Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study

Am J Kidney Dis. 2015 Nov;66(5):775-82. doi: 10.1053/j.ajkd.2015.05.012. Epub 2015 Jun 26.


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.

Study design: Prospective cohort study.

Setting & participants: 9,818 individuals from the general population (Rotterdam Study).

Predictor: PPI use and H2RA use compared to no use.

Outcomes & measurements: 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.

Limitations: 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.

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).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cohort Studies
  • Cross-Sectional Studies
  • Diet / statistics & numerical data
  • Histamine H2 Antagonists / therapeutic use*
  • Linear Models
  • Magnesium / blood*
  • Multivariate Analysis
  • Prospective Studies
  • Proton Pump Inhibitors / therapeutic use*
  • Risk Factors
  • Sodium Potassium Chloride Symporter Inhibitors / therapeutic use
  • Water-Electrolyte Imbalance / epidemiology*


  • Histamine H2 Antagonists
  • Proton Pump Inhibitors
  • Sodium Potassium Chloride Symporter Inhibitors
  • Magnesium