From Nexium and Prilosec to Prevacid, we all recognize the names. Many of us struggle with the conditions, like acid reflux and ulcers, that these drugs are used to treat. But how many patients recognize the risks of proton pump inhibitors?
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Huge Revenues, Despite Concerns Over PPI Risks
Since their first approval in 1988, proton pump inhibitors have rocketed to extreme popularity. These heartburn drugs, which reduce the amount of gastric acid released into the stomach, are some of the most widely-prescribed medications in the world. In 2013, the top ten proton pump inhibitors raked in over $8.5 billion in US revenue alone for pharmaceutical companies. Today, the world’s patients spend more money on only one class of drugs: statins, which are used to lower cholesterol levels.
Of course, this popularity has come with a downside. Proton pump inhibitors are now “overused,” according to doctors across the country, “exposing patients to an increasing number of potential risks.”
Those words were written in 2012 by a group of four Michigan doctors, who noted five major dangers of inappropriate PPI use. Their list, which included Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with the metabolism of antiplatelet agents, is now incomplete. Add to those significant risks a possible increase in the rate of dementia, heart attacks, and potentially deadly kidney disorders and you’ll begin to understand the wide range of dangers to which proton pump inhibitors have been linked.
Potential Proton Pump Inhibitor Side Effects
Over the last 28 years, researchers have identified the following proton pump inhibitor side effects:
- kidney failure, or End Stage Renal Disease
- chronic kidney disease
- acute interstitial nephritis
- heart attacks
- bone fractures
- vitamin and mineral deficiencies, including the dangerous magnesium deficiency known as hypomagnesemia
- infections, including Clostridium difficile (C. diff)
It’s a long, and terrifying, list, one that may get longer in the future. Many doctors are still prescribing proton pump inhibitors in inappropriate situations. But patients are also taking the drugs for longer periods of time, according to Medscape Multispecialty. This is a crucial point. Researchers generally agree that PPIs cause only minimal side effects when used as a short course of treatment. We know far less about the long-term consequences of taking proton pump inhibitors, but some of the possible dangers are becoming clear.
Risks To Kidney Health
For some time, researchers have suspected that proton pump inhibitors, like Nexium, Prilosec and Prevacid can contribute to the development of acute interstitial nephritis, an inflammation in the kidneys.
Acute Interstitial Nephritis
In some cases, the condition can be spurred on by an infection, but more often than not, it’s caused by a medication. In one study, conducted by researchers at the Mayo Clinic in 2014, proton pump inhibitors were identified as the direct cause of nephritis in 14% of 133 patients. While a far higher proportion of the cases were caused by antibiotics, the most frequent cause of acute interstitial nephritis was a PPI. That drug, omeprazole, the active ingredient in Prilosec, contributed to 12% of the total cases.
Numerous case reports have attested to the same causal link between proton pump inhibitors and nephritis, which most often causes symptoms of fever, rash, and swollen kidneys. Acute interstitial nephritis has a rapid onset, and some patients won’t experience any immediate symptoms, but the eventual consequences are dire. Kidney function will certainly be impaired, and the risks of acidosis, in which the blood becomes filled by dangerous acids, and even total kidney failure are ever-present.
Chronic Kidney Disease
More recent research has raised concerns that the effect of proton pump inhibitors on kidney health may go far beyond nephritis.
In February 2016, an international group from Yale, Johns Hopkins and Australia’s Royal Brisbane and Women’s Hospital published the troubling results of their investigation into the link between proton pump inhibitors and chronic kidney disease (CKD).
First, the researchers followed the health progress of more than 10,400 patients from February 1, 1996, to January 30, 1999. Without adjusting for potential confounders, those patients who took proton pump inhibitors were 45% more likely to develop chronic kidney disease. After eliminating the possibility of socioeconomic factors that may also increase the risk for CKD, the association actually strengthened, to a 50% increased risk. Comparing PPI users directly to patients taking H2 receptor antagonists, another medication for heartburn, the risk remained elevated, at 39%.
To check their results, the team replicated the study, using 248,751 patients logged in a separate health care database. Again, proton pump inhibitor users were more likely to develop chronic kidney disease, over a number of analyses that attempted to eliminate potentially confounding factors. In addition, an increase in PPI use was linked to an increase in the risk of chronic kidney disease. Patients who took a proton pump inhibitor once daily were around 15% more likely to get CKD, while people who took two pills per day were at a 46% increased risk.
