PROTON PUMP INHIBITOR-INDUCED HYPOMAGNESEMIA: CURRENT EVIDENCE ON MECHANISMS, RISK FACTORS, DIAGNOSIS AND CLINICAL MANAGEMENT
DOI:
https://doi.org/10.31435/ijitss.3(51).2026.6661Keywords:
Proton Pump Inhibitors, Hypomagnesemia, Magnesium, Magnesium Homeostasis, Magnesium DeficiencyAbstract
Objective: Proton pump inhibitors (PPIs) are a group of medicines most commonly used to inhibit gastric acid secretion. Long-term treatment may lead to the development of hypomagnesemia. The aim of this review was to summarise the current evidence on proton pump inhibitor-induced hypomagnesemia (PPIH), focusing on its pathophysiological mechanisms, risk factors, clinical presentation, diagnosis and management.
Methods: A narrative review was conducted of English-language literature published between 2002 and 2026, retrieved from the PubMed/MEDLINE database between June and August 2026.
Results: The data reported in the literature indicate a link between the use of PPIs and an increased risk of hypomagnesemia. However, there is considerable heterogeneity amongst the studies, which makes it impossible to determine the exact extent of this risk. Reduced intestinal absorption of magnesium is considered the most likely mechanism underlying PPI-induced hypomagnesemia (PPIH). This is thought to be associated, amongst other things, with changes in pH and disturbances in magnesium transport across the intestinal epithelium. The risk depends on the dose and duration of PPI use, as well as on the presence of other factors affecting magnesium homeostasis. Clinically, PPI-induced hypomagnesemia (PPIH) may be asymptomatic or may cause neuromuscular, neurological and cardiovascular disorders, as well as leading to hypokalemia and hypocalcemia.
Conclusions: To diagnose PPI-induced hypomagnesemia (PPIH), it is necessary to consider exposure to PPIs and to rule out other causes of magnesium deficiency. Management involves correcting the Mg²⁺ deficiency and assessing whether continued PPI therapy is appropriate. Further prospective studies are needed to better identify at-risk groups and determine the optimal strategies for monitoring magnesium levels in patients on long-term PPI therapy.
References
Thurber, K. M., Otto, A. O., & Stricker, S. L. (2023). Proton pump inhibitors: Understanding the associated risks and benefits of long-term use. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists, 80(8), 487–494. https://doi.org/10.1093/ajhp/zxad009
Andrawes, M., Andrawes, W., Das, A., & Siau, K. (2025). Proton pump inhibitors (PPIs)-An Evidence-Based review of indications, efficacy, harms, and deprescribing. Medicina (Kaunas, Lithuania), 61(9), 1569. https://doi.org/10.3390/medicina61091569
Maideen N. M., P. (2023). Adverse effects associated with Long-Term use of proton pump inhibitors. Chonnam medical journal, 59(2), 115–127. https://doi.org/10.4068/cmj.2023.59.2.115
Sheen, E., & Triadafilopoulos, G. (2011). Adverse effects of long-term proton pump inhibitor therapy. Digestive diseases and sciences, 56(4), 931–950. https://doi.org/10.1007/s10620-010-1560-3
Rosner, M. H., Ha, N., Palmer, B. F., & Perazella, M. A. (2023). Acquired disorders of hypomagnesemia. Mayo Clinic proceedings, 98(4), 581–596. https://doi.org/10.1016/j.mayocp.2022.12.002
Papagiannidou, A., Mitropoulou, M., Papantzikos, K., Petropoulou, D., Tsilingiris, D., Magkos, F., & Dalamaga, M. (2026). Hypomagnesemia: A clinical and nutritional update. Current nutrition reports, 15(1), 30. https://doi.org/10.1007/s13668-026-00745-5
