Proton pump inhibitors should be taken at the lowest dose for the shortest possible time.
By David Dunaief, M.D.
Sometimes referred to as “reflux” or “heartburn,” Gastroesophageal reflux disease (GERD) is one of the most treated diseases in the U.S. Technically, heartburn is a symptom of GERD, so this is a bit of a misnomer.
Proton pump inhibitors (PPIs), first launched in 1989, have become one of the top-10 drug classes prescribed or taken over-the-counter (OTC). PPIs currently available OTC include Prilosec (omeprazole), Nexium (esomeprazole), Prevacid (lansoprazole), Protonix (pantoprazole), and Aciphex (rabeprazole). These and others are also available by prescription.
Their appeal among physicians has been their possible role in the reduction of esophageal cancer resulting from Barrett’s Esophagus. Interestingly, recent studies note that this perceived benefit may not be real (1).
PPIs are not intended for long-term use, because of their robust side effect profile. The FDA currently suggests that OTC PPIs should be taken for no more than a 14-day treatment once every four months. Prescription PPIs should be taken for 4 to 8 weeks (2).
However, their OTC availability can lead patients to take them too long or too often to manage reflux rebound effects when PPIs are discontinued without physician oversight. In addition, some existing medical risks are heightened by PPIs.
Among potential associations with long-term use are chronic kidney disease, dementia, bone fractures, increased cardiac and vascular risks, vitamin malabsorption issues and Clostridium difficile, a bacterial infection of the gastrointestinal tract.
PPIs and the kidneys
In two separate studies, results showed that there was an increase in chronic kidney disease with prolonged PPI use (3). All of the patients started study with normal kidney function, based on glomerular filtration rate (GFR). In the Atherosclerosis Risk in Communities (ARIC) study, there was a 50 percent increased risk of chronic kidney disease, while the Geisinger Health System cohort study found there was a 17 percent increased risk.
The first study had a 13-year duration, and the second had about a six-year duration. Both demonstrated modest, but statistically significant, increased risk of chronic kidney disease. But as you can see, the medications were used on a chronic basis for years. In an accompanying editorial to these published studies, the author suggests that there is overuse of the medications or that they are used beyond the resolution of symptoms and suggests starting with diet and lifestyle modifications as well as a milder drug class, H2 blockers (4).
Increased dementia risk
A German study looked at health records from a large public insurer and found there was a 44 percent increased risk of dementia in the elderly who were using PPIs, compared to those who were not (5). These patients were at least age 75. The authors surmise that PPIs may cross the blood-brain barrier and potentially increase beta-amyloid levels, markers for dementia. With occasional use, meaning once every 18 months for a few weeks to a few months, there was a much lower increased risk of 16 percent.
The researchers also suggested that PPIs may be significantly overprescribed in the elderly. Unfortunately, there were confounding factors that may have conflated the risk. Researchers also did not take into account high blood pressure, excessive alcohol use or family history of dementia, all of which influence dementia occurrence.
Increased fracture risk
In a meta-analysis of 18 observational studies, results showed that PPIs can increase the risk of hip fractures, spine fractures and any-site fractures (6). Interestingly, when it came to bone fractures, it did not make a difference whether patients were taking PPIs for more or less than a year.
They found increased fracture risks of 58, 26 and 33 percent for spine, hip and any site, respectively. It is not clear what may potentially increase the risk; however, it has been proposed that it may have to do with calcium absorption. PPIs reduce acid, which may be needed to absorb insoluble calcium salts. In another study, seven days of PPIs were shown to lower the absorption of calcium carbonate supplements when taken without food (7).
Vitamin absorption issues
In addition to calcium absorption issues, PPIs may have lower absorption effects on magnesium and B12. In one observational study, PPIs combined with diuretics caused a 73 percent increased risk of hospitalization due to low magnesium (8). Diuretics are commonly prescribed for high blood pressure, heart failure and swelling.
A second study, a meta-analysis of nine studies, confirmed these results: PPIs increased the risk of low magnesium in patients by 43 percent, and when researchers looked only at higher quality studies, the risk increased to 63 percent (9). The authors note that a significant reduction in magnesium could lead to cardiovascular events.
Another study’s results showed long-term use of over two years increased vitamin B12 deficiency risk by 65 percent (10).
The bottom line
It’s best if you confer with your doctor before starting PPIs. You may not need PPIs, but rather a milder medication, such as an H2 blocker (Zantac, Pepcid). In addition, PPIs may interfere with other drugs you are taking, such as Plavix (clopidogrel).
Even better, start with lifestyle modifications including diet, not eating later at night, raising the head of the bed, losing weight and stopping smoking, if needed, and then consider medications (11).
If you do need medication, recognize that PPIs don’t give immediate relief and should only be taken for a short duration to minimize their side effects.
(1) PLoS One. 2017; 12(1): e0169691. (2) fda.gov. (3) JAMA Intern Med. 2016;176(2). (4) JAMA Intern Med. 2016;176(2):172-174. (5) JAMA Neurol. online Feb 15, 2016. (6) Osteoporos Int. online Oct 13, 2015. (7) Am J Med. 118:778-781. (8) PLoS Med. 2014;11(9):e1001736. (9) Ren Fail. 2015;37(7):1237-1241. (10) Mayo Clinic Proceedings. 2018 Feb;93(2):240-246. (11) Am J Gastroenterol 2015; 110:393–400.
Dr. David Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, visit www.medicalcompassmd.com or consult your personal physician.