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Erschienen in: Diabetologia 9/2011

01.09.2011 | Article

Long-term effects of insulin glargine on the risk of breast cancer

verfasst von: S. Suissa, L. Azoulay, S. Dell’Aniello, M. Evans, J. Vora, M. Pollak

Erschienen in: Diabetologia | Ausgabe 9/2011

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Abstract

Aims/hypothesis

There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer.

Methods

We used the UK’s General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002–2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer.

Results

The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7–1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8–4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1–6.5).

Conclusions/interpretation

The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine.
Literatur
1.
Zurück zum Zitat Werner H, Weinstein D, Bentov I (2008) Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Arch Physiol Biochem 114:17–22PubMedCrossRef Werner H, Weinstein D, Bentov I (2008) Similarities and differences between insulin and IGF-I: structures, receptors, and signalling pathways. Arch Physiol Biochem 114:17–22PubMedCrossRef
2.
Zurück zum Zitat Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMedCrossRef Kurtzhals P, Schaffer L, Sorensen A et al (2000) Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes 49:999–1005PubMedCrossRef
3.
Zurück zum Zitat Sommerfeld MR, Muller G, Tschank G et al (2010) In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLoS ONE 5:e9540PubMedCrossRef Sommerfeld MR, Muller G, Tschank G et al (2010) In vitro metabolic and mitogenic signaling of insulin glargine and its metabolites. PLoS ONE 5:e9540PubMedCrossRef
5.
Zurück zum Zitat Mayer D, Chantelau E (2010) Treatment with insulin glargine (Lantus) increases the proliferative potency of the serum of patients with type-1 diabetes: a pilot study on MCF-7 breast cancer cells. Arch Physiol Biochem 116:73–78PubMedCrossRef Mayer D, Chantelau E (2010) Treatment with insulin glargine (Lantus) increases the proliferative potency of the serum of patients with type-1 diabetes: a pilot study on MCF-7 breast cancer cells. Arch Physiol Biochem 116:73–78PubMedCrossRef
6.
Zurück zum Zitat Hemkens LG, Grouven U, Bender R et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCrossRef Hemkens LG, Grouven U, Bender R et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52:1732–1744PubMedCrossRef
7.
Zurück zum Zitat Colhoun HM (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52:1755–1765PubMedCrossRef Colhoun HM (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52:1755–1765PubMedCrossRef
8.
Zurück zum Zitat Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G (2009) Insulin glargine use and short-term incidence of malignancies: a population-based follow-up study in Sweden. Diabetologia 52:1745–1754PubMedCrossRef Jonasson JM, Ljung R, Talback M, Haglund B, Gudbjornsdottir S, Steineck G (2009) Insulin glargine use and short-term incidence of malignancies: a population-based follow-up study in Sweden. Diabetologia 52:1745–1754PubMedCrossRef
9.
Zurück zum Zitat Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777PubMedCrossRef Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777PubMedCrossRef
10.
Zurück zum Zitat Mannucci E, Monami M, Balzi D et al (2010) Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33:1997–2003PubMedCrossRef Mannucci E, Monami M, Balzi D et al (2010) Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33:1997–2003PubMedCrossRef
11.
Zurück zum Zitat Pocock SJ, Smeeth L (2009) Insulin glargine and malignancy: an unwarranted alarm. Lancet 374:511–513PubMedCrossRef Pocock SJ, Smeeth L (2009) Insulin glargine and malignancy: an unwarranted alarm. Lancet 374:511–513PubMedCrossRef
12.
Zurück zum Zitat Hernandez-Diaz S, Adami HO (2010) Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia 53:802–808PubMedCrossRef Hernandez-Diaz S, Adami HO (2010) Diabetes therapy and cancer risk: causal effects and other plausible explanations. Diabetologia 53:802–808PubMedCrossRef
16.
Zurück zum Zitat Home PD, Lagarenne P (2009) Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52:2499–2506PubMedCrossRef Home PD, Lagarenne P (2009) Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52:2499–2506PubMedCrossRef
17.
Zurück zum Zitat Hemkens LG, Grouven U, Bender R, Sawicki PT (2010) Insufficient evaluation of adverse events is not a proof of safety. Diabetologia 53:790–792PubMedCrossRef Hemkens LG, Grouven U, Bender R, Sawicki PT (2010) Insufficient evaluation of adverse events is not a proof of safety. Diabetologia 53:790–792PubMedCrossRef
18.
Zurück zum Zitat Walley T, Mantgani A (1997) The UK General Practice Research Database. Lancet 350:1097–1099PubMedCrossRef Walley T, Mantgani A (1997) The UK General Practice Research Database. Lancet 350:1097–1099PubMedCrossRef
19.
Zurück zum Zitat Opatrny L, Dell'Aniello S, Assouline S, Suissa S (2008) Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 115:169–175PubMed Opatrny L, Dell'Aniello S, Assouline S, Suissa S (2008) Hormone replacement therapy use and variations in the risk of breast cancer. BJOG 115:169–175PubMed
20.
Zurück zum Zitat Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308PubMedCrossRef Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR (2010) Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care 33:1304–1308PubMedCrossRef
21.
Zurück zum Zitat Heinzl H, Kaider A, Zlabinger G (1996) Assessing interactions of binary time-dependent covariates with time in cox proportional hazards regression models using cubic spline functions. Stat Med 15:2589–2601PubMedCrossRef Heinzl H, Kaider A, Zlabinger G (1996) Assessing interactions of binary time-dependent covariates with time in cox proportional hazards regression models using cubic spline functions. Stat Med 15:2589–2601PubMedCrossRef
22.
Zurück zum Zitat Yehezkel E, Weinstein D, Simon M, Sarfstein R, Laron Z, Werner H (2010) Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. Diabetologia 53:2667–2675PubMedCrossRef Yehezkel E, Weinstein D, Simon M, Sarfstein R, Laron Z, Werner H (2010) Long-acting insulin analogues elicit atypical signalling events mediated by the insulin receptor and insulin-like growth factor-I receptor. Diabetologia 53:2667–2675PubMedCrossRef
23.
Zurück zum Zitat Law JH, Habibi G, Hu K et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68:10238–10246PubMedCrossRef Law JH, Habibi G, Hu K et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68:10238–10246PubMedCrossRef
24.
Zurück zum Zitat Cox ME, Gleave ME, Zakikhani M et al (2009) Insulin receptor expression by human prostate cancers. Prostate 69:33–40PubMedCrossRef Cox ME, Gleave ME, Zakikhani M et al (2009) Insulin receptor expression by human prostate cancers. Prostate 69:33–40PubMedCrossRef
25.
Zurück zum Zitat Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO (1994) Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331:5–9PubMedCrossRef Lambe M, Hsieh C, Trichopoulos D, Ekbom A, Pavia M, Adami HO (1994) Transient increase in the risk of breast cancer after giving birth. N Engl J Med 331:5–9PubMedCrossRef
26.
Zurück zum Zitat Welch HG, Black WC (1997) Using autopsy series to estimate the disease "reservoir" for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 127:1023–1028PubMed Welch HG, Black WC (1997) Using autopsy series to estimate the disease "reservoir" for ductal carcinoma in situ of the breast: how much more breast cancer can we find? Ann Intern Med 127:1023–1028PubMed
27.
Zurück zum Zitat Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928PubMedCrossRef Pollak M (2008) Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 8:915–928PubMedCrossRef
28.
Zurück zum Zitat Hansen BF, Danielsen GM, Drejer K et al (1996) Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J 315:271–279PubMed Hansen BF, Danielsen GM, Drejer K et al (1996) Sustained signalling from the insulin receptor after stimulation with insulin analogues exhibiting increased mitogenic potency. Biochem J 315:271–279PubMed
29.
Zurück zum Zitat Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H, Mayer D (2009) Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. Endocr Relat Cancer 16:429–441PubMedCrossRef Shukla A, Grisouard J, Ehemann V, Hermani A, Enzmann H, Mayer D (2009) Analysis of signaling pathways related to cell proliferation stimulated by insulin analogs in human mammary epithelial cell lines. Endocr Relat Cancer 16:429–441PubMedCrossRef
30.
Zurück zum Zitat Jorgensen L, Dideriksen L, Drejen K (1992) Carcinogenic effect of human insulin and B10Asp in female rats. Diabetologia 35(Suppl 1):A3 Jorgensen L, Dideriksen L, Drejen K (1992) Carcinogenic effect of human insulin and B10Asp in female rats. Diabetologia 35(Suppl 1):A3
31.
Zurück zum Zitat Brange J, Ribel U, Hansen JF et al (1988) Monomeric insulins obtained by protein engineering and their medical implications. Nature 333:679–682PubMedCrossRef Brange J, Ribel U, Hansen JF et al (1988) Monomeric insulins obtained by protein engineering and their medical implications. Nature 333:679–682PubMedCrossRef
32.
Zurück zum Zitat Dejgaard A, Lynggaard H, Rastam J, Krogsgaard TM (2009) No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia 52:2507–2512PubMedCrossRef Dejgaard A, Lynggaard H, Rastam J, Krogsgaard TM (2009) No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis. Diabetologia 52:2507–2512PubMedCrossRef
33.
Zurück zum Zitat Michels KB, Solomon CG, Hu FB et al (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 26:1752–1758PubMedCrossRef Michels KB, Solomon CG, Hu FB et al (2003) Type 2 diabetes and subsequent incidence of breast cancer in the Nurses' Health Study. Diabetes Care 26:1752–1758PubMedCrossRef
34.
Zurück zum Zitat Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H (2009) Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 180:385–397PubMedCrossRef Singh SR, Ahmad F, Lal A, Yu C, Bai Z, Bennett H (2009) Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ 180:385–397PubMedCrossRef
35.
Zurück zum Zitat Horvath K, Jeitler K, Berghold A et al. Long-acting insulin analogues vs NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007, Issue 2. Art. No.: CD005613. doi:10.1002/14651858.CD005613.pub3 Horvath K, Jeitler K, Berghold A et al. Long-acting insulin analogues vs NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007, Issue 2. Art. No.: CD005613. doi:10.​1002/​14651858.​CD005613.​pub3
Metadaten
Titel
Long-term effects of insulin glargine on the risk of breast cancer
verfasst von
S. Suissa
L. Azoulay
S. Dell’Aniello
M. Evans
J. Vora
M. Pollak
Publikationsdatum
01.09.2011
Verlag
Springer-Verlag
Erschienen in
Diabetologia / Ausgabe 9/2011
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-011-2190-9

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