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GI Update 2019: Proton-Pump Inhibitor (PPI) Therapy is Safe By TERENCE ANGTUACO, MD

Over the past few years, safety issues associated with PPIs have come to the forefront of discussion in the field of Gastroenterology. Many studies on the long-term use of PPIs have reported adverse effects such as fractures, hypomagnesemia, acute and chronic kidney disease, dementia, and Clostridium difficile infection. These have become a source of major concern to both patients and physicians. Some patients discontinued their PPI therapy abruptly or inappropriately, and prescribers withheld or underdosed the treatment of their patients because of this. Up until recently, all the published results were based on retrospective and observational studies. They were unable to establish a definite association and could not prove cause and effect between PPI use and the development of serious adverse events. It is important to determine the long-term safety of this class of drug because many people depend on it, and yet, we do not want to endanger their well-being because of it.

ment of Veteran Affairs national databases and assessed the renal outcomes of 173,321 new PPI users compared to 20,270 new H2RA users over 5 years. PPI users were found to have a 28 percent increased risk of CKD. Antoniou T et al (CMAJ Open. 2015;3(2):E166-171) reported a 2.5-times increased risk of acute kidney injury and 3-times increased risk of acute interstitial nephritis in elderly patients recently

started on PPI’s. This was a populationbased study of 290,592 patients older than 65-years-old. The mechanism for development of CKD may be due to untreated subclinical acute interstitial nephritis that progressed over time. Dementia. Two prospective studies investigated the association of PPI use and the risk of dementia. Haenisch et al (Eur Arch Psychiatry Clin Neurosci.

2015;265(5):419-428) studied 3,076 patients 75 years or older with no history of dementia and found a 38 percent increased risk of dementia in PPI users. Gomm et al (JAMA Neurol 2016;73(4):410-416) studied 73,679 individuals 75 years or older with no history of dementia and found that regular PPI users had a 44 percent increased risk of dementia. On the other hand, there were (CONTINUED ON PAGE 8)

Retrospective Studies on PPI Use and Development of Adverse Events:

Fractures. A meta-analysis of 18 observational studies reported a 33 percent increased risk of fracture at any site, 26 percent higher risk of hip fracture, and 58 percent increase in risk of spine fracture. Both short-term (<1 year) and long-term use of PPI were associated with increased risk of hip fracture. (Zhou B et al, Osteoporos Int. 2016;27(1):339-47). The proposed mechanism is reduced calcium absorption resulting in decreased bone mineral density (BMD). Although a placebo-controlled, double-blind, crossover trial found decreased calcium carbonate absorption after 1 week of Omeprazole treatment (O’Connell M et al, Am J Med 2005;118(7):778-781), there is no evidence to show that PPI are associated with development of osteoporosis. A study on 4,512 patients who received continuous PPI treatment and followed over 10 years, did not show a significant rate of change in BMD (Targownik L et al, Am J Gastroenterol 2012;107(9):1361-69). The association of short-term PPI use with fractures as reported by Zhou B et al in 2016, also lead us to conclude that PPI-associated fractures are unlikely due to osteoporosis. Hypomagnesemia. A meta-analysis of 9 observational studies that included 109,798 patients, reported a 43 percent increased risk of hypomagnesemia (Cheungpasitporn W et al, Ren Fail 2015;37(7):123741). Magnesium level normalized with discontinuation of PPI treatment. In 2011, the U.S. FDA issued a safety warning regarding this association and recommended monitoring of magnesium levels in patients on long-term PPI therapy. Acute and chronic kidney disease (CKD). Xie et al (J Am Soc Nephrol 2016;27(10):3153-63) used the Departarkansasmedicalnews

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