Association Between Statins and Cancer Incidence in Diabetes: a Cohort Study of Japanese Patients with Type 2 Diabetes

Abstract

Background

The antitumor effect of statins has been highlighted, but clinical study results remain inconclusive. While patients with diabetes are at high risk of cancer, it is uncertain whether statins are effective for cancer chemoprevention in this population.

Objective

This study evaluated the association between statins and cancer incidence/mortality in patients with type 2 diabetes.

Design

This study was a follow-up observational study of the Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) trial, which was a randomized controlled trial of low-dose aspirin in Japanese patients with type 2 diabetes.

Participants

This study enrolled 2536 patients with type 2 diabetes, age 30–85 years, and no history of atherosclerotic cardiovascular disease, from December 2002 until May 2005. All participants recruited in the JPAD trial were followed until the day of any fatal event or July 2015. We defined participants taking any statin at enrollment as the statin group (n = 650) and the remainder as the no-statin group (n = 1886).

Main Measures

The primary end point was the first occurrence of any cancer (cancer incidence). The secondary end point was death from any cancer (cancer mortality).

Key Results

During follow-up (median, 10.7 years), 318 participants developed a new cancer and 123 died as a result. Cancer incidence and mortality were 10.5 and 3.7 per 1000 person-years in the statin group, and 16.8 and 6.3 per 1000 person-years in the no-statin group, respectively. Statin use was associated with significantly reduced cancer incidence and mortality after adjustment for confounding factors (cancer incidence: adjusted hazard ratio [HR], 0.67; 95% CI, 0.49–0.90, P = 0.007; cancer mortality: adjusted HR, 0.60; 95% CI, 0.36–0.98, P = 0.04).

Conclusions

Statin use was associated with a reduced incidence and mortality of cancer in Japanese patients with type 2 diabetes.

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

Figure 1
Figure 2

References

  1. 1.

    Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2019;139:e1082-e1143.

    PubMed  Google Scholar 

  2. 2.

    Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts)Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016;37:2315-2381.

    Article  Google Scholar 

  3. 3.

    American Diabetes Association. 10. Cardiovascular disease and risk management: standards of medical care in diabetes-2019. Diabetes Care. 2019;42:S103-S123.

  4. 4.

    Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N Engl J Med 2012;367:1792-1802.

    CAS  Article  Google Scholar 

  5. 5.

    Kim MK, Myung SK, Tran BT, Park B. Statins and risk of cancer: a meta-analysis of randomized, double-blind, placebo-controlled trials. Indian J Cancer 2017;54:470-477.

    CAS  Article  Google Scholar 

  6. 6.

    Sopkova J, Vidomanova E, Strnadel J, Skovierova H, Halasova E. The role of statins as therapeutic agents in cancer. Gen Physiol Biophys 2017;36:501-511.

    CAS  Article  Google Scholar 

  7. 7.

    Ahmadi Y, Karimian R, Panahi Y. Effects of statins on the chemoresistance-the antagonistic drug-drug interactions versus the anti-cancer effects. Biomed Pharmacother 2018;108:1856-1865.

    CAS  Article  Google Scholar 

  8. 8.

    Altwairgi AK. Statins are potential anticancerous agents (review). Oncol Rep 2015;33:1019-1039.

    CAS  Article  Google Scholar 

  9. 9.

    Cholesterol Treatment Trialists C, Emberson JR, Kearney PM, et al. Lack of effect of lowering LDL cholesterol on cancer: meta-analysis of individual data from 175,000 people in 27 randomised trials of statin therapy. PLoS One. 2012;7:e29849.

    Article  Google Scholar 

  10. 10.

    May MB, Glode A. Novel uses for lipid-lowering agents. J Adv Pract Oncol 2016;7:181-187.

    PubMed  PubMed Central  Google Scholar 

  11. 11.

    Wang A, Aragaki AK, Tang JY, et al. Statin use and all-cancer survival: prospective results from the Women’s Health Initiative. Br J Cancer 2016;115:129-135.

    CAS  Article  Google Scholar 

  12. 12.

    Giovannucci E, Harlan DM, Archer MC, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674-1685.

    Article  Google Scholar 

  13. 13.

    Noto H, Osame K, Sasazuki T, Noda M. Substantially increased risk of cancer in patients with diabetes mellitus: a systematic review and meta-analysis of epidemiologic evidence in Japan. J Diabetes Complications 2010;24:345-353.

    Article  Google Scholar 

  14. 14.

    Emerging Risk Factors C, Seshasai SR, Kaptoge S, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829-841.

    Article  Google Scholar 

  15. 15.

    Kasuga M, Ueki K, Tajima N, et al. Report of the JDS/JCA Joint Committee on Diabetes and Cancer. Diabetology International 2013;4:81-96.

