The association between long-acting insulin analogs and colorectal cancer is uncertain, with previous studies reporting discrepant findings.
To determine whether the use of long-acting insulin analogs is associated with an increased risk of colorectal cancer, when compared with use of intermediate-acting human insulins among patients with type 2 diabetes.
We conducted a population-based study using the United Kingdom Clinical Practice Research Datalink (CPRD). We identified patients newly treated with either a long-acting insulin analog or an intermediate-acting human insulin between September 1, 2002 and January 31, 2018, with follow-up until January 31, 2019. Each long-acting insulin analog user was propensity score-matched to one intermediate-acting human insulin user, and a lag of 1 year was imposed. Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of colorectal cancer, comparing long-acting insulin analogs with intermediate-acting human insulin. Secondary analysis was conducted to assess whether there was a duration–response relationship.
A total of 10,734 new long-acting insulin analog users were matched to 10,734 new intermediate-acting human insulin users. After a median follow-up of 2.8 years, the use of long-acting insulin analogs was not associated with an increased risk of colorectal cancer, compared with intermediate-acting human insulin (1.80 vs. 1.87 per 1000 person-years, respectively; HR 0.96, 95% CI 0.70–1.34). There was no evidence of a duration–response relationship.
The results of this population-based study indicate that use of long-acting insulin analogs is not associated with an overall increased risk of colorectal cancer.
This is a preview of subscription content, log in to check access.
Buy single article
Instant access to the full article PDF.
Price includes VAT for USA
Gualandi-Signorini AM, Giorgi G. Insulin formulations—a review. Eur Rev Med Pharmacol Sci. 2001;5:73–83.
Rolla A. Pharmacokinetic and pharmacodynamic advantages of insulin analogues and premixed insulin analogues over human insulins: impact on efficacy and safety. Am J Med. 2008;121:S9–19.
Grunberger G. Insulin analogs-are they worth it? Yes! Diabetes Care. 2014;37:1767–70.
Hvid H, Blouin M-J, Birman E, Damgaard J, Poulsen F, Fels JJ, et al. Treatment with insulin analog X10 and IGF-1 increases growth of colon cancer allografts. PloS One. 2013;8:e79710.
Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H. Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev. 2009;25:41–9.
Janssen JAMJL, Varewijck AJ. Insulin analogs and cancer: a note of caution. Front Endocrinol. 2014;5:79.
Wu JW, Filion KB, Azoulay L, Doll MK, 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.
Morden NE, Liu SK, Smith J, Mackenzie TA, 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.
Ruiter R, Visser LE, van Herk-Sukel MPP, Coebergh JWW, Haak HR, Geelhoed-Duijvestijn PH, et al. 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.
Stürmer T, Marquis MA, Zhou H, Meigs JB, Lim S, Blonde L, et al. Cancer incidence among those initiating insulin therapy with glargine versus human NPH insulin. Diabetes Care. 2013;36:3517–25.
Fagot J-P, Blotière P-O, 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.
Habel LA, Danforth KN, Quesenberry CP, Capra A, Van Den Eeden SK, Weiss NS, et al. Cohort study of insulin glargine and risk of breast, prostate, and colorectal cancer among patients with diabetes. Diabetes Care. 2013;36:3953–60.
Ljung R, Talbäck M, Haglund B, Jonasson JM, Gudbjörnsdòttir S, Steineck G. Insulin glargine use and short-term incidence of malignancies—a three-year population-based observation. Acta Oncol Stockh Swed. 2011;50:685–93.
Chang C-H, Toh S, Lin J-W, Chen S-T, Kuo C-W, Chuang L-M, et al. Cancer risk associated with insulin glargine among adult type 2 diabetes patients—a nationwide cohort study. PloS One. 2011;6:e21368.
Colhoun HM, SDRN Epidemiology Group. Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia. 2009;52:1755–65.
But A, De Bruin ML, Bazelier MT, Hjellvik V, Andersen M, Auvinen A, et al. Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study. Diabetologia. 2017;60:1691–703.
ORIGIN Trial Investigators, Gerstein HC, Bosch J, Dagenais GR, Díaz R, Jung H, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367:319–28.
Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst. 2005;97:1679–87.
Herrett E, Gallagher AM, Bhaskaran K, Forbes H, Mathur R, van Staa T, et al. Data resource profile: clinical practice research datalink (CPRD). Int J Epidemiol. 2015;44:827–36.
Herrett E, Thomas SL, Schoonen WM, Smeeth L, Hall AJ. Validation and validity of diagnoses in the general practice research database: a systematic review. Br J Clin Pharmacol. 2010;69:4–14.
Boggon R, van Staa TP, Chapman M, Gallagher AM, Hammad TA, Richards MA. Cancer recording and mortality in the general practice research database and linked cancer registries. Pharmacoepidemiol Drug Saf. 2013;22:168–75.
