Proton pump inhibitors (PPIs) are very popular medications because they are extremely efficient at shutting down the production of acid in the stomach. This might seem like a great idea for those suffering from “heartburn” or gastroesophageal reflux disease. GERD is inflammation of the esophagus (the tube connecting the throat to the stomach) caused by acid backing up from the stomach into the esophagus. But it is an even better idea to take a step back and look at the big picture before you make the decision to take a PPI. Medical practitioners are becoming aware of the hazards of PPI use and many are reaching the conclusion that these medications should be used sparingly and only for serious and chronic stomach problems. (1,2,3)
The first thing to point out is that there are ways to prevent heartburn without taking drugs. Heartburn is not caused by an excess of stomach acid but by the movement of acid from the stomach up into the esophagus, a part of the digestive system that is not designed to handle acid. In heartburn, the lower esophageal sphincter, the valve that separates stomach contents from the esophagus, is not working properly. In addition, the movement of food from the stomach and into the intestinal tract is hindered. (4) The good news is that by simply making better lifestyle choices these two situations can often be completely remedied.
Note that PPIs do not stop the backing up of acid into the esophagus. They work by reducing the acidity of the stomach fluid through the blocking of an enzyme necessary for the secretion of hydrochloric acid into the stomach. With little acid in the stomach fluid, the symptoms of burning which are caused by the acid are substantially reduced or stopped altogether. (5) PPIs take several days to exert their full effect on stomach acid production and must be taken once or twice every day to continue to work (6).
The bottom line of this matter is that the acid is present in your stomach to perform a variety of important functions. For instance, it helps to prevent harmful bacteria and viruses that may be in the food you eat from entering your bloodstream; it breaks down protein into amino acids, the form in which they are most efficiently absorbed into the body; it aids the absorption of bone-building calcium and magnesium; it ensures that the pH in the stomach is low so that digestive enzymes work properly; and it plays a part in the regulation of stomach functions including peristalsis, the forceful back-and-forth churning movement in the walls of the digestive tract that breaks down food into smaller components, as well as the coordinated wave-like movements that urge food along its way through the digestive system. (7,8,9)
What are PPI medications?
There are six PPIs available in Canada through a prescription from a medical practitioner. These are omeprazole (Losec), esomeprazole (Nexium), lansoprazole (Prevacid), pantoprazole (Pantoloc), rabeprazole (Pariet) and dexlansoprazole (Dexilant). Many of these have generic choices as well. The omeprazole product, Olex, is available without a prescription. Another prescription product, Vimovo, is a combination of the anti-inflammatory medication naproxen and the PPI esomeprazole. (10) PPIs take several days to exert their full effect on stomach acid production and must be taken once or twice every day to continue to work (6).
As research on PPIs continues, their use is now associated with a number of noteworthy health issues.
The Dangerous Side of PPIs
A study from 2020 found that the more often a person takes a PPI and/or the higher the dose of the PPI, the greater the risk of Covid-19 disease. (11)
People taking a PPI once a day were found to be twice as likely to test positive for Covid compared to people not taking a PPI.
People taking a PPI twice a day were found to be four times more likely to test positive for Covid compared to people not taking a PPI.
Other studies show that taking a PPI is associated with more severe illness from Covid-19. These links may be due to the low stomach acid caused by PPIs allowing SARS-CoV2, the virus that causes Covid-19, to survive longer in the digestive tract. (8)
Cardiovascular Disease (12,13)
There is accumulating evidence that PPI use, especially in high doses or taken long-term, is linked with substantial increases in cardiovascular events including stroke, myocardial infarction, and death due to cardiovascular disease. This effect seems to be due to a reduction in the level of nitric oxide within blood vessels. The endothelium, the thin inner lining of blood vessels, produces a gas called nitric oxide that is responsible for relaxation of the smooth muscles within the blood vessel walls, allowing them to dilate when more blood flow is needed. In addition, nitric oxide reduces inflammation and plaque build-up on the inner wall of the vessels. Research has discovered that PPIs bind to and inhibit an enzyme that is required to allow the production of nitric oxide (13). More study is needed to determine the details of the adverse effects of PPIs on the cardiovascular system.
