems were associated with nutrient.
 

haidut

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PPI’s are also associated with a THREE-fold risk of stomach cancer. Again, famotidine and its cousins did NOT have this risk. For PPI users younger than 40 years old, the association with stomach cancer apparently rises more than TWENTY TWO times. (The risk for younger users appears so high I would appreciate if other readers double check my understanding.)

Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden
“Among 797 067 individuals on maintenance PPI therapy, the SIR[Standardised incidence ratios] of gastric cancer was over threefold increased (SIR=3.38…). Increased SIRs were found in both sexes and all age groups, but were especially increased among PPI users younger than 40 years (SIR=22.76…)
“…Long-term users of histamine 2 receptor antagonists, which have the same indications as PPIs, were not at any increased risk.”

Every major pharma category deserves scrutiny, because of numbers of people. The PPI problems, or “risks” and “adverse effects” list is ridiculously large. Imagine the outrage if these problems were associated with nutrient.

I don't know of any other drug that is so easily prescribed to any person, regardless of age or other health conditions, yet so many side effects and risks. Unlike pretty much all the other drugs prescribed can you think of any officially listed contraindication (other than allergy) that would make a doctor prescribe something other than PPI? I am not aware of any, meaning the doctor will push for a PPI until either the patient caves in or finds another doctor. Guess which one happens more often :):
 

Mito

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“........A direct carcinogenic effect of PPI use on the oesophageal mucosa may be unlikely, and we hypothesize that the increased oesophageal cancer risk is instead due to a disruption of the gastrointestinal microbiome [34]. The blocked gastric acid secretion could decrease the defence against pathogenic bacteria [35,36], and increase bacterial colonization (including non-gastric microorganisms) [37,38]. In particular, the potential increase of bacteria that produce nitrosamines may play a role, since nitrosamines are well-established risk factors for gastric and potentially also oesophageal cancer of both histological types [39]. Other possible pathways include bile salt toxicity because of the increased pH in the stomach, which may cause mucosal metaplasia in the oesophagus [40]. All these potential mechanisms could help explain our finding of an increased risk of both adenocarcinoma and squamous cell carcinoma of the oesophagus.”
 

haidut

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“........A direct carcinogenic effect of PPI use on the oesophageal mucosa may be unlikely, and we hypothesize that the increased oesophageal cancer risk is instead due to a disruption of the gastrointestinal microbiome [34]. The blocked gastric acid secretion could decrease the defence against pathogenic bacteria [35,36], and increase bacterial colonization (including non-gastric microorganisms) [37,38]. In particular, the potential increase of bacteria that produce nitrosamines may play a role, since nitrosamines are well-established risk factors for gastric and potentially also oesophageal cancer of both histological types [39]. Other possible pathways include bile salt toxicity because of the increased pH in the stomach, which may cause mucosal metaplasia in the oesophagus [40]. All these potential mechanisms could help explain our finding of an increased risk of both adenocarcinoma and squamous cell carcinoma of the oesophagus.”

Bogus explanation IMO, even though that explanation would account for the increase in small intestine cancers due to uncontrolled SIBO. The lack of gastric acid does directly cause SIBO. Microbiome has little to no influence on EC development.
 

aguilaroja

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...we hypothesize that the increased oesophageal cancer risk is instead due to a disruption of the gastrointestinal microbiome [34]. The blocked gastric acid secretion could decrease the defence against pathogenic bacteria [35,36], and increase bacterial colonization (including non-gastric microorganisms)...

Bogus explanation IMO, even though that explanation would account for the increase in small intestine cancers due to uncontrolled SIBO. The lack of gastric acid does directly cause SIBO. Microbiome has little to no influence on EC development.

This excerpt describs issue of what a mess the PPI treatment category is, types of harm, and the skill needed to assess things in life, instead of for sales. The authors are from multiple specialties in Italy.

Adverse events of proton pump inhibitors: potential mechanisms. - PubMed - NCBI
“PPIs may cause potentially harmful effects by several mechanisms, including endothelial dysfunction, hypomagnesemia, drug interactions, reduced absorption of selected nutrients, increased gastric microbiota and small intestine bacterial overgrowth, reduced immune response, tubular-interstitial inflammation, increased bone turnover, accumulation of amyloid in the brain. Clinical and epidemiologic evidence is not consistent in regard to some negative outcomes during PPI treatment. Data from randomized clinical trials seem to deny most of them, but they are usually designed to investigate efficacy of drugs in ideal conditions and are not powered enough to detect adverse events. Besides being at special risk of experiencing negative outcomes during long-term treatment with PPIs, older and complex patients treated with polypharmacy regimens are persistently excluded from randomized clinical trials. Thus, large observational studies involving real-world patients should be considered as an important informative source about potential risks related to PPIs.”
 

freyasam

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Sending this to my dad. His doctor prescribes PPI medication long term for GERD. He's asked about the cancer risk because of my prodding yet the doctor shrugs off his concerns. I am so fed up with negligent doctors.

