Proton-pump inhibitor use is associated with low serum magnesium concentrations
2013; Elsevier BV; Volume: 83; Issue: 4 Linguagem: Inglês
10.1038/ki.2012.452
ISSN1523-1755
AutoresJohn Danziger, Jeffrey H. William, Daniel Scott, Joon Lee, Li-wei H. Lehman, Roger G. Mark, Michael D. Howell, Leo Anthony Celi, Kenneth J. Mukamal,
Tópico(s)Gastroesophageal reflux and treatments
ResumoAlthough case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy. Although case reports link proton-pump inhibitor (PPI) use and hypomagnesemia, no large-scale studies have been conducted. Here we examined the serum magnesium concentration and the likelihood of hypomagnesemia (<1.6mg/dl) with a history of PPI or histamine-2 receptor antagonist used to reduce gastric acid, or use of neither among 11,490 consecutive adult admissions to an intensive care unit of a tertiary medical center. Of these, 2632 patients reported PPI use prior to admission, while 657 patients were using a histamine-2 receptor antagonist. PPI use was associated with 0.012mg/dl lower adjusted serum magnesium concentration compared to users of no acid-suppressive medications, but this effect was restricted to those patients taking diuretics. Among the 3286 patients concurrently on diuretics, PPI use was associated with a significant increase of hypomagnesemia (odds ratio 1.54) and 0.028mg/dl lower serum magnesium concentration. Among those not using diuretics, PPI use was not associated with serum magnesium levels. Histamine-2 receptor antagonist use was not significantly associated with magnesium concentration without or with diuretic use. The use of PPI was not associated with serum phosphate concentration regardless of diuretic use. Thus, we verify case reports of the association between PPI use and hypomagnesemia in those concurrently taking diuretics. Hence, serum magnesium concentrations should be followed in susceptible individuals on chronic PPI therapy. Although proton-pump inhibitors (PPIs) are extremely widely used, with over 100 million US prescriptions in 2007,1.IMS Health INSP, Top Therapy Classes by United States Dispensed Presciptions, Data from 2007. Accessed March 2011. Available at: http://www.imshealth.com/portal/site/imsGoogle Scholar increasing attention has focused on the adverse effects of this class of medicine, including respiratory infections,2.Herzig S.J. Howell M.D. Ngo L.H. et al.Acid-suppressive medication use and the risk for hospital-acquired pneumonia.JAMA. 2009; 301: 2120-2128Crossref PubMed Scopus (374) Google Scholar renal failure,3.Ray S. Delaney M. Muller A.F. Proton pump inhibitors and acute interstitial nephritis.BMJ. 2010; 341: c4412Crossref PubMed Scopus (32) Google Scholar,4.Sierra F. Suarez M. 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Hlatky M.A. Antman E.M. et al.ACCF/ACG/AHA 2010 expert consensus document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents.J Am Coll Cardiol. 2010; 56: 2051-2066Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar Recently, a potential association between chronic PPI use and hypomagnesemia has been reported. Approximately 30 cases of severe hypomagnesemia in patients on PPI therapy have been identified in the literature, with symptoms ranging from cardiovascular instability to neuroexcitability, including tetany and seizures.9.Epstein M. McGrath S. Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism.N Engl J Med. 2006; 355: 1834-1836Crossref PubMed Scopus (145) Google Scholar, 10.Metz D.C. 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Proton Pump Inhibitor drugs (PPIs): Drug Safety Communication—Low Magnesium Levels Can Be Associated With Long-Term Use. (updated 03 March 2011; cited); Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245275.htmGoogle Scholar Magnesium, as the second most common intracellular cation, is important in a wide range of cellular functions, including protein synthesis, enzymatic reactions, and the regulation of ion channels. The classic symptoms of severe hypomagnesemia include tetany, convulsions, bradycardia, hypotension, and death.22.Flink E.B. Magnesium deficiency. Etiology and clinical spectrum.Acta Med Scand Suppl. 