Proton Pump Inhibitors and Hypomagnesemia in the General Population

A Population-Based Cohort Study

Brenda C.T. Kieboom, MD; Jessica C. Kiefte–de Jong, RD, PhD; Mark Eijgelsheim, MD, PhD; Oscar H. Franco, MD, PhD; Ernst J. Kuipers, MD, PhD; Albert Hofman, MD, PhD; Robert Zietse, MD, PhD; Bruno H. Stricker, MMed, PhD; Ewout J. Hoorn, MD, PhD


Am J Kidney Dis. 2015;66(5):775-782. 

In This Article

Abstract and Introduction


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.


Proton pump inhibitors (PPIs) are currently the main therapy for gastroesophageal reflux disease, peptic ulcer disease, non-ulcer dyspepsia, and prevention of gastropathy with the use of nonsteroidal anti-inflammatory drugs.[1] The broad spectrum of indications and the favorable safety profile have made them one of the most frequently used pharmaceuticals.[1,2] Because of their widespread and often long-term use, the safety of PPIs has received attention since their first introduction. Since 2006, cases of severe hypomagnesemia have been reported in association with the use of PPIs, sometimes accompanied by secondary hypokalemia and hypocalcemia.[3] Severe hypomagnesemia may result in tetany, convulsions, or cardiac arrhythmias.[4] Although mild hypomagnesemia is often asymptomatic, it may still be relevant because population studies have shown that even mild hypomagnesemia is associated with increased risk of diabetes mellitus,[5] osteoporosis,[6] cardiovascular disease,[7,8] and mortality.[9] Cases of severe hypomagnesemia have not been reported with the use of histamine 2 receptor antagonists (H2RAs), although a recent study showed that their long-term use is also associated with hypomagnesemia.[10]

At present, the evidence for the association between PPI use and hypomagnesemia is based on case reports (for review, see[1]), 6 studies in hospitalized patients,[2,11–15] and 1 study in ambulatory patients.[10] The latter study was important because of its size (95,000 participants) and the suggestion that PPI-induced hypomagnesemia also occurs in the community. Our objective was to analyze the association between PPI use and risk of hypomagnesemia in a population-based cohort with systematic measurements of serum magnesium. We also analyzed whether prolonged duration of PPI use and concomitant diuretic use were associated with increased risk of hypomagnesemia. Finally, we also assessed the association between the use of H2RAs and hypomagnesemia.