Long-term use of proton pump inhibitors (PPIs) to an increased risk of dementia, cardiovascular disease and renal failure
Previous studies have linked regular, long-term use of proton pump inhibitors (PPIs) to an increased risk of dementia, cardiovascular disease and renal failure, but until now, scientists haven’t known exactly why. Results published Tuesday in the journal Circulation Research signal a plausible answer, researchers say: Vascular cells chronically exposed in vitro to PPIs led to a buildup of cellular garbage in cellular linings, thus accelerating blood vessel aging.
“I’m perplexed that the pharmaceutical industry didn’t run across this first,” senior study author John P. Cooke, chair of cardiovascular disease research at the Houston Methodist Research Institute, told FoxNews.com. “This is something that should have been apparent a long time ago and should have been investigated.”
An estimated one in 14 Americans uses an over-the-counter PPI like omeprazole, sold as Prilosec, to treat gastroesophageal reflux disease (GERD), also called heartburn or acid reflux. Considered the most effective treatment for GERD, PPIs are approved by the Food and Drug Administration (FDA) for use four weeks at a time, but research suggests up to 70 percent of PPI use may be inappropriate.
Cooke helped author research in 2013 that suggested PPIs decrease nitric oxide in endothelial cells, which line blood cells in the body— an effect that can have an adverse impact on cardiovascular health. He also worked on a 2015 study that linked regular, long-term PPI use to a 20 percent increased risk of heart attack among a database of 3 million patients.
“We now have a plausible mechanism that unifies how PPIs are associated with heart attack, vascular dementia and renal failure,” said Cooke, who is also director of the Center for Cardiovascular Regeneration at the Houston Methodist Research Institute.
For his latest study, Cooke and his colleagues exposed endothelial cells over weeks— roughly equal to months or years in a clinical model— to the PPI esomeprazole, or Nexium, as well as another PPI that isn’t commercially available, and to an H2 blocker, another type of medication for GERD.
The vascular cells chronically exposed to PPIs had a “fried egg” look, Cooke said.
“That was not expected, and then we thought, ‘What could be causing them to age faster if that’s the case?’” he said.
Cooke and his team proved that was the case by using a stain called beta-gal to expose markers for aging. Next, it occurred to them that vascular cells have tiny organelles inside called lysosomes, which act like garbage disposals, or stomachs. It’s well known that if lysosomes are impaired, garbage accumulates and aging accelerates.
Researchers found that while the H2 blockers had no effect on vascular aging, chronic use of the PPIs indeed impaired the lysosomes, preventing them from generating acid.
“We also saw the telomeres shortening— they’re on the tips of chromosomes and like our biological clock,” Cooke added. “Those vascular cells couldn’t proliferate or divide as well, and that’s necessary for repairing a wound in the vessel.”
Previous research has associated free radical generation and telomere shortening with expedited cell aging. Free radical accumulation in particular can trigger oxidative damage, an effect linked with age-related chronic conditions such as neurodegenerative disorders, like Alzheimer’s disease, as well as cardiovascular disease and cancer.
Nick Leeper, associate professor and chief of vascular medicine at Stanford University, was not involved in the current study but called the new findings “provocative.” Medicine at Stanford University
“I think that this is yet another piece of data which all points to a potential risk that should be studied in a prospective, randomized fashion,” Leeper, who worked with Cooke on the 2015 study linking PPIs to an increased heart attack risk, told FoxNews.com. “I think it’s important to note, as the authors point out, that these medicines are frequently used for much longer than the approved indication and are also available over the counter. And so I think that, given this pattern of potential harm that’s been seen in this series of studies described here, that regulators should consider whether additional prospective studies are necessary.”
Cooke said a prospective, randomized trial is the next step for researchers, as the main limitation of his team’s new study is that, although its model is clinically relevant, it was conducted in vitro.
However, he thinks his team’s findings warrant action among regulators and doctors.
“I’m not saying these drugs should be pulled off the market— they’re safe and effective as approved by the FDA,” Cooke said, “but I do think it’s time to reconsider their use over the counter and re-educate ourselves.”
Drugs that help millions of people cope with acid reflux may also cause cardiovascular disease, report scientists from Houston Methodist Hospital and two other institutions in an upcoming issue of Circulation (now online). It is the first time researchers have shown how proton pump inhibitors, or PPIs, might cause cardiovascular problems.
In human tissue and mouse models, the researchers found PPIs caused the constriction of blood vessels. If taken regularly, PPIs could lead to a variety of cardiovascular problems over time, including hypertension and a weakened heart. In the paper, the scientists call for a broad, large-scale study to determine whether PPIs are dangerous.
“The surprising effect that PPIs may impair vascular health needs further investigation,” said John Cooke, M.D., Ph.D., the study’s principal investigator. “Our work is consistent with previous reports that PPIs may increase the risk of a second heart attack in people that have been hospitalized with an acute coronary syndrome. Patients taking PPIs may wish to speak to their doctors about switching to another drug to protect their stomachs, if they are at risk for a heart attack.”
Commonly used proton pump inhibitors in the United States are lansoprazole and omeprazole, and these drugs are purchasable over the counter as brands or generics. The FDA estimates about 1 in 14 Americans has used them. In 2009, PPIs were the third-most taken type of drug in the U.S., accounting for $13 billion in sales. PPIs are used to treat a wide range of disorders, including gastroesophageal reflux disease, or GERD, infection by the ulcer-causing Helicobacter pylori, Zollinger-Ellison syndrome, and Barrett’s esophagus.
Recent studies of proton pump inhibitors use by people who’ve already experienced severe cardiovascular events have raised concern about the anti-reflux drugs, at least for this subgroup of patients, said Cooke, chair of the Department of Cardiovascular Sciences and director of the Center for Cardiovascular Regeneration at Houston Methodist DeBakey Heart & Vascular Center.
PPIs are initially inert. After oral consumption, they are activated by specialized cells in the stomach. Once active, the molecules suppress the movement of protons into the intestine, which reduces the amount of acid present there and in the stomach.
In mouse models and cultures of human endothelial cells, Cooke and lead author Yohannes Ghebramariam, Ph.D., found that PPIs suppressed the enzyme DDAH, dimethylarginine dimethylaminohydrolase. That caused an increase in the blood levels of ADMA (asymmetric dimethylarginine), an important chemical messenger. They found ADMA in turn suppressed the production of another chemical messenger, nitric oxide, or NO, proven by 1998 Nobel Prize winners Furchgott, Ignarro, and Murad to impact cardiovascular function. Quantitative studies in mouse models showed animals fed PPIs were more likely than controls to have tense vascular tissue.
“We found that PPIs interfere with the ability of blood vessels to relax,” said Ghebremariam, a Houston Methodist molecular biologist. “PPIs have this adverse effect by reducing the ability of human blood vessels to generate nitric oxide. Nitric oxide generated by the lining of the vessel is known to relax, and to protect, arteries and veins.”
The researchers found PPIs led to an approximately 25 percent increase in ADMA in mouse and tissue cultures, and reduced the ability of mouse blood vessels to relax by over 30 percent on average.
Also contributing to this report were Paea LePendu, Ph.D., Jerry Lee, Daniel Erlanson, Ph.D., and Nigam H. Shah, Ph.D. (Stanford University) and Anna Slaviero, Ph.D., and James Leiper, Ph.D. (Imperial College London). Work was funded with grants from the National Institutes of Health, the American Heart Association, the Stanford SPARK program, and the Stanford Translational Research and Applied Medicine (TRAM) program.
Circulation is published by the American Heart Association.
The Methodist Hospital recently changed its name to Houston Methodist Hospital.
The above post is reprinted from materials provided by Methodist Hospital, Houston. Note: Materials may be edited for content and length.
1.Y. T. Ghebremariam, P. LePendu, J. C. Lee, D. A. Erlanson, A. Slaviero, N. H. Shah, J. Leiper, J. P. Cooke. An Unexpected Effect of Proton Pump Inhibitors: Elevation of the Cardiovascular Risk Factor ADMA. Circulation, 2013; DOI: 10.1161/CIRCULATIONAHA.113.003602
Methodist Hospital, Houston. “Acid reflux drug may cause heart disease, study suggests.” ScienceDaily. ScienceDaily, 10 July 2013. <www.sciencedaily.com/releases/2013/07/130710114225.htm>.
There are four primary consequences of acid stopping drugs:
1.Increased bacterial overgrowth
2.Impaired nutrient absorption
3.Decreased resistance to infection
4.Increased risk of cancer and other diseases
I had originally intended to cover all four of these issues in this article, but as I started to write I realized it would be far too long. So I will cover increased bacterial overgrowth and impaired nutrient absorption in this article, and decreased resistance to infection and increased risk of cancer and other diseases in the next article.
A stomach full of germs
The connection between low stomach acid and bacterial overgrowth was the focus of Part II and Part III.
To review, low stomach acid causes bacterial overgrowth in the stomach and other parts of the intestine. Bacterial overgrowth causes maldigestion of carbohydrates, which in turn produces gas. This gas increases the pressure in the stomach, causing the lower esophageal sphincter (LES) to malfunction. The malfunction of the LES allows acid from the stomach to enter the esophagus, thus producing the symptoms of heartburn and GERD.
Bacterial overgrowth has a number of other undesirable effects, including reducing nutrient absorption, increasing inflammation, and raising the risk of stomach cancer. Studies have confirmed that proton-pump inhibitors (PPIs) can profoundly alter the gastrointestinal bacterial population by suppressing stomach acid. Researchers in Italy detected small bowel bacterial overgrowth (SIBO) in 50% of patients using PPIs, compared to only 6% of healthy control subjects. The prevalence of SIBO increased after one year of treatment with PPIs.
The link between heartburn drugs and dementia