Health Risks of Acid Reflux Medications

Heartburn is defined medically as gastroesophageal reflux disease (GERD).

GERD is caused by the incomplete closure of the sphincter valve between the stomach and the esophagus. This incomplete closure allows harsh stomach contents to reflux back up into the delicate lining of the esophagus, throat, and other tissues.

GERD usually manifests as occasional or chronic pain in the center of the chest and can progress to esophagitis, premalignant changes (Barrett’s esophagus), and esophageal cancer.

Contrary to popular belief, excess stomach acid is not the cause of GERD. Since the advent of drugs such as Nexium^®, Prilosec^®, and Prevacid^®, however, the public thinks all that needs to be done to protect against GERD is to block stomach acid production. This misconception can have deadly consequences.

While proton-pump inhibiting drugs (like Prilosec^®) provide merciful relief from the symptoms and some of the pathological effects of GERD, chronic use of these drugs can lead to nutritional deficiencies, bone fractures, and heart disease.

While proton-pump inhibiting drugs impede acid production, they don’t stop the reflux of digestive enzymes, bile, and corrosive food/drinks into the esophageal lining.

Adenocarcinoma of the esophagus has been climbing at an alarming rate and cures elude the majority of patients. Interestingly, this increase in esophageal cancer comes at a time when tobacco use has plummeted.

Tobacco use sharply increases risk of squamous cell carcinoma, but the more prevalent adenocarcinoma is thought to be more related to obesity, which exacerbates the volume of stomach contents that reflux back up into the esophagus.

This article identifies the health risks associated with the overuse of proton-pump inhibiting drugs and provides some alternative treatment considerations.

About 40% of Americans suffer from heartburn attacks every month (with more than 20% experiencing attacks weekly). Long-term therapy is needed for those with more than occasional heartburn.^1,2

The danger is that, after prolonged exposure to harsh stomach contents, the cells of the lower esophagus undergo precancerous changes that can lead to esophageal cancer, a growing cause of cancer deaths in older adults.^3,4

For chronic GERD sufferers, most physicians prescribe oral drugs that reduce acid secretion in the stomach. Prominent among such drugs are the proton pump inhibitors, which include omeprazole, lansoprazole, pantoprazole, esomeprazole, and rabeprazole, sold under a variety of trade names such as Nexium^®, Prilosec^®, and Prevacid^®.

Unfortunately for GERD victims, long-term use of these drugs brings with them a host of side effects, all related to the drugs’ successful lowering of stomach acid production.

These complications, while not immediately life-threatening, are beginning to concern experts because of their potential impact on quality of life and on long-term health ranging from the heart to the bones and even to the risk for infection, particularly among older adults.

GERD, Proton Pump Inhibitors, and Long-Term Health

 

The human stomach is an extreme environment, constantly churning with muscular action, boiling with hydrochloric acid at a pH near 1, and laden with protein-destroying enzymes. This environment is essential for proper breakdown of large food molecules in preparation for further digestion and absorption in the small intestine. Fortunately, the stomach is well protected against these threats, producing a thick lining of mucus that separates the stomach contents from the delicate walls of the stomach itself.

But the esophagus, the long, flexible tube that connects the mouth to the stomach, lacks protection against acid and other digestive contents. Instead, the esophagus is protected by gravity and a relatively weak sphincter muscle at the lower end of the esophagus to keep stomach contents in place.

After a heavy meal, particularly a fat-rich one that can slow stomach emptying, the pressure in the stomach can overwhelm the lower esophageal sphincter, allowing highly corrosive stomach contents to reflux, or wash back, into the esophagus.⁵ And many people suffer from transient relaxation of this sphincter, which permits reflux to occur unpredictably.

Symptoms of reflux include the burning sensation referred to as heartburn and are often accompanied by uncomfortable belching and a sour taste in the mouth.

