Use of Proton Pump Inhibitors Associated with Increased Risk of Hypomagnesemia in General Population

In the general population, the use proton pump inhibitors is associated with hypomagnesemia, and prolonged use of a PPI with concomitant loop diuretic use are associated with a stronger increase in risk. Those were two findings of a cross-sectional analysis conducted recently by Brenda C. T. Kieboom, MD, and colleagues. The researchers reported results of the prospective cohort study in the American Journal of Kidney Diseases [2015;66(5):775-782].

PPIs are prescribed as the primary therapy for gastroesophageal reflux disease, peptic ulcer disease, non-ulcer dyspepsia, and for the prevention of gastropathy with the use of nonsteroidal anti-inflammatory drugs.

PPIs have a broad spectrum of indications and favorable safety profiles, making them among the most frequently prescribed pharmaceuticals. Since 2006, there have been reports of an association between the use of PPIs and cases of severe hypomagnesemia, which can also be accompanied by secondary hypokalemia and hypocalcemia.

The objective of this study was to analyze the association between PPI use and the risk of hypomagnesemia in a population-based cohort with systematic measurements of serum magnesium. The researchers also sought to determine whether prolonged use of PPIs and concomitant diuretic use were associated with an increase in the risk of hypomagnesemia. They also wished to examine the association between the use of histamine 2 receptor antagonists (H2RAs) and hypomagnesemia.

The primary outcomes and measurements were serum magnesium and hypomagnesemia, defined as serum magnesium ≤1.44 mEq/L. The analyses were adjusted for age, sex, body mass index, kidney function, comorbidities, and alcohol and diuretic use.

The study population included 9818 individuals; 96.0% were of European ancestry. Of the total cohort, 56.7% were female, mean age was 65 years, mean BMI was 27.3 kg/m2, and the mean energy-adjusted magnesium intake was 300.0 mg/d. Comorbid conditions among the study population included diabetes mellitus (10.4%), hypertension (62.7%), coronary heart disease (7.0%), and history of stroke (3.5%). Mean estimated glomerular filtration rate was 79.6, and 2.5% (n=247) had hypomagnesemia (serum magnesium ≤1.44 mEq/L).

A total of 724 participants used PPIs, with 1.6 defined daily doses. Five percent of PPI users (n=36) had hypomagnesemia. In the total study population, 2.5% (n=250) of the participants used H2RAs, with 0.9 defined daily doses. Of the H2RA users, 4.8% had hypomagnesemia.

There was an association of use of a PPI with significantly lower serum magnesium levels (–0.024 [95% confidence interval (CI), –0.034 to –0.016] mEq/L) compared with no use. The association persisted following multivariable adjustment (–0.022 [95% CI, –0.032 to –0.014] mEq/L).

The analyses found significant interaction between PPI use and loop diuretic use (P for interaction = .03). There was a greater reduction in serum magnesium levels seen in participants who concomitantly used PPIs and loop diuretics (–0.070 [95% CI, –0.120 to –0.020] mEq/L) compared with individuals who used none of these drugs. There was no significant interaction between PPI use and thiazide diuretic use or the presence of diabetes mellitus.

There was an association of use of a PPI with a higher risk of hypomagnesemia compared with no use; the association remained following adjustment potential confounders (odds ratios [ORs] of 2.27 [95% CI, 1.58-3.27] and 2.00 [95% CI, 1.36-2.93], respectively. There was also an increased risk of hypomagnesemia associated with use of H2RAs, before and after adjustment for potential confounders (ORs, 2.91 [95% CI, 1.21-3.93] and 2.00 [95% CI, 1.08-3.72], respectively) compared with no use.

A duration-of-use analysis demonstrated that the increased risk of hypomagnesemia was mainly present in participants in the highest tertile of duration of PPI use (P for trend <.001). The risk of hypomagnesemia was nearly tripled in those in the highest tertile of duration of use (>111 days; OR, 2.55; 95% CI, 0.99-6.58; P for trend = .02) compared with no use.

The researchers cited some limitations to the study, including the availability of only one serum magnesium measurement per participant, limiting the possibility of studying the course of serum magnesium following initiation of PPI treatment, and the lack of information for over-the-counter use of PPIs.

“In conclusion, this study confirms the association between PPI use and risk of hypomagnesemia in the general population. The risk of hypomagnesemia is further increased with PPI use if prolonged (>6 months) or combined with the use of loop diuretics. Healthcare professionals should consider monitoring serum magnesium levels periodically in patients expected to be on prolonged treatment or those who combine PPIs with medication that may cause hypomagnesemia, such as diuretics. Although H2RAs had similar effects on serum magnesium level and risk of hypomagnesemia, these effects were weaker and further studies are needed before the precautions for PPIs should also be recommended for H2RAs,” the researchers said.

Takeaway Points

  1. This study was designed to determine whether proton pump inhibitor use is associated with hypomagnesemia in the general population; the study also aimed to examine whether an increased risk of hypomagnesemia is associated with histamine 2 receptor antagonist use.
  2. Compared with no PPI use, serum magnesium levels were lower in those using PPIs. PPI use was associated with increased risk of hypomagnesemia; in those using loop diuretics, PPI use was associated with a further increased risk of hypomagnesemia.
  3. The increased risk of PPIs was only seen after prolonged use; the risk nearly tripled in those in the highest tertile of duration use (>111 days).