Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Epidemiology

Long-term use of antihypertensive medications, hypertension and colorectal cancer risk and mortality: a prospective cohort study

British Journal of Cancer volume 127, pages 1974–1982 (2022)Cite this article

Subjects

Abstract

Background

Hypertension and the use of antihypertensive medications have been intensively investigated in relation to colorectal cancer (CRC). Prior epidemiologic studies have not been able to examine this topic with adequate confounding control and follow-up time, or disentangle the effects of antihypertensive agents and hypertension.

Methods

Eligible participants in the Nurses’ Health Study and Health Professionals Follow-up Study were followed for up to 28 years, with repeat assessments of exposures. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals.

Results

In fully adjusted analyses based on both new-user and prevalent-user designs, there was no association between the use of beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, furosemide, other antihypertensive drugs and CRC risk and mortality reached the statistically significant threshold after Bonferroni correction. The results remained similar in sensitivity analyses among participants with hypertension. Before Bonferroni correction, suggestive associations between beta-blocker use and CRC risk and between furosemide use and CRC-specific mortality were observed specifically in analyses using a new-user design. Hypertension was not associated with CRC risk in analyses based on both new-user and prevalent-user designs.

Conclusions

Hypertension and long-term use of major classes of antihypertensive medications are unlikely to be associated with CRC risk and mortality.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Data availability

Data described in the manuscript may be made available upon application to and approval by the Channing Division of Network Medicine at Brigham and Women’s Hospital, and Harvard T.H. Chan School of Public Health. Further information, including the procedures to obtain and access data from the Nurses’ Health Study and Health Professionals Follow-up Study, is described at https://www.nurseshealthstudy.org/researchers (email: nhsaccess@channing.harvard.edu) and https://sites.sph.harvard.edu/hpfs/for-collaborators/.

References

  1. Xuan K, Zhao T, Sun C, Patel AS, Liu H, Chen X, et al. The association between hypertension and colorectal cancer: a meta-analysis of observational studies. Eur J Cancer Prev. 2021;30:84–96.

    Article  CAS  PubMed  Google Scholar 

  2. Makar GA, Holmes JH, Yang YX. Angiotensin-converting enzyme inhibitor therapy and colorectal cancer risk. J Natl Cancer Inst. 2014;106:djt374.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Dai YN, Wang JH, Zhu JZ, Lin JQ, Yu CH, Li YM. Angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy and colorectal cancer: a systematic review and meta-analysis. Cancer Causes Control. 2015;26:1245–55.

    Article  PubMed  Google Scholar 

  4. Hicks BM, Filion KB, Yin H, Sakr L, Udell JA, Azoulay L. Angiotensin converting enzyme inhibitors and risk of lung cancer: population based cohort study. BMJ. 2018;363:k4209.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Cronin-Fenton D. Angiotensin converting enzyme inhibitors and lung cancer. BMJ. 2018;363:k4337.

    Article  PubMed  Google Scholar 

  6. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, et al. Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 1998;352:179–84.

    Article  CAS  PubMed  Google Scholar 

  7. Boudreau DM, Koehler E, Rulyak SJ, Haneuse S, Harrison R, Mandelson MT. Cardiovascular medication use and risk for colorectal cancer. Cancer Epidemiol Biomark Prev. 2008;17:3076–80.

    Article  CAS  Google Scholar 

  8. Michels KB, Rosner BA, Walker AM, Stampfer MJ, Manson JE, Colditz GA, et al. Calcium channel blockers, cancer incidence, and cancer mortality in a cohort of U.S. women: the nurses’ health study. Cancer 1998;83:2003–7.

    Article  CAS  PubMed  Google Scholar 

  9. Chen X, Yi CH, Ya KG. Renin-angiotensin system inhibitor use and colorectal cancer risk and mortality: a dose-response meta analysis. J Renin Angiotensin Aldosterone Syst. 2020;21:1470320319895646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Engineer DR, Burney BO, Hayes TG, Garcia JM. Exposure to ACEI/ARB and beta-blockers is associated with improved survival and decreased tumor progression and hospitalizations in patients with advanced colon cancer. Transl Oncol. 2013;6:539–45.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bangalore S, Kumar S, Kjeldsen SE, Makani H, Grossman E, Wetterslev J, et al. Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol. 2011;12:65–82.