Whether it is called heartburn, reflux, or GERD, the condition is both painful and potentially dangerous. The danger is that, after prolonged exposure to the acids and protein-digesting enzymes in stomach fluid, the cells of the lower esophagus undergo precancerous changes. A so-called Barrett’s esophagus, with a large number of abnormal cells in it, is a precursor to esophageal cancer, a growing cause of cancer deaths in older adults.^6,7

What You Need to Know

Health Risks of Proton Pump Inhibitors

• Heartburn or gastroesophageal reflux disease (GERD) is a major problem affecting millions of older Americans.
• The condition is caused by reflux of acidic, enzyme-rich stomach contents flowing backwards out of the stomach and into the esophagus.
• Chronic exposure to stomach contents can alter the esophageal lining, eventually making it cancer-prone.
• Reduction of GERD symptoms and effects is therefore an important part of modern medicine.
• A highly effective class of drugs called proton pump inhibitors (PPIs) has emerged. PPIs are capable of suppressing stomach acid production and mitigating symptoms.
• Large numbers of people are now using PPI therapy for prolonged periods, leading to unanticipated consequences.
• These consequences include diminished absorption of vitamins and minerals, poor bone quality, and an increased risk for fracture and even cardiovascular abnormalities that can increase the risks of heart attack or stroke.
• Several natural supplements are now available for people who take PPIs but want to reduce their risk.
• Other supplements may help individuals avoid use of PPIs entirely, because they suppress GERD symptoms effectively on their own.

Modern Day Relief

As a result of all this pain, discomfort, and risk, drug companies, physicians, and patients have eagerly sought a way to reduce the symptoms and cancer threats of GERD. One way of mitigating GERD is to reduce stomach acid production. A number of medications have been developed to do just that, with the category of proton pump inhibitors (PPIs) clearly in the lead.

PPIs work by blocking the action of the cellular “proton pump” in stomach lining cells.⁸ That pump generates protons (hydrogen ions) from the bloodstream and pushes them out into the stomach.⁸ The harder that pump works, the more acidic the stomach contents become.

Using one of the PPI drugs reduces the amount of acid that goes into the stomach, which in turn reduces the amount of acid that can reflux, or wash back, into the esophagus to produce heartburn or GERD.⁹

Proton pump inhibitors do a very good job of reducing symptoms of acid reflux. Such a good job, in fact, that they are the third largest-selling class of drugs, with more than 119 million prescriptions written annually. They generate nearly $14 billion in sales.^2,9,10

Originally marketed as prescription drugs for intermittent use, these drugs have been available over the counter for more than a decade, and, though still clearly labeled for limited duration use, many patients with moderate to severe GERD take them as long-term maintenance drugs.²

But, because PPI drugs are so effective at reducing symptoms, and because they are so widely used for such extended periods, some findings are now being reported that were not apparent when these drugs first hit the market.

We should note here that none of the PPI side effects pose immediate, urgent health threats, so it is important that each patient consult with his or her physician about the balance of risks and benefits. Nonetheless, many of the effects of PPIs can, over the long term, raise the risk for significant diseases, such as cardiovascular disease, osteoporosis, infections, and others.^2,9,11

PPIs Interfere with Vitamin and Mineral Absorption

 

Vitamin B12, like most vitamins, must be obtained from the diet, where it is bound to proteins.^2,12,13 Deficiencies in vitamin B12 can produce anemia, depression, and disrupted nerve signaling (including decreased taste and numbness or tingling in the extremities).¹⁴

But an acidic stomach environment is essential for proper vitamin B12 absorption because the acid is required to break down dietary proteins to which the vitamin is bound, and release it for absorption.^2,15 Reducing stomach acid, especially by proton pump inhibitors, is likely to interfere with our ability to extract vitamin B12 from our foods.

