Skip to main content
SpringerLink
Log in

Independent Association Between Use of Proton Pump Inhibitors and Muscle Wasting in Patients with Heart Failure: A Single-Center, Ambispective, Observational Study

  • Original Research Article
  • Published:
Drugs & Aging Aims and scope Submit manuscript

Abstract

Background

Although proton pump inhibitors (PPIs) play a pivotal role in the prevention and treatment of gastric acid-related diseases and gastrointestinal adverse events caused by antiplatelet therapies, the safety of long-term use of PPIs has been questioned.

Objective

The aim of this study was to determine the effects of use of PPIs on muscle mass and bone mineral density in heart failure (HF) patients.

Methods

This was a single-center, ambispective (combined retrospective and prospective), observational study. HF patients (n = 747; 72 years of age; males, 54%) who received a dual-energy x-ray absorptiometry scan were enrolled. Muscle wasting was defined as appendicular skeletal muscle mass index (ASMI) < 7.0 kg/m2 in males and <5.4 kg/m2 in females. Propensity scores for the use of PPIs were calculated using a multivariate logistic regression model to minimize selection bias.

Results

Before propensity score matching, ASMI was significantly lower in patients receiving PPIs than in patients not receiving PPIs, resulting in a higher prevalence of muscle wasting in the PPI group. Such a relationship between use of PPIs and muscle wasting remained after propensity score matching. In multivariate Cox regression analyses, use of PPIs was independently associated with presence of muscle wasting (hazard ratio 1.68, 95% confidence interval 1.05–2.69) after adjustment for established risk factors of sarcopenia. On the other hand, there were no differences in bone mineral density between the PPI group and the no-PPI group.

Conclusion

Use of PPIs is associated with a high risk of muscle wasting in HF patients. Caution is warranted when long-term PPI treatment is performed in sarcopenic HF patients and HF patients with several risk factors for muscle wasting.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Strand DS, Kim D, Peura DA. 25 years of proton pump inhibitors: a comprehensive review. Gut Liver. 2017;11:27–37.

    CAS  PubMed  Google Scholar 

  2. Nehra AK, Alexander JA, Loftus CG, Nehra V. Proton pump inhibitors: review of emerging concerns. Mayo Clin Proc. 2018;93:240–6.

    CAS  PubMed  Google Scholar 

  3. Lai KC, Lam SK, Chu KM, Wong BC, Hui WM, Hu WH, et al. Lansoprazole for the prevention of recurrences of ulcer complications from long-term low-dose aspirin use. N Engl J Med. 2002;346:2033–8.

    CAS  PubMed  Google Scholar 

  4. Valgimigli M, Bueno H, Byrne RA, Collet JP, Costa F, Jeppsson A, et al.; ESC Scientific Document Group; ESC Committee for Practice Guidelines (CPG); ESC National Cardiac Societies. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2018;39:213–60.

  5. Steffel J, Collins R, Antz M, Cornu P, Desteghe L, Haeusler KG, External reviewers, et al. European Heart Rhythm Association practical guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Europace. 2021;2021(23):1612–76.

    Google Scholar 

  6. Luo H, Fan Q, Xiao S, Chen K. Changes in proton pump inhibitor prescribing trend over the past decade and pharmacists’ effect on prescribing practice at a tertiary hospital. BMC Health Serv Res. 2018;18:537.

    PubMed  PubMed Central  Google Scholar 

  7. Liu Y, Zhu X, Li R, Zhang J, Zhang F. Proton pump inhibitor utilisation and potentially inappropriate prescribing analysis: insights from a single-centred retrospective study. BMJ Open. 2020;10: e040473.

    PubMed  PubMed Central  Google Scholar 

  8. Schoenfeld AJ, Grady D. Adverse effects associated with proton pump inhibitors. JAMA Intern Med. 2016;176:172–4.

    PubMed  Google Scholar 

  9. Park CH, Kim EH, Roh YH, Kim HY, Lee SK. 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.

    PubMed  PubMed Central  Google Scholar 

  10. Cheungpasitporn W, Thongprayoon C, Kittanamongkolchai W, Srivali N, Edmonds PJ, Ungprasert P, et al. Proton pump inhibitors linked to hypomagnesemia: a systematic review and meta-analysis of observational studies. Ren Fail. 2015;37:1237–41.