So does this quote below mean aspirin increases the risk of EC as well??

For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96–3.71) and 2.06 (95% CI 1.60–2.60), respectively.
 

Mito

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This mass prescription materialized despite serious concerns surrounding the animal studies with PPI, showing increased incidence of gastric cancer, osteoporosis, neurodegenerative disease and mental health issues.
There is a lot of confusion because of studies like this one. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874135/pdf/WJG-16-2323.pdf which attempts to explain away the cancer, osteoporosis and other concerns. “Thus, in summary, the PPIs are a safe class of medications to use long- term in persons in whom there is a clear need for the maintenance of extensive acid inhibition.”
I’d be interested to know who funded that study suggesting PPI’s are safe long term.

And then there is this study (Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. - PubMed - NCBI) that says “PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract.”
 
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haidut

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There is a lot of confusion because of studies like this one. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874135/pdf/WJG-16-2323.pdf which attempts to explain away the cancer, osteoporosis and other concerns. “Thus, in summary, the PPIs are a safe class of medications to use long- term in persons in whom there is a clear need for the maintenance of extensive acid inhibition.”
I’d be interested to know who funded that study suggesting PPI’s are safe long term.

And then there is this study (Potential anti-inflammatory effects of proton pump inhibitors: a review and discussion of the clinical implications. - PubMed - NCBI) that says “PPIs have been found to have anti-oxidant properties and direct effects on neutrophils, monocytes, endothelial, and epithelial cells that might prevent inflammation. Those anti-inflammatory effects of the PPIs might influence a variety of inflammatory disorders, both peptic and non-peptic, within and outside of the gastrointestinal tract.”

The indisputable fact is that despite massive prescriptions for PPI, the rates of esophageal cancer continue to rise. Those rises in both prescription and EC rates match rather well, but even if one does not want to blame the drugs as part of the cause it is hard to deny that they are pretty useless as prevention (which is the main reason they were approved to start with).
 

haidut

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Sending this to my dad. His doctor prescribes PPI medication long term for GERD. He's asked about the cancer risk because of my prodding yet the doctor shrugs off his concerns. I am so fed up with negligent doctors.

So does this quote below mean aspirin increases the risk of EC as well??

For example, the SIRs among participants using maintenance PPI therapy because of maintenance treatment with non-steroidal anti-inflammatory drugs and aspirin were 2.74 (95% CI 1.96–3.71) and 2.06 (95% CI 1.60–2.60), respectively.

It is not correct to say aspirin increased the risk of EC. More like, people already using aspirin for other reasons and adding a PPI on top of that had increased risk of EC compared to average risk for EC in the general population. Given that people using only PPI had higher EC risk (3.93), then we can say the ones who used aspirin and PPI actually had lower EC risk (2.06). The risk would still be higher though compared to people who took only aspirin and no PPI, but at least the aspirin provided some protection - almost 50% reduction in risk to be precise!

"...The overall SIR of oesophageal adenocarcinoma was 3.93 (95% CI 3.63–4.24) in both sexes combined, 4.22 (95% 3.87–4.58) in men and 2.89 (95% 2.36–3.50) in women (Table 2)."
 

Mito

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I don't know of any other drug that is so easily prescribed to any person, regardless of age or other health conditions, yet so many side effects and risks. Unlike pretty much all the other drugs prescribed can you think of any officially listed contraindication (other than allergy) that would make a doctor prescribe something other than PPI? I am not aware of any, meaning the doctor will push for a PPI until either the patient caves in or finds another doctor. Guess which one happens more often :):
Any speculation as to the mechanism of PPI’s harmful effects? Does it slow down the movement of hydrogen ions in the electron transport chain systemically? I know it’s supposed to target gastric parietal cells but I think I’ve heard that it inhibits other cells somewhat as well. Or is it just due to reduced stomach acid causing nutritional deficiencies and or microbiome overgrowth?
 

haidut

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Any speculation as to the mechanism of PPI’s harmful effects? Does it slow down the movement of hydrogen ions in the electron transport chain systemically? I know it’s supposed to target gastric parietal cells but I think I’ve heard that it inhibits other cells somewhat as well. Or is it just due to reduced stomach acid causing nutritional deficiencies and or microbiome overgrowth?

