Proton pump inhibitors in the light of clinical studies and the safety profile of long-term use

Česká verzia

Authors: Martin Ďuriček ; Peter Bánovčin ; R. Hyrdel
Authors place of work: Interná klinika – gastroenterologická JLF UK a UNM
Published in the journal: Gastroent Hepatol 2018; 72(5): 432-440
Category: Klinická a experimentální gastroenterologie: přehledová práce
doi: https://doi.org/10.14735/amgh2018432

Summary

Proton pump inhibitors are currently one of the most frequently used medicinal drugs. However, although they were initially used primarily for the treatment of gastroesophageal reflux disease and peptic ulcer disease, their indications have considerably widened recently. With the rising prescription rate, the potential adverse effects of long-term treatment with these drugs, described in a growing number of recent reports, is contributing to the increasing concern doctors have about prescribing these drugs and to patient anxiety related to their use, despite clear-cut and correct indications. In this article, we describe the most common undesirable effects of long-term treatment with proton pump inhibitors. The individual effects are supplemented with potential pathophysiological base of origin and quotation of principal studies and interpretations of their results. In the context of recent studies, we conclude that these drugs are safe and when indications for their use are clear, their benefits exceed their possible risks.

Key words:

proton pump inhibitors – safety – risks – adverse effects

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

Submitted: 6. 5. 2018

Accepted: 7. 9. 2018

Zdroje

134. doi: 10.1177/1060028016670414.

2. Hill AB. The environment and disease: association or causation? 1965. J R Soc Med 2015; 108 (1): 32–37. doi: 10.1177/0141076814562718.

3. Venerito M, Varbanova M, Röhl FW et al. Oxyntic gastric atrophy in Helicobacter pylori gastritis is distinct from autoimmune gastritis. J Clin Pathol 2016; 69 (8): 677–685. doi: 10.1136/jclinpath-2015-203405.

4. Lam JR, Schneider JL, Zhao W et al. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA 2013; 310 (22): 2435–2442. doi: 10.1001/jama.2013.280490.

5. Hirschowitz BI, Worthington J, Mohnen J. Vitamin B12 deficiency in hypersecretors during long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 2008; 27 (11): 1110–1121. doi: 10.1111/j.1365-2036.2008.03658.x.

6. Attwood SE, Ell C, Galmiche JP et al. Long-term safety of proton pump inhibitor therapy assessed under controlled, randomised clinical trial conditions: data from the SOPRAN and LOTUS studies. Aliment Pharmacol Ther 2015; 41 (11): 1162–1174. doi: 10.1111/apt.13194.

7. Stabler SP. Clinical practice. Vitamin B12 deficiency. N Engl J Med 2013; 368 (2): 149-60.

8. de la Coba Ortiz C, Argüelles Arias F, Martín de Argila de Prados C et al. Proton-pump inhibitors adverse effects: a review of the evidence and position statement by the Sociedad Española de Patologia Digestiva. Rev Esp Enferm Dig 2016; 108 (4): 207–224. doi: 10.17235/reed.2016.4232/2016.

9. Malfertheiner P, Kandulski A, Venerito M. Proton-pump inhibitors: understanding the complications and risks. Nat Rev Gastroenterol Hepatol 2017; 14 (12): 697–710. doi: 10.1038/nrgastro.2017.117.

10. O‘Leary F, Allman-Farinelli M, Samman S. Vitamin B12 status, cognitive decline and dementia: a systematic review of prospective cohort studies. Br J Nutr 2012; 108 (11): 1948–1961. doi: 10.1017/S0007114512004175.

11. Reynolds E. Vitamin B12, folic acid, and the nervous system. Lancet Neurol 2006; 5 (11): 949–960. doi: 10.1016/S1474-4422 (06) 70598-1.

12. Gomm W, von Holt K, Thomé F et al. Association of proton pump inhibitors with risk of dementia: A pharmacoepidemiological claims data analysis. JAMA Neurol 2016 73 (4): 410–406. doi: 10.1001/jamaneurol.2015.4791.

13. Haenisch B, von Holt K, Wiese B et al. Risk of dementia in elderly patients with the use of proton pump inhibitors. Eur Arch Psychiatry Clin Neurosci 2015 265 (5): 419–428. doi: 10.1007/s00406-014-0554-0.