The paper, published in the Journal of the American Medical Association Internal Medicine, inspired a flurry of responses from other researchers. But surprisingly, few experts were willing to question the study’s primary findings. In one editorial, Italian researchers said: “we agree with and support this hypothesis.” In another letter, scientists from Beijing even suggested a theory to explain the link, pointing a finger at “altered gut microbial composition and metabolism,” a well-known consequence of changing the amount of gastric acid released into the stomach.
Chronic kidney disease is a major problem, especially considering its eventual consequence, end-stage renal disease or kidney failure.
In another study, published in April 2016, researchers from St. Louis’ Veterans Affairs office looked even further into the association, expanding their investigation to include both chronic kidney disease and kidney failure. They also tweaked the study’s design, comparing PPI users to people on H2 receptor antagonists from the start.
Compared to 20,270 H2 receptor antagonist users, the more than 173,000 PPI patients were at a 28% increased risk of developing chronic kidney disease. More disturbingly, people taking proton pump inhibitors were 96% more likely to suffer kidney failure, when the organ becomes so impaired it can no longer sustain daily body functions. Much like the previous study, the researchers observed an increase in these risks as patients took PPIs for longer and longer periods of time.
The study appeared in the Journal of the American Society of Nephrology on April 14, 2016.
In 2006, a Journal of the American Medical Association paper identified a new, potential risk of proton pump inhibitors: broken bones. In their study, doctors at the University of Pennsylvania looked at 13,556 patients who had broken their hips, and compared their use of proton pump inhibitors to more than 135,000 patients who had not sustained hip fractures. PPI users were around 44% more likely to have suffered broken hips overall. People who had been taking proton pump inhibitors for a long time, however, were at a much higher risk, about 2.65 times more likely to have broken hips.
This was just the first in a long series of studies to associate proton pump inhibitors with an increased risk for broken bones. The same year, researchers in Denmark found that PPI use increased the risk of:
- fractures overall by 18%
- hip fractures by 45%
- spine fractures by 60%
H2 receptor antagonists, on the other hand, were associated with a decrease in the risk of bone fractures. While these increased risks were considered minimal, these early studies sparked concern. More research was conducted, and a theory soon came to light.
Do Proton Pump Inhibitors Impair Calcium Absorption?
Stomach acid, after all, is critical to breaking down foods, unlocking their nutrients and helping the body absorb essential minerals and vitamins. But proton pump inhibitors cut down on the amount of stomach acid performing this vital work. It’s quite possible, researchers suggested, that PPIs were inhibiting the body’s ability to absorb calcium, the mineral fundamental to bone health.
In more recent years, this theory has been called into question. If PPIs actually reduce the integrity of bones, you would expect patients taking proton pump inhibitors to have lower bone mineral densities than other people. But several studies have found that contrary to our expectations, bone mineral density doesn’t seem to differ between patients taking PPIs and people not taking them.
FDA Updates PPI Labeling With Fracture Warning
Even so, the FDA stepped in to warn patients of the risk’s possibility. In 2010, the agency decided to revise the labeling of proton pump inhibitors, including “new safety information about a possible increased risk of fractures of the hip, wrist, and spine.”
The following year, FDA reviewers revised their decision, announcing that over-the-counter proton pump inhibitors wouldn’t be required to warn about a possible fracture risk. The agency explained its new-found reservations in these words: “following a thorough review of available safety data, FDA has concluded that fracture risk with short-term, low dose PPI use is unlikely.” Unlike prescription proton pump inhibitors, over-the-counter versions like Nexium 24HR only come in low doses. Moreover, the drugs are only intended to be taken for short periods of time. When used as indicated, the FDA has determined that any fracture risk entailed by these OTC versions is likely to be very low.
But discontinuing the use of a proton pump inhibitor is difficult, as this recent story from NPR makes clear. Many patients become trapped in a vicious cycle. Take a proton pump inhibitor and your heartburn or indigestion disappears; stop taking it and your symptoms return, quite possibly even worse than before. PPIs lend themselves to long-term use, but as we’ve seen, with long-term use comes major consequences.