The mechanisms of action are so many that I don't know where to start. The depletion of magnesium and elevation of prolactin are probably near the top of the list, as the latter one suggests the PPI are estrogenic and there is a well-known link between high estrogen + low androgens in many cancers, including EC.
Esomeprazole induced galactorrhea: a novel side effect. - PubMed - NCBI
Hyperprolactinaemia induced by proton pump inhibitor
Estrogen, male dominance and esophageal adenocarcinoma: Is there a link?
 

ubiety

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The mechanisms of action are so many that I don't know where to start. The depletion of magnesium and elevation of prolactin are probably near the top of the list, as the latter one suggests the PPI are estrogenic and there is a well-known link between high estrogen + low androgens in many cancers, including EC.
Esomeprazole induced galactorrhea: a novel side effect. - PubMed - NCBI
Hyperprolactinaemia induced by proton pump inhibitor
Estrogen, male dominance and esophageal adenocarcinoma: Is there a link?

Is famotidine as harmful as other PPIs? There are discussions on these forums about the benefits of famotidine - helps hypoglycemia, etc.
 

haidut

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Is famotidine as harmful as other PPIs? There are discussions on these forums about the benefits of famotidine - helps hypoglycemia, etc.

Famotidine is NOT a PPI, it is an H2 antagonists. This is why I mentioned it in my post - i.e. H2 antagonists like famotidine do not increase risk of EC.
 
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freyasam

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I went looking for a study that compared the risk of esophagael cancer in PPI users to those with untreated GERD. Since untreated GERD can also cause EC, and that's what the doctors tell my dad to get him to continue using PPIs. Do you know of any, Haidut? Thanks for all the help!
 

haidut

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I went looking for a study that compared the risk of esophagael cancer in PPI users to those with untreated GERD. Since untreated GERD can also cause EC, and that's what the doctors tell my dad to get him to continue using PPIs. Do you know of any, Haidut? Thanks for all the help!

I am sure there are but they are probably older because newer studies consider it unethical to have a true placebo group, so I'd look for studies before 1980s. Maybe @aguilaroja has some info on that.
 

aguilaroja

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I went looking for a study that compared the risk of esophagael cancer in PPI users to those with untreated GERD. Since untreated GERD can also cause EC, and that's what the doctors tell my dad to get him to continue using PPIs....

Please have your father’s doctor note that BOTH the studies noting association of PPI’s with increased esophageal cancer AND with increased stomach cancer found that BY COMPARISON the GERD-relieving H2 blockers (famotidine and its cousins) did NOT increase the cancer risk.

That is, the H2-blocker category is more safe relating to cancer risk, to treat the same condition. There’s no question that H2 blockers are sometimes effective for relieving GERD. Other pharmaceutical categories have effectiveness for GERD too. The specialty “position papers”-FOR ADULTS-say that PPI’s work better. (It is too time intensive to critique these studies.) I know many people who switched from PPI’s to famotidine and got at least as good relief from GERD while eliminating some PPI side effects.

Plus, if the doctor(s) are concerned about esophageal cancer prevention, are they considering aspirin or assisting, if applicable, with smoking cessation?
http://cancerpreventionresearch.aacrjournals.org/content/9/11/828.long
“There is medium-level evidence of a preventive effect of tobacco smoking cessation in relation to the risk of EAC.”
“Use of NSAIDs, both aspirin and non-aspirin, seems to prevent EAC[Esophageal adenocarcinoma], and results from RCTs are approaching.”

https://www.ncbi.nlm.nih.gov/pubmed/28954042
“Eight studies demonstrated that both proton pump inhibitors and histamine H2 receptor antagonists were effective against typical manifestations of gastroesophageal reflux disease, and that there was no evidence of benefit in combining the latter to the former or in routinely prescribing long-term maintenance treatments.”
“CONCLUSION: Proton pump inhibitors or histamine H2 receptor antagonists may be used to treat children with gastroesophageal reflux disease,…”
 

aguilaroja

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aguilaroja said:
Other pharmaceutical categories have effectiveness for GERD too.
Can you share what those are?
Excuse me, I was thinking that once a new medication is promoted for sale, previous effective categories are shoved aside.

Before PPI’s and the H2-blocker were marketed, antacids and coating agents(Sucralfate) were used for heatburn and ulcers, and provided some relief. (Sucralfate includes aluminum in its chemical complex. Some antacids also contain aluminum. Aluminum intake is concerning, and potentially dangerous. But the category of coating agent as an idea may be superior to “proton pump inhibitor”.) Doctors rarely emphasized that antacids had a short-lasting action, and needed to be used repeatedly through the day/night. Cimetidine (Tagamet) came along, and once/twice daily dosing became usual.

https://www.health.harvard.edu/staying-healthy/gerd-heartburn-and-more
https://www.health.harvard.edu/diseases-and-conditions/gastroesophageal-reflux-disease

I suppose “prokinetic”/GI motility agents like metoclopramide are also a category of GERD-treatment agents. There may be more drug options, and also other remedies.
 

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