14. Booker A, Jacob LE, Rapp M et al. Risk factors for dementia diagnosis in German primary care practices. Int Psychogeriatr 2016; 28 (7): 1059–1065. doi: 10.1017/S1041610215002082.

15. Voets T, Nilius B, Hoefs S et al. TRPM6 forms the Mg2+ influx channel involved in intestinal and renal Mg2+ absorption. J Biol Chem 2004; 279 (1): 19–25. doi: 10.1074/jbc.M311201200.

16. Toh JW, Ong E, Wilson R. Hypomagnesaemia associated with long-term use of proton pump inhibitors. Gastroenterol Rep (Oxf) 2015; 3 (3): 243–253. doi: 10.1093/gastro/gou054.

17. Faulhaber GA, Ascoli BM, Lubini A et al. Serum magnesium and proton-pump inhibitors use: a cross-sectional study. Rev Assoc Med Bras (1992) 2013; 59 (3): 276–279. doi: 10.1016/j.ramb.2012.12.007.

18. Schlingmann KP, Weber S, Peters M et al. Hypomagnesemia with secondary hypocalcemia is caused by mutations in TRPM6, a new member of the TRPM gene family. Nat Genet 2002; 31 (2): 166–170. doi: 10.1038/ng889.

19. 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 (9): e1001736. doi: 10.1371/journal.pmed.1001736.

20. Sumukadas D, McMurdo ME, Habicht D. Proton pump inhibitors are associated with lower magnesium levels in older people with chronic kidney disease. J Am Geriatr Soc 2012; 60 (2): 392–393. doi: 10.1111/j.1532-5415.2011.03808.x.

21. Danziger J, William JH, Scott DJ et al. Proton-pump inhibitor use is associated with low serum magnesium concentrations. Kidney Int 2013; 83 (4): 692–699. doi: 10.1038/ki.2012.452.

22. Misra PS, Alam A, Lipman ML et al. The relationship between proton pump inhibitor use and serum magnesium concentration among hemodialysis patients: a cross-sectional study. BMC Nephrol 2015; 16: 136. doi: 10.1186/s12882-015-0139-9.

23. 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 (2): 317–321. doi: 10.1016/j.cgh.2015.10.012.

24. 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 (11): e112558. doi: 10.1371/journal.pone.0112558.

25. Thongon N, Krishnamra N. Apical acidity decreases inhibitory effect of omeprazole on Mg (2+) absorption and claudin-7 and -12 expression in Caco-2 monolayers. Exp Mol Med 2012; 44 (11): 684–693. doi: 10.3858/emm.2012.44.11.077.

26. Negri AL, Valle EE. Hypomagnesaemia/hypokalemia associated with the use of esomeprazole. Curr Drug Saf 2011; 6 (3): 204–206.

27. Deroux A, Khouri C, Chabre O et al. Severe acute neurological symptoms related to proton pump inhibitors induced hypomagnesemia responsible for profound hypoparathyroidism with hypocalcemia. Clin Res Hepatol Gastroenterol 2014; 38 (5): e103-5. doi: 10.1016/j.clinre.2014.03.005.

28. Wright MJ, Sullivan RR, Gaffney-Stomberg E et al. Inhibiting gastric acid production does not affect intestinal calcium absorption in young, healthy individuals: a randomized, crossover, controlled clinical trial. J Bone Miner Res 2010; 25 (10): 2205–2011. doi: 10.1002/jbmr.108.

29. Freedberg DE, Kim LS, Yang YX. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology 2017; 152 (4): 706–715. doi: 10.1053/j.gastro.2017.01.031.

30. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue Int 2006; 79 (2): 76–83. doi: 10.1007/s00223-006-0021-7.

31. Yang YX, Lewis JD, Epstein S et al. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA 2006; 296 (24): 2947–2953. doi: 10.1001/jama.296.24.2947.

32. Targownik LE, Lix LM, Metge CJ et al. Use of proton pump inhibitors and risk of osteoporosis-related fractures. CMAJ 2008; 179 (4): 319–326. doi: 10.1503/cmaj.071330.

33. Ngamruengphong S, Leontiadis GI, Radhi S et al. Proton pump inhibitors and risk of fracture: a systematic review and meta-analysis of observational studies. Am J Gastroenterol 2011; 106 (7): 1209–1218. doi: 10.1038/ajg.2011.113.

34. Corley DA, Kubo A, Zhao W et al. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010; 139 (1): 93–101. doi: 10.1053/j.gastro.2010.03.055.

35. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients without major risk factors. Pharmacotherapy 2008; 28 (8): 951–959. doi: 10.1592/phco.28.8.951.

36. Vaezi MF, Yang YX, Howden CW. Complications of proton pump inhibitor therapy. Gastroenterology 2017; 153 (1): 35–48. doi: 10.1053/j.gastro.2017.04.047.

37. Moayyedi P, Yuan Y, Leontiadis G et al. Canadian Association of Gastroenterology position statement: hip fracture and proton pump inhibitor therapy-a 2013 update. Can J Gastroenterol 2013; 27 (10): 593–595.

38. U.S. Food & Drug Administration. FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors. [online]. Dostupné z: https: //www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm.

39. Perazella MA, Markowitz GS. Drug-induced acute interstitial nephritis. Nat Rev Nephrol 2010; 6 (8): 461–470. doi: 10.1038/nrneph.2010.71.

40. Lazarus B, Coresh J, Grams ME. Adverse effects of proton pump inhibitors in chronic kidney disease-reply. JAMA Intern Med 2016; 176 (6): 869–870. doi: 10.1001/jamainternmed.2016.1863.

41. Lazarus B, Chen Y, Wilson FP et al. Proton pump inhibitor use and the risk of chronic kidney disease. JAMA Intern Med 2016; 176 (2): 238–246. doi: 10.1001/jamainternmed.2015.7193.

42. Muriithi AK, Leung N, Valeri AM et al. Biopsy-proven acute interstitial nephritis, 1993–2011: a case series. Am J Kidney Dis 2014; 64 (4): 558–566.

43. Blank ML, Parkin L, Paul C et al. A nationwide nested case–control study indicates an increased risk of acute interstitial nephritis with proton pump inhibitor use. Kidney Int 2014; 86 (4): 837–844. doi: 10.1038/ki.2014.74.

44. Moledina DG, Perazella MA. Proton pump inhibitors and CKD. J Am Soc Nephrol 2016; 27 (10): 2926–2928. doi: 10.1681/ASN.2016020192.

45. Clark DW, Strandell J. Myopathy including polymyositis: a likely class adverse effect of proton pump inhibitors? Eur J Clin Pharmacol 2006; 62 (6): 473–479.

46. Aggarwal N. Drug-induced subacute cutaneous Lupus Erythematosus associated with proton pump inhibitors. Drugs Real World Outcomes 2016; 3 (2): 145–154. doi: 10.1007/s40801-016-0067-4.

47. Wandall JH. Effects of omeprazole on neutrophil chemotaxis, super oxide production, degranulation, and translocation of cytochrome b–245. Gut 1992; 33 (5): 617–621.

48. Fohl AL, Regal RE. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all? World J Gastrointest Pharmacol Ther 2011; 2 (3): 17–26. doi: 10.4292/wjgpt.v2.i3.17.

49. Laheij RJ, Sturkenboom MC, Hassing RJ et al. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA 2004; 292 (16): 1955–1960. doi: 10.1001/jama.292.16.1955.

50. Filion KB, Chateau D, Targownik LE et al. Proton pump inhibitors and the risk of hospitalisation for community-acquired pneumonia: replicated cohort studies with meta-analysis. Gut 2014; 63 (4): 552–558. doi: 10.1136/gutjnl-2013-304738.

51. Sarkar M, Hennessy S, Yang YX. Proton-pump inhibitor use and the risk for community-acquired pneumonia. Ann Intern Med 2008; 149 (6): 391–398.

52. Gulmez SE, Holm A, Frederiksen H et al. Use of proton pump inhibitors and the risk of community-acquired pneumonia: a population-based case-control study. Arch Intern Med 2007; 167 (9): 950–955. doi: 10.1001/archinte.167.9.950.

53. Lundell L. The physiological background behind and course of development of the first proton pump inhibitor. Scand J Gastroenterol 2015; 50 (6): 680–684. doi: 10.3109/00365521.2015.1013981.

54. Reimer C, Søndergaard B, Hilsted L et al. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009; 137 (1): 80–87. doi: 10.1053/j.gastro.2009.03.058.

55. Sanduleanu S, De Bruïne A, Stridsberg M et al. Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur J Clin Invest 2001; 31 (9): 802–811.

