- Email: [email protected]
Diabetes and cancer mortality: A multifaceted association
diabetes research and clinical practice 106 (2014) e86–e89
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Diabetes and cancer mortality: A multifaceted association Ugo Fedeli b,*, Giacomo Zoppini a, Nicola Gennaro b, Mario Saugo b a
Section of Endocrinology and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy b SER – Regional Epidemiological Department, Veneto Region, Italy
article info
abstract
Article history:
In a large cohort of subjects with diabetes cancer mortality increased by 30%, possibly due to
Received 26 June 2014
lower survival, reverse causality, and an etiologic role of diabetes in cancer. A two-fold
Received in revised form
increased mortality from liver and pancreatic cancer was confirmed in both genders
27 August 2014
irrespective of follow-up period or disease duration. # 2014 Elsevier Ireland Ltd. All rights reserved.
Accepted 15 September 2014 Available online 5 October 2014 Keywords: Diabetes Cancer risk Mortality
1.
Introduction
Evidence from the literature indicates an increased risk of cancer mortality from colorectal, breast, endometrium, kidney, liver and pancreas cancer among persons with diabetes [1–8]. It is, nevertheless, still unclear whether diabetes should be considered an independent risk factor for these neoplasms. To explain the increased cancer mortality among diabetic patients three main mechanisms can be hypothesized: 1. Diabetes is a well-recognized prognostic factor for cancer patients. One of the most widely applied comorbidity scores including diabetes, the Charlson index [9], was validated from survival data of women with breast cancer: patients with cancer carry a higher mortality risk if affected also by diabetes. 2. A new onset of diabetes is often considered by clinicians a marker of occult cancer, or of progression of a known
disease (reverse causality: diabetes is a consequence of cancer). For example, there is debate as to whether diabetes increases the risk of pancreatic cancer, or if the onset of diabetes is due to a pre-clinical cancer [10]. 3. Diabetes is etiologically associated with specific cancer sites: diabetes can be a cause of cancer, or a common etiologic pathway could lead to both diabetes and cancer (e.g., through overweight). Aim of the study was to explore these hypotheses in a large cohort of diabetic patients.
2.
Methods
Mortality was investigated in diabetic patients identified from the regional archive of subjects exempt from medical charges due to diabetes in the Veneto Region (North-Eastern Italy).
* Corresponding author at: SER – Epidemiological Department, Veneto Region, Passaggio Gaudenzio 1, 35131 Padova, PD, Italy. Tel.: +39 049 8778251; fax: +39 049 8778235. E-mail address: [email protected] (U. Fedeli). http://dx.doi.org/10.1016/j.diabres.2014.09.027 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
e87
diabetes research and clinical practice 106 (2014) e86–e89
Table 1 – Standardized mortality ratios (SMR) with 95% confidence intervals (CI) in a cohort of 167,621 diabetic patients followed-up for three years: analysis of the underlying cause of death. Cause of death (ICD-10 codes)
Males
All causes All neoplasms (C00-D48) All malignant neoplasms (C00-C97) Malignant neoplasms of Lip, oral cavity and pharynx (C00-C14) Esophagus (C15) Stomach (C16) Colon, rectum and anus (C18-C21) Liver and intrahepatic bile ducts (C22) Pancreas (C25) Larynx (C32) Trachea, bronchus and lung (C33-C34) Melanoma of skin (C43) Female breast (C50) Uterus (C53-C55) Ovary (C56) Prostate (C61) Kidney and renal pelvis (C64-C65) Bladder (C67) Central nervous system (C70-C72) Non-Hodgkin’s lymphoma (C82-C85) Multiple myeloma (C90) Leukemia (C91-C95)
n
SMR (CI)
n
SMR (CI)
9866 3425 3300
1.49 (1.46–1.52) 1.30 (1.26–1.34) 1.31 (1.26–1.35)
7268 1893 1810
