People who use common heartburn drugs for months to years may face heightened risks of dying from heart disease

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People who use common heartburn drugs for months to years may face heightened risks of dying from heart disease, kidney failure or stomach cancer, a new study suggests.

The study included more than 200,000 U.S. veterans.

It’s the latest to raise concerns over drugs called proton pump inhibitors (PPIs).


The stomach is the only organ that secretes acidic fluid as low as pH 2. Such gastric secretion is important not only for sterilization of bacteria contained in ingested foods, but also for digestion and absorption of various nutritional factors, such as protein, iron, calcium, and vitamin B12.

However, since secreted acid may damage the gastrointestinal tract, various types of protective mechanisms, including mucosal mucous/bicarbonate secretion and sphincter contraction of the gastroesophageal junction, are present to prevent gastric secretion-induced gastroesophageal damage.

When those protective mechanisms are overcome by acid secretion, gastrointestinal mucosa can become damaged and irritated, resulting in unpleasant symptoms or even organic disease.

Such pathological conditions are referred to as acid-related diseases and include gastroduodenal ulcers, gastroesophageal reflux disease (GERD), Barrett’s esophagus, and functional dyspepsia.

For treatment of acid-related diseases, various inhibitors of gastric acid secretion and neutralizing agents have been developed.

were employed. However, the effects of those for acid inhibition are limited and their use frequently has adverse effects, including cardio-vascular events, diarrhea, and constipation.

In addition, acid-neutralizing drugs are prone to interact with other drugs in the gastrointestinal tract and change the bioavailability of co-administered medication.

Therefore, those originally used for acid-related diseases have been nearly completely replaced by histamine H2 receptor antagonists (H2RAs), which were developed in the late 1970s.

An H2RA cancels the acid secretory effects of histamine.

Because of the stimulating effects of gastrin and acetylcholine, especially during the post-prandial period, an H2RA most effectively inhibits gastric acid secretion during the nocturnal period.1 

Accordingly, H2RAs are not potent enough for treatment of GERD with post-prandial reflux, though they are effective for gastroduodenal ulcers.

Thereafter, along with the increase in prevalence of GERD from 1980 to 1990, proton pump inhibitors (PPIs) were developed for more potent acid inhibition during the daytime period and used as first-line treatment for acid-related diseases.2

Employment of PPIs steadily and remarkably increased after starting clinical use for treatment of acid-related diseases, and they are now some of the most frequently prescribed drugs throughout the world,3 with large numbers of affected patients provided ongoing treatment with PPI administration for several years.

Along with their popularity, adverse events possibly related to long-term administration of PPIs have been reported, though the level of risk is not high.

In this review, we describe the pharmacological characteristics of PPIs and compare them with those of H2RAs. Furthermore, we present a balanced interpretation of reports concerning the advantages and disadvantages of PPI use.

Pharmacological Characteristics of Proton Pump Inhibitors

H2RAs competitively bind to histamine H2 receptors on the basolateral plasma membrane of parietal cells and inhibit binding of histamine to these receptors, resulting in inhibition of gastric acid secretion mainly during the nocturnal period, since histamine-stimulated acid secretion is important at that time.1,4 

H2RAs do not effectively inhibit gastrin- or acetylcholine-induced stimulation of gastric acid secretion, which is important in regard to post-prandial acid secretion.

The acid suppressing effect of an H2RA quickly appears when its concentration in plasma increases after the first dose.5 

However, as with many types of receptor antagonists, H2RAs show gradually weakened acid suppression, a tolerance phenomenon, following repetitive administration of only approximately 2 weeks.1,4 

Thus, H2RAs are considered to be short-distance track sprinters and not long-distance marathon runners.

Potassium competitive acid blockers (P-CABs) inhibit acid secretion by binding to the potassium binding site of alpha-subunit of proton pumps with iron bonds.6,7 

Although P-CABs show a very quick acid suppressing effect with oral administration, their superior clinical benefits as compared to conventional PPIs are not confirmed, except for Helicobacter pylori eradication therapy and for PPI-resistant GERD.811 

Various P-CABs have indeed been found to have therapeutic effects similar to those of standard PPIs when used for treatment of uncomplicated GERD.12,13 In fact, revaprazan and vonoprazan, P-CABs available throughout the world, are now used only in several countries including Korea and Japan, different from standard PPIs.

PPIs are the most widely used medication for gastric acid inhibition in the world.

All the PPIs available in Japan, including omeprazole, esomeprazole, lansoprazole, and rabeprazole, have a benzimidazole nucleus in their molecules along with various types of branch structures.

These drugs covalently bind to SH residues of cysteine molecules in the alpha-subunit of proton pumps on the secretary canalicular membranes of gastric parietal cells and inhibit the acid secretory function of those pumps, resulting in inhibition of gastric acid secretion.

Since all currently available PPIs share the same molecular structure, they also have similar pharmacological characteristics.

A PPI is unstable in an acidic condition.

Therefore, an enteric coating or co-administration with an acid-neutralizing agent such as sodium bicarbonate is necessary to obtain adequate per-oral bioavailability.

