title: Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study.
abstract: BACKGROUND
  Proton pump inhibitor (PPI) use has been associated with hypomagnesemia in case reports and hospital-based cohort studies. Our objective was to determine whether PPI use is associated with hypomagnesemia in the general population and whether this is also found in histamine 2 receptor antagonist (H2RA) users.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  9,818 individuals from the general population (Rotterdam Study).
  
  
  METHODS
  PPI use and H2RA use compared to no use.
  
  
  METHODS
  Serum magnesium and hypomagnesemia (serum magnesium ≤ 1.44 mEq/L). Analyses were adjusted for age, sex, body mass index, kidney function, comorbid conditions, and alcohol and diuretic use.
  
  
  RESULTS
  Serum magnesium level was 0.022 mEq/L lower in PPI users (n=724; 95% CI, -0.032 to -0.014 mEq/L) versus those with no use. PPI use was associated with increased risk of hypomagnesemia (n=36; OR, 2.00; 95% CI, 1.36-2.93) compared to no use. Effect modification was found between the use of PPIs and loop diuretics; in participants using loop diuretics (n=270), PPI use was associated with a further increased risk of hypomagnesemia (n=5; OR, 7.22; 95% CI, 1.69-30.83) compared to no use. The increased risk with PPIs was only seen after prolonged use (range, 182-2,618 days; OR, 2.99; 95% CI, 1.73-5.15). Including dietary magnesium intake into the model did not alter results (available for 2,504 participants, including 231 PPI users). H2RA users (n=250) also had a lower serum magnesium level (-0.016 [95% CI, -0.032 to -0.002] mEq/L) and increased risk of hypomagnesemia (n=12; OR, 2.00; 95% CI, 1.08-3.72) compared to those with no use, but no interaction with loop diuretics.
  
  
  CONCLUSIONS
  Cross-sectional analysis with single serum magnesium measurement.
  
  
  CONCLUSIONS
  PPI use is associated with hypomagnesemia in the general population. Prolonged PPI use and concomitant loop diuretic use are associated with a stronger risk increase. Similar but weaker associations were found in H2RA users, except for interaction with loop diuretics.
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Inspectorate of Health Care, Utrecht, the Netherlands.
authors.forename: Brenda C T
authors.initials: BC
authors.lastname: Kieboom
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Leiden University College, The Hague, the Netherlands.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Kiefte-de Jong
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Mark
authors.initials: M
authors.lastname: Eijgelsheim
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Franco
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Kuipers
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Albert
authors.initials: A
authors.lastname: Hofman
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Robert
authors.initials: R
authors.lastname: Zietse
authors.affiliation: Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Inspectorate of Health Care, Utrecht, the Netherlands. Electronic address: b.stricker@erasmusmc.nl.
authors.forename: Bruno H
authors.initials: BH
authors.lastname: Stricker
authors.affiliation: Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.
authors.forename: Ewout J
authors.initials: EJ
authors.lastname: Hoorn
mesh_terms: D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004032:Diet / Q000706:statistics & numerical data; D006635:Histamine H2 Antagonists / Q000627:therapeutic use*; D016014:Linear Models; D008274:Magnesium / Q000097:blood*; D015999:Multivariate Analysis; D011446:Prospective Studies; D054328:Proton Pump Inhibitors / Q000627:therapeutic use*; D012307:Risk Factors; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000627:therapeutic use; D014883:Water-Electrolyte Imbalance / Q000453:epidemiology*
chemical_list: D006635:Histamine H2 Antagonists; D054328:Proton Pump Inhibitors; D049994:Sodium Potassium Chloride Symporter Inhibitors; D008274:Magnesium
keywords: Epidemiology; Rotterdam Study; TRPM6; acid-suppressive medication; diuretics; drug safety; histamine 2 receptor antagonist (H2RA); hypomagnesemia; intestinal magnesium loss; magnesium; population-based cohort; proton pump inhibitor (PPI)