56. Savarino V, Dulbecco P, Savarino E. Are proton pump inhibitors really so dangerous? Dig Liver Dis 2016; 48 (8): 851–859. doi: 10.1016/j.dld.2016.05.018.

57. Poulsen AH, Christensen S, McLaughlin JK et al. Proton pump inhibitors and risk of gastric cancer: a population-based cohort study. Br J Cancer 2009; 100 (9): 1503–1507. doi: 10.1038/sj.bjc.6605024.

58. Tran-Duy A, Spaetgens B, Hoes AW et al. Use of proton pump inhibitors and risks of fundic gland polyps and gastric cancer: systematic review and meta–analysis. Clin Gastroenterol Hepatol 2016; 14 (12): 1706–1719.e5. doi: 10.1016/j.cgh.2016.05.018.

59. Han YM, Park JM, Kangwan N et al. Role of proton pump inhibitors in preventing hypergastrinemia-associated carcinogenesis and in antagonizing the trophic effect of gastrin. J Physiol Pharmacol 2015; 66 (2): 159–167.

60. Kearns MD, Boursi B, Yang YX. Proton pump inhibitors on pancreatic cancer risk and survival. Cancer Epidemiol 2017; 46: 80–84. doi: 10.1016/j.cane 2016.12.006.

61. Logan RP, Walker MM, Misiewicz JJ et al. Changes in the intragastric distribution of Helicobacter pylori during treatment with omeprazole. Gut 1995; 36 (1): 12–16.

62. Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet 2009; 374 (9699): 1449–1461. doi: 10.1016/S0140-6736 (09) 60938-7.

63. Malfertheiner P, Megraud F, O‘Morain CA et al. Management of Helicobacter pylori infection-the Maastricht V/Florence consensus Report. Gut 2017; 66 (1): 6–30. doi: 10.1136/gutjnl-2016-312288.

64. Lombardo L, Foti M, Ruggia O et al. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clin Gastroenterol Hepatol 2010; 8 (6): 504–8. doi: 10.1016/j.cgh.2009.12.022.

65. Ratuapli SK, Ellington TG, O‘Neill MT et al. Proton pump inhibitor therapy use does not predispose to small intestinal bacterial overgrowth. Am J Gastroenterol 2012; 107 (5): 730–735. doi: 10.1038/ajg.2012.4.

66. Lewis SJ, Franco S, Young G et al. Altered bowel function and duodenal bacterial overgrowth in patients treated with omeprazole. Aliment Pharmacol Ther 1996; 10 (4): 557–61.

67. Jacobs C, Coss Adame E, Attaluri A et al. Dysmotility and proton pump inhibitor use are independent risk factors for small intestinal bacterial and/or fungal overgrowth. Aliment Pharmacol Ther 2013; 37 (11): 1103–1111. doi: 10.1111/apt.12304.

68. Jump RL, Pultz MJ, Donskey CJ. Vegetative Clostridium difficile survives in room air on moist surfaces and in gastric contents with reduced acidity: a potential mechanism to explain the association between proton pump inhibitors and C. difficile-associated diarrhea? Antimicrob Agents Chemother 2007; 51 (8): 2883–2887. doi: 10.1128/AAC.01443-06.

69. Doorduyn Y, Van Den Brandhof WE, Van Duynhoven YT et al. Risk factors for Salmonella Enteritidis and Typhimurium (DT104 and non-DT104) infections in The Netherlands: predominant roles for raw eggs in Enteritidis and sandboxes in Typhimurium infections. Epidemiol Infect 2006; 134 (3): 617–626.

70. Bavishi C, Dupont HL. Systematic review: the use of proton pump inhibitors and increased susceptibility to enteric infection. Aliment Pharmacol Ther 2011; 34 (11–12): 1269–1281. doi: 10.1111/j.1365-2036.2011.04874.x.

71. Kwok CS, Arthur AK, Anibueze CI et al. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol 2012; 107 (7): 1011–1019. doi: 10.1038/ajg.2012.108.

72. Tleyjeh IM, Bin Abdulhak AA, Riaz M et al. Association between proton pump inhibitor therapy and clostridium difficile infection: a contemporary systematic review and meta-analysis. PLoS One 2012; 7 (12): e50836. doi: 10.1371/journal.pone.0050836.