    CAS  PubMed  Google Scholar 

  11. Toh JW, Ong E, Wilson R. Hypomagnesaemia associated with long-term use of proton pump inhibitors. Gastroenterol Rep (Oxf). 2015;3:243–53.

    PubMed  Google Scholar 

  12. Lam JR, Schneider JL, Zhao W, Corley DA. Proton pump inhibitor and histamine 2 receptor antagonist use and vitamin B12 deficiency. JAMA. 2013;310:2435–42.

    CAS  PubMed  Google Scholar 

  13. Lo WK, Chan WW. Proton pump inhibitor use and the risk of small intestinal bacterial overgrowth: a meta-analysis. Clin Gastroenterol Hepatol. 2013;11:483–90.

    CAS  PubMed  Google Scholar 

  14. Su T, Lai S, Lee A, He X, Chen S. Meta-analysis: proton pump inhibitors moderately increase the risk of small intestinal bacterial overgrowth. J Gastroenterol. 2018;53:27–36.

    CAS  PubMed  Google Scholar 

  15. Vinke P, Wesselink E, van Orten-Luiten W, van Norren K. The use of proton pump inhibitors may increase symptoms of muscle function loss in patients with chronic illnesses. Int J Mol Sci. 2020;21:323.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. von Haehling S, Garfias Macedo T, Valentova M, et al. Muscle wasting as an independent predictor of survival in patients with chronic heart failure. J Cachexia Sarcopenia Muscle. 2020;11:1242–9.

    Google Scholar 

  17. Konishi M, Akiyama E, Matsuzawa Y, et al. Prognostic impact of muscle and fat mass in patients with heart failure. J Cachexia Sarcopenia Muscle. 2021;12:568–76.

    PubMed  PubMed Central  Google Scholar 

  18. Konishi M, Kagiyama N, Kamiya K, et al. Impact of sarcopenia on prognosis in patients with heart failure with reduced and preserved ejection fraction. Eur J Prev Cardiol. 2021;28:1022–9.

    PubMed  Google Scholar 

  19. Ohori K, Yano T, Katano S, Kouzu H, Honma S, Shimomura K, et al. High percent body fat mass predicts lower risk of cardiac events in patients with heart failure: an explanation of the obesity paradox. BMC Geriatr. 2021;21:16.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Katano S, Yano T, Tsukada T, Kouzu H, Honma S, Inoue T, et al. Clinical risk factors and prognostic impact of osteoporosis in patients with chronic heart failure. Circ J. 2020;84:2224–34.

    CAS  PubMed  Google Scholar 

  21. Tsutsui H, Isobe M, Ito H, Ito H, Okumura K, Ono M, et al. JCS 2017/JHFS 2017 guideline on diagnosis and treatment of acute and chronic heart failure—digest version. Circ J. 2019;83:2084–184.

    PubMed  Google Scholar 

  22. Ohori K, Yano T, Katano S, Kouzu H, Inoue T, Takamura Y, et al. Independent link between peripheral artery disease and muscle wasting in patients with heart failure. ESC Heart Fail. 2020;7:3252–6.

    PubMed  PubMed Central  Google Scholar 

  23. Kouzu H, Katano S, Yano T, Ohori K, Nagaoka R, Inoue T, et al. Plasma amino acid profiling improves predictive accuracy of adverse events in patients with heart failure. ESC Heart Fail. 2021;8:5045–56.

    PubMed  PubMed Central  Google Scholar 

  24. Chen LK, Liu LK, Woo J, et al. Sarcopenia in Asia: consensus report of the Asian Working Group for Sarcopenia. J Am Med Dir Assoc. 2014;15:95–101.

    PubMed  Google Scholar 

  25. Katano S, Yano T, Kouzu H, Ohori K, Shimomura K, Honma S, et al. Energy intake during hospital stay predicts all-cause mortality after discharge independently of nutritional status in elderly heart failure patients. Clin Res Cardiol. 2021;110:1202–20.

