Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality.
We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure.
Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32–1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0−I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40–1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24–1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality.
PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.
Subscribe to Journal
Get full journal access for 1 year
only $4.96 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Data used for this study cannot be shared, but the original data from the registries can be obtained by application to Swedish National Board of Health and Welfare.
Hálfdánarson ÓÖ, Pottegård A, Björnsson ES, Lund SH, Ogmundsdottir MH, Steingrímsson E, et al. Proton-pump inhibitors among adults: a nationwide drug-utilization study. Ther Adv Gastroenterol. 2018;11:175628481877794.
Lassalle M, Le Tri T, Bardou M, Biour M, Kirchgesner J, Rouby F, et al. Use of proton pump inhibitors in adults in France: a nationwide drug utilization study. Eur J Clin Pharmacol. 2020;76:449–57.
Daniels B, Pearson S-A, Buckley NA, Bruno C, Zoega H. Long-term use of proton-pump inhibitors: whole-of-population patterns in Australia 2013–2016. Ther Adv Gastroenterol. 2020;13:175628482091374.
Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E. The appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal. Eur J Intern Med. 2017;37:19–24.
Freedberg DE, Kim LS, Yang Y-X. 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.
Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8.
Saus E, Iraola-Guzmán S, Willis JR, Brunet-Vega A, Gabaldón T. Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol Asp Med. 2019;69:93–106.
Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sørensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case–control study. Gastroenterology. 2007;133:755–60.
Lei W-Y, Wang J-H, Yi C-H, Liu T-T, Hung J-S, Wong M-W, et al. Association between use of proton pump inhibitors and colorectal cancer: a nationwide population-based study. Clin Res Hepatol Gastroenterol. 2021;45:101397.
Hwang IC, Chang J, Park SM. Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: a Korean nationwide prospective cohort study. PLoS ONE. 2017;12:e0189114.
Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT. Colorectal cancer risk in relation to use of acid suppressive medications. Pharmacoepidemiol Drug Saf. 2009;18:540–4.
Siersema PD, Yu S, Sahbaie P, Steyerberg EW, Simpson PW, Kuipers EJ, et al. Colorectal neoplasia in veterans is associated with Barrett’s esophagus but not with proton-pump inhibitor or aspirin/NSAID use. Gastrointest Endosc. 2006;63:581–6.
Yang Y, Hennessy S, Propert K, Hwang W, Sedarat A, Lewis JD. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology. 2007;133:748–54.
Lee JK, Merchant SA, Schneider JL, Jensen CD, Fireman BH, Quesenberry CP, et al. Proton pump inhibitor use and risk of gastric, colorectal, liver, and pancreatic cancers in a community-based population. Am J Gastroenterol. 2020;115:706–15.
van Soest EM, van Rossum LGM, Dieleman JP, van Oijen MGH, Siersema PD, Sturkenboom MCJM, et al. Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol. 2008;103:966–73.
Graham C, Orr C, Bricks CS, Hopman WM, Hammad N, Ramjeesingh R. A retrospective analysis of the role of proton pump inhibitors in colorectal cancer disease survival. Curr Oncol. 2016;23:583.
Tvingsholm SA, Dehlendorff C, Østerlind K, Friis S, Jäättelä M. Proton pump inhibitor use and cancer mortality. Int J Cancer. 2018;143:1315–26.
Brusselaers N, Wahlin K, Engstrand L, Lagergren J. Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden. BMJ Open. 2017;7:e017739.
Brusselaers N, Tamimi RM, Konings P, Rosner B, Adami H-O, Lagergren J. Different menopausal hormone regimens and risk of breast cancer. Ann Oncol. 2018;29:1771–6.
Ma Y, Brusselaers N. Maintenance use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk. Prostate Cancer Prostatic Dis. 2018;21:147–52.
Doorakkers E, Lagergren J, Engstrand L, Brusselaers N. Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population. Gut. 2018;67:2092–6.
Brusselaers N, Lagergren J, Engstrand L. Duration of use of proton pump inhibitors and the risk of gastric and oesophageal cancer. Cancer Epidemiol. 2019;62:101585.
Loikas D, Wettermark B, von Euler M, Bergman U, Schenck-Gustafsson K. Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden. BMJ Open. 2013;3:e002378.
Suissa S. Immortal time bias in pharmacoepidemiology. Am J Epidemiol. 2008;167:492–9. 7
Pottegård A, Friis S, Stürmer T, Hallas J, Bahmanyar S. Considerations for pharmacoepidemiological studies of drug-cancer associations. Basic Clin Pharm Toxicol. 2018;122:451–9.
Pottegård A, Hallas J. New use of prescription drugs prior to a cancer diagnosis: use of prescription drugs prior to cancer diagnosis. Pharmacoepidemiol Drug Saf. 2017;26:223–7.
Tamim H, Monfared AAT, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidemiol Drug Saf. 2007;16:250–8.