In the past, PPIs were thought to have anti-cancer activity. A less acidic stomach environment appeared to enhance the activity of tumour-fighting lymphocytes and high concentrations of PPIs in some studies seemed to show an ability to kill some types of cancer cells or sensitize them to chemotherapy. In fact, PPIs are often prescribed to cancer patients to offset side effects of cancer drugs. However, until recently, the effect of PPIs on cancer mortality were largely unknown. In 2018, a large retrospective cohort study from Denmark uncovered an association between PPI use and statistically significant increases in death caused by cancer when compared to nonusers. This link was found in most types of cancer except for cancer of the esophagus, cervix and pancreas. (14)
Specifically, this research found the following increases in death from PPIs; (14)
A 35% increase in the risk of death from cancer of the ovary
A 30% increase in the risk of death from cancer of the breast
A 25% increase in the risk of death from cancer of the prostate
In addition, these researchers ran trials using mice and observed an acceleration in the growth of cancer tumours. They concluded that PPIs may worsen the prognosis of cancer patients and should not be used as a supplement to cancer therapy. (14)
In March 2022 a new study looked at drug interactions between PPIs and cancer medications. Results revealed that PPIs can decrease the effectiveness of some anti-cancer therapies directly through drug-to-drug interactions and also indirectly through the actions of PPIs on the microbiome. Researchers noted that further studies on this topic are warranted but physicians need to be aware of the potential consequences of the prescribing of PPIs in cancer patients. (15)
Other recent studies have revealed additional correlations between the use of PPIs and cancer. PPIs reduce the secretion of stomach acid which leads to a rise in gastrin levels and can result in an increase in the growth of cancers such as neuroendocrine tumours and carcinomas of the gastrointestinal tract (16,17). PPIs also encourage colonization by Helicobacter pylori bacteria in the stomach because of the reduction of stomach acid. (The presence of Helicobacter pylori in the stomach is associated with the development of stomach ulcers and stomach cancer.) (16)
NOTE: Gastrin is produced by specialized cells in the lining of the stomach through the presence of food in the stomach. Gastrin causes the release of hydrochloric acid into the stomach to help break down and digest foods. (18)
Chronic Kidney Disease
Case reports of a correlation between the use of PPIs and the development of kidney disease began to emerge soon after the introduction of these medications and subsequent scientific research has continued to corroborate this effect. Studies report significantly higher risk for Chronic Kidney Disease (CKD) among chronic PPI users when compared to non-users of PPIs. In addition, a dose-dependent relationship was observed that exposed a higher CKD risk with twice daily dosing of PPIs compared to once daily dosing. (12)
The mechanisms for this effect have not yet been clarified but PPI treatment is connected to the occurrence of acute interstitial nephritis (inflammation of the kidneys characterized by swelling and scarring (19)). In addition, lack of magnesium, another consequence of long-term PPI use, can lead to injury in the tubules within the kidneys. Inflammation and oxidative stress can also cause dysfunction of the endothelium that lines blood vessels. Researchers note that it is very important to monitor kidney function in patients taking PPIs and to withdraw the medication if any sign of renal dysfunction is discovered. (17,2)
Liver disease (17)
Chronic PPI use has been linked to increased risk of complications due to cirrhosis of the liver including liver cancer. Patients using PPIs for more than one year exhibit twice the risk of liver cancer compared to patients not taking a PPI. This effect may be due to bacterial overgrowth in the intestines because of the lack of stomach acid and/or alterations in the composition of the gut microbiome by PPIs.