73. Kandel CE, Gill S, McCready J et al. Re-ducing co-administration of proton pump inhibitors and antibiotics using a computerized order entry alert and prospective audit and feedback. BMC Infect Dis 2016; 16: 355. doi: 10.1186/s12879-016-1679-8.

74. McDonald EG, Jones J, Green L et al. Reduction of inappropriate exit prescriptions for proton pump inhibitors: A before-after study using education paired with a web-based quality-improvement tool. J Hosp Med 2015; 10 (5): 281–286. doi: 10.1002/jhm.2330.

75. U.S. Food & Drug Administration. FDA Drug Safety Communication: Clostridium difficile associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs) 2012. [online]. Dostupné z: https: //www.fda.gov/Drugs/DrugSafety/ucm290510.htm.

76. Keszthelyi D, Jansen SV, Schouten GA et al. Proton pump inhibitor use is associated with an increased risk for microscopic colitis: a case-control study. Aliment Pharmacol Ther 2010; 32 (9): 1124–1128. doi: 10.1111/j.1365-2036. 2010.04453.x.

77. Verhaegh B, de Vries F, Masclee AA et al. High risk of drug-induced microscopic colitis with concomitant use of NSAIDs and proton pump inhibitors. Aliment Pharmacol Ther 2016; 43 (9): 1004–1013. doi: 10.1111/apt.13583.

78. Martínek J, Lukáš M. Inhibitory protonové pumpy – up to date. Gastroent Hepatol 2011; 65 (6): 331-342.

79. Crauwels H, van Heeswijk RP, Stevens M et al. Clinical perspective on drug-drug interactions with the non-nucleoside reverse transcriptase inhibitor rilpivirine. AIDS Rev 2013; 15 (2): 87–101.

80. Suzuki K, Doki K, Homma M et al. Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy. Br J Clin Pharmacol 2009; 67 (1): 44–49. doi: 10.1111/j.1365-2125.2008.03303.x.

81. Ollier E, Delavenne X. Direct oral anticoagulant, useful pharmacological characteristics in clinical practice. Therapie 2015; 70 (3): 243–249. doi: 10.2515/therapie/2014206.

82. Bolek T, Samoš M, Stančiaková L et al. The impact of proton pump inhibition on dabigatran levels in patients with atrial fibrillation. Am J Ther 2017. doi: 10.1097/MJT.0000000000000599.

83. Reilly A, Lehr T, Haertter S et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (randomized evaluation of long-term anticoagulation therapy). J Am Coll Cardiol 2014; 63 (4): 321–8. doi: 10.1016/j.jacc.2013.07.104.

84. Špičák J. Inhibitory protonové pumpy: vedlejší účinky a interakce. Gastroent Hepatol 2013; 67 (4): 289-297.

85. Simon T, Verstuyft C, Mary-Krause M et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009; 360 (4): 363–375. doi: 10.1056/NEJMoa0808227.

86. Venerito M, Kandulski A, Malfertheiner P. Dilemma between gastroprotection and cardiovascular prevention. Dtsch Med Wochenschr 2010; 135 (44): 2193–2198. doi: 10.1055/s-0030-1267498.

87. Bhatt DL, Cryer BL, Contant CF et al. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J Med 2010; 363 (20): 1909–1917. doi: 10.1056/NEJMoa1007964.

88. O‘Donoghue ML, Braunwald E, Antman EM et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374 (9694): 989–997. doi: 10.1016/S0140-6736 (09) 61525-7.

89. Goodman SG, Clare R, Pieper KS et al. Association of proton pump inhibitor use on cardiovascular outcomes with clopidogrel and ticagrelor: insights from the platelet inhibition and patient outcomes trial. Circulation 2012; 125 (8): 978–986. doi: 10.1161/CIRCULATIONAHA.111.032912.

90. Li XQ, Andersson TB, Ahlström M et al. Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities. Drug Metab Dispos 2004; 32 (8): 821–827.

91. European Medicines Agency. Public statement: Interaction between clopidogrel and proton pump inhibitors 2010. [online]. Dostupné z: https: //www.ema.europa.eu/documents/public-statement/public-statement-interaction-between-clopidogrel-proton-pump-inhibitors_en.pdf.

92. Agewall S, Cattaneo M, Collet JP et al. Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy. Eur Heart J 2013; 34 (23): 1708–1713. doi: 10.1093/eurheartj/eht042.

93. Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 2014; 37 (4): 201–211. doi: 10.1007/s40264-014-0144-0.