1.53 (1.49–1.56) 1.32 (1.26–1.38) 1.33 (1.27–1.39)
76 57 151 328 486 343 46 812 24
1.26 0.91 1.14 1.22 2.40 2.16 0.99 1.15 0.97
(0.99–1.58) (0.69–1.18) (0.96–1.33) (1.09–1.36) (2.19–2.62) (1.93–2.40) (0.73–1.33) (1.08–1.24) (0.62–1.44)
174 71 101 47 77 43 83
1.02 1.12 1.10 1.03 1.22 0.98 1.05
(0.88–1.19) (0.88–1.42) (0.90–1.34) (0.75–1.37) (0.96–1.52) (0.71–1.32) (0.83–1.30)
Details have been previously published [11]. Briefly, records of patients aged 30–89 years registered with diabetes in December 2007 were anonymized and linked with the archive of causes of death. Subjects were followed from January 1, 2008 either until death, 90 years of age, or December 31, 2010, whichever came first. The archive did not include the date of diagnosis, but that of diabetes registration. This date could follow the diagnosis by several years, but allowed us to identify a sub-cohort of subjects (registered before 2001) with at least seven years of diabetes duration at the beginning of the follow-up. Standardized Mortality Ratios (SMR) with 95% confidence intervals based on the Poisson distribution were the ratios between cancer deaths observed in the cohort, and those expected according to age-gender-specific regional mortality rates. SMRs were assessed for the whole cohort, and for the sub-cohort with longer disease duration. Furthermore, SMRs were computed separately for each year of follow-up.
3.
15 21 78 188 140 237 1 201 12 268 73 65
0.93 1.39 1.25 1.13 1.86 1.95 0.40 1.13 1.00 1.32 1.65 1.10
(0.52–1.53) (0.86–2.12) (0.99–1.56) (0.98–1.31) (1.56–2.19) (1.71–2.22) (0.01–2.21) (0.98–1.30) (0.52–1.75) (1.17–1.49) (1.30–2.08) (0.85–1.40)
33 22 26 51 40 61
1.25 1.13 0.93 1.13 1.28 1.30
(0.86–1.76) (0.71–1.71) (0.61–1.37) (0.84–1.49) (0.91–1.74) (0.99–1.67)
Results
167,621 subjects with diabetes (54.6% men) were identified in December 2007 and through follow-up 17,134 deaths (10.2% of the cohort) were recorded. Malignant neoplasms accounted for 29.8% of deaths. Both genders experienced a more than 30% increased risk of dying from malignant neoplasms overall, and a two-fold increased risk of dying from liver and pancreatic cancers (Table 1). Mortality from colorectal and lung cancer in males, and from breast and uterus cancer in females was significantly higher than that expected from regional rates. The increased mortality risk from liver and pancreatic cancer did not decline through follow-up, while the excess risk of mortality from other-site cancers combined decreased from 26% to 9% (Fig. 1).
2,5
2,25 2,13
SMR
Females
2,13 2,13 1,82
1,64
1,6
1,58
1,16
1,09
1,26 1 2nd Year of follow-up
1st Liver
Pancreas
Other malignant
3rd Non-malignant
Fig. 1 – Standardized mortality ratios (SMR, logarithmic scale) for selected cancer sites in a cohort of 167,621 diabetic patients, by year since the beginning of follow-up.
e88
diabetes research and clinical practice 106 (2014) e86–e89
Table 2 – Standardized mortality ratios (SMR) with 95% Confidence intervals (CI) in the whole cohort (1st year of follow-up excluded) and in the sub-cohort of patients (n = 74,392) with at least seven years of length of disease. Males (M) and females (F) combined. Cause of death
SMR (CI) Whole cohort (1st year of follow-up excluded)
All non-malignant causes (M + F) Liver and intrahepatic bile ducts (M + F) Pancreas (M + F) Malignant neoplasms, liver/pancreas excluded (M + F) Trachea, bronchus and lung (M + F) Colon, rectum and anus (M + F) Female breast (F) Uterus (F)
Mortality risks did not show major changes when early mortality was accounted for by excluding the 1st year of follow-up, or when analyses were restricted to the sub-cohort (n = 74,392) with at least 7 years of diabetes duration. Except for lung cancer, the increased risks found for liver, pancreatic, colorectal, female breast, and uterus cancers remained statistically significant (Table 2).