Following absorption in the small intestine, a significant percentage of first-generation PPIs (omeprazole and lansoprazole) are degraded by hepatic enzymes including CYP2C19.

In contrast, second-generation PPIs (esomeprazole and rabeprazole) are more stable and their plasma concentration is not strongly influenced by different CYP2C19 hepatic enzyme activities.14,15 

Although their plasma half-life is only 2–3 hours, these drugs remain bind to proton pumps for an extended period and inhibit pump activity, until new pumps are finally synthesized and replace the old ones in parietal cells.

According to a previous study, 25% of proton pumps in a parietal cell will be replaced by newly synthesized pumps within 1 day.16,17

PPIs must be activated by highly concentrated hydrogen irons before binding to proton pumps. For that activation, the parietal cells must actively secrete hydrogen irons into the secretory canaliculi when the PPI reaches that network.

When gastric acid secretion has been inhibited by a pathological condition or medication, even partially, complete activation of the PPI may be prevented and its acid suppressing effect weakened.

Only after acid-induced activation has occurred, PPIs bind to SH residues of proton pump cysteines.17 Since only a part of the proton pump is in an active acid secreting state when a PPI is administered, repeated administrations of the drug are necessary for adequate and complete inhibition of proton pumps.

Even during the period of stable acid inhibition following several initial oral doses, acid inhibition during the nocturnal period is weaker with a once daily morning dose, since approximately 25% of proton pumps are replaced by newly synthesized ones within 24 hours and the newly synthesized pumps after the morning PPI administration will begin to secrete acid during the nocturnal period.18

PPIs are almost exclusively metabolized by the liver and not by the kidneys, thus their potency is not influenced by impaired renal function.

Furthermore, their acid inhibitory effect does not decrease even after long-term continuous administration, which is different from H2RAs. Therefore, PPIs are effective for long-term acid inhibition, especially during the daytime period, because of their lack of tolerance phenomenon. PPIs are considered to be long-range marathon runners and not short-range track sprinters.Go to:

Advantages of Long-term Proton Pump Inhibitor Use

PPIs potently inhibit gastric acid secretion, especially during the daytime period following a daily single morning dose.

Acid inhibition provided by per-oral administration gradually increases during the first 3–5 days after the start of administration.

PPIs do not show tolerance phenomenon, even after long-term treatment.

Since nocturnal acid inhibition is not so strong and intra-gastric pH during the nocturnal period remains at around 2.0 in the majority of administered cases, the pre-breakfast plasma gastrin concentration measured in the early morning does not show a remarkable elevation.

These characteristics of PPIs may be considered to be advantageous for long-term control of gastric acid secretion.

Long-term inhibition of gastric acid secretion is necessary for GERD maintenance therapy and prevention of occurrence of gastroduodenal ulcers during administration of aspirin or NSAIDs.1923 

For control of dyspepsia, which affects patients with functional dyspepsia (FD), acid inhibitors are intermittently administered or given on an on-demand basis, but not continuously.

Therefore, GERD maintenance therapy and prevention of drug-related ulcer recurrence are 2 important conditions that necessitate long-term PPI administration.

Patients with GERD mainly complain of reflux symptoms after meals, since gastroesophageal refluxes frequently occur during the postprandial period. Since the acid suppressing effect of a single morning dose of a PPI remains potent during the daytime period, PPIs are reported to be effective to prevent recurrence of reflux symptoms and esophageal erosions/ulcers.1921 

With their continuous administration, recurrence of GERD during maintenance therapy for 1 year is reported to be less than 15%, while recurrence within 1 year without maintenance therapy is estimated to be greater than 50%.24,25

 When the preventive effect of PPIs for GERD recurrence was compared with that of H2RAs, PPIs were found to be much more effective.

heir long-term administration may also be effective for prevention of neoplastic transition of Barrett’s esophagus to dysplastic Barrett’s esophagus, such as an adenocarcinoma.

It has not been completely established whether PPIs effectively prevent dysplastic changes of Barrett’s esophagus. However, no report has indicated that these drugs aggravate dysplastic changes, though several have suggested that they effectively prevent dysplastic changes.26 

Thus, long-term maintenance therapy with a PPI is effective for preventing recurrence of GERD and may also prevent neoplastic progression of Barrett’s esophagus.

Long-term PPI administration is also helpful for preventing recurrence of aspirin-induced gastroduodenal ulcers and is more effective than H2RAs, with a decrease in recurrence to approximately one-tenth of that seen in placebo-treated groups.23,2729 

Similarly, in cases administered with an NSAID, PPIs were reported to decrease the recurrence rate to one-tenth of that of a placebo group over a 6- to 12-month observation period.22 

Since many patients with cerebrovascular or cardiovascular diseases are treated with aspirin as an anti-thrombotic drug, prevention of aspirin-induced ulcers is critically important for prevention of NSAID-induced ulcers.

Thus, PPIs are first-line drugs used for the prevention of aspirin/NSAID-related ulcer recurrence, and their continuous administration is effective and potent for the prevention of recurrence as well as maintenance therapy of GERD.

Disadvantages of Long-term Proton Pump Inhibitors Use

All clinical drugs have both therapeutic and adverse effects, including PPIs. Since the basic chemical structure of available PPIs is similar, the adverse effects of the drugs are also similar and can be divided into 2 types, those related and unrelated to acid inhibition.

The majority of acid inhibition-related adverse effects are observed during long-term treatment with a PPI, while those unrelated to acid inhibition are observed in patients with long-term as well as those with short-term treatment (Table).

Table

Adverse Events Reported in Patients Treated With Proton Pump Inhibitors

Adverse events unrelated to acid inhibitionAdverse events related to acid inhibition
Allergic reaction to drug chemicalsPneumonia
Collagenous colitisGastrointestinal infection
Acute interstitial nephritisGastric carcinoid tumor
Chronic kidney diseaseGastric fundic mucosal hypertrophy
Drug interactionChanges in gut microbiome
DementiaSmall intestinal bacterial overgrowth
Cerebral ischemic diseasesIron deficiency
Ischemic cardiac diseasesBone fracture
Vitamin B12 deficiency
Hypomagnesemia
Gastric fundic gland polyps
Gastric cancer
Colon cancer
Spontaneous bacterial peritonitis
Hepatic encephalopathy
Drug interaction


They include prescription and over-the-counter drugs like Prilosec (omeprazole), Prevacid (lansoprazole) and Nexium (esomeprazole). And they rank among the top-selling medications in the United States.

Research in recent years has linked prolonged PPI use to increased risks of various diseases and premature death.

These latest findings point to the specific causes of death tied to the drugs, said lead researcher Dr. Ziyad Al-Aly.

He stressed that the excess risks were relatively small.

For example, over 10 years, 13% of PPI users died of a cardiovascular condition, including heart disease or stroke.

That compared with just over 11% of people who used H2 blockers, another class of heartburn drug.

When the researchers weighed other factors – such as patients’ age and chronic health conditions – PPI use was tied to a roughly 18% higher risk of cardiovascular death.

However, based on patients’ medical records, many of those with PPI prescriptions had no documented need for one.

“That’s unsettling,” said Al-Aly, an assistant professor at Washington University School of Medicine in St. Louis.

“It suggests a lot of people were using a PPI without actually needing one,” he said. “They could be taking a risk without deriving any benefit.”

But an expert not involved in the study said it’s unclear whether PPIs, themselves, are responsible for the higher death rates.

Dr. Lawrence Kim is a member of the American Gastroenterological Association’s governing board. He said the current study, like others before it, is “observational”—that is, it used medical records to track patients’ outcomes.

Those types of studies cannot prove cause and effect, Kim said. There may be other explanations for the higher risks seen among PPI users.

In 2017, Kim said, the gastroenterological association published a review of the research into the issue.

“The report concluded that the evidence supporting all of these risks was low- to very-low quality,” he said. “Therefore, there’s insufficient evidence to conclude that these adverse outcomes are likely to be an effect of the PPI therapy.”

PPIs work by blocking the enzyme system that creates stomach acid.

They are commonly prescribed for gastroesophageal reflux disease (GERD), where stomach acid chronically escapes into the esophagus (the tube connecting the mouth and stomach).

Many people with GERD can take a PPI for just a short time, Al-Aly said.

That allows damaged tissue in the esophagus to heal.

Then patients can switch to a different treatment, like an H2 blocker.

Those medications include drugs such as Tagamet (cimetidine), Pepcid (famotidine) and Zantac (ranitidine).

“Most people don’t need to be on a PPI for months or years,” Al-Aly said.

In this study, the risks linked to PPIs rose with prolonged use.

The odds of death over 10 years were 63% to 71% higher among patients who’d used the drugs for at least a year, versus those who’d used them for a few months.

However, some GERD patients do need long-term PPI treatment, Al-Aly and Kim said. That includes people with recurrent stomach ulcers or Barrett’s esophagus—serious damage to the esophageal lining that can raise the risk of cancer.

Before you start a PPI, Al-Aly said, be sure you actually need one. The drugs are available over the counter, but they should not be used for more than a couple weeks without talking to a doctor, he said.

If you’ve used a PPI for a long time, Kim said, talk to your doctor about whether you need to continue.

According to the study, more than 15 million Americans have PPI prescriptions. And millions more buy them over the counter without a doctor’s knowledge.

The findings were published recently in the journal BMJ.

The veterans in the study—mostly older men – started on a PPI or H2 blocker between 2002 and 2004.

Over the next 10 years, 38% of PPI users died, as did nearly 36% of those on H2 blockers.

If PPIs contribute to deaths, it’s unclear why. According to Al-Aly, lab research has hinted the drugs may cause dysfunction in the lining of the blood vessels, or disrupt the gut’s immune function and normal bacterial makeup.

More information: The U.S. National Institute on Diabetes and Digestive and Kidney Diseases has more on treating GERD.

Journal information:British Medical Journal (BMJ)

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