Kröse, J. L., & de Baaij, J. H. F. (2024). Magnesium biology. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 39(12), 1965–1975. https://doi.org/10.1093/ndt/gfae134
van der Wijst, J., Bindels, R. J., & Hoenderop, J. G. (2014). Mg2+ homeostasis: The balancing act of TRPM6. Current opinion in nephrology and hypertension, 23(4), 361–369. https://doi.org/10.1097/01.mnh.0000447023.59346.ab
Kothari, M., Wanjari, A., Shaikh, S. M., Tantia, P., Waghmare, B. V., Parepalli, A., Hamdulay, K. F., & Nelakuditi, M. (2024). A comprehensive review on understanding magnesium disorders: Pathophysiology, clinical manifestations, and management strategies. Cureus, 16(9), e68385. https://doi.org/10.7759/cureus.68385
Hess, M. W., Hoenderop, J. G., Bindels, R. J., & Drenth, J. P. (2012). Systematic review: Hypomagnesaemia induced by proton pump inhibition. Alimentary pharmacology & therapeutics, 36(5), 405–413. https://doi.org/10.1111/j.1365-2036.2012.05201.x
Florentin, M., & Elisaf, M. S. (2012). Proton pump inhibitor-induced hypomagnesemia: A new challenge. World journal of nephrology, 1(6), 151–154. https://doi.org/10.5527/wjn.v1.i6.151
William, J. H., & Danziger, J. (2016). Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms. World journal of nephrology, 5(2), 152–157. https://doi.org/10.5527/wjn.v5.i2.152
Toh, J. W., Ong, E., & Wilson, R. (2015). Hypomagnesaemia associated with long-term use of proton pump inhibitors. Gastroenterology report, 3(3), 243–253. https://doi.org/10.1093/gastro/gou054
Srinutta, T., Chewcharat, A., Takkavatakarn, K., Praditpornsilpa, K., Eiam-Ong, S., Jaber, B. L., & Susantitaphong, P. (2019). Proton pump inhibitors and hypomagnesemia: A meta-analysis of observational studies. Medicine, 98(44), e17788. https://doi.org/10.1097/MD.0000000000017788
Liao, S., Gan, L., & Mei, Z. (2019). Does the use of proton pump inhibitors increase the risk of hypomagnesemia: An updated systematic review and meta-analysis. Medicine, 98(13), e15011. https://doi.org/10.1097/MD.0000000000015011
Hoorn, E. J., van der Hoek, J., de Man, R. A., Kuipers, E. J., Bolwerk, C., & Zietse, R. (2010). A case series of proton pump inhibitor-induced hypomagnesemia. American journal of kidney diseases : the official journal of the National Kidney Foundation, 56(1), 112–116. https://doi.org/10.1053/j.ajkd.2009.11.019
Kim, S., Lee, H., Park, C. H., Shim, C. N., Lee, H. J., Park, J. C., Shin, S. K., Lee, S. K., Lee, Y. C., Kim, H. Y., & Kang, D. R. (2015). Clinical predictors associated with proton pump inhibitor-induced hypomagnesemia. American journal of therapeutics, 22(1), 14–21. https://doi.org/10.1097/MJT.0b013e31829c4c71
Douwes, R. M., Gomes-Neto, A. W., Schutten, J. C., van den Berg, E., de Borst, M. H., Berger, S. P., Touw, D. J., Hak, E., Blokzijl, H., Navis, G., & Bakker, S. J. L. (2019). Proton-Pump inhibitors and hypomagnesaemia in kidney transplant recipients. Journal of clinical medicine, 8(12), 2162. https://doi.org/10.3390/jcm8122162
de Baaij, J. H., Hoenderop, J. G., & Bindels, R. J. (2015). Magnesium in man: Implications for health and disease. Physiological reviews, 95(1), 1–46. https://doi.org/10.1152/physrev.00012.2014
Morrison A., R. (2023). Magnesium homeostasis: Lessons from human genetics. Clinical journal of the American Society of Nephrology : CJASN, 18(7), 969–978. https://doi.org/10.2215/CJN.0000000000000103
