A Clinical Review


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Review

Magnesium Deficiency and Proton-Pump Inhibitor Use: A Clinical Review

The Journal of Clinical Pharmacology 2015, 00(0) 1–9  C 2015, The American College of Clinical Pharmacology DOI: 10.1002/jcph.672

Jeffrey H. William, MD,and John Danziger, MD, MPhil

Abstract The association of proton-pump inhibitor (PPI) use and hypomagnesemia has garnered much attention over the last 5 years. A large body of observational data has linked chronic PPI use with hypomagnesemia, presumably due to decreased intestinal absorption and consequent magnesium deficiency. However, despite the increasing prevalence of this highly popular class of medicine, and despite potential significant risks associated with magnesium depletion, including cardiac arrhythmias and seizures, there are no well-designed studies to delineate the nature of this observed association. Consequently, providers must use best judgment to inform clinical decision making. This review summarizes the current body of evidence linking PPI use with hypomagnesemia, acknowledges the possibility of significant residual confounding in the observational data, explains potential physiologic mechanisms, and offers clinical recommendations.

Keywords magnesium, proton pump inhibitor, hypomagnesemia

Introduction to the Physiology of Magnesium Magnesium is the fourth most abundant intracellular ion and has many important biologic functions in cell metabolism. Magnesium is primarily stored within bone cells, with a much smaller pool circulating in blood, containing only 1% of the total body magnesium content. Magnesium homeostasis depends on the balance among intake, absorption, and excretion, as well as the relative ratio between the serum and bone compartments.1

Magnesium Intake and Absorption The average magnesium dietary intake is approximately 350 to 400 mg daily. Magnesium is absorbed in the small and large bowel via 2 pathways. Paracellular movement occurs down a concentration gradient as magnesium crosses between intestinal epithelial cells in the small bowel. A more active process occurs in the cecum and large bowel, whereby proteins within the enterocyte apical cell membrane transport magnesium from the intestinal lumen into the bloodstream. These cell membrane proteins, identified as transient receptor potential melastatins (TRPM) 6 and 7, have a high affinity for magnesium and help the body maintain magnesium balance during periods of sparse dietary magnesium intake.2–5 On average, approximately 30% of dietary magnesium is absorbed into the bloodstream, although this percentage can increase to nearly 80% in times of dietary magnesium restriction.6

Magnesium Excretion Magnesium excretion primarily occurs through 2 routes: gastrointestinal and renal elimination. It is estimated that approximately 200 mg is eliminated in the feces daily, whereas about 100 mg is excreted by the kidneys.7,8 The thick ascending loop of Henle (TAL) of the nephron is primarily responsible for magnesium reabsorption, accounting for 50%–70% reclamation of the filtered load. This occurs via a paracellular pathway dependent on tight junction proteins in the “claudin” family. Claudins 16 and 19 have been identified as those most important for magnesium permeability, and in vitro studies have revealed that mutations of these proteins lead to renal magnesium wasting.9 In vivo and in vitro studies have also demonstrated that claudins 16 and 19 have interdependence, relying on each other for proper insertion into tight junctions.10 The distal convoluted tubule (DCT) determines the final urinary concentration of magnesium, as this is the only location where TRPM6 transporters are expressed in the kidney, allowing high-affinity magnesium reclamation. TRPM6 activity is regulated by intracellular

Division of Nephrology, Beth Israel Deaconess Medical Center, Boston, MA Submitted for publication 4 September 2015; accepted 30 October 2015. Corresponding author: Jeffrey H. William MD, Beth Israel Deaconess Medical Center, Libby 2, Boston, MA 02215 Email: [email protected]

2 magnesium and modulated by dietary magnesium intake and pH.11,12 The enterocyte and a composite renal tubular cell (TAL and DCT) are shown side-by-side in Figure 1.

Perturbations of Magnesium Homeostasis This fine-tuning between dietary absorption and fecal/urinary excretion allows the body to maintain circulating serum magnesium concentrations within a reasonably small range (1.6 to 2.6 mg/dL typically). Deviations from this may result in cardiac and neurologic instability in the form of arrhythmias and seizure activity. Unlike other serum ions such as calcium, there is no known hormonal axis primarily dedicated to the physiologic regulation of serum magnesium. Consequently, changes in magnesium balance, either through intestinal or renal loss, affect the serum concentration until equilibration occurs from the much larger intracellular skeletal pool. In some cases measurement of the serum magnesium concentration does not reflect total body stores, and intracellular or skeletal magnesium depletion may even coexist with normal serum magnesium levels.1