1981; 647: 125-137PubMed Google Scholar, 23.Vallee B.L. Wacker W.E. Ulmer D.D. The magnesium-deficiency tetany syndrome in man.N Engl J Med. 1960; 262: 155-161Crossref PubMed Scopus (72) Google Scholar, 24.Moore M.J. Flink E.B. 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Cardiac fibrogenesis in magnesium deficiency: a role for circulating angiotensin II and aldosterone.Am J Physiol Heart Circ Physiol. 2006; 291: H436-H440Crossref PubMed Scopus (19) Google Scholar hypertension,28.Sontia B. Touyz R.M. Magnesium transport in hypertension.Pathophysiology. 2007; 14: 205-211Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,29.Sontia B. Touyz R.M. Role of magnesium in hypertension.Arch Biochem Biophys. 2007; 458: 33-39Crossref PubMed Scopus (140) Google Scholar endothelial function,30.Barbagallo M. Dominguez L.J. Galioto A. et al.Oral magnesium supplementation improves vascular function in elderly diabetic patients.Magnes Res. 2010; 23: 131-137PubMed Google Scholar and insulin resistance.31.Barbagallo M. Dominguez L.J. Magnesium metabolism in type 2 diabetes mellitus, metabolic syndrome and insulin resistance.Arch Biochem Biophys. 2007; 458: 40-47Crossref PubMed Scopus (260) Google Scholar Beyond case reports and a case series,32.Gau J.T. Yang Y.X. Chen R. et al.Uses of proton pump inhibitors and hypomagnesemia.Pharmacoepidemiol Drug Saf. 2012; 21: 553-559Crossref PubMed Scopus (69) Google Scholar little is known about the potential effect of PPI use on magnesium concentrations, with no large-scale data currently available. This lack of robust data is particularly important given the costs associated with surveillance of magnesium levels among patients taking PPIs and the potential risks of hypomagnesemia. To address these questions, we examined the association of acid-suppressive medication use with serum magnesium concentrations in a large sample of patients admitted to a single medical center in whom information on current outpatient medication use and admission serum magnesium levels was available. Given that the indications for PPI and histamine-2 receptor antagonist (H2RA) use are similar, we compared both PPIs and H2RA users to those not taking acid-suppressive medications. Of the 11,490 unique intensive care unit (ICU) admissions from 2001 to 2008, we documented PPI use in 23% (n=2632) before admission, compared with 6% (n=657) on a H2RA. As seen in Table 1, PPI users tended to be older, had worse renal function, and had a higher prevalence of comorbidities than those on neither medication.Table 1Baseline characteristics by acid suppression medicationProton-pump inhibitors (n=2632)H2 receptor antagonists (n=657)No acid-suppressive medications (n=8201)P-valueaP-values reflect across-group differences.Age, mean (s.d.), years67.8 (15.4)66.9 (15.9)61.1 (19.2)<0.001Male, no. (%)1403 (53.3)368 (56.3)4796 (58.5)<0.001Ethnicity, no. (%) White2022 (76.8)496 (75.5)6054 (73.8)<0.001 African American245 (9.3)61 (9.3)682 (8.3)<0.001 Hispanic or Latino79 (3.0)19 (2.9)292 (3.6)<0.001 Asian59 (2.2)14 (2.1)225 (2.7)<0.001 Other52 (2.0)10 (1.52)244 (3.0)<0.001 Unknown175 (6.7)57 (8.7)704 (8.6)<0.001Past medical history, no. (%) Hypertension1009 (38.4)253 (38.5)2749 (33.5)<0.001 Diabetes749 (28.5)184 (28.0)1671 (20.4)<0.001 Congestive heart failure623 (23.7)143 (21.8)1215 (14.8)<0.001 Liver disease210 (8.0)36 (5.5)331 (4.0)<0.001 Renal failure164 (6.2)41 (6.2)255 (3.1)<0.001 Metastatic cancer158 (6.0)41 (6.2)382 (4.7)0.010 Alcohol abuse120 (4.6)22 (3.4)555 (6.8)<0.001 Psychoses95 (3.6)30 (4.6)330 (4.0)0.46Vital signs, mean (s.d·) Temperature, °C36.8 (0.59)36.8 (0.57)36.9 (0.60)<0.001 Systolic blood pressure, mmHg119.8 (17.5)120.5 (16.6)120.1 (16.8)0.60 Heart rate, /min75.4 (13.6)76.0 (13.1)76.1 (13.5)0.067Laboratory values on admission, mean (s.d·) Magnesium, mg/dl1.93 (0.41)1.93 (0.38)1.91 ( 0.40)0.24 Calcium, mg/dl8.61 (0.83)8.65 (0.88)8.57 (0.87)0.004 Phosphate, mg/dl3.68 (1.28)3.66 (1.14)3.58 (1.17)<0.001 Creatinine, mg/dl1.50 (1.52)1.34 (1.22)1.22 (1.20)<0.001 Ratio of 24h/baseline serum creatinine0.99 (0.31)1.06 (0.60)1.01 (0.34)<0.001 Glucose, mg/dl153.1 (90.5)154.6 (92.8)152.2 (98.3)0.77 Hematocrit, %33.6 (6.4)34.5 (6.3)35.5 (6.7)<0.001Diuretic use, no. (%)1034 (39.3)229 (34.9)2023 (24.7)<0.001Abbreviation: H2, histamine-2.a P-values reflect across-group differences. Open table in a new tab Abbreviation: H2, histamine-2. As shown in Table 2, baseline unadjusted magnesium concentrations did not differ by type of acid-suppressive medication. However, after adjusting for patient demographics and renal function (Model I), and in the fully adjusted model (Model II), PPI exposure was significantly associated with lower magnesium concentrations compared with those not taking acid-suppressive therapy, in a model adjusted for diuretic use. Age and renal function were both important independent confounders that accounted for the change in directionality of the effect of PPIs on magnesium concentrations. We did not find a significant association between H2RA exposure and magnesium concentration in either model, although the s.e’s for this less prevalent exposure were comparatively larger.Table 2Association between acid suppression therapy and serum magnesium concentrationProton-pump inhibitorsH2 receptor antagonistsNo acid-suppressive medicationsβ-Coefficient±s.e.P-valueβ-Coefficient±s.e.P-valueReferenceUnadjusted model0.007±0.0040.120.007±0.0080.41—Model IaModel I includes age, gender, ethnicity, and renal function.-0.011±0.0040.01-0.005±0.0080.53—Model IIbModel II includes all variables in Model I and the addition of systolic blood pressure, heart rate, temperature, serum calcium, serum phosphate, serum glucose, hematocrit, diuretic use, and 30 comorbidities.-0.012±0.0040.005-0.008±0.0070.30—Stratified analysiscStratified analysis: when entered into Model II, a multiplicative interaction term between proton-pump inhibitor (PPI) and diuretic use was significant (P=0.03), and the analysis is presented stratified by diuretic exposure. An interaction term between H2RA use was not significant. Diuretic use (n=3286)-0.028±0.007<0.001-0.009±0.0130.50— No diuretic use (n=8204)-0.003±0.0050.61-0.008±0.0090.38—Abbreviation: H2, histamine-2.Reference category is those on no acid-suppressive medications. β-Coefficients±s.e’s and P-values are provided for each variable.a Model I includes age, gender, ethnicity, and renal function.b Model II includes all variables in Model I and the addition of systolic blood pressure, heart rate, temperature, serum calcium, serum phosphate, serum glucose, hematocrit, diuretic use, and 30 comorbidities.c Stratified analysis: when entered into Model II, a multiplicative interaction term between proton-pump inhibitor (PPI) and diuretic use was significant (P=0.03), and the analysis is presented stratified by diuretic exposure. An interaction term between H2RA use was not significant. Open table in a new tab Abbreviation: H2, histamine-2. Reference category is those on no acid-suppressive medications. β-Coefficients±s.e’s and P-values are provided for each variable. Diuretic use significantly modified the effect of PPI exposure on magnesium concentrations (P=0.03 for multiplicative interaction term). As seen in Table 3, diuretic users were similar in age, gender, ethnicity, and presence of comorbidities, regardless of PPI or H2RA exposure, but had significantly worse renal function. In unadjusted analysis of diuretic users, those on a PPI medication had significantly lower magnesium concentrations than those not taking acid-suppressive therapies (P=0.002). In multivariable analysis of those on diuretics (Table 2), PPI use was associated with a 0.028 (±0.007) mg/dl lower serum magnesium concentration. In diuretic naive individuals, PPI use was not associated with a change in serum magnesium concentration. There was no association between H2RA use and serum magnesium concentration in either diuretic or non-diuretic group. An interaction term between H2RA use and diuretic use was not significant (P=0.9).Table 3Baseline characteristics