Skip to main content
SpringerLink
Log in

Insulin glargine use and cancer risk among patients with type 2 diabetes mellitus: a real-world study in Shanghai, China

  • Original Article
  • Published:
International Journal of Diabetes in Developing Countries Aims and scope Submit manuscript

Abstract

Objective

The association of insulin glargine with overall and site-specific cancer risk remains uncertain. This study aims to provide relevant evidence from mainland China.

Methods

Based on the Shanghai Link Healthcare Database, patients newly treated with insulin glargine or neutral protamine Hagedorn (NPH) insulin between January 1, 2013 and December 31, 2020 were identified and followed up until December 31, 2021. In addition to the original cohort, we created a 1:1 propensity score-matched cohort with balanced baseline characteristics. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incident cancers, comparing insulin glargine with NPH insulin.

Results

A total of 26,810 insulin glargine users and 47,765 NPH insulin users were enrolled in the final analysis. During a median follow-up of 4.18 years, 3903 patients developed cancer. Including a 1-year lag period, insulin glargine use was not associated with increased cancer risk compared to NPH insulin use in both the original cohort (HR 1.02, 95% CI 0.95–1.10) and the propensity score-matched cohort (HR 1.01, 95% CI 0.94–1.09). In stratified analyses by sex, age, and cancer site, as well as in sensitivity analyses at different lag periods, the estimated cancer risk, although fluctuating, remained uncorrelated without any substantial change.

Conclusion

Insulin glargine is not associated with the risk of overall and site-specific cancers compared to NPH insulin among patients with type 2 diabetes mellitus.

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

Data availability

The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, Pollak M, Regensteiner JG, Yee D. Diabetes and cancer: a consensus report. CA Cancer J Clin. 2010;60:207–21. https://doi.org/10.3322/caac.20078.

    Article  PubMed  Google Scholar 

  2. Qi J, He P, Yao H, Song R, Ma C, Cao M, Cui B, Ning G. Cancer risk among patients with type 2 diabetes: a real-world study in Shanghai, China. J Diabetes. 2019;11:878–83. https://doi.org/10.1111/1753-0407.12926.

    Article  PubMed  Google Scholar 

  3. Hemkens L, Grouven U, Bender R, Günster C, Gutschmidt S, Selke G, Sawicki P. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732–44. https://doi.org/10.1007/s00125-009-1418-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Jonasson JM, Ljung R, Talbäck M, Haglund B, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia. 2009;52:1745–54. https://doi.org/10.1007/s00125-009-1444-2.

    Article  CAS  PubMed  Google Scholar 

  5. Colhoun H. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755–65. https://doi.org/10.1007/s00125-009-1453-1.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia. 2009;52:1766–77. https://doi.org/10.1007/s00125-009-1440-6.

    Article  CAS  PubMed  Google Scholar 

  7. Ljung R, Talbäck M, Haglund B, Jonasson J, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies-a three-year population-based observation. Acta oncologica (Stockholm, Sweden). 2011;50:685–93. https://doi.org/10.3109/0284186x.2011.558913.

    Article  PubMed  Google Scholar 

  8. Morden N, Liu S, Smith J, Mackenzie T, Skinner J, Korc M. Further exploration of the relationship between insulin glargine and incident cancer: a retrospective cohort study of older Medicare patients. Diabetes Care. 2011;34:1965–71. https://doi.org/10.2337/dc11-0699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Chang CH, Toh S, Lin JW, Chen ST, Kuo CW, Chuang LM, Lai MS. Cancer risk associated with insulin glargine among adult type 2 diabetes patients–a nationwide cohort study. PLoS One. 2011;6:e21368. https://doi.org/10.1371/journal.pone.0021368.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Buchs AE, Silverman BG. Incidence of malignancies in patients with diabetes mellitus and correlation with treatment modalities in a large Israeli health maintenance organization: a historical cohort study. Metabolism. 2011;60:1379–85. https://doi.org/10.1016/j.metabol.2011.05.002.