    Article  Google Scholar 

  16. 16.

    Nakamura J, Kamiya H, Haneda M, et al. Causes of death in Japanese patients with diabetes based on the results of a survey of 45,708 cases during 2001-2010: report of the Committee on Causes of Death in Diabetes Mellitus. J Diabetes Investig 2017;8:397-410.

    CAS  Article  Google Scholar 

  17. 17.

    Okada S, Morimoto T, Ogawa H, et al. Effect of aspirin on cancer chemoprevention in Japanese patients with type 2 diabetes: 10-year observational follow-up of a randomized controlled trial. Diabetes Care 2018;41:1757-1764.

    CAS  Article  Google Scholar 

  18. 18.

    Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-2141.

    CAS  Article  Google Scholar 

  19. 19.

    Saito Y, Okada S, Ogawa H, et al. Low-dose aspirin for primary prevention of cardiovascular events in patients with type 2 diabetes mellitus: 10-year follow-up of a randomized controlled trial. Circulation 2017;135:659-670.

    CAS  Article  Google Scholar 

  20. 20.

    Sasco AJ, Secretan MB, Straif K. Tobacco smoking and cancer: a brief review of recent epidemiological evidence. Lung Cancer 2004;45 Suppl 2:S3-9.

    Article  Google Scholar 

  21. 21.

    Zhao W, Guan J, Horswell R, et al. HDL cholesterol and cancer risk among patients with type 2 diabetes. Diabetes Care 2014;37:3196-3203.

    CAS  Article  Google Scholar 

  22. 22.

    Gallagher EJ, LeRoith D. Obesity and diabetes: the increased risk of cancer and cancer-related mortality. Physiol Rev 2015;95:727-748.

    CAS  Article  Google Scholar 

  23. 23.

    Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol 2016;27:2184-2195.

    CAS  Article  Google Scholar 

  24. 24.

    Ripamonti E, Azoulay L, Abrahamowicz M, Platt RW, Suissa S. A systematic review of observational studies of the association between pioglitazone use and bladder cancer. Diabet Med 2019;36:22-35.

    CAS  Article  Google Scholar 

  25. 25.

    Asano K, Kubo M, Yonemoto K, et al. Impact of serum total cholesterol on the incidence of gastric cancer in a population-based prospective study: the Hisayama study. Int J Cancer 2008;122:909-914.

    CAS  Article  Google Scholar 

  26. 26.

    Iso H, Ikeda A, Inoue M, Sato S, Tsugane S, Group JS. Serum cholesterol levels in relation to the incidence of cancer: the JPHC study cohorts. Int J Cancer 2009;125:2679-2686.

    CAS  Article  Google Scholar 

  27. 27.

    Nago N, Ishikawa S, Goto T, Kayaba K. Low cholesterol is associated with mortality from stroke, heart disease, and cancer: the Jichi Medical School Cohort Study. J Epidemiol 2011;21:67-74.

    Article  Google Scholar 

  28. 28.

    Yang X, So W, Ko GT, et al. Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus. CMAJ 2008;179:427-437.

    Article  Google Scholar 

  29. 29.

    Kuzu OF, Noory MA, Robertson GP. The role of cholesterol in cancer. Cancer Res 2016;76:2063-2070.

    CAS  Article  Google Scholar 

  30. 30.

    Murai T. Cholesterol lowering: role in cancer prevention and treatment. Biol Chem. 2015;396:1-11.

    CAS  Article  Google Scholar 

  31. 31.

    Yang X, So WY, Ma RC, et al. Low LDL cholesterol, albuminuria, and statins for the risk of cancer in type 2 diabetes: the Hong Kong diabetes registry. Diabetes Care 2009;32:1826-1832.

    CAS  Article  Google Scholar 

  32. 32.

    Iannelli F, Lombardi R, Milone MR, et al. Targeting mevalonate pathway in cancer treatment: repurposing of statins. Recent Pat Anticancer Drug Discov 2018;13:184-200.

    CAS  Article  Google Scholar 

  33. 33.

    Yang X, Lee HM, Chan JC. Drug-subphenotype interactions for cancer in type 2 diabetes mellitus. Nat Rev Endocrinol 2015;11:372-379.

    CAS  Article  Google Scholar 

  34. 34.

    Yang XL, Ma RC, So WY, Kong AP, Xu G, Chan JC. Addressing different biases in analysing drug use on cancer risk in diabetes in non-clinical trial settings--what, why and how? Diabetes Obes Metab 2012;14:579-585.