of diuretic usersProton-pump inhibitors (n=1034)H2 receptor antagonists (n=229)No acid-suppressive medications (n=2023)P-valueaP-values reflect across-group differences.Age, mean (s.d.), years70.6 (13.8)71.3 (13.2)71.4 (13.8)0.29Male, no. (%)513 (49.6)115 (50.2)1084 (53.6)0.10Ethnicity, no. (%) White776 (75.1)173 (75.6)1506 (74.4)0.35 African American117 (11.3)26 (11.4)219 (10.8)0.35 Hispanic or Latino36 (3.5)6 (2.6)46 (2.3)0.35 Asian18 (1.7)2 (0.87)34 (1.7)0.35 Other23 (2.2)4 (1.8)41 (2.0)0.35 Unknown64 (6.2)18 (7.9)177 (8.8)0.35Past medical history, no. (%) Hypertension425 (41.1)98 (42.8)868 (42.9)0.63 Diabetes344 (33.3)77 (33.6)648 (32.0)0.74 Congestive heart failure391 (37.8)81 (35.4)636 (31.4)0.002 Liver disease123 (11.9)16 (7.0)91 (4.5)<0.001 Renal failure55 (5.3)14 (6.1)102 (5.0)0.78 Metastatic cancer39 (3.8)11 (4.8)82 (4.1)0.77 Alcohol abuse49 (4.7)9 (3.9)66 (3.3)0.14 Psychoses33 (3.2)2 (0.9)54 (2.7)0.09Vital signs, mean (s.d·) Temperature, °C36.8 (0.60)36.7 (0.56)36.8 (0.58)0.50 Systolic blood pressure, mmHg120.0 (18.2)120.4 (16.8)119.3 (17.0)0.43 Heart rate, /min73.9 (13.3)73.9 (13.7)73.5 (12.8)0.70Laboratory values on admission, mean (s.d·) Magnesium, mg/dl1.96 (0.42)2.0 (0.39)2.0 (0.41)0.002 Calcium, mg/dl8.66 (0.82)8.74 (0.85)8.72 (0.80)0.15 Phosphate, mg/dl3.76 (1.32)3.78 (1.14)3.74 (1.23)0.82 Creatinine, mg/dl1.57 (1.28)1.45 (1.08)1.44 (1.10)0.008 Ratio of 24h/baseline serum creatinine0.97 (0.23)1.02 (0.28)1.01 (0.31)<0.001 Glucose, mg/dl156.4 (92.0)153.8 (97.9)162.1 (113.2)0.25 Hematocrit, %33.4 (6.33)33.5 (6.10)34.5 (6.70)<0.001Abbreviation: H2, histamine-2.a P-values reflect across-group differences. Open table in a new tab Abbreviation: H2, histamine-2. We next assessed whether PPI use was related to frank hypomagnesemia, defined as a serum magnesium concentration <1.6mg/dl. In a fully adjusted analysis, neither PPI nor H2RA exposure was associated with hypomagnesemia. However, diuretic use again significantly modified the effect of PPI exposure on magnesium concentrations (P<0.001). As seen in Table 4, PPI use was associated with a 54% increased odds of hypomagnesemia in diuretic users compared with diuretic users not taking acid-suppressive therapy. PPI use was not associated with an increased risk of hypomagnesemia among patients not taking diuretics.Table 4Association between acid suppression therapy and hypomagnesemiaaAdjusted analysis using all variables from Model II, with magnesium dichotomized at <1.6mg/dl.Proton-pump inhibitorsH2 receptor antagonistsNo acid-suppressive medicationsCases, n (%)Odds ratio (95% CI)P-valueCases, n (%)Odds ratio (95% CI)P-valueCases, n (%)Ref.Study populationbA multiplicative interaction term between proton-pump inhibitor (PPI) and diuretic use was significant (P<0.001). A multiplicative interaction term between histamine-2 receptor antagonist (H2RA) and diuretic use was also significant (P=0.01).405 (15.3)1.10 (0.96–1.25)0.1894 (14.3)0.97 (0.76–1.23)0.811362 (16.6)—Diuretic use (n=3286)161 (15.6)1.54 (1.22–1.95)<0.00117 (7.4)0.63 (0.36–1.03)0.07223 (11.0)—No diuretic use (n=8204)244 (15.2)0.92 (0.78–1.09)0.3577 (18.0)1.14 (0.85–1.49)0.391139 (18.4)—Abbreviations: H2, histamine-2; Ref., reference category.Reference category is those on no acid-suppressive medications.a Adjusted analysis using all variables from Model II, with magnesium dichotomized at <1.6mg/dl.b A multiplicative interaction term between proton-pump inhibitor (PPI) and diuretic use was significant (P 0.05), in whole cohort analysis or in the subset of diuretics users (all P-values >0.05). In this large hospital-based cross-sectional study, PPI exposure before admission was associated with lower serum magnesium concentrations in those patients concurrently using diuretics. The combination of diuretic and PPI exposure was associated with an almost 55% increased odds of hypomagnesemia compared with those on diuretics who were not taking acid-suppressive medications. PPI use was not associated with magnesium in diuretic naive individuals. Although the risk of hypomagnesemia has been suggested