Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies

Figures & data

Figure 1. Forest plot of the included studies comparing risk of hypomagnesemia in patients who used PPI and those who did not; square data markers represent risk ratios (RRs); horizontal lines, the 95% CIs with marker size reflecting the statistical weight of the study using random-effects meta-analysis. A diamond data marker represents the overall RR and 95% CI for the outcome of interest. IV, inverse variance; SE, standard error.

Table 1. Main characteristics of the studies included in this meta-analysis.

	Gau et al.18	Koulouridis et al.24	Kim et al.19	Faulhaber et al.29	Danziger et al.5
Country	USA	USA	Korea	Brazil	USA
Study design	Cross-sectional study	Case-control study	Cohort study	Cross-sectional study	Cross-sectional study
Year	2012	2013	2013	2013	2013
Total number	487	804 (402 cases and 402 age- and sex-matched control)	112	151	11,490
Study sample	Hospitalized patients; aged ≥ 50 years	Hospitalized patients with ICD-9 diagnosis code for disorders of esophagus, stomach and duodenum	Patients who were treated with PPI ≥30 days; aged ≥ 20 years	Hospitalized patients with acute disease in internal medicine division without the conditions that are commonly associated with hypomagnesemia	Adult patients who were admitted to surgical and medical ICUs
Exposure definition	PPI use	Out-of-hospital PPI	Duration of PPI use over 1 year	PPI use	Any PPI listed as preadmission medication
Exposure measurement	Medical record review	Medical record review	Medical record review	Medical record review	Medical record review using Natural Language Processing algorithm
Outcome definition	Magnesium levels < 1.7 mg/dL	Magnesium level < 1.7 mg/dL	Magnesium levels < 1.7 mg/dL	Not defined	Magnesium level < 1.6 mg/dL
Outcome ascertainment	The first serum magnesium level measured during admission	Magnesium at the time of hospital admission or the next day	Serum magnesium levels were collected and categorized as pre-PPI treatment levels, during PPI treatment levels, and post-PPI treatment levels	Magnesium measured in hospital	The first magnesium level recorded within 36 hours of admission to hospital
Adjusted OR or relative risk	2.50 (1.43–4.36)	0.82 (0.61–1.11)	5.39 (1.06–27.49)	n/a*	1.10 (0.96–1.25) In diuretic user 1.54 (1.22–1.95) In non-diuretic user 0.92 (0.78–1.09)
Confounder adjusted	Age, sex, diabetes mellitus, congestive heart failure, diuretics use, supplementation of potassium and magnesium, discharge diagnosis of any acute GI illness, serum albumin, potassium and creatinine	Charlson/Deyo comorbidity index, diabetes mellitus, GERD, use of diuretics and eGFR	Other electrolytes, laboratory Data, such as sodium, potassium, calcium, blood urea nitrogen, creatinine, albumin, age, gender, comorbidities and the use of other medications	None	Age, gender, ethnicity, renal function, systolic blood pressure, heart rate, temperature, serum calcium, phosphate, glucose, hematocrit, diuretic use and 30 comorbidities
Quality assessment  (Newcastle–Ottawa scale)	Selection: 3 Comparability: 2 Outcome: 3	Selection: 2 Comparability: 2 Exposure: 3	Selection: 3 Comparability: 2 Outcome: 3	Selection: 2 Comparability: 0 Outcome: 3	Selection: 4 Comparability: 2 Outcome: 3

Note: eGFR, estimated glomerular filtration rate; GERD, gastroesophageal reflux disease; GI, gastrointestinal; ICD, the international classification of diseases; ICUs, intensive care units; PPIs, proton pump inhibitors.

*No hypomagenesemia occurred in both groups.

Figure 2. Funnel plot of nine studies included in the meta-analysis for the risk of hypomagnesemia in patients with PPI use. The plot did not show significant publication bias of included studies. RR = risk ratio, SE = standard error.

Gau JT, Yang YX, Chen R, Kao TC. Uses of proton pump inhibitors and hypomagnesemia. Pharmacoepidemiol Drug Saf. 2012;21:553–559

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Koulouridis I, Alfayez M, Tighiouart H, et al. Out-of-hospital use of proton pump inhibitors and hypomagnesemia at hospital admission: A nested case-control study. Am J Kidney Dis. 2013;62:730–737

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Kim S, Lee H, Park CH, et al. Clinical predictors associated with proton pump inhibitor-induced hypomagnesemia. Am J Ther. 2015;22:14--21

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Faulhaber GA, Ascoli BM, Lubini A, et al. Serum magnesium and proton-pump inhibitors use: A cross-sectional study. Rev Assoc Med Bras. 2013;59:276–279

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Danziger J, William JH, Scott DJ, et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int. 2013;83:692–699

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