Studies show that most oral acid-suppressing medications, including PPIs, decrease absorption of vitamin B12 from foods.^2,12 In one compelling study, 75% of PPI users were deficient in vitamin B12, compared with just 11% in non-users, a significant difference.^2,16 Other studies document a nearly 4-fold increase in the risk of B12 deficiency among users of oral acid suppressant drugs, both PPIs and H2 blockers, now a second-line drug.^2,17

Experts recommend that, based on current information, people taking PPI therapy for long periods should have their vitamin B12 levels checked and consider supplementation.^18,19 Vitamin B12 supplied as a crystalline supplement appears to be better absorbed in people taking PPIs than is vitamin B12 supplied in food.^2,18 That is because it does not have to be separated from foods in the stomach.

Iron is an essential nutrient, especially for formation of red blood cells and proper muscle function. Like vitamin B12, stomach acid is an important requirement for proper absorption.²⁰ That’s because about one-third of our iron intake comes from non-animal sources, where it is bound to plant chemicals that inhibit its absorption, while stomach acid breaks down those inhibitory molecules.²⁰ This problem is especially important in people who eat little to no meat, since obviously the proportion of iron from plant sources they receive is considerably larger.

Furthermore, studies show that people with conditions that naturally produce low stomach acid concentrations, a condition known as hypochloridia, have difficulty absorbing iron, and are more prone to developing iron-deficiency anemia.²⁰ And animal studies verify that PPI treatment decreases iron absorption, particularly in animals on a low-iron diet.^2,20 Some human studies demonstrate that long-term PPI use reduces iron absorption and produces the expected biochemical disturbances in blood tests.^2,21 Indeed, for patients with a problem storing too much iron, which results in tissue toxicity, PPI therapy has been deliberately used to reduce dietary iron absorption, demonstrating the potency with which these drugs can interfere with iron metabolism.^2,13

Magnesium is another essential mineral that is important for the functioning of numerous enzyme systems, energy management, and nerve conduction. Deficiency of magnesium is surprisingly common, with just 32% of Americans meeting their daily recommended intake.²² There have been reports of low blood magnesium levels in chronic PPI users.^2,23-25 One review study found severe symptoms of low magnesium, including fatigue, unsteadiness, numbness/tingling, seizures, heart rhythm disturbances, and hospitalization, in people who had been taking PPIs for an average of just over eight years. When PPI therapy was stopped in these patients, magnesium levels returned to normal and symptoms resolved, but when therapy was once again started, low levels and symptoms recurred.²⁶

PPIs Increase Risk of Bone Fractures

Possibly as a result of disturbances in calcium absorption from the diet under conditions of low stomach acid, a growing number of studies show an increased risk of bone fractures in long-term PPI users.²

It is known that stomach acid secretion can boost calcium absorption, while acid-suppressive therapy, including PPIs, reduces such absorption, with a negative impact on bone mineral density.^2,27-29 As with the other nutrients, stomach acid facilitates release of calcium from its dietary form, allowing it to be absorbed, so reducing acid levels will reduce the amount of dietary calcium that reaches the bloodstream and eventually the bones.^2,28,29

In one study of people older than 50, the use of PPIs for more than a year was associated with a 44% increase in hip fracture risk.²⁹ In that study, the risk of fractures was significantly higher (165%) in people taking doses above 35 mg (the average daily dose is 20 mg), and the risk continued to escalate the longer the patients took the PPI medication.²⁹

Another study showed similar results on the risk of hip fractures (increased by 45%), though neither dose nor duration appeared to have an effect in this case.³⁰ And a still more strongly designed study demonstrated, among postmenopausal women, a 3.1-fold increased risk for spinal fractures in PPI users compared to non-users.³¹

Taken together, these studies and others have led the US Food and Drug Administration (FDA) to warn users of PPIs of a “… possible increased risk of fractures of the hip, wrist, and spine with high doses or long-term use of a class of medications called proton pump inhibitors.”³² The required product labeling was also changed to reflect this increased risk.^2,32

PPIs and Cardiovascular Risk

Despite some encouraging trends in recent years, cardiovascular disease (heart attacks, heart failure, strokes) remains the leading cause of death in American men and women.^33,34 The use of PPI medications is emerging as one such risk factor.