Gommers, L. M. M., Hoenderop, J. G. J., & de Baaij, J. H. F. (2022). Mechanisms of proton pump inhibitor-induced hypomagnesemia. Acta physiologica (Oxford, England), 235(4), e13846. https://doi.org/10.1111/apha.13846
Schuchardt, J. P., & Hahn, A. (2017). Intestinal absorption and factors influencing bioavailability of Magnesium-An update. Current nutrition and food science, 13(4), 260–278. https://doi.org/10.2174/1573401313666170427162740
Schlingmann, K. P., Weber, S., Peters, M., Niemann Nejsum, L., Vitzthum, H., Klingel, K., Kratz, M., Haddad, E., Ristoff, E., Dinour, D., Syrrou, M., Nielsen, S., Sassen, M., Waldegger, S., Seyberth, H. W., & Konrad, M. (2002). Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nature genetics, 31(2), 166–170. https://doi.org/10.1038/ng889
William, J. H., Nelson, R., Hayman, N., Mukamal, K. J., & Danziger, J. (2014). Proton-pump inhibitor use is associated with lower urinary magnesium excretion. Nephrology (Carlton, Vic.), 19(12), 798–801. https://doi.org/10.1111/nep.12330
Souza, C. C., Rigueto, L. G., Santiago, H. C., Seguro, A. C., Girardi, A. C., & Luchi, W. M. (2024). Multiple electrolyte disorders triggered by proton pump inhibitor-induced hypomagnesemia: Case reports with a mini-review of the literature. Clinical nephrology. Case studies, 12, 6–11. https://doi.org/10.5414/CNCS111284
Floris, M., Angioi, A., Lepori, N., Piras, D., Cabiddu, G., Pani, A., & Rosner, M. H. (2025). The clinical spectrum of acquired hypomagnesemia: From etiology to therapeutic approaches. Biomedicines, 13(8), 1862. https://doi.org/10.3390/biomedicines13081862
Ayuk, J., & Gittoes, N. J. (2014). Treatment of hypomagnesemia. American journal of kidney diseases : the official journal of the National Kidney Foundation, 63(4), 691–695. https://doi.org/10.1053/j.ajkd.2013.07.025
Famularo, G., Gasbarrone, L., & Minisola, G. (2013). Hypomagnesemia and proton-pump inhibitors. Expert opinion on drug safety, 12(5), 709–716. https://doi.org/10.1517/14740338.2013.809062
Kheir, K., Al Jassem, O., El Koubayati, G., & Haddad, F. (2024). A case of severe proton pump Inhibitor-Induced hypomagnesemia refractory to continuous oral and intravenous magnesium replenishment. Cureus, 16(2), e54483. https://doi.org/10.7759/cureus.54483
Schuchardt, J. P., & Hahn, A. (2017). Intestinal absorption and factors influencing bioavailability of Magnesium-An update. Current nutrition and food science, 13(4), 260–278. https://doi.org/10.2174/1573401313666170427162740
Freedberg, D. E., Kim, L. S., & Yang, Y. X. (2017). The risks and benefits of long-term use of proton pump inhibitors: Expert review and best practice advice from the American gastroenterological association. Gastroenterology, 152(4), 706–715. https://doi.org/10.1053/j.gastro.2017.01.031
Park, C. H., Kim, E. H., Roh, Y. H., Kim, H. Y., & Lee, S. K. (2014). The association between the use of proton pump inhibitors and the risk of hypomagnesemia: A systematic review and meta-analysis. PloS one, 9(11), e112558. https://doi.org/10.1371/journal.pone.0112558
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Copyright (c) 2026 Julia Sadowska, Karolina Strzelecka, Zuzanna d'Obyrn, Ewa Weronika Pływak, Weronika Patrycja Polar, Julia Kamińska, Ewa Jagodzińska, Martyna Stawicka, Alicja Szemberg
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