    Article  CAS  PubMed  Google Scholar 

  12. Bhaskaran K, Douglas I, Evans S, van Staa T, Smeeth L. Angiotensin receptor blockers and risk of cancer: cohort study among people receiving antihypertensive drugs in UK General Practice Research Database. BMJ. 2012;344:e2697.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC. Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol. 2010;11:627–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Jansen L, Weberpals J, Kuiper JG, Vissers PAJ, Wolkewitz M, Hoffmeister M, et al. Pre- and post-diagnostic beta-blocker use and prognosis after colorectal cancer: results from a population-based study. Int J Cancer. 2017;141:62–71.

    Article  CAS  PubMed  Google Scholar 

  15. Jansen L, Below J, Chang-Claude J, Brenner H, Hoffmeister M. Beta blocker use and colorectal cancer risk: population-based case-control study. Cancer 2012;118:3911–9.

    Article  CAS  PubMed  Google Scholar 

  16. Ahl R, Matthiessen P, Sjolin G, Cao Y, Wallin G, Ljungqvist O, et al. Effects of beta-blocker therapy on mortality after elective colon cancer surgery: a Swedish nationwide cohort study. BMJ Open. 2020;10:e036164.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Musselman RP, Bennett S, Li W, Mamdani M, Gomes T, van Walraven C, et al. Association between perioperative beta blocker use and cancer survival following surgical resection. Eur J Surg Oncol. 2018;44:1164–9.

    Article  PubMed  Google Scholar 

  18. Ahl R, Matthiessen P, Cao Y, Sjolin G, Ljungqvist O, Mohseni S. The relationship between severe complications, beta-blocker therapy and long-term survival following emergency surgery for colon cancer. World J Surg. 2019;43:2527–35.

    Article  PubMed  Google Scholar 

  19. Hicks BM, Murray LJ, Powe DG, Hughes CM, Cardwell CR. beta-Blocker usage and colorectal cancer mortality: a nested case-control study in the UK Clinical Practice Research Datalink cohort. Ann Oncol. 2013;24:3100–6.

    Article  CAS  PubMed  Google Scholar 

  20. Cui Y, Wen W, Zheng T, Li H, Gao YT, Cai H, et al. Use of Antihypertensive medications and survival rates for breast, colorectal, lung, or stomach cancer. Am J Epidemiol. 2019;188:1512–28.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Grimaldi-Bensouda L, Klungel O, Kurz X, de Groot MC, Maciel Afonso AS, de Bruin ML, et al. Calcium channel blockers and cancer: a risk analysis using the UK Clinical Practice Research Datalink (CPRD). BMJ Open. 2016;6:e009147.

    Article  PubMed  PubMed Central  Google Scholar 

  22. George AJ, Thomas WG, Hannan RD. The renin-angiotensin system and cancer: old dog, new tricks. Nat Rev Cancer. 2010;10:745–59.

    Article  CAS  PubMed  Google Scholar 

  23. Mravec B, Horvathova L, Hunakova L. Neurobiology of cancer: the role of beta-adrenergic receptor signaling in various tumor environments. Int J Mol Sci. 2020;21:7958.

  24. Chin CC, Li JM, Lee KF, Huang YC, Wang KC, Lai HC, et al. Selective beta2-AR blockage suppresses colorectal cancer growth through regulation of EGFR-Akt/ERK1/2 signaling, G1-phase arrest, and apoptosis. J Cell Physiol. 2016;231:459–72.

    Article  CAS  PubMed  Google Scholar 

  25. Mason RP. Calcium channel blockers, apoptosis and cancer: is there a biologic relationship? J Am Coll Cardiol. 1999;34:1857–66.

    Article  CAS  PubMed  Google Scholar 

  26. Janne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med. 2000;342:1960–8.

    Article  CAS  PubMed  Google Scholar 

  27. Giovannucci E. Aspirin and delayed chemoprevention of colorectal cancer. Clin Chem. 2018;64:1668–9.

    Article  CAS  PubMed  Google Scholar 

  28. Cuzick J, Otto F, Baron JA, Brown PH, Burn J, Greenwald P, et al. Aspirin and non-steroidal anti-inflammatory drugs for cancer prevention: an international consensus statement. Lancet Oncol. 2009;10:501–7.