There are two major ways that PPI therapy raises cardiovascular risk. The first has to do with PPI effects on blood clotting systems, particularly on platelets, the tiny cell fragments that initiate a clot. Most patients who are known to be at elevated risk for heart attack or stroke are placed on some kind of antiplatelet medication to lower their likelihood of developing an artery-blocking clot.^11,35

Because antiplatelet medications raise the risk for bleeding and ulcer formation in the stomach, however, most such patients are also advised to use a PPI to suppress stomach acid and decrease the risk of catastrophic bleeding.^11,35 But recent studies now suggest that the PPI medications may inhibit the effectiveness of the antiplatelet drugs themselves, defeating the entire purpose of this multidrug cocktail.¹¹

This effect is especially important with the antiplatelet drug clopidogrel (Plavix^®), which requires activation in the liver by a specific enzyme (CYP2C19).^11,36,37 PPI drugs, particularly omeprazole, interfere with that enzyme’s activity, hence reducing the amount of active clopidogrel available to prevent platelet clotting.¹¹

These biochemical effects have real impact on human lives. Studies now reveal a variety of negative effects among people with heart attack risk who take PPI medication along with antiplatelet therapy:^11,38

• Increased risk of cardiovascular “events” (e.g., heart attacks, need for interventional surgery),
• Increased risk of dying from a major acute cardiac event (in high-risk patients),
• Increased risk for recurrent attacks of acute coronary syndrome (angina, heart attacks), and
• Increased risk of re-infarction (death of heart tissue) after treatment for a first infarction.

The second, independent way that PPI drugs may increase risk of cardiovascular disease is their impact on production of artery-relaxing nitric oxide. The cells that line the blood vessels (endothelium) produce nitric oxide as a signaling molecule that tells arterial wall muscles to relax, allowing increased blood flow to oxygen-hungry tissues, particularly the brain and heart. Healthy nitric oxide production means brisk and efficient control of blood flow in these vital organs.

Recent studies show that PPI drugs lead to a reduction in nitric oxide, producing sluggish responses by arteries to the need to increase blood flow, and an increase in the risk of an infarction, ultimately producing a heart attack, stroke, or other catastrophe.⁹

How Nutritional Supplementation Can Help

 

Clearly, one needs to balance the benefits provided by effective heartburn medications against the risks of long-term use. For some people, the decision may be to continue using PPI medications periodically, while attempting to lower some of the risks we’ve identified above. Some ways to do that include:

• Having a vitamin B12 level checked regularly, and supplementing with B12 in the event of low or borderline levels. Remember that, unlike B12 from foods, reduced stomach acid does not appear to impair absorption of crystalline B12 from supplements.² A blood test for B12 should nonetheless be done when using PPIs and if there is a B12 deficiency, then ask your doctor to prescribe a B12 shot (1 mg) to be injected into a muscle two to three times a week.
• Periodically checking iron and magnesium levels, and supplementing with these minerals if levels are borderline or low.
• Monitoring bone mineral density for evidence of developing osteoporosis, with appropriate supplementation with calcium and vitamin D as required.
• Taking pomegranate extracts to protect nitric oxide from oxidative destruction, and thus improving otherwise impaired endothelial function resulting from PPI use.³⁹

Other people, particularly those with milder or more intermittent episodes of heartburn/GERD, should explore natural alternatives to PPI medication. This may help them sidestep the increased risks entirely.