A systematic search and meta-analysis of the literature was performed in 2016 looking at the relationship between PPIs and fracture risk. Results revealed that PPI use both short term (less than 1 year) and long-term (more than 1 year) was linked to (20)…
…an increase in the risk of hip fracture by 26%
…an increase in the risk of spine fracture by 58%
…an increase in the risk of fracture in any site by 33%
A study from 2019 investigated recent research and exposed the correlation between PPI use and elevated bone fracture risk in multiple studies. The instigators of this association are thought to be increased production of gastrin and reduced acid in the stomach, both of which have detrimental effects on mineral absorption and bone remodeling. (21)
From 2021 comes a meta-analysis that illustrates increased risk of fragility fractures, mainly hip fractures, from long-term/high-dose PPI use. Suggested mechanisms of this effect include impaired absorption of micronutrients, high levels of gastrin and increased secretion of histamine. Researchers note that further studies are needed to clarify details of the effects of PPIs on bone. (22)
A German study from 2016 concluded that older people taking PPIs may be at increased risk of developing dementia. The neuropsychological health and medical history of over 73,000 dementia-free patients aged 75 or over were tracked from 2004 to 2011. Results showed that those who used PPIs regularly (at least one prescription every 3 months) had a 44% higher risk of developing dementia compared to patients not taking PPIs. (23) The proposed mechanism for this heightened risk is that PPIs interfere with the activity of scavenger enzymes which perform the job of cleaning up beta amyloid in the brain, thus allowing it to accumulate. Beta amyloid is implicated in the development and progression of dementias such as Alzheimer’s disease. (2)
A 2022 prospective analysis of data from the UK Biobank looked at over 500,000 females aged 40 to 70, with no dementia at baseline, and tracked their cognitive health from 2006 to 2010 along with a final follow-up check in 2018. Increased risks of dementia were observed in those taking a PPI compared with those not taking a PPI as follows (24);
20% increased risk for dementia from all causes
46% increased risk of dementia in those carrying the APOE ε4 gene, an already established major genetic risk factor for cognitive decline and late-onset Alzheimer’s disease
Some experts hypothesize that PPIs affect the brain indirectly by instigating unusually low levels of Vitamin B12 and magnesia in the brain. Others suggest that PPIs may cause unusual types of tau protein to collect inside neurons. (8)
Conversely, other studies have found no evidence of a link between PPI use and dementia. For instance, a 2020 study from Wales using their electronic health-data observed no correlation between those taking a PPI and increased dementia risk (25). More study is needed to determine if PPI use is responsible for the observed relationship between PPIs and an increase in the risk of dementia. (26)
PPIs are known to affect the gut microbiota and such alterations cause changes in the host immune system, often inducing the development of autoimmune diseases. A 2021 study from Taiwan used a database of nearly 300,000 patients and revealed increases of more than 300% in the risk of developing an autoimmune disease in those taking a PPI. The autoimmune diseases affected include Graves disease, Hashimoto thyroiditis, rheumatoid arthritis, primary Sjogren syndrome, systemic lupus erythematosis, psoriasis, systemic scleroderma, autoimmune hemolytic anemia, immune thrombocytopenic purpura, myasthenia gravis, ankylosing spondylitis, and more. In addition, this research showed that these increased risks were evident no matter what dose of PPI was being taken. Researchers proposed that PPIs negatively alter the makeup of the gut microbiome. (27,8)
Clostridium difficile infections (8,17,2)
Infections caused by the bacteria Clostridium difficile (in short, C. difficile or C diff), once mainly a problem in hospitalized patients taking antibiotics, are now becoming more common in the general community. New strains of C. difficile have appeared that are antibiotic resistant and very difficult to treat and, unfortunately, C. difficile infections are serious and potentially fatal. Because PPI drugs reduce the acidity of the gut, it appears that they can allow the C. difficile bacteria to flourish, causing significant changes in the microbiome of the gut and especially decreasing its diversity. Studies report that C. difficile infections occur at almost two times the rate in PPI users compared to non-PPI users.
Several studies from the late 1990s and early 2000s indicated an association between the use of PPIs and the development of community-acquired pneumonia. This link is not found with the use of less potent agents for stomach problems such as H2 receptor blockers or antacids (see “Alternatives to PPIs” below). However, it is becoming apparent that any acid suppression in the stomach can be connected with the development of pneumonia.
The reason for this effect is thought to be that the low level of stomach acid caused by PPIs can promote bacterial overgrowth that can end up as pneumonia. PPIs may also impair immune cell function which also has the potential to increase the risk of infections. The overall quality of the evidence available for the influence of PPIs on pneumonia is low and more study is needed.
Research from 2021 that included over 80,000 young girls showed that the incidence rate of asthma in children taking PPIs was 57% higher than the incidence rate of children not taking PPIs. The risk of asthma was increased across all age groups and was highest for infants and toddlers whose risk was 83% to 91% higher. The mechanism of this effect may be interruptions in the balance between healthy and unhealthy species of microbes in the gut and lung. (28)
A recent meta-analysis discovered that pregnant women who used PPIs were associated with a 30% to 34% increase in the risk of delivering babies who subsequently developed asthma. (29)
Risk of low blood magnesium levels (2)
Magnesium is a mineral required for optimal health in humans. Magnesium decreases inflammation, reduces platelet aggregation (sticking together and forming a blood clot) and prevents arrhythmias. Chronic low magnesium levels may increase the risk of cardiovascular disease, diabetes and osteoporosis. PPI use seems to be a contributor to low blood magnesium. One possible cause of this is the reduction of the pH of the digestive system by PPIs which decreases the transport of magnesium from the intestine into the bloodstream.