    Article  CAS  PubMed  Google Scholar 

  29. Zhang Y, Chan AT, Meyerhardt JA, Giovannucci EL. Timing of aspirin use in colorectal cancer chemoprevention: a prospective cohort study. J Natl Cancer Inst. 2021;113:841–51.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Zhang Y, Wu K, Chan AT, Meyerhardt JA, Giovannucci EL. Long-term statin use, total cholesterol level, and risk of colorectal cancer: a prospective cohort study. Am J Gastroenterol. 2022;117:158–66.

    Article  PubMed  Google Scholar 

  31. Bibbins-Domingo K. Force USPST. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016;164:836–45.

    Article  PubMed  Google Scholar 

  32. Belanger CF, Hennekens CH, Rosner B, Speizer FE. The nurses’ health study. Am J Nurs. 1978;78:1039–40.

    CAS  PubMed  Google Scholar 

  33. Harvard School of Public Health. Health professionals follow-up study. https://sites.sph.harvard.edu/hpfs/ (Accessed September 10, 2022).

  34. Yoshida K, Solomon DH, Kim SC. Active-comparator design and new-user design in observational studies. Nat Rev Rheumatol. 2015;11:437–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Colditz GA, Martin P, Stampfer MJ, Willett WC, Sampson L, Rosner B, et al. Validation of questionnaire information on risk factors and disease outcomes in a prospective cohort study of women. Am J Epidemiol. 1986;123:894–900.

    Article  CAS  PubMed  Google Scholar 

  36. Lee DH, Keum N, Giovannucci EL. Colorectal cancer epidemiology in the Nurses’ Health Study. Am J Public Health. 2016;106:1599–607.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Keum N, Giovannucci E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol. 2019;16:713–32.

    Article  PubMed  Google Scholar 

  38. Stampfer MJ, Willett WC, Speizer FE, Dysert DC, Lipnick R, Rosner B, et al. Test of the national death index. Am J Epidemiol. 1984;119:837–9.

    Article  CAS  PubMed  Google Scholar 

  39. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020;16:223–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Samanic CM, Barbour KE, Liu Y, Fang J, Lu H, Schieb L, et al. Prevalence of self-reported hypertension and antihypertensive medication use among adults—United States, 2017. MMWR Morb Mortal Wkly Rep. 2020;69:393–8.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

  42. Song M, Giovannucci EL. Antihypertension and colorectal cancer prevention: getting two birds with one stone. J Natl Cancer Inst. 2014;106:djt438.

    Article  PubMed  Google Scholar 

  43. Nissen SE. Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Lancet Oncol. 2010;11:605–6.

    Article  PubMed  Google Scholar 

  44. Cheung KS, Chan EW, Seto WK, Wong ICK, Leung WK. ACE (angiotensin-converting enzyme) inhibitors/angiotensin receptor blockers are associated with lower colorectal cancer risk: a territory-wide study with propensity score analysis. Hypertension 2020;76:968–75.

    Article  CAS  PubMed  Google Scholar 

  45. Brasky TM, Flores KF, Larson JC, Newton AM, Shadyab AH, Watanabe JH, et al. Associations of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with colorectal cancer risk in the Women’s Health Initiative. Cancer Epidemiol Biomarkers Prev. 2021;30:1029–32.

  46. Htoo PT, Sturmer T, Jonsson-Funk M, Pate V, Simpson RJ Jr., Lund JL. Renin-angiotensin-aldosterone system-based antihypertensive agents and the risk of colorectal cancer among medicare beneficiaries. Epidemiology 2019;30:867–75.