Among good choices are:

 

• Raft-forming alginates. These are acid-activated gels that form a foamy “raft” that floats on top of stomach contents. They have the advantage of blocking not only stomach acid, but also destructive protein-degrading enzymes from rising into the esophagus.^40-42 Use raft-forming alginates to take a break from PPIs, while also sparing the esophagus from other corrosive digestive stomach contents (enzymes, bile, food and drink).
• Avoid foods and beverages associated with GERD symptoms. This includes coffee, chocolate, spicy foods, carbonated beverages, and alcohol. Additional foods that may cause symptoms include tomatoes (cooked and raw), milk, cheese, citrus foods, cakes, and pastries.^43-48
• Quit smoking. According to a long-term study, daily long-term (20 plus years) smoking resulted in a 70% increase in the occurrence of reflux episodes compared to those who smoked less than a year.⁴⁹
• Lose weight. Increased body mass and abdominal adiposity increases pressure on the stomach and lower esophagus. This can stress the lower esophageal valve, hampering its ability to maintain a seal against gastric reflux. Sustained abdominal pressure can also increase the risk of hiatal hernia.⁵⁰ Based upon a survey of seven studies, overweight individuals averaged a 43% increase and obese individuals a 94% increase in GERD symptoms over individuals with a normal body mass.⁵¹ Esophageal adenocarcinoma incidence was more frequent in overweight individuals in most of these studies.
• Monitor meal size and macronutrient composition. Dietary fat delays gastric emptying, which may increase the probability of reflux in susceptible patients. High-fat meals are also associated with increased risk of esophageal cancer.⁵² Whereas high-calorie, high-fat meals appear to elicit GERD,^53,54 reducing fat content in meals has had beneficial effects in some studies.^55,56 Low-carbohydrate (< 20 gram) meals reduced some reflux symptoms in a small trial in obese subjects.⁵⁷ Aside from their direct effects on GERD, limitation of fat, carbohydrate, and total calorie intake are effective methods for weight reduction, which itself is an effective anti-reflux strategy. Weight reduction is also an effective way to positively impact many additional aspects of health and potentially enhance longevity.
• Avoid eating close to bedtime. GERD patients have long been advised to avoid eating close to bedtime in order to give the stomach adequate time to empty before lying down.⁵⁸ Clinical studies, however, have had mixed results regarding the minimization of GERD symptoms.^59-61
• Elevate the head of the bed while sleeping. Several studies have suggested that raising the head of the bed 8-11 inches, or sleeping on a “wedge,” can reduce the number and duration of reflux episodes.⁶² This approach uses gravity to help keep stomach contents out of the esophagus. Left lateral recumbency (sleeping on the left side) may also reduce GERD symptoms by potentially keeping the lower esophageal sphincter above the level of the stomach and reducing pressure on the valve.⁶²
• Limit aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). Some evidence suggests that NSAID use is associated with GERD.⁶³ NSAIDs exert their anti-inflammatory activity by inhibiting the activity of pro-inflammatory cyclooxygenase (COX) enzymes. However, the COX-1 enzyme is also important for promoting the formation of the protective mucus lining of the stomach.

Summary

 

Loss of control of the lower esophageal sphincter muscle results in painful heartburn, also known as GERD. GERD affects millions of people, particularly older adults, and most of those people turn to oral acid suppressive medications for relief.

The leading acid-suppressing drugs are in the category of proton pump inhibitors, which are known to be highly effective at reducing heartburn symptoms.

But these drugs, called PPIs, are proving to have concerning side effects, particularly when used over the long term. Reduced acid secretion in the stomach can impair absorption of essential nutrients like vitamin B12, and minerals, such as iron, magnesium, and calcium.

Poor calcium absorption and other effects of PPI use raises the risk for bone fractures, already a major concern among older adults.

And, by at least two independent mechanisms, PPIs are associated with elevated risk for cardiovascular disease and even death from these conditions. PPIs impair the actions of antiplatelet drugs used to reduce the risk of clotting, and they also inhibit normal production of nitric oxide, a signaling molecule vital for normal blood vessel function.

Some people may choose to accept the risk of PPI medication in light of their substantial symptom relief. For those people, supplementing with vitamin B12 and pomegranate may help to offset some of the risks.

Other people may wish to use heartburn-reducing therapy that does not involve PPI medications at all. Such therapies include raft-forming alginates, which physically block stomach contents from rising up the esophagus.

If you have any questions on the scientific content of this article, please call a Life Extension^® Health Advisor at 1-866-864-3027.

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