PPI safety

This paper published in Current Opinions in Gastroenterology in 2019, "Proton Pump Inhibitors: Placing Putative Adverse Effects in Proper Perspective" warned:

"Although generally considered well tolerated, epidemiologic studies that mine large databases have reported a panoply of putative adverse effects associated with PPIs. It should be emphasized that the quality of the evidence underlying most of these associations is very low and the studies, by design, cannot ascribe cause and effect. These associations continue to be sensationalized in the media and misinterpreted by providers and patients. The unintended consequences are that patients who require PPIs, such as those taking dual antiplatelet agents, are not being prescribed or taking these necessary medications."

Cardiovascular risk?

In a 2024 paper from the American Journal of Gastroenterology found no link between PPI use and risk of cardiovascular events, the meta-analaysis of randomised controlled events, Researchers included data from 52 placebo-controlled trials, with 14,988 patients finding "Cardiovascular outcomes were infrequent in randomized trials of PPIs."

However a Chinese paper in 2024 "provides evidence supporting a causal relationship between GERD and alterations in blood pressure components, lipid profile, and increased risk of cardiovascular diseases". 

Kidney Disease?

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."

A 2023 paper looking at Proton Pump Inhibitors and Kidney Damage, observed; "The causality between PPI use and increased mortality and disease risk can be questioned since most studies are observational. Confounding variables can greatly affect an observational study and explain the wide-ranging associations with the use of PPIs. Patients on PPIs are generally older, obese, sicker with a higher number of baseline morbidities, and on more medications than the compared PPI non-users. These findings suggest that PPI users are at a higher risk of mortality and complications based on pre-existing conditions."

Dementia?

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 number of observational studies, cognitive decline and dementia in the elderly ... linked to the use of PPIs" prompted this 2024 study from Current Alzheimer's Research, "Proton Pump Inhibitors and Cognitive Health: Review on Unraveling the Dementia Connection and Co-morbid Risks suggesting "These drugs might also alter the pH of brain cells, resulting in the accumulation of amyloid-beta (Aβ) peptides and the development of Alzheimer's disease (AD), but concluding however, "Despite the compelling evidence supporting the association of PPIs with dementia, the results of studies remain inconsistent. The absence of a correlation between PPI use and cognitive decline in some studies emphasizes the need for additional research. "

Cancers?

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."

Osteoporosis

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.

Other Cancers

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"

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 13 October 2025