    Article  PubMed  PubMed Central  Google Scholar 

  47. Zhu X, Liang J, Shrubsole MJ, Ness RM, Cai Q, Long J, et al. Calcium intake and ion transporter genetic polymorphisms interact in human colorectal neoplasia risk in a 2-phase study. J Nutr. 2014;144:1734–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhao J, Zhu X, Shrubsole MJ, Ness RM, Hibler EA, Cai Q, et al. Interactions between calcium intake and polymorphisms in genes essential for calcium reabsorption and risk of colorectal neoplasia in a two-phase study. Mol Carcinog. 2017;56:2258–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank all participants and staff of the Nurses’ Health Study and Health Professionals Follow-up Study for their contributions to this research. The authors thank the Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School for leading the Nurses’ Health Study. The authors would like to acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention’s National Program of Cancer Registries (NPCR) and/or the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program. Central registries may also be supported by state agencies, universities, and cancer centers. Participating central cancer registries include the following: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Delaware, Florida, Georgia, Hawaii, Idaho, Indiana, Iowa, Kentucky, Louisiana, Massachusetts, Maine, Maryland, Michigan, Mississippi, Montana, Nebraska, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oklahoma, Oregon, Pennsylvania, Puerto Rico, Rhode Island, Seattle SEER Registry, South Carolina, Tennessee, Texas, Utah, Virginia, West Virginia, Wyoming. The authors assume full responsibility for the analyses and interpretation of these data.

Funding

Nurses’ Health Study and Health Professionals Follow-up Study was supported by grants UM1 CA186107, U01 CA176726, P01 CA87969, and U01 CA167552 from the National Institutes of Health (NIH). This work was additionally supported by the American Cancer Society Mentored Research Scholar Grant MRSG-17–220–01-NEC and the NIH grant R00 CA215314 (Dr. Song); NIH grants R01 CA137178, R35 CA253185 (Dr. Chan); and a grant from the World Cancer Research Fund (Dr. Giovannucci). Dr. Zhang is supported by Irene M. & Fredrick J. Stare Nutrition Education Fund Doctoral Scholarship and Mayer Fund Doctoral Scholarship. Dr. Chan is a Stuart and Suzanne Steele MGH Research Scholar. The funding sources played no role in the study design, data collection, data analysis and interpretation of the results, or the decisions made in the preparation and submission of the article.

Author information

Authors and Affiliations

  1. Department of Nutrition, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Yin Zhang, Mingyang Song, Walter C. Willett & Edward L. Giovannucci

  2. Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Mingyang Song & Andrew T. Chan

  3. Clinical and Translational Epidemiology Unit and Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Mingyang Song & Andrew T. Chan

  4. Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, USA

    Mingyang Song, Walter C. Willett & Edward L. Giovannucci

  5. Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, MA, USA

    Andrew T. Chan

  6. Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

    Jeffrey A. Meyerhardt

Authors
  1. Yin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mingyang Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew T. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jeffrey A. Meyerhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Walter C. Willett
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edward L. Giovannucci
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Concept and design: YZ, WCW and ELG. Acquisition, analysis or interpretation of the data: YZ. Drafting of the manuscript: YZ. Critical revision of the manuscript for important intellectual content: ELG, WCW, JAM, ATC and MS. Statistical analysis: YZ. Obtained funding: YZ, MS, ATC and ELG. Administrative, technical or material support: ELG and WCW. Supervision: ELG. The authors assume full responsibility for the analyses and interpretation of these data.

Corresponding author

Correspondence to Edward L. Giovannucci.

Ethics declarations

Competing interests

Dr. Meyerhardt declares institutional research funding from Boston Biomedical and consulting for Ignyta, Taiho Pharmaceutical, and Cota, outside the submitted work. Dr. Chan declares research funding from Bayer and consulting for Bayer, Pfizer Inc. and Boehringer Ingelheim, outside the submitted work. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The Nurses’ Health Study and Health Professionals Follow-up Study were approved by the Institutional Review Boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health (Boston, MA), and those of participating registries as required. Written informed consent was required to retrieve medical records.

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor 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

Zhang, Y., Song, M., Chan, A.T. et al. Long-term use of antihypertensive medications, hypertension and colorectal cancer risk and mortality: a prospective cohort study. Br J Cancer 127, 1974–1982 (2022). https://doi.org/10.1038/s41416-022-01975-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41416-022-01975-4

This article is cited by

Search

Advanced search

Quick links