    Article  CAS  PubMed  Google Scholar 

  11. Suissa S, Azoulay L, Dell’Aniello S, Evans M, Vora J, Pollak M. Long-term effects of insulin glargine on the risk of breast cancer. Diabetologia. 2011;54:2254–62. https://doi.org/10.1007/s00125-011-2190-9.

    Article  CAS  PubMed  Google Scholar 

  12. Ruiter R, Visser L, van Herk-Sukel M, Coebergh J, Haak H, Geelhoed-Duijvestijn P, Straus S, Herings R, Stricker B. Risk of cancer in patients on insulin glargine and other insulin analogues in comparison with those on human insulin: results from a large population-based follow-up study. Diabetologia. 2012;55:51–62. https://doi.org/10.1007/s00125-011-2312-4.

    Article  CAS  PubMed  Google Scholar 

  13. Blin P, Lassalle R, Dureau-Pournin C, Ambrosino B, Bernard M, Abouelfath A, Gin H, Le Jeunne C, Pariente A, Droz C, Moore N. Insulin glargine and risk of cancer: a cohort study in the French National Healthcare Insurance Database. Diabetologia. 2012;55:644–53. https://doi.org/10.1007/s00125-011-2429-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kostev K. Risk of breast cancer in patients on long-acting insulin analogues in comparison with those on human insulin. Diabetologia. 2012;55:1554–5. https://doi.org/10.1007/s00125-012-2497-1.

    Article  CAS  PubMed  Google Scholar 

  15. Lind M, Fahlen M, Eliasson B, Oden A. The relationship between the exposure time of insulin glargine and risk of breast and prostate cancer: an observational study of the time-dependent effects of antidiabetic treatments in patients with diabetes. Prim Care Diabetes. 2012;6:53–9. https://doi.org/10.1016/j.pcd.2011.10.004.

    Article  PubMed  Google Scholar 

  16. Ljung R, Talbäck M, Haglund B, Jonasson J, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of breast cancer-a four-year population-based observation. Acta oncologica (Stockholm, Sweden). 2012;51:400–2. https://doi.org/10.3109/0284186x.2011.624118.

    Article  CAS  PubMed  Google Scholar 

  17. van Staa T, Patel D, Gallagher A, de Bruin M. Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia. 2012;55:654–65. https://doi.org/10.1007/s00125-011-2390-3.

    Article  CAS  PubMed  Google Scholar 

  18. Fagot J, Blotière P, Ricordeau P, Weill A, Alla F, Allemand H. Does insulin glargine increase the risk of cancer compared with other basal insulins?: a French nationwide cohort study based on national administrative databases. Diabetes Care. 2013;36:294–301. https://doi.org/10.2337/dc12-0506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Stürmer T, Marquis MA, Zhou H, Meigs JB, Lim S, Blonde L, Macdonald E, Wang R, Lavange LM, Pate V, Buse JB. Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care. 2013;36:3517–25. https://doi.org/10.2337/dc13-0263.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Lim S, Stember K, He W, Bianca P, Yelibi C, Marquis A, Stürmer T, Buse J, Meigs J. Electronic medical record cancer incidence over six years comparing new users of glargine with new users of NPH insulin. PloS one. 2014;9:e109433. https://doi.org/10.1371/journal.pone.0109433.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  21. Habel LA, Danforth KN, Quesenberry CP, Capra A, Van Den Eeden SK, Weiss NS, Ferrara A. Cohort study of insulin glargine and risk of breast, prostate, and colorectal cancer among patients with diabetes. Diabetes Care. 2013;36:3953–60. https://doi.org/10.2337/dc13-0140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Peeters PJ, Bazelier MT, Leufkens HG, Auvinen A, van Staa TP, de Vries F, De Bruin ML. Insulin glargine use and breast cancer risk: associations with cumulative exposure. Acta Oncol. 2016;55:851–8. https://doi.org/10.3109/0284186x.2016.1155736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Wu J, Azoulay L, Majdan A, Boivin J, Pollak M, Suissa S. Long-term use of long-acting insulin analogs and breast cancer incidence in women with type 2 diabetes. J Clin Oncol. 2017;35:3647–53. https://doi.org/10.1200/jco.2017.73.4491.