Alternatives to PPIs
The efficiency of PPIs in reducing and eliminating stomach symptoms has undoubtedly led to their excessive usage. Current evidence suggests that 25 to 70% of prescriptions written for PPIs are for unapproved indications such as the overtreatment of indigestion and heartburn. In addition, PPI use is often continued for months or years in spite of its suggested use for only 2 to 12 weeks. As medical practitioners become more aware of the negative and unintended consequences of PPI use, changes in their use are inevitable. New recommendations are appearing that suggest the use of PPIs only when clearly indicated, for serious conditions and after less risky antacid agents and H2-receptor blockers have been tried. Regular monitoring of patients taking PPIs is a must, the dosage should be kept at the lowest effective level and the length of PPI use needs to be minimized. Certainly, an occasional case of mild heartburn should not be treated with a PPI. (2,3,12,31)
Happily, there are a number of alternate choices for the therapy of inflamed stomach tissues that can avoid the need for a PPI.
The following list of lifestyle adjustments can make a big difference in heartburn/GERD symptoms and can often get rid of them entirely. (8,28,32,33).
- Stop smoking
- Lose weight if needed
- Eat more fiber. Studies show that a fiber-enriched diet will lead to an increase in the resting pressure of the lower esophageal sphincter resulting in decreased frequency of heartburn (36). Fiber is only found in plant-sourced foods such as vegetables, fruits, grains, nuts and seeds
- Eat less fat. Dietary fats slow the rate at which the stomach empties, often resulting in acid reflux into the esophagus. Lower your intake of meats and dairy products, baked goods, desserts and added oils and fats.
- Check out foods that have been associated with worsening stomach symptoms and avoid them if they aggravate your problem. These suspects include spicy foods, citrus fruit, carbonated beverages, onions, garlic, tomatoes and caffeine.
- Avoid chocolate and peppermint. They can relax the lower esophageal sphincter allowing stomach fluids to travel backward up into the esophagus.
- Avoid snacks before bedtime
- Limit alcohol consumption and especially avoid drinking alcoholic drinks within two or three hours of bedtime
- Eat several small meals a day instead of three large ones
- Avoid lying down for at least three hours and preferably four hours after eating so that the stomach has time to empty completely
- Reduce stress
- Limit the use of non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen and naproxen. Use of these medications are known to increase the risk of GERD.
- Elevate the head of your bed by about six inches. This step gets gravity working for you to help empty the stomach.
If stomach symptoms continue despite lifestyle changes here are some other options that are much safer than PPI medications. (8)
Simple Antacids are old standbys for the short-term relief of stomach symptoms. They work quickly to neutralize stomach acid. They come in the form of suspensions and effervescent or chewable tablets. Antacids include Alka-Seltzer Effervescent Tablets (citric acid, acetylsalicylic acid and sodium bicarbonate), Maalox Suspension (aluminum hydroxide and magnesium hydroxide), Mylanta Suspension (aluminum hydroxide, magnesium hydroxide, and simethicone), Rolaid Chewable Tablets (calcium carbonate and magnesium hydroxide), and Tums Chewable Tablets (calcium carbonate). The side effects of antacids are generally mild ones such as diarrhea and constipation. (9,34)
H2 receptor blockers such as cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid) and ranitidine (Zantac) are available by prescription and over-the-counter for an inflamed stomach, peptic ulcers and GERD symptoms. They are actually more effective than a PPI for a mild, short-term stomach acid problem because they go to work quickly whereas PPIs take several days to develop their full effects.
H2 receptor blockers reduce stomach acid but work in a different way than the PPIs. A chemical produced by the body called histamine stimulates cells in the stomach lining to make hydrochloric acid. H2 receptor blockers bind to histamine receptors in the stomach thereby reducing the production of hydrochloric acid. H2 receptor blockers work within 60 minutes and their effect lasts from 4 to 10 hours. They can be taken when needed for reducing stomach acidity symptoms and allowing inflamed tissues to heal. Common side effects include constipation, diarrhea, dry mouth, dry skin, headaches, difficulty sleeping and trouble with urination. More serious but rare side effects include blistered skin, confusion, hallucinations, agitation, vision changes and wheezing. (35,6)
If you are experiencing symptoms of stomach discomfort, it is important for your health not to reach immediately for a PPI. Try out the many lifestyle changes that can help. It will be worth it when you find you’re no longer experiencing the ongoing pain of heartburn or GERD and that you have achieved this by avoiding a drug that may lead you into further health troubles in the future. On the other hand, if lifestyle alterations are not working, that is the time to contact your medical practitioner and see if you should be taking a PPI.
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