by smaller observational studies, this study is the first to our knowledge to provide an analysis between PPI use and magnesium concentrations in a large sample, and supports the notion that PPI use may lead to hypomagnesemia in susceptible individuals. The mechanism as to how PPI use may lead to hypomagnesemia is not certain. Magnesium homeostasis depends on the balance between intestinal absorption and renal excretion. Intestinal absorption occurs through two major pathways: active and passive. Active transcellular transport across the apical lumen occurs via the channel transient receptor potential melastatin 6.33.Schlingmann K.P. 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: 166-170Crossref PubMed Scopus (647) Google Scholar Passive movement down a concentration gradient occurs paracellularly, modulated by the tight junction proteins claudin-16 and claudin-19,34.Hou J. Renigunta A. Konrad M. et al.Claudin-16 and claudin-19 interact and form a cation-selective tight junction complex.J Clin Invest. 2008; 118: 619-628PubMed Google Scholar and is postulated to be the major route of magnesium absorption. Renal excretion primarily depends on tubular reclamation in the proximal tubule and thick ascending limb via paracellular absorption,35.Quamme G.A. Control of magnesium transport in the thick ascending limb.Am J Physiol. 1989; 256: F197-F210PubMed Google Scholar with some active absorption in the distal convoluted tubule.36.Dai L.J. Ritchie G. 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Furthermore, repletion with intravenous magnesium rapidly corrected serum concentrations, whereas for many,9.Epstein M. McGrath S. Law F. Proton-pump inhibitors and hypomagnesemic hypoparathyroidism.N Engl J Med. 2006; 355: 1834-1836Crossref PubMed Scopus (145) Google Scholar,11.Shabajee N. Lamb E.J. Sturgess I. et al.Omeprazole and refractory hypomagnesaemia.BMJ. 2008; 337: a425Crossref PubMed Scopus (87) Google Scholar but not all,13.Broeren M.A. Geerdink E.A. Vader H.L. et al.Hypomagnesemia induced by several proton-pump inhibitors.Ann Intern Med. 2009; 151: 755-756Crossref PubMed Google Scholar oral magnesium seemed to have less of an effect. Recent cell culture data suggest that PPIs may impair passive magnesium absorption across intestinal epithelial cells.37.Thongon N. Krishnamra N. Omeprazole decreases magnesium transport across Caco-2 monolayers.World J Gastroenterol. 2011; 17: 1574-1583Crossref PubMed Scopus (44) Google Scholar Although H2RA use affects the pH of the gastric epithelium, H2RA use has not been associated with hypomagnesemia, suggesting a pH-independent mechanism. Our study results also support this distinction. Although the observed effect size of PPI exposure on magnesium concentration is modest, it may reflect larger differences in magnesium homeostasis that are clinically important. Because magnesium is primarily stored within the skeleton,38.Wallach S. Effects of magnesium on skeletal metabolism.Magnes Trace Elem. 1990; 9: 1-14PubMed Google Scholar magnesium efflux from the bone may maintain serum concentrations, despite a net negative balance. In a manner similar to net acid retention seen in chronic kidney disease, where despite a loss of renal hydrogen excretion, serum bicarbonate levels are maintained by efflux of bicarbonate from the bone, PPI exposure may lead to a net negative magnesium balance with modest changes in serum magnesium concentration. Chronic magnesium egress may induce bone mineral loss, potentially explaining the association between long-term PPI use and osteoporosis in several observational studies,39.Yang Y.X. Lewis J.D. Epstein S. et al.Long-term proton pump inhibitor therapy and risk of hip fracture.JAMA. 2006; 296: 2947-2953Crossref PubMed Scopus (1005) Google Scholar,40.Targownik L.E. Lix L.M. Metge C.J. et al.Use of proton pump inhibitors and risk of osteoporosis-related fractures.CMAJ. 2008; 179: 319-326Crossref PubMed Scopus (348) Google Scholar although not confirmed by others.41.Targownik L.E. Lix L.M. 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