    PubMed  PubMed Central  Google Scholar 

  26. Katano S, Yano T, Shimizu M, Ohori K, Kouzu H, Koyama M, et al. Does renin-angiotensin system inhibition have impacts on muscle mass and bone mineral density in heart failure patients? ESC Heart Fail. 2021;8:2617–24.

    PubMed  PubMed Central  Google Scholar 

  27. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev. 2015;95:1–46.

    PubMed  Google Scholar 

  28. Dominguez LJ, Barbagallo M, Lauretani F, Bandinelli S, Bos A, Corsi AM, et al. Magnesium and muscle performance in older persons: the InCHIANTI study. Am J Clin Nutr. 2006;84:419–26.

    CAS  PubMed  Google Scholar 

  29. Verlaan S, Aspray TJ, Bauer JM, Cederholm T, Hemsworth J, Hill TR, et al. Nutritional status, body composition, and quality of life in community-dwelling sarcopenic and non-sarcopenic older adults: a case-control study. Clin Nutr. 2017;36:267–74.

    PubMed  Google Scholar 

  30. Ter Borg S, de Groot LC, Mijnarends DM, de Vries JH, Verlaan S, Meijboom S, et al. Differences in nutrient intake and biochemical nutrient status between sarcopenic and nonsarcopenic older adults—results from the Maastricht Sarcopenia Study. J Am Med Dir Assoc. 2016;17:393–401.

    PubMed  Google Scholar 

  31. Rock E, Astier C, Lab C, Vignon X, Gueux E, Motta C, Rayssiguier Y. Dietary magnesium deficiency in rats enhances free radical production in skeletal muscle. J Nutr. 1995;125:1205–10.

    CAS  PubMed  Google Scholar 

  32. Latham CM, Brightwell CR, Keeble AR, Munson BD, Thomas NT, Zagzoog AM, et al. Vitamin D promotes skeletal muscle regeneration and mitochondrial health. Front Physiol. 2021;12: 660498.

    PubMed  PubMed Central  Google Scholar 

  33. Remelli F, Vitali A, Zurlo A, Volpato S. Vitamin D deficiency and sarcopenia in older persons. Nutrients. 2019;11:2861.

    PubMed  PubMed Central  Google Scholar 

  34. Liu C, Cheung WH, Li J, Chow SK, Yu J, Wong SH, et al. Understanding the gut microbiota and sarcopenia: a systematic review. J Cachexia Sarcopenia Muscle. 2021;12:1393–407.

    PubMed  PubMed Central  Google Scholar 

  35. 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;152:706–15.

    CAS  PubMed  Google Scholar 

  36. van Diepen S, Majumdar SR, Bakal JA, McAlister FA, Ezekowitz JA. Heart failure is a risk factor for orthopedic fracture: a population-based analysis of 16,294 patients. Circulation. 2008;118:1946–52.

    PubMed  Google Scholar 

  37. Sennerby U, Melhus H, Gedeborg R, Byberg L, Garmo H, Ahlbom A, et al. Cardiovascular diseases and risk of hip fracture. JAMA. 2009;302:1666–73.

    CAS  PubMed  Google Scholar 

  38. Sattayalertyanyong O, Thitilertdecha P, Auesomwang C. The inappropriate use of proton pump inhibitors during admission and after discharge: a prospective cross-sectional study. Int J Clin Pharm. 2020;42:174–83.

    PubMed  Google Scholar 

  39. Matsumoto A, Yoshimura Y, Nagano F, Bise T, Kido Y, Shimazu S, et al. Polypharmacy and potentially inappropriate medications in stroke rehabilitation: prevalence and association with outcomes. Int J Clin Pharm. 2022;44:749–61.

    CAS  PubMed  Google Scholar 

  40. von Haehling S, Ebner N, Dos Santos MR, Springer J, Anker SD. Muscle wasting and cachexia in heart failure: mechanisms and therapies. Nat Rev Cardiol. 2017;14:323–41.

    Google Scholar 

  41. Yano T, Katano S, Kouzu H, Nagaoka R, Inoue T, Takamura Y, et al. Distinct determinants of muscle wasting in nonobese heart failure patients with and without type 2 diabetes mellitus. J Diabetes. 2021;13:7–18.

    CAS  PubMed  Google Scholar 

  42. Ishikawa S, Naito S, Iimori S, Takahashi D, Zeniya M, Sato H, et al. Loop diuretics are associated with greater risk of sarcopenia in patients with non-dialysis-dependent chronic kidney disease. PLoS ONE. 2018;13: e0192990.

    PubMed  PubMed Central  Google Scholar 

  43. Hanai T, Shiraki M, Miwa T, Watanabe S, Imai K, Suetsugu A, et al. Effect of loop diuretics on skeletal muscle depletion in patients with liver cirrhosis. Hepatol Res. 2019;49:82–95.

    CAS  PubMed  Google Scholar 

  44. Nakano I, Tsuda M, Kinugawa S, Fukushima A, Kakutani N, Takada S, et al. Loop diuretic use is associated with skeletal muscle wasting in patients with heart failure. J Cardiol. 2020;76:109–14.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cardiology, Hokkaido Cardiovascular Hospital, Sapporo, Japan

    Katsuhiko Ohori

  2. Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan

    Katsuhiko Ohori, Toshiyuki Yano, Hidemichi Kouzu, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada & Masato Furuhashi

  3. Division of Rehabilitation, Sapporo Medical University Hospital, Sapporo, Japan

    Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano & Yusuke Fujisawa

  4. Department of Public Health, Sapporo Medical University School of Medicine, Sapporo, Japan

    Masayuki Koyama

Authors
  1. Katsuhiko Ohori
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiyuki Yano
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Satoshi Katano
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ryohei Nagaoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ryo Numazawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kotaro Yamano
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yusuke Fujisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hidemichi Kouzu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masayuki Koyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Nobutaka Nagano
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takefumi Fujito
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ryo Nishikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Wataru Ohwada
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Masato Furuhashi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiyuki Yano.

Ethics declarations

Conflicts of interests

Katsuhiko Ohori, Toshiyuki Yano, Satoshi Katano, Ryohei Nagaoka, Ryo Numazawa, Kotaro Yamano, Yusuke Fujisawa, Hidemichi Kouzu, Masayuki Koyama, Nobutaka Nagano, Takefumi Fujito, Ryo Nishikawa, Wataru Ohwada, and Masato Furuhashi declare they have no conflicts of interest.

Funding

This study was supported by Grant-in-Aid for Young Scientists (Katano S) from the Japan Society for the Promotion of Science KAKENHI (grant numbers JP18K17677 and 22K11288), Tokyo, Japan. The funding body played no role in the design of the study; the collection, analysis, and interpretation of data; or writing of the manuscript.

Ethics approval

This study was conducted in strict adherence to the principles of the Declaration of Helsinki and was approved by the Clinical Investigation Ethics Committee of Sapporo Medical University Hospital (Number 302-104).

Consent to participate

Given the retrospective and anonymized nature of this study, the Clinical Investigation Ethics Committee of Sapporo Medical University Hospital waived the need for informed consent from the patients who participated in this study from November 1, 2015 to April 10, 2019. An opt-out option on our website allowed patients to decline the inclusion of their data in this study. In addition, informed consent was obtained from patients who participated in this study from April 11, 2019 to April 30, 2022.

Consent for publication

All authors provide this content.

Data availability

The datasets generated and/or analyzed during the current study are not publicly available because a research agreement from all authors is required for data sharing, but are available from the corresponding author on reasonable request.

Code availability

Not applicable.

Author’s contributions

All authors have read and approved the manuscript. In addition, we confirm that all listed authors meet the authorship criteria and that all authors are in agreement with the content of this manuscript. KO, TY, and SK designed the study. KO, TY, SK, RNa, RNu, KY, YF, HK, MK, NN, TF, RNi, and WO collected the patients’ data. KO, TY, SK, and MF analyzed and discussed the data. KO, TY and SK performed the statistical analyses. KO, TY, and MF drafted the manuscript.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 7510 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ohori, K., Yano, T., Katano, S. et al. Independent Association Between Use of Proton Pump Inhibitors and Muscle Wasting in Patients with Heart Failure: A Single-Center, Ambispective, Observational Study. Drugs Aging 40, 731–739 (2023). https://doi.org/10.1007/s40266-023-01035-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40266-023-01035-3

Search

Navigation