Brooke HL, Talbäck M, Hörnblad J, Johansson LA, Ludvigsson JF, Druid H, et al. The Swedish cause of death register. Eur J Epidemiol. 2017;32:765–73.
Barlow L, Westergren K, Holmberg L, Talbäck M. The completeness of the Swedish Cancer Register—a sample survey for year 1998. Acta Oncol. 2009;48:27–33.
Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. AJCC cancer staging manual. 6th. American Joint Committee on Cancer. 2002.
Nordic Medico-Statistical Committee. NOMESCO classification of surgical procedures (NCSP). Copenhagen: Nordic Medico-Statistical Committee, 2011.
Bastiaannet E, Sampieri K, Dekkers OM, de Craen AJM, van Herk-Sukel MPP, Lemmens V, et al. Use of Aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012;106:1564–70.
Din FVN, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, et al. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut. 2010;59:1670–9.
Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007;369:1603–13.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.
Sadr-Azodi O, Oskarsson V, Discacciati A, Videhult P, Askling J, Ekbom A. Pancreatic cancer following acute pancreatitis: a population-based Matched Cohort Study. Am J Gastroenterol. 2018;113:1711–9.
Tamim H, Monfared AT, LeLorier J. Application of lag‐time into exposure definitions to control for protopathic bias. Pharmacoepidemiol. Drug Saf. 2007;16:250–8.
Kearns MD, Boursi B, Yang Y-X. Proton pump inhibitors on pancreatic cancer risk and survival. Cancer Epidemiol. 2017;46:80–4.
Ayyagari S, Tan MC, Liu Y, El-Serag HB, Thrift AP. Use of acid-suppressant medications after diagnosis increases mortality in a subset of gastrointestinal cancer patients. Dig. Dis. Sci. 2020;65:2691–9.
Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;29:l1580.
Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019;394:1467–80.
Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649–58.
Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S, Wang TC, et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 2015;149:883–885.e9.
Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661–72.
Chu MP, Hecht JR, Slamon D, Wainberg ZA, Bang Y-J, Hoff PM, et al. Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial. JAMA Oncol. 2017;3:767.
Sun J, Ilich AI, Kim CA, Chu MP, Wong GG, Ghosh S, et al. Concomitant administration of proton pump inhibitors and capecitabine is associated with increased recurrence risk in early stage colorectal cancer patients. Clin Colorectal Cancer. 2016;15:257–63.
Lundell L, Vieth M, Gibson F, Nagy P, Kahrilas PJ. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharm Ther. 2015;42:649–63.
Watson SA, Smith AM. Hypergastrinemia promotes adenoma progression in the APC(Min−/+) mouse model of familial adenomatous polyposis. Cancer Res. 2001;61:625–31.
Colucci R, Blandizzi C, Tanini M, Vassalle C, Breschi MC, Tacca MD. Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production: Gastrin, cyclooxygenase-2 and colon cancer growth. Br J Pharmacol. 2005;144:338–48.
Yepuri G, Sukhovershin R, Nazari-Shafti TZ, Petrascheck M, Ghebre YT, Cooke JP. Proton pump inhibitors accelerate endothelial senescence. Circ Res. 2016;118:e36-42.
FASS (Farmacevtiska specialiteter i Sverige/ Farmaceutical specialities in Sweden). http://www.fass.se. Accessed 21 August 2020.
Team AP. Early Stage Colon Cancer-Clinical Practice Guideline GI-004. Alberta Health Services, Alberta. 2008.
Wong GG, Ha V, Chu MP, Dersch-Mills D, Ghosh S, Chambers CR, et al. Effects of proton pump inhibitors on FOLFOX and CapeOx regimens in colorectal cancer. Clin Colorectal Cancer. 2019;18:72–9.
Zhang J-L, Liu M, Yang Q, Lin S-Y, Shan H-B, Wang H-Y, et al. Effects of omeprazole in improving concurrent chemoradiotherapy efficacy in rectal cancer. World J Gastroenterol. 2017;23:2575.
We thank all the patients, healthcare workers and the Swedish National Board of Health and Welfare for their contributions to data collection.
This work was supported by Svenska Läkaresallskapet (SLS-788731, SLS-788751 SLS-783091) and The Swedish Research Council/Vetenskapsrådet (2020-01058). HZ was supported by a UNSW Scientia Fellowship. None of these sponsors had any role in the study design, the collection, analysis and interpretation of data.
The authors report no conflict of interest. HZ works at the Centre for Big Data Research in Health, UNSW Sydney, which has received funding from AbbVie Australia to conduct research, unrelated to the present study. AbbVie did not have any knowledge of, or involvement in, the present study.
Ethics approval and consent to participate
Individual consent from the participants was waived for this register-based study. Ethical approval of the study has been obtained from the Regional Ethical Review Board in Stockholm (reference number: 2014/129 - 31/4).
Consent to publish
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Wang, X., Liu, Q., Halfdanarson, Ó.Ö. et al. Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study. Br J Cancer 125, 893–900 (2021). https://doi.org/10.1038/s41416-021-01480-0