TAW432042098613482484Therapeutic Advances in Drug SafetyHeidelbaugh 4824842013 Therapeutic Advances in Drug Safety Review Ther Adv Drug Saf Proton pump inhibitors and risk of (2013) 4(3) 125 –133 DOI: 10.1177/ vitamin and mineral deficiency: 2042098613482484 © The Author(s), 2013. evidence and clinical implications Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav Joel J. Heidelbaugh Abstract: Proton pump inhibitors (PPIs) remain the superior choice worldwide in antisecretory therapy in the evidence-based treatment of upper gastrointestinal disorders including gastroesophageal reflux disease, erosive esophagitis, dyspepsia and peptic ulcer disease. PPI overutilization in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. Nonjudicious use of PPIs creates both preventable financial as well as medical concerns. PPIs have been associated with an increased risk of vitamin and mineral deficiencies impacting vitamin B12, vitamin C, calcium, iron and magnesium metabolism. While these risks are considered to be relatively low in the general population, they may be notable in elderly and malnourished patients, as well as those on chronic hemodialysis and concomitant PPI therapy. No current evidence recommends routine screening or supplementation for these potential vitamin and mineral deficiencies in patients on either short- or long-term PPI therapy. Reducing inappropriate prescribing of PPIs can minimize the potential risk of vitamin and mineral deficiencies. Keywords: antisecretory therapy, calcium, iron, magnesium, mineral deficiency proton pump inhibitor(s), vitamin B12, vitamin C, vitamin deficiency Introduction overutilization is considered a direct result of the Correspondence to: Joel J. Heidelbaugh, MD Evidence-based guidelines supporting proton lack of determination of need for continuous ther- University of Michigan, pump inhibitor (PPI) use as the superior option for apy in many nonhospitalized patients. Substantial Ypsilanti Health Center, 200 Arnet Suite 200, antisecretory therapy (AST) for treatment of non- expenditure on PPIs has led researchers to create Ypsilanti, MI 48198, USA erosive gastroesophageal reflux disease (GERD), cost-effective and evidence-based paradigms of [email protected] erosive esophagitis, dyspepsia and peptic ulcer treatment strategies for GERD, including on- disease have guided clinicians in the treatment of demand and step-down therapy, yet even after a these conditions since their inception in the 1980s, decade of conception few clinicians follow such while demonstrating dramatically improved symp- guidelines [Inadomi, 2002; Inadomi et al. 2003; tomatic outcomes in large numbers of patients Metz et al. 2007]. It has also been proven that [DeVault and Castell, 2005; Kahrilas et al. 2008; PPIs are substantially overutilized for stress ulcer University of Michigan Health System, 2012]. The prophylaxis in nonintensive care unit patients, PPIs continue to be universally heralded as a safe leading to significant yet controllable cost expend- pharmacotherapeutic option with an extremely iture both in the hospital setting and after dis- low theoretical risk of the development of gastric charge [Heidelbaugh and Inadomi, 2006; Pham cancer secondary to hypergastrinemia and achlo- et al. 2006]. rhydria [Poulsen et al. 2009]. Cost utilization data from 2010 show that brand The strong evidence supporting PPI efficacy, as name PPIs accounted for ~US$7.2 billion and well as a favorable safety profile, may have con- generic PPIs accounted for ~US$2.5 billion in tributed to the widely held concern that PPIs US sales, with Nexium® (esomeprazole; Astra are overutilized. Moreover, the practice of PPI Zeneca) ranking first in brand name prescription http://taw.sagepub.com 125 Therapeutic Advances in Drug Safety 4 (3) expenditure and pantoprazole and omeprazole concentration by several hundred to thousand fold both ranking in the top five in generic prescrip- [McColl, 2009]. Their mechanism of action cent- tion expenditure [Drug Topics, 2012a, 2012b]. ers on inhibition of the H+/K+ ATPase enzyme in Approximately 80% of PPIs in the US are pur- gastric mucosal parietal cells, which is responsible chased without either a prescription or physician for hydrogen ion secretion in exchange for evaluation of upper gastrointestinal symptoms potassium ions in the gastric lumen [Sheen and [Heidelbaugh et al. 2009a]. Triadafilopoulos, 2011]. As a result, PPIs can modify the bioavailability and absorption of essen- The last decade has produced landmark publica- tial vitamins and minerals both in the stomach and tions across multiple specialties including pri- duodenum, which may also affect more distal mary care, managed care, gastroenterology and absorption. Recent case reports and retrospective pharmacology highlighting the potential risks literature reviews have posited a potential adverse associated with nonjudicious and inappropriate association between both short- and long-term short- and long-term use of PPIs in both hospital PPI utilization and vitamin and mineral deficien- and ambulatory care practices [Heidelbaugh et al. cies. At present time, the clinical significance of 2009a, 2009b]. The reported adverse effects asso- this hypothesis remains largely unknown with ciated with PPIs include an increased risk of regard to extrapolation to every day clinical practice, enteric infections including Clostridium difficile- given a lack of large cohort, rigorous, prospective, associated diarrhea [Aseeri et al. 2008; Jayatilaka outcomes-based trials examining both associated et al. 2007; Dial et al. 2005; Yearsley et al. 2006]; risk(s) and clinical symptomatology. community-acquired pneumonia [Laheij et al. 2004; Gulmez et al. 2007; Sarkar et al. 2008]; altered metabolism of antiplatelet agents (e.g. Vitamin deficiencies clopidogrel) [Gilard et al. 2008; Siller-Matula et al. 2009; Small et al. 2008; Ho et al. 2009]; Vitamin B12 osteoporotic-related fracture, and interference Vitamin B12 (cobalamin) is an essential water- with vitamin and mineral absorption and metabo- soluble nutrient acquired from animal-derived lism. The latter concern has received under- food sources including meats, fish, shellfish, poul- whelming attention in the general public until the try, eggs and dairy products. Lacto-ovo vegetari- US Food and Drug Administration (FDA) issued ans are generally not considered to be at risk for warnings in 2010 and 2011 postulating a relation- deficiency, while true vegans may risk deficiency ship between long-term PPI use and osteoporosis- unless they consume supplements or vitamin B12 related fracture and hypomagnesemia, respectively fortified foods including cereals and soy-based [FDA, 2010, 2011]. products. Since the common human diet contains substantially more vitamin B12 than is required, a A computerized literature search was performed large functional reserve with respect to vitamin using the MEDLINE database from 1966 through B12 absorption is assumed [Howden, 2000]. October 2012 to identify all publications using the following terms: proton pump inhibitor(s), Vitamin B12 absorption involves peptic enzymes vitamin/mineral deficiency, vitamin/mineral mal- to cleave dietary B12 from dietary proteins. This absorption, vitamin B12, vitamin C, calcium, iron is performed primarily by pepsin, which requires and magnesium. The search was limited to stud- gastric acid to activate it from its pepsinogen pre- ies involving human subjects published in the cursor. Without gastric acid, vitamin B12 would English language. Abstracts and book chapters not be cleaved from dietary protein and would not were excluded from the search, although case be able to bind to R-proteins, which in turn pro- studies were included given the specificity and tect vitamin B12 from pancreatic digestion [Festen, nature of the search topics. Bibliographies from 1991]. It has been hypothesized that since gastric index citations were reviewed for additional rele- acidity is required for vitamin B12 absorption, acid vant studies. suppression may lead to malabsorption and ultimately vitamin B12 deficiency from atrophic gastritis and achlorhydria [Howden, 2000]. Mechanism of action PPIs are the most potent inhibitors of gastric acid It has been estimated that vitamin B12 deficiency secretion, with a potential to increase intragastric affects up to 20% of the elderly, and has been pH by several units, as well as hydrogen ion linked to impaired gastrointestinal absorption 126 http://taw.sagepub.com Heidelbaugh syndromes and pernicious anemia [Andres et al. deficiency compared with 500 control subjects 2004]. Most clinical cases are undetected and are [Force et al. 2003]. More than 18% of patients found incidentally, while more profound cases who received vitamin B12 supplementation had may present with neuropsychiatric and hemato- been given AST with either PPIs or H2RAs over logic findings (e.g. macrocytic anemia) that may a 12-month period compared with 11% in the be a harbinger of more severe underlying disease. control group (odds ratio [OR] = 1.82; p = 0.025). The reduction in upper small intestine gastric Another case-control study in a US university- acid via PPI therapy may promote bacterial over- based geriatric primary care setting identified 53 growth allowing for increased bacterial consump- patients with cobalamin deficiency and compared tion of cobalamin, but the clinical correlation of them with