How often does long-term PPI therapy cause clinically significant hypomagnesemia?

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Clinical Inquiries

How often does long-term PPI therapy cause clinically significant hypomagnesemia?

J Fam Pract. 2018 September;67(9):576-577

By

Timothy Plaut, MD

Katelyn Graeme, DO

Sue Stigleman, MLS

Stephen Hulkower, MD

Tasha Woodall, PharmD

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EVIDENCE-BASED ANSWER:

Rarely. Proton pump inhibitors (PPIs) may be associated with decreases in serum magnesium laboratory values to below 1.6 to 1.8 mg/dL, especially when used concurrently with diuretics and loop diuretics (strength of recommendation [SOR]: C, disease-oriented outcomes based on cohort, case-control, and cross-sectional studies). Clinically significant or symptomatic hypomagnesemia (below 1.2 mg/dL) appears to be quite rare, however.

References

1. Park CH, Kim EH, Roh YH, et al. The association between the use of proton pump inhibitors and the risk of hypomagnesemia: a systematic review and meta-analysis. PLoS One. 2014;9:e112558.

2. Sharara AI, Chalhoub JM, Hammoud N, et al. Low prevalence of hypomagnesemia in long-term recipients of proton pump inhibitors in a managed care cohort. Clin Gastroenterol Hepatol. 2016;14:317-321.

3. Kieboom BC, Kiefte-de Jong JC, Eijgelsheim M, et al. Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study. Am J Kidney Dis. 2015;66:775-782.

4. Biyik M, Solak Y, Ucar R, et al. Hypomagnesemia among outpatient long-term proton pump inhibitor users. Am J Ther. 2014;24:e52-e55.

5. Zipursky J, Macdonald EM, Hollands S, et al. Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study. PLoS Med. 2014;11:e1001736.

6. United States Food and Drug Administration. FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs). 03/02/2011. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm245011.htm. Accessed August 24, 2018.

EVIDENCE SUMMARY

A systematic review and meta-analysis of observational studies examined the risk of hypomagnesemia, defined in various studies as serum magnesium levels of 1.6, 1.7, or 1.8 mg/dL.¹ Two cohort studies, one case-control study, and 6 cross-sectional studies met inclusion criteria; 115,455 patients were enrolled. The studies were significantly heterogeneous (I²=89.1%), because of varying study designs, population sizes, and population characteristics.

PPI use increased the risk of hypomagnesemia (pooled odds ratio [OR]=1.5; 95% confidence interval [CI], 1.1-2.0) after adjustment for possible confounders such as use of diuretics.

Risk rises with long-term use, but severe hypomagnesemia is rare

Two more recent cohort studies produced conflicting results. Of 414 patients in a managed care cohort who received long-term PPIs, only 8 had mild hypomagnesemia (1.2-1.5 mg/dL) on nearly 14% of their combined 289 measurements. At final measurement, all patients had normal serum magnesium levels.²

A cross-sectional analysis of data from a retrospective cohort analysis of 9818 patients in the Netherlands found that any PPI use during the previous year was associated with an increased risk of hypomagnesemia (serum magnesium <1.73 mg/dL) compared with no use (adjusted OR=2; 95% CI, 1.4-2.9).³ The risk was greatest with use longer than 182 days (OR=3.0; 95% CI, 1.7-5.2). As with studies included in the meta-analysis, this study examined laboratory values exclusively. Only 3 of 724 PPI users had a serum magnesium level below 1.2 mg/dL, the point at which symptoms usually occur.

Case-control studies produce conflicting results

Two recent case-control studies also produced conflicting results. The first compared 154 outpatients who used PPIs for at least 6 months (mean, 27.5 months) with 84 nonusers.⁴ No association was found with hypomagnesemia (2.17 mg/dL vs 2.19 mg/dL), and none of the patients had a serum magnesium level below 1.7 mg/dL. The control group was poorly defined, however, and the study excluded patients taking diuretics.

Conversely, a study that compared 366 patients hospitalized with a primary or secondary diagnosis of hypomagnesemia (determined from an insurance claims database and defined as the presence of ICD-10 codes for hypomagnesemia or magnesium deficiency) with 1464 matched controls found that hospitalized patients with hypomagnesemia were more likely than controls to be current PPI users (adjusted OR=1.4; 95% CI, 1.1-1.9).⁵ Whether hypomagnesemia was the cause of the hospitalizations or an incidental finding wasn’t clear.

Concurrent use of diuretics and loop diuretics can increase risk

In a subgroup analysis of the second case-control study, PPI users who also used diuretics had an increased risk of hypomagnesemia (adjusted OR=1.7; 95% CI, 1.1-2.7) compared with patients who weren’t taking diuretics (adjusted OR=1.3; 95% CI, 0.8-1.9).⁵

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Evidence-based answers from the Family Physicians Inquiries Network

How often does long-term PPI therapy cause clinically significant hypomagnesemia?

EVIDENCE-BASED ANSWER:

References

EVIDENCE SUMMARY

Risk rises with long-term use, but severe hypomagnesemia is rare

Case-control studies produce conflicting results

Concurrent use of diuretics and loop diuretics can increase risk

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