    Article  CAS  PubMed  Google Scholar 

  24. But A, De Bruin ML, Bazelier MT, Hjellvik V, Andersen M, Auvinen A, Starup-Linde J, Schmidt MK, Furu K, de Vries F, Karlstad O, Ekstrom N, Haukka J. Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. Diabetologia. 2017;60:1691–703. https://doi.org/10.1007/s00125-017-4312-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pradhan R, Yin H, Yu O, Azoulay L. The use of long-acting insulin analogs and the risk of colorectal cancer among patients with type 2 diabetes: a population-based cohort study. Drug Saf. 2020;43:103–10. https://doi.org/10.1007/s40264-019-00892-5.

    Article  CAS  PubMed  Google Scholar 

  26. Simó R, Plana-Ripoll O, Puente D, Morros R, Mundet X, Vilca L, Hernández C, Fuentes I, Procupet A, Tabernero J, Violán C. Impact of glucose-lowering agents on the risk of cancer in type 2 diabetic patients. The Barcelona case-control study. PloS one. 2013;8:e79968. https://doi.org/10.1371/journal.pone.0079968.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  27. Grimaldi-Bensouda L, Cameron D, Marty M, Barnett A, Penault-Llorca F, Pollak M, Charbonnel B, Riddle M, Mignot L, Boivin J, Khachatryan A, Rossignol M, Bénichou J, Alpérovitch A, Abenhaim L. Risk of breast cancer by individual insulin use: an international multicenter study. Diabetes Care. 2014;37:134–43. https://doi.org/10.2337/dc13-0695.

    Article  PubMed  Google Scholar 

  28. Mannucci E, Monami M, Balzi D, Cresci B, Pala L, Melani C, Lamanna C, Bracali I, Bigiarini M, Barchielli A, Marchionni N, Rotella C. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2010;33:1997–2003. https://doi.org/10.2337/dc10-0476.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wu J, Filion K, Azoulay L, Doll M, Suissa S. Effect of long-acting insulin analogs on the risk of cancer: a systematic review of observational studies. Diabetes Care. 2016;39:486–94. https://doi.org/10.2337/dc15-1816.

    Article  CAS  PubMed  Google Scholar 

  30. Pocock SJ, Smeeth L. Insulin glargine and malignancy: an unwarranted alarm. Lancet. 2009;374:511–3. https://doi.org/10.1016/s0140-6736(09)61307-6.

    Article  PubMed  Google Scholar 

  31. Tamim H, Monfared A, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidem Dr S. 2007;16:250–8. https://doi.org/10.1002/pds.1360.

    Article  CAS  Google Scholar 

  32. Johnson J, Bowker S, Richardson K, Marra C. Time-varying incidence of cancer after the onset of type 2 diabetes: evidence of potential detection bias. Diabetologia. 2011;54:2263–71. https://doi.org/10.1007/s00125-011-2242-1.

    Article  CAS  PubMed  Google Scholar 

  33. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015;34:3661–79. https://doi.org/10.1002/sim.6607.

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  34. Rosenstock J, Fonseca V, McGill J, Riddle M, Hallé J, Hramiak I, Johnston P, Davis M. Similar risk of malignancy with insulin glargine and neutral protamine Hagedorn (NPH) insulin in patients with type 2 diabetes: findings from a 5 year randomised, open-label study. Diabetologia. 2009;52:1971–3. https://doi.org/10.1007/s00125-009-1452-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Home P, Lagarenne P. Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia. 2009;52:2499–506. https://doi.org/10.1007/s00125-009-1530-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, Maggioni AP, Pogue J, Probstfield J, Ramachandran A, Riddle MC, Rydén LE, Yusuf S. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28. https://doi.org/10.1056/NEJMoa1203858.