    CAS  Article  Google Scholar 

Download references

Acknowledgments

The authors thank M. Ohtorii for her roles in data management and statistical analyses. The authors also thank M. Nagahiro, M. Okamoto, and M. Aoyama, and Y. Wada, Y. Kamada, and M. Miyagawa for their secretarial work. The authors also thank all members of the JPAD trial investigators, described in the Appendix, for data collection.

This study was supported by the Ministry of Health, Labour and Welfare of Japan (H16-Junkanki-004, and H27-Junkanki-Ippan-001), the Japan Heart Foundation, and JSPS KAKENHI Grant Number 17K18022.

This study has not been presented at any conference.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yoshihiko Saito MD, PhD.

Ethics declarations

Conflict of Interest

Dr. Okada reports personal fees from Novo Nordisk, Mitsubishi Tanabe, Sumitomo Dainippon, Arkray, Bayer, Eli Lilly, Boehringer Ingelheim, Ono, AstraZeneca, Sanofi, and Takeda, outside the submitted work. Dr. Morimoto reports personal fees from AstraZeneca, Bayer, Daiichi Sankyo, Japan Lifeline, Kyocera, Mitsubishi Tanabe, Novartis, Pfizer, Asahi Kasei, Bristol-Myers Squibb, and Boston Scientific, outside the submitted work. Dr. Ogawa reports personal fees from MSD, Daiichi Sankyo, Ono, Mochida, AstraZeneca, Pfizer, Bristol-Myers Squibb, Mitsubishi Tanabe, Kyowa Kirin, Sanofi, and Medtronic, outside the submitted work. Dr. Soejima reports grants from Boehringer Ingelheim, outside the submitted work. Dr. Matsumoto has nothing to disclose. Dr. Sakuma reports personal fees from Enomoto Pharmaceutical, outside the submitted work. Dr. Nakayama reports personal fees from Bayer, Shionogi, Takeda, Daiichi Sankyo, Sanofi, Boehringer Ingelheim, Sumitomo Dainippon, Fujifilm Medical, Kowa, Pfizer, and Astellas, outside the submitted work. Dr. Doi reports personal fees from Daiichi Sankyo, Mitsubishi Tanabe, Takeda, Otsuka, Astellas, Boehringer Ingelheim, Abbott, Bayer, Medtronic, Pfizer, Kowa, MSD, and Actelion, outside the submitted work. Dr. Jinnouchi reports grants and personal fees from MSD, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Takeda, Taisho Toyama, Astellas, Bayer, Sanofi, Sanwa Kagaku Kenkyusho, Eli Lilly, AstraZeneca; grants from Chugai, GlaxoSmithKline, Ono, Pfizer, Shionogi; personal fees from Abbott, Terumo, Kyowa Kirin, Teijin, Mitsubishi Tanabe, outside the submitted work. Dr. Waki reports grants and personal fees from Sanofi, AstraZeneca; personal fees from MSD, Astellas, Amgen Astellas BioPharma, Otsuka, Ono, Kowa, Kyowa Kirin, Novartis, Sanwa Kagaku Kenkyusho, Johnson & Johnson, Daiichi Sankyo, Taisho Toyama, Sumitomo Dainippon, Takeda, Mitsubishi Tanabe, Teijin, Eli Lilly, Novo Nordisk, Bayer, Pfizer, Boehringer Ingelheim, Abbott, outside the submitted work. Dr. Masuda reports personal fees from AstraZeneca, Ono, Takeda, Astellas, Bayer, Boehringer Ingelheim, Eli Lilly, Daiichi Sankyo, Kowa, Kyowa Kirin, MSD, Novartis, Shionogi, Mitsubishi Tanabe, outside the submitted work. Dr. Saito reports grants and personal fees from Bayer, Otsuka, Novartis, Ono, Mitsubishi Tanabe, Astellas, Asahi Kasei, Daiichi Sankyo, Sumitomo Dainippon, Fuji Yakuhin, Kowa, Kyowa Kirin, MSD, Sanofi, Takeda; grants from Terumo, Amgen Astellas BioPharma, Shionogi, Teijin, St. Jude Medical, Actelion, Boston Scientific, Chugai, Eisai, Medtronic, Nihon Medi-Physics, Zeria; personal fees from Boehringer Ingelheim, Pfizer, Taisho Toyama, Toa Eiyo, outside the submitted work.

Additional information

Publisher’s Note

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

Electronic supplementary material

ESM 1

(DOCX 37.6 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Okada, S., Morimoto, T., Ogawa, H. et al. Association Between Statins and Cancer Incidence in Diabetes: a Cohort Study of Japanese Patients with Type 2 Diabetes. J GEN INTERN MED (2020). https://doi.org/10.1007/s11606-020-06167-5

Download citation

KEY WORDS

  • statin
  • cancer
  • diabetes