Margulis AV, Fortuny J, Kaye JA, Calingaert B, Reynolds M, Plana E, et al. Validation of cancer cases using primary care, cancer registry, and hospitalization data in the United Kingdom. Epidemiol Camb Mass. 2018;29:308–13.
Dregan A, Moller H, Murray-Thomas T, Gulliford MC. Validity of cancer diagnosis in a primary care database compared with linked cancer registrations in England. Population-based cohort study. Cancer Epidemiol. 2012;36:425–9.
Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46:399–424.
Austin PC. A comparison of 12 algorithms for matching on the propensity score. Stat Med. 2014;33:1057–69.
Varewijck AJ, Goudzwaard JA, Brugts MP, Lamberts SWJ, Hofland LJ, Janssen JA. MJL. Insulin glargine is more potent in activating the human IGF-I receptor than human insulin and insulin detemir. Growth Horm IGF Res Off J Growth Horm Res Soc Int IGF Res Soc. 2010;20:427–31.
Tennagels N, Werner U. The metabolic and mitogenic properties of basal insulin analogues. Arch Physiol Biochem. 2013;119:1–14.
Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology. Epidemiol Camb Mass. 2000;11:550–60.
Hernán MA, Brumback B, Robins JM. Marginal structural models to estimate the causal effect of zidovudine on the survival of HIV-positive men. Epidemiol Camb Mass. 2000;11:561–70.
Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol. 2008;168:656–64.
Hicks BM, Yin H, Yu OHY, Pollak MN, Platt RW, Azoulay L. Glucagon-like peptide-1 analogues and risk of breast cancer in women with type 2 diabetes: population based cohort study using the UK Clinical Practice Research Datalink. BMJ. 2016;355:i5340.
Cook NR, Rosner BA, Hankinson SE, Colditz GA. Mammographic screening and risk factors for breast cancer. Am J Epidemiol. 2009;170:1422–32.
Koo S, Neilson LJ, Von Wagner C, Rees CJ. The NHS bowel cancer screening program: current perspectives on strategies for improvement. Risk Manag Healthc Policy. 2017;10:177–87.
Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
Hemkens LG, Grouven U, Bender R, Günster C, Gutschmidt S, Selke GW, et al. Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia. 2009;52:1732–44.
Swinnen SG, Hoekstra JB, DeVries JH. Insulin therapy for type 2 diabetes. Diabetes Care. 2009;32(Suppl 2):S253–9.
Peeters PJHL, Bazelier MT, Leufkens HGM, de Vries F, De Bruin ML. The risk of colorectal cancer in patients with type 2 diabetes: associations with treatment stage and obesity. Diabetes Care. 2015;38:495–502.
Hvid H, Jørgensen MS, Blume N, Slaaby R, Lützen A, Hansen BF. Activation of insulin receptors and IGF-1 receptors in COLO-205 colon cancer xenografts by insulin and insulin analogue X10 does not enhance growth under normo- or hypoglycaemic conditions. Diabetologia. 2018;61:2447–57.
Clemmons D, Maile L, Xi G, Shen X, Radhakrishnan Y. Igf-I signaling in response to hyperglycemia and the development of diabetic complications. Curr Diabetes Rev. 2011;7:235–45.
Luo J, Khan NF, Manetti T, Rose J, Kaloghlian A, Gadhe B, et al. Implementation of a health plan program for switching from analogue to human insulin and glycemic control among Medicare beneficiaries with type 2 diabetes. JAMA. 2019;321:374–84.
Lipska KJ, Hirsch IB, Riddle MC. Human insulin for type 2 diabetes: an effective, less-expensive option. JAMA. 2017;318:23–4.
American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of Medical care in diabetes-2019. Diabetes Care. 2019;42:S90–102.
Conflict of interest
Laurent Azoulay has received consulting fees from Janssen for work unrelated to this study. Richeek Pradhan, Hui Yin, and Oriana Yu have no relevant conflicts of interest to disclose.
This study was funded by the foundation scheme grant from the Canadian Institutes of Health Research (FDN-14328). Richeek Pradhan is the recipient of a training grant from the Canadian Institutes of Health Research Drug Safety and Effectiveness Training Program. Oriana Yu holds a Chercheur-Boursier Clinicien Junior 1 award from the Fonds de Recherche du Québec-Santé (FRQS). Laurent Azoulay holds a Chercheur-Boursier Senior award from the FRQS and is the recipient of a William Dawson Scholar award from McGill University.
The study protocol was approved by the Independent Scientific Advisory Committee of the Clinical Practice Research Datalink (protocol No. 15_005R) and the Research Ethics Board of the Jewish General Hospital, Montreal, Canada.
Due to the data sharing policy of the Clinical Practice Research Datalink protecting patient privacy, it is not possible to share patient-level data.
Electronic supplementary material
Below is the link to the electronic supplementary material.
About this article
Cite this article
Pradhan, R., Yin, H., Yu, O.H.Y. et al. 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 43, 103–110 (2020). https://doi.org/10.1007/s40264-019-00892-5