    Article  CAS  PubMed  Google Scholar 

  37. Bordeleau L, Yakubovich N, Dagenais G, Rosenstock J, Probstfield J, Chang YuP, Ryden L, Pirags V, Spinas G, Birkeland K, Ratner R, Marin-Neto J, Keltai M, Riddle M, Bosch J, Yusuf S, Gerstein H. The association of basal insulin glargine and/or n-3 fatty acids with incident cancers in patients with dysglycemia. Diabetes Care. 2014;37:1360–6. https://doi.org/10.2337/dc13-1468.

    Article  CAS  PubMed  Google Scholar 

  38. Sciacca L, Vella V, Frittitta L, Tumminia A, Manzella L, Squatrito S, Belfiore A, Vigneri R. Long-acting insulin analogs and cancer. Nutr Metab Cardiovasc Dis. 2018;28:436–43. https://doi.org/10.1016/j.numecd.2018.02.010.

    Article  CAS  PubMed  Google Scholar 

  39. Vigneri R, Sciacca L, Vigneri P. Rethinking the relationship between insulin and cancer. Trends Endocrinol Metab. 2020;31:551–60. https://doi.org/10.1016/j.tem.2020.05.004.

    Article  CAS  PubMed  Google Scholar 

  40. Ter Braak B, Siezen C, Kannegieter N, Koedoot E, van de Water B, van der Laan J. Classifying the adverse mitogenic mode of action of insulin analogues using a novel mechanism-based genetically engineered human breast cancer cell panel. Arch Toxicol. 2014;88:953–66. https://doi.org/10.1007/s00204-014-1201-2.

    Article  CAS  PubMed  Google Scholar 

  41. Kurtzhals P, Schäffer L, Sørensen A, Kristensen C, Jonassen I, Schmid C, Trüb T. Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000;49:999–1005. https://doi.org/10.2337/diabetes.49.6.999.

    Article  CAS  PubMed  Google Scholar 

  42. Gallagher E, Zelenko Z, Tobin-Hess A, Werner U, Tennagels N, LeRoith D. Non-metabolisable insulin glargine does not promote breast cancer growth in a mouse model of type 2 diabetes. Diabetologia. 2016;59:2018–25. https://doi.org/10.1007/s00125-016-4000-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yoshida K, Solomon D, Kim S. Active-comparator design and new-user design in observational studies. Nat Rev Rheumatol. 2015;11:437–41. https://doi.org/10.1038/nrrheum.2015.30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The authors thank all the researchers involved in this study for their valuable contributions.

Funding

This study was funded by the National Key R&D Program of China (no. 2018YFC1314802).

Author information

Author notes

  1. Jiying Qi, Ping He, and Huayan Yao contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiying Qi, Zizheng Zhang, Bin Cui & Guang Ning

  2. Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Jiying Qi, Zizheng Zhang, Bin Cui & Guang Ning

  3. Link Healthcare Engineering and Information Department, Shanghai Hospital Development Center, Shanghai, China

    Ping He

  4. Computer Net Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Huayan Yao

  5. Wonders Information Co. Ltd., Shanghai, China

    Wen Sun & Ping Lu

Authors
  1. Jiying Qi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ping He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huayan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wen Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ping Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zizheng Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bin Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guang Ning
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jiying Qi: formal analysis, investigation, writing—original draft. Ping He: data curation, resources. Huayan Yao: data curation, software. Wen Sun: data curation, software. Zizheng Zhang: formal analysis. Bin Cui: conceptualization, funding acquisition, methodology, writing—original draft, writing—review and editing. Guang Ning: conceptualization, project administration, supervision, writing—review and editing.

Corresponding authors

Correspondence to Bin Cui or Guang Ning.

Ethics declarations

Ethics approval

This study was approved by the Ethics Committee of Ruijin Hospital (2020-226Y).

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's note

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

Supplementary information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 22.2 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

Qi, J., He, P., Yao, H. et al. Insulin glargine use and cancer risk among patients with type 2 diabetes mellitus: a real-world study in Shanghai, China. Int J Diabetes Dev Ctries 44, 137–144 (2024). https://doi.org/10.1007/s13410-023-01230-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13410-023-01230-3

Keywords

Search

Navigation