Diagnosing Magnesium Deficiency In most laboratories low serum magnesium concentrations (<1.6 mg/dL, otherwise known as hypomagnesemia) suggest magnesium deficiency. However, serum magnesium levels do not always reflect magnesium stores and unfortunately, accurate measures of intracellular magnesium or skeletal magnesium concentrations are not readily available. Therefore, diagnosing magnesium deficiency can be challenging. Additional diagnostic tests to assess magnesium deficiency have been suggested, including the intravenous magnesiumloading test, whereby the balance of intravenously infused magnesium and the amount excreted in the urine are used to estimate total body magnesium balance. In normal individuals who are magnesium replete, only 10% of intravenously infused magnesium is retained, while the other 90% is excreted in the urine. In individuals with intracellular magnesium depletion, the absorption rate should increase to greater than 50%. Generally speaking, magnesium-loading tests allow for the quantification of the magnesium required to achieve homeostasis. This can be described as the “exchangeable pool of magnesium,” which more accurately reflects magnesium content vs serum magnesium concentrations. It should be noted, however, that this test is rarely done in clinical practice, so there is no standardization of results. In the great majority of cases, clinicians rely on serum magnesium concentrations to assess magnesium homeostasis.

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Association of Hypomagnesemia With Clinical Outcomes Hypomagnesemia is very common, occurring in up to 12% of hospitalized patients and up to 60% of intensive care unit patients.13 Hypomagnesemia typically leads to 2 types of clinical symptoms: neuromuscular and cardiovascular.14 Neuromuscular symptoms include seizures, tremor, convulsions, and weakness, whereas cardiovascular complications include alterations of electrical conductivity and arrhythmias. These symptoms typically occur at very low magnesium concentrations, less than 1.0 to 1.2 mg/dL. Concurrent electrolyte abnormalities, including hypocalcemia, may accompany severe hypomagnesemia, which may also lead to cardiovascular and neuromuscular instability.15–17 Magnesium is essential in the G-protein–coupled signaling pathways of the calcium-sensing receptor of the parathyroid gland, leading to decreased PTH release in states of hypomagnesemia, and consequent hypocalcemia. The conversion of 25-hydroxyvitamin D to the active 1,25 form, central to calcium reabsorption, also relies on magnesium as a cofactor.18,19 Mutations in the TRPM6 gene, primarily responsible for the active transport of divalent cations, have been identified as responsible for familial cases of hypomagnesemia and secondary hypocalcemia, providing another potential physiologic explanation for this co-occurrence of electrolyte abnormalities.20,21 Beyond the neurologic, cardiac, and calcium-related manifestations of hypomagnesemia, magnesium has been linked to a wide range of diseases in the popular and the professional literature. Given magnesium’s intracellular nature and biologic complexity, teasing out its specific role in disease pathways is challenging. There have been myriad clinical studies that have investigated a potential role of magnesium on outcomes such as cardiovascular disease, diabetes, immunity, and death, with a range of conclusions that can be difficult to interpret. A daunting challenge in interpreting how serum concentrations of magnesium relate to outcomes is to account for residual confounding due to the effect of diet and lifestyle. Because dietary intake, which cannot be accurately characterized in clinical studies, is such an important determinant of magnesium concentrations, it remains impossible to distinguish whether observed associations between magnesium serum concentration and outcomes are due to the magnesium level itself or to the underlying diet and lifestyle behaviors that lead to changes in magnesium levels. Magnesium-rich foods include dark leafy greens such as raw spinach, nuts, fish, legumes, whole grains such as brown rice, and fruit. These are foods that we most naturally associate

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Figure 1. Gastrointestinal and renal reabsorption of magnesium. Active transport of Mg2+ ions via a specific pore within the 6-transmembranedomain structure of the TRPM6/7 channel is shown with a solid arrow. Paracellular (passive) transport is shown with a dotted arrow. Panel A represents the enterocyte of the cecum/large bowel. PPI-induced hypomagnesemia is believed to involve the lack of reabsorption of Mg2+ via the colonic enterocyte’s active transport channels (TRPM6/7), but the mechanism remains unclear. Panel B shows a composite of the cells of the thick ascending limb (TAL) of the loop of Henle and the distal convoluted tubule (DCT). Passive Mg2+ movement occurs via claudins 16/19 in the TAL, and the DCT reabsorbs Mg2+ actively through TRPM6/7. This is accomplished through the generation of a Na+ gradient, with the NaCl cotransporter and Na,K-ATPase pump driving the reabsorption of Mg2+ ions into the systemic circulation. (Note that this figure represents the TAL and DCT as a single “renal tubular cell” for simplicity.)