4.
Discussion
The present data confirm increased mortality in diabetic patients from multiple cancer sites: liver, pancreas, colonrectum, breast, and uterus. Different possible biologic pathways leading to cancer risk in diabetes have been proposed: hyperinsulinemia, which promotes cancer growth directly [12] or through the effect of insulin-like growth factor-1 [13]; hyperglycemia, reported to promote tumor cell proliferation and metastasis in type 2 diabetes [14–16]; the permanent proinflammatory condition that characterize diabetes especially under poor metabolic control [17]. The report has both limits and strengths to explore different mechanisms underlying the association between diabetes and cancer. Among limits, the short follow-up restricted analyses on the temporal association between diabetes and cancer. Moreover, since follow-up was based on mortality and not incidence data, it is difficult to disentangle an association due to lower survival of cancer patients with diabetes, or to an increased cancer incidence in diabetic subjects. To complicate the scenario, another recently introduced issue is the influence of different anti-diabetic drugs on cancer risk [18,19], but we could not explore this issue because data on treatment were lacking. Among strengths, the study is based on a large number of observed cancer deaths. For some cancer site – including liver and pancreas – with poor survival, mortality is a proxy of incidence, and available data allowed exploration of initial time trends in cancer risk through the follow-up period. Moreover, a sub-cohort of patients with long disease duration was available to confirm mortality figures. In view of the above the main findings were: (1) a two-fold increased mortality for liver and pancreatic cancer in both genders, irrespective of follow-up period or disease duration. Due to the low survival for these cancer
1.59 2.32 1.98 1.13 1.10 1.13 1.25 1.71
(1.56–1.63) (2.10–2.55) (1.78–2.19) (1.08–1.17) (1.02–1.19) (1.02–1.26) (1.06–1.45) (1.27–2.26)
Diagnosed before 2001 1.82 2.32 1.78 1.13 1.07 1.17 1.26 1.57
(1.78–1.87) (2.06–2.59) (1.56–2.02) (1.08–1.19) (0.97–1.18) (1.03–1.33) (1.04–1.50) (1.08–2.20)
sites, mortality approximates incidence and the findings suggest a causal role of diabetes. Additional studies are warranted to investigate a potential modifying effect of different anti-diabetic drugs. (2) a 15% excess risk of mortality for other cancers combined. Although decreasing through the follow-up period, the risk did not return to unity at the end of follow-up, nor in the subcohort with longer disease duration. This could be due to a lower survival of cancer patients with diabetes, or to a causal association with specific tumor sites, as colon-rectum or female reproductive system. These latter associations need to be further examined with cancer incidence data.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Buysschaert M, Sadikot S. Diabetes and cancer: a 2013 synopsis. Diabetes Metab Syndr: Clin Res Rev 2013;7:247–50. [2] Shikata K, Ninomiya T, Kiyohara Y. Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer Sci 2013;104:9–14. [3] De Bruijn KM, Arends LR, Hansen BE, Leeflang S, Ruiter R, van Eijck CH. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg 2013;100:1421–9. [4] McAuliffe JC, Christein JD. Type 2 diabetes mellitus and pancreatic cancer. Surg Clin N Am 2013;93:619–27. [5] Walker JJ, Brewster DH, Colhoun HM, Fischbacher CM, Lindsay RS, Wild SH, Scottish Diabetes Research Network (SDRN) Epidemiology Group. Cause-specific mortality in Scottish patients with colorectal cancer with and without type 2 diabetes (2000–2007). Diabetologia 2013;56:1531–41. [6] Grote VA, Becker S, Kaaks R. Diabetes mellitus type 2 – an independent risk factor for cancer. Exp Clin Endocrinol Diabetes 2010;118:4–8. [7] Verlato G, Zoppini G, Bonora E, Muggeo M. Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care 2003;26:1047–51.
diabetes research and clinical practice 106 (2014) e86–e89
[8] Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674–85. [9] 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. [10] Liao KF, Lai SW, Li CI, Chen WC. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol 2012;27:709–13. [11] Zoppini G, Fedeli U, Gennaro N, Saugo M, Targher G, