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How often does long-term PPI therapy cause clinically significant hypomagnesemia?
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
Continue to: A comparison of the use of loop diuretics and...
A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).3
RECOMMENDATIONS
In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.6
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
Continue to: A comparison of the use of loop diuretics and...
A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).3
RECOMMENDATIONS
In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.6
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
Continue to: A comparison of the use of loop diuretics and...
A comparison of the use of loop diuretics and thiazides by patients taking PPIs found that concurrent use of loop diuretics increased serum magnesium reduction (−0.08 mg/dL; 95% CI, −0.14 to −0.02), but thiazides didn’t. Numbers were small: Of the 45 participants taking both a PPI and a loop diuretic, only 5 had hypomagnesemia (OR=7.2; 95% CI, 1.7-30.8).3
RECOMMENDATIONS
In 2011, the US Food and Drug Administration (FDA) warned of a possible increased risk of hypomagnesemia in patients taking PPIs long-term. The FDA advisory panel recommended evaluating serum magnesium before beginning long-term PPI therapy and in patients concurrently taking diuretics, digoxin, or other medications associated with hypomagnesemia.6
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.
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-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.