with healthy lifestyle and habits. For example, 100 g of nuts contains approximately 534 mg of magnesium, whereas cheese pizza has less than 25 mg. Therefore, whether any potential link between hypomagnesemia and outcome is due to the low magnesium concentration, or instead, the unhealthy eating habits and lifestyle that likely contribute to hypomagnesemia,22 is difficult to determine. Although clinical studies routinely try to account for diet and lifestyle, these endpoints are difficult to accurately characterize and are likely a source of significant residual confounding. There has been interest in what role magnesium may play in vascular biology, with a potential link to cardiovascular disease, including hypertension, stroke, and mortality. A large observational study supports a role for magnesium in blood pressure regulation,23 as suggested by small physiology and clinical studies.24 However, more recent studies have shown little effect of magnesium supplementation on blood pressure,25,26 and 2 well-designed clinical studies have failed to find an association between hypomagnesemia and hypertension.27,28 Although 2 recent studies have suggested that low serum magnesium levels are associated with thickening of the cardiac wall29 as well as cardiovascular and all-cause mortality,30 these studies failed to account for confounding due to dietary and lifestyle habits. A better-designed study from the well-known Framingham Heart Study Offspring Cohort concluded that hypomagnesemia was not related to incident hy-

pertension, cardiovascular disease, or mortality,28 and dietary magnesium intake has not been associated with the risk of coronary heart disease.31

Proton Pump Inhibitor Exposure and Hypomagnesemia In 2006 the first case report linking proton pump inhibitor (PPI) use to hypomagnesemia was published.32 Over subsequent years approximately 45 case reports have emerged with similar findings. Patients typically have many years of PPI exposure (average 10–15 years) and present with symptoms ranging from cardiovascular instability to neuroexcitability, including tetany and seizures. In approximately half of these case reports, other sources of magnesium deficiency were present, including gastrointestinal loss from chronic diarrhea or malabsorption, poor dietary intake from malnutrition or alcohol use, or renal magnesium excretion from diuretic use. Multiple different PPIs have been implicated, including omeprazole, pantoprazole, lansoprazole, and rabeprazole, and the described association is generally considered a class effect. Among the initial case reports, hypomagnesemia improved after cessation of the PPI. In 13 cases where PPI were resumed at a later date, hypomagnesemia recurred. Conversely, in patients who were prescribed a different class of gastric acid suppression medicine, namely histamine-2 receptor antagonists (eg, ranitidine), the hypomagnesemia did not recur.

4 These early published cases, along with increased reporting of the phenomenon to their Adverse Events Reporting System (AERS), prompted the US Food and Drug Administration to release a “drug safety communication” regarding the risk of PPI-induced hypomagnesemia.33 The alert suggested that health care professionals should consider obtaining baseline and periodic follow-up serum magnesium concentrations for those patients expected to be long-term PPI users, particularly among those on diuretics and other medicines that could predispose to hypomagnesemia. Although the exact usage of PPIs is unknown, this drug class is extremely prevalent with over a 100 million new prescriptions per year. Using the US Food and Drug Administration AERS data, Luk and colleagues demonstrated that PPI exposure is associated with a nearly 3-fold increased risk for hypomagnesemia, especially among those greater than 65 years old.34 Multiple clinical studies have investigated the association between PPI use and hypomagnesemia (Table 1) with differing results. In a large study of over 11 000 critically ill patients at a single medical center, PPI use was associated with hypomagnesemia, particularly among those concurrently prescribed a diuretic.35 Among diuretic users, PPI use was associated with a 54% increased risk of hypomagnesemia, as defined by a serum magnesium <1.6 mg/dL. In nondiuretic users, a significant association between PPI use and hypomagnesemia was not found. The association between PPI use and hypomagnesemia has been reproduced by others36 and has been extended to the non–critically ill populations. Zipursky and colleagues reported a 43% increased risk of hypomagnesemia in hospitalized patients,37 and Lindner and colleagues demonstrated a 2-fold increased risk of hypomagnesemia among PPI users presenting to the emergency department.38 Many of these observational studies have been limited by the inability to accurately document the duration of PPI exposure for each subject. Because the FDA statement about PPI-induced hypomagnesemia refers to the increased risk of long-term PPI users, Markovits and colleagues designed a cross-sectional study in which duration of PPI exposure was measured.39 Surprisingly, associations between PPI use and hypomagnesemia were found among both “casual” or intermittent PPI users, and those taking the medication for greater than 4 months. On the contrary, 2 other studies of modest size (150 to 400 patients) found that PPI use was not associated with hypomagnesemia.40,41 Both of these studies targeted outpatients but had strict inclusion/exclusion criteria that may have eliminated patients at higher risk for PPI-induced hypomagnesemia. Koulouridis and colleagues included only those with known upper

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gastrointestinal tract disorders (ie, gastroesophageal reflux disease or peptic ulcer disease) to detect those who were presumably prescribed PPIs appropriately. However, there is significant evidence to suggest that PPI use is largely inappropriate among patients, and those prescribed PPIs often remain on them for longer periods of time without clear indications.42 Faulhaber and colleagues conducted a smaller study of emergency department patients that, similarly, excluded many of the patients at highest risk for PPI-induced hypomagnesemia. There have been few studies on whether PPI use is associated with hypomagnesemia-related clinical outcomes rather than simply changes in serum magnesium concentrations. However, a recent study examined PPI exposure and the risk of arrhythmias, hypothesizing that if PPI use leads to chronic decreased magnesium absorption, and therefore magnesium deficiency, PPI use should be associated with an increased risk of arrhythmias. However, in 8000 patients admitted to a single-center intensive care unit, PPI use was not associated with an increased risk of arrhythmia.43 Given the difficulty in accurately measuring magnesium homeostasis, as described earlier, it is at least plausible that chronic PPI use might lead to intracellular magnesium depletion while not affecting serum magnesium concentrations. Because magnesium is primarily stored within the skeleton, it is possible that PPI use could lead to skeletal magnesium depletion. PPIs, especially with concurrent bisphosphonate administration, have been associated with worsening osteoporosis in some, but not all, studies.44–47 However, this may be due to drug-drug interactions rather than an independent contribution of PPIs. Without well-designed studies that specifically address magnesium balance, carefully weighing magnesium intake and magnesium excretion before and after PPI exposure, much conjecture will remain.

Potential Mechanisms of PPI-Induced Hypomagnesemia Putative mechanisms whereby PPI use could cause hypomagnesemia have been suggested, although with scant confirmatory data. An early case report first elucidated the mechanism of PPI-associated hypomagnesemia using intravenous magnesium testing. Magnesium infusion was associated with low urinary magnesium in PPI users, suggesting that urinary wasting was not the cause of magnesium deficiency.17 Subsequently, most case reports have suggested appropriate renal magnesium conservation. A recent “magnesium balance” study examined the effect of PPI on 24-hour urine magnesium excretion and found that PPI users had lower urinary magnesium in a model

Retrospective cohort

Cross-sectional

Cross-sectional

Cross-sectional

Case-control

Cross-sectional

Cross-sectional

2014

2014

2014

2014

2014

2013

2013

Alhosaini et al54

Lindner et al38

Markovits et al39

William et al48

Zipursky et al37

Danziger et al35

El-Charabaty et al55

Study Design

Year of Publication

Study Authors

Inpatients (critical care unit)

Inpatients (intensive care unit)

Inpatients

Outpatients with documented nephrolithiasis

Outpatients

Outpatients, admitted as inpatients

Chronic hemodialysis patients

Participants and Setting

Inclusion/Exclusion Criteria

Excluded: acute/chronic diarrheal illness, chronic inflammatory bowel disease, malabsorptive conditions, ESRD, preeclampsia, and primary hyperparathyroidism; transfers from other hospitals Included: diagnosed with unstable angina, NSTEMI, or STEMI Excluded: pregnant women, patients with cognitive impairment, chronic atrial fibrillation

Excluded: hyperparathyroidism, inflammatory bowel diseases, hospitalization within 1 month of index date

Included: First urine collections from nephrolithiasis patients who underwent urinary testing for stone evaluation

Excluded: ESRD patients

None stated

Included: ESRD patients

Table 1. Comparison of Recently Published Observational Studiesa

421

11 490

1830 (366 cases)

278

95 205

5118

62

Total No. of Patients

Study Conclusions

Slightly higher cutoffs for hypomagnesemia (equivalent to 1.8 mg/dL). Unable to confirm prescription-free use or duration of use of PPI or magnesium supplements Slightly higher cutoffs for significant hypomagnesemia (less than equivalent of 1.3 mg/dL considered “severe”)

Not generalizable to the majority of patients on PPIs

Limitations

(Continued)

Not generalizable due to ICU Association of PPI use with PPI use may lead to serum magnesium levels hypomagnesemia and cardiac population Exclusion criteria without and the development of arrhythmias in susceptible attention paid to conditions cardiac arrhythmias individuals influencing both PPI use and magnesium levels

Prevalence and risk factors Hypomagnesemia was more of hypomagnesemia and common in those using PPIs whether PPI use (especially more severe increases this risk hypomagnesemia), with associations in both casual use and those who used PPIs for >4 months, regardless of risk factors 24-hour urine magnesium PPI users had lower urinary Not a balance study, as no in PPI vs non-PPI users magnesium, suggesting PPI measure of magnesium exposure decreases intake; no concurrent serum intestinal magnesium magnesium measurements absorption Association of PPI use with PPI use associated with a 43% Serum magnesium levels were hypomagnesemia increased risk of not measured, and authors requiring hospitalization hypomagnesemia, effect relied upon appropriate modified by diuretic use, and coding a small increased risk for hospitalization Association of PPI use with Combination of diuretic and Observational study of ICU serum magnesium PPI use resulted in 55% patients, so unable to concentrations increased odds of developing measure causality; potential hypomagnesemia under-reporting of PPI use and unable to determine duration of use

Association of PPI use and Lower serum magnesium hypomagnesemia in concentrations among PPI patients on hemodialysis users vs nonusers 3 times weekly Risk of hypomagnesemia in PPI users have a 2-fold those on PPIs as increased risk of outpatients hypomagnesemia, independent of diuretic use

Primary Outcome of Interest

William and Danziger

5

Cross-sectional

Case-control

2013

2013

2013

2013

Faulhaber et al41

Koulouridis et al40

Luk et al34

Gau et al36

Inclusion/Exclusion Criteria

Total No. of Patients

Primary Outcome of Interest

Inpatients

Two data sets, combined: ages 50 and older, no exclusion criteria enforced; ages 65 and older excluded the following: ESRD, metastatic cancer, respiratory failure, aspiration pneumonia, dysphagia, gastroduodenal feeding

487

Small study; excessive exclusion criteria, instead of including some of these in regression model

No knowledge of diuretic use among subjects Regression models not clearly stated

Limitations

Negative study. Out-of-hospital Restricted to hospitalized PPI use among those with patient with known upper GI upper GI tract disorders was tract disorders, without not associated with lower including those serum magnesium levels on inappropriately on PPIs; hospital admission underpowered for rare events

Negative study. No patient demonstrated hypomagnesemia, with or without PPI use

Study Conclusions

PPI exposure leads to nearly Minimal factors included in 3-fold higher risk of regression models (age, sex, hypomagnesemia, especially PPI use) and not available for among men >65 years old. many subjects. No Clear associations of knowledge of concurrent hypomagnesemia with diuretics/other medications hypocalcemia and or comorbidities hypokalemia Association of PPI use with PPI use, especially higher doses, Single center, small study. serum magnesium are associated with lower Unable to confirm duration concentrations serum magnesium levels and of PPI use 2.5-fold risk of developing hypomagnesemia

Excluded: diarrhea, vomiting, 151 Serum magnesium levels chronic alcohol use, poorly among PPI users controlled diabetes mellitus, chronic laxative or diuretic use (and other medications that cause magnesium wasting) Outpatient to Included: first hospitalization of 804 (402 Association of inpatient patients >18 years old, with pairs of cases out-of-hospital PPI use ICD-9 codes for disorders of and controls) and hypomagnesemia the upper gastrointestinal tract Excluded: acute and chronic diarrheal illness, surgery, alcoholism, pancreatitis, and kidney transplantation; surgical, obstetric, oncologic, or psychiatric/substance abuse hospitalizations Patients reported Report cases of at least 1 adverse 66 102 (1% Risk of hypomagnesemia to FDA Adverse event of PPI use to the with hypowith PPI exposure Event Reporting Adverse Events Reporting magnesemia) System (AERS) System of the FDA database

Emergency department patients

Participants and Setting

a The following studies were not included in this table due to inability to access the full manuscript for review: Biyik et al. Hypomagnesemia among outpatient long-term proton pump inhibitor users. Am J Ther.56 Kim et al. Clinical predictors associated with proton pump inhibitor-induced hypomagnesemia. Am J Ther.57 Van Ende et al. Proton-pump inhibitors do not influence serum magnesium levels in renal transplant recipients. J Nephrol.53

Cross-sectional

Cross-sectional

Study Design

Year of Publication

Study Authors

Table 1. Continued

6 The Journal of Clinical Pharmacology / Vol 00 No 0 2015

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that accounted for other measures of dietary intake, suggesting decreased intestinal magnesium intake.48 Other studies support that chronic PPI use might block intestinal magnesium absorption.49 By increasing the pH of the intestinal lumen, PPIs might reduce TRPM 6/7 channel affinity for magnesium. TRPM6 activity seems to increase with lower pH or greater extrusion of protons into the intestinal lumen, so slight elevations in luminal pH created by PPIs may lead to inappropriately reduced magnesium reabsorption in periods of low total body magnesium content.50,51 Although a compensatory overexpression of TRPM6 may help mitigate intestinal magnesium malabsorption, individual variations in this response may account for why PPI-induced hypomagnesemia is not a universal phenomenon. Because the PPI effect is localized to the intestinal epithelial cell, and not to renal handling, intravenous magnesium rapidly improves magnesium serum concentrations, whereas oral magnesium repletion does not overcome the PPI effect. Intravenous magnesium is often required on an ongoing basis (weekly to monthly) to account for the lack of intestinal/dietary absorption. Magnesium levels usually normalize quickly (days to weeks) after removal of the PPI exposure.52

Risk Factors for PPI-Associated Hypomagnesemia Clearly, given the widespread use of PPIs, and even considering potential underreporting, PPI use is unlikely to cause hypomagnesemia in the majority of patients. The challenge is to identify the patients who are most likely to develop hypomagnesemia. There are a number of risk factors that have been identified. Patient demographics and comorbidities, duration of PPI or diuretic therapy, and individual pharmacogenetics may all contribute to the degree of severity of hypomagnesemia and its clinical manifestations. Special attention should be paid to elderly PPI users, as published case reports suggest increased risk in this population.17,34 Because dietary intake and absorption of magnesium are essential for the maintenance of magnesium balance, malnourishment associated with alcoholism or eating disorders as well as other organic malabsorptive conditions are increasingly recognized risk factors for hypomagnesemia. Additionally, many hypertensive patients are on concurrent diuretic therapy, which might exacerbate the risk of hypomagnesemia.35 Those who develop hypokalemia and hypocalcemia from diuretic use or otherwise should be monitored closely, as these electrolyte abnormalities frequently accompany hypomagnesemia. Patients with chronic kidney disease do not seem to be predisposed to the development of hypomagnesemia, al-

Table 2. Clinical Recommendations for Proton-Pump Inhibitor Use and Monitoring of Magnesium 1. Prescribe with caution in malnourished patients. Patients with evidence of malnourishment from eating disorders, alcoholism, or organic malabsorptive conditions should be monitored closely, as their magnesium intake is limited. 2. Consider monitoring serum magnesium levels in those on concurrent diuretic therapy. From the case reports in the literature, concomitant diuretic and PPI usage portends greater risk of the development of hypomagnesemia. 3. Concurrent electrolyte abnormalities are common. Hypomagnesemia can be accompanied by hypocalcemia and/or hypokalemia. If either of these is detected first, consider checking a serum magnesium level. 4. Ensure an appropriate indication for PPI use. It is not uncommon for patients to continue taking PPIs indefinitely for reflux symptoms or after a hospitalization (for GI prophylaxis) despite the recommendation that these courses should be limited. Often, the PPI therapy can be discontinued. 5. For those at greatest risk of hypomagnesemia, consider trying an H2 receptor antagonist (H2 RA) first. Although less potent and shorter-acting, H2 RAs can still be effective for many patients with reflux-type symptoms. Because hypomagnesemia is a class effect observed among PPIs but not other acid-suppressive medications, H2 RAs can be prescribed without increasing concern for the development of hypomagnesemia.

though no study of PPI exposure has focused on this population. In a single study dedicated to renal transplant recipients, PPI use was not independently associated with lower serum magnesium levels, although many are on calcineurin inhibitors and mTOR inhibitors that can lead to hypomagnesemia.53 The chronicity of PPI ingestion seems to be directly proportional to the risk of developing magnesium deficiency. Potential genetic mutations of TRPM6/7 may explain PPI susceptibility in a small portion of the population.20,21 Since PPIs are highly effective medications when used for appropriate indications, they will continue to be prescribed with regularity. Given the widespread availability of over-the-counter PPI therapy, it is possible that the prevalence of PPI-associated hypomagnesemia may even increase. Although PPI-induced hypomagnesemia is relatively rare, the clinical effects can be life-threatening. Our clinical recommendations are summarized in Table 2.

Limitations Despite the above-described studies on the association of PPI use and hypomagnesemia, definitive conclusions are not possible. The primary challenge in interpreting the observational data is delineating whether PPI use causes, or is simply associated with, hypomagnesemia due to what is termed “confounding by indication.” Because PPI use presumably affects intestinal magnesium absorption, controlling for other factors that

8 might influence magnesium dietary intake is critical in cross-sectional analyses of patient data. The primary indication for PPI prescription is typically due to some type of gastrointestinal disease, including reflux, esophagitis, and gastric ulcers, all of which are likely associated with a change in dietary patterns, so it is very difficult to know if the observed association between PPI use and hypomagnesemia is related to the PPI exposure itself or to the dietary changes associated with the underlying disease which prompted the PPI prescription. This residual confounding is notoriously difficult to overcome in cross-sectional studies, particularly because nutritional intake is a very difficult variable to characterize.

Conclusions As of this time, there are sufficient observational data to link PPI exposure to hypomagnesemia in susceptible individuals. However, whether this association is causal has not been determined, and any conclusions will remain speculative until further studies have been completed. Given the widespread use of PPI, even if a causal link is established, it is clear that hypomagnesemia does not occur in the overwhelming majority of patients, prompting an investigation for other contributing factors in apparent cases. Underlying host comorbidities, including diarrhea, diuretic dose, renal function, and individual pharmacogenetics, might be contributory. Given the prevalence of PPI use and the risk of hypomagnesemia, further well-designed studies are needed. References 1. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95:1–46. 2. Hardwick LL, Jones MR, Buddington RK, Clemens RA, Lee DB. Comparison of calcium and magnesium absorption: in vivo and in vitro studies. Am J Physiol. 1990;259(5 Pt 1):G720–726. 3. Schweigel M, Martens H. Magnesium transport in the gastrointestinal tract. Front Biosci. 2000;5:D666–677. 4. Schmitz C, Perraud AL, Johnson CO, et al. Regulation of vertebrate cellular Mg2+ homeostasis by TRPM7. Cell. 2003;114(2):191–200. 5. Nadler MJ, Hermosura MC, Inabe K, et al. LTRPC7 is a Mg·ATP-regulated divalent cation channel required for cell viability. Nature. 2001;411(6837):590–595. 6. Graham LA, Caesar JJ, Burgen AS. Gastrointestinal absorption and excretion of Mg 28 in man. Metabolism. 1960;9:646– 659. 7. Quamme GA. Magnesium homeostasis and renal magnesium handling. Miner Electrolyte Metab. 1993;19(4-5):218–225. 8. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52(5):1180– 1195. 9. Konrad M, Schaller A, Seelow D, et al. Mutations in the tightjunction gene claudin 19 (CLDN19) are associated with renal magnesium wasting, renal failure, and severe ocular involvement. Am J Hum Genet. 2006;79(5):949–957.

The Journal of Clinical Pharmacology / Vol 00 No 0 2015 10. Hou J, Renigunta A, Gomes AS, et al. Claudin-16 and claudin19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium. Proc Natl Acad Sci USA. 2009;106(36):15350–15355. 11. Voets T, Nilius B, Hoefs S, et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem. 2004;279(1):19–25. 12. Thebault S, Cao G, Venselaar H, Xi Q, Bindels RJ, Hoenderop JG. Role of the alpha-kinase domain in transient receptor potential melastatin 6 channel and regulation by intracellular ATP. J Biol Chem. 2008;283(29):19999–20007. 13. Tong GM, Rude RK. Magnesium deficiency in critical illness. J Intens Care Med. 2005;20(1):3–17. 14. Graber ML. Magnesium deficiency: pathophysiologic and clinical overview. Am J Kidney Dis. 1995;25(6):973. 15. Shabajee N, Lamb EJ, Sturgess I, Sumathipala RW. Omeprazole and refractory hypomagnesaemia. BMJ. 2008;337:a425. 16. Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors—a review. Neth J Med. 2009;67(5):169–172. 17. Cundy T, Dissanayake A. Severe hypomagnesaemia in longterm users of proton-pump inhibitors. Clin Endocrinol (Oxf). 2008;69:338–341. 18. Levine BS, Coburn JW. Magnesium, the mimic/antagonist to calcium. N Engl J Med. 1984;310(19):1253–1255. 19. Rude RK, Oldham SB, Singer FR. Functional hypoparath yroidism and parathyroid hormone end-organ resistance in human magnesium deficiency. Clin Endocrinol (Oxf). 1976;5(3):209–224. 20. Schlingmann KP, Weber S, Peters M, et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet. 2002;31(2):166–170. 21. Schlingmann KP, Sassen MC, Weber S, et al. Novel TRPM6 mutations in 21 families with primary hypomagnesemia and secondary hypocalcemia. J Am Soc Nephrol. 2005;16(10):3061– 3069. 22. Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu Heart Study. Am J Clin Nutr. 1987;45(2): 469–475. 23. Moskowitz A, Lee J, Donnino MW, Mark R, Celi LA, Danziger J. The association between admission magnesium concentrations and lactic acidosis in critical illness. J Intens Care Med. 2014; Epub ahead of print. 24. Hatzistavri LS, Sarafidis PA, Georgianos PI, et al. Oral magnesium supplementation reduces ambulatory blood pressure in patients with mild hypertension. Am J Hypertens. 2009;22(10):1070–1075. 25. Patki PS, Singh J, Gokhale SV, Bulakh PM, Shrotri DS, Patwardhan B. Efficacy of potassium and magnesium in essential hypertension: a double-blind, placebo controlled, crossover study. BMJ. 1990;301(6751):521–523. 26. Cappuccio FP, Markandu ND, Beynon GW, Shore AC, Sampson B, MacGregor GA. Lack of effect of oral magnesium on high blood pressure: a double blind study. BMJ. 1985;291(6490):235–238. 27. Peacock JM, Folsom AR, Arnett DK, Eckfeldt JH, Szklo M. Relationship of serum and dietary magnesium to incident hypertension: the Atherosclerosis Risk in Communities (ARIC) Study. Ann Epidemiol. 1999;9(3):159–165. 28. Khan AM, Sullivan L, McCabe E, Levy D, Vasan RS, Wang TJ. Lack of association between serum magnesium and the risks of hypertension and cardiovascular disease. Am Heart J. 2010;160(4):715–720. 29. Reffelmann T, Dorr M, Ittermann T, et al. Low serum magnesium concentrations predict increase in left ventricular mass over

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5 years independently of common cardiovascular risk factors. Atherosclerosis. 2010;213(2):563–569. Reffelmann T, Ittermann T, Dorr M, et al. Low serum magnesium concentrations predict cardiovascular and all-cause mortality. Atherosclerosis. 2011;219(1):280–284. Chiuve SE, Sun Q, Curhan GC, et al. Dietary and plasma magnesium and risk of coronary heart disease among women. J Am Heart Assoc. 2013;2(2):e000114. Epstein M, McGrath S, Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism. N Engl J Med. 2006;355(17):1834–1836. FDA Drug Safety Communication. Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs). http://www.fda.gov/Drugs/DrugSafety/ucm245011 .htm. Accessed August 3, 2015. Luk CP, Parsons R, Lee YP, Hughes JD. Proton pump inhibitorassociated hypomagnesemia: what do FDA data tell us? Ann Pharmacother. 2013;47:773–780. Danziger J, William JH, Scott DJ, et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int. 2013;83:692–699. Gau JT, Yang YX, Chen R, Kao TC. Uses of proton pump inhibitors and hypomagnesemia. Pharmacoepidemiol Drug Saf. 2012;21(5):553–559. Zipursky J, Macdonald EM, Hollands S, et al. Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study. PLoS Med. 2014;11:e1001736. Lindner G, Funk GC, Leichtle AB, et al. Impact of proton pump inhibitor use on magnesium homoeostasis: a cross-sectional study in a tertiary emergency department. Int J Clin Pract. 2014;68(11):1352–1357. Markovits N, Loebstein R, Halkin H, et al. The association of proton pump inhibitors and hypomagnesemia in the community setting. J Clin Pharmacol. 2014;54(8):889– 895. Koulouridis I, Alfayez M, Tighiouart H, et al. Out-of-hospital use of proton pump inhibitors and hypomagnesemia at hospital admission: a nested case-control study. Am J Kidney Dis. 2013;62(4):730–737. Faulhaber GA, Ascoli BM, Lubini A, et al. Serum magnesium and proton-pump inhibitors use: a cross-sectional study. Rev Assoc Med Bras. 2013;59(3):276–279. Kelly OB, Dillane C, Patchett SE, Harewood GC, Murray FE. The inappropriate prescription of oral proton pump inhibitors in the hospital setting: a prospective cross-sectional study. Dig Dis Sci. 2015;60(8):2280–2286.

9 43. Chen KP, Lee J, Mark RG, et al. Proton pump inhibitor use is not associated with cardiac arrhythmia in critically ill patients. J Clin Pharmacol. 2015;55(7):774–779. 44. Yang SD, Chen Q, Wei HK, et al. Bone fracture and the interaction between bisphosphonates and proton pump inhibitors: a meta-analysis. Int J Clin Exp Med. 2015;8(4):4899–4910. 45. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture efficacy of alendronate. Arch Intern Med. 2011;171(11):998–1004. 46. Kwok CS, Yeong JK, Loke YK. Meta-analysis: risk of fractures with acid-suppressing medication. Bone. 2011;48(4):768– 776. 47. Lee J, Youn K, Choi NK, et al. A population-based case-control study: proton pump inhibition and risk of hip fracture by use of bisphosphonate. J Gastroenterol. 2013;48(9):1016–1022. 48. William JH, Nelson R, Hayman N, Mukamal KJ, Danziger J. Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology (Carlton). 2014;19(12):798– 801. 49. Thongon N, Krishnamra N. Omeprazole decreases magnesium transport across Caco-2 monolayers. World J Gastroenterol. 2011;17(12):1574–1583. 50. Lameris AL, Hess MW, van Kruijsbergen I, Hoenderop JG, Bindels RJ. Omeprazole enhances the colonic expression of the Mg(2+) transporter TRPM6. Pflugers Arch. 2013;465(11):1613– 1620. 51. Li M, Du J, Jiang J, et al. Molecular determinants of Mg2+ and Ca2+ permeability and pH sensitivity in TRPM6 and TRPM7. J Biol Chem. 2007;282(35):25817–25830. 52. Mackay JD, Bladon PT. Hypomagnesaemia due to protonpump inhibitor therapy: a clinical case series. Q J Med. 2010;103(6):387–395. 53. Van Ende C, Van Laecke S, Marechal C, et al. Proton-pump inhibitors do not influence serum magnesium levels in renal transplant recipients. J Nephrol. 2014; Epub ahead of print. 54. Alhosaini M, Walter JS, Singh S, Dieter RS, Hsieh A, Leehey DJ. Hypomagnesemia in hemodialysis patients: role of proton pump inhibitors. Am J Nephrol. 2014;39:204–209. 55. El-Charabaty E, Saifan C, Abdallah M, et al. Effects of proton pump inhibitors and electrolyte disturbances on arrhythmias. Int J Gen Med. 2013;6:515–518. 56. Biyik M, Solak Y, Ucar R, et al. Hypomagnesemia among outpatient long-term proton pump inhibitor users. Am J Ther. 2014; Epub ahead of print. 57. Kim S, Lee H, Park CH, et al. Clinical predictors associated with proton pump inhibitor-induced hypomagnesemia. Am J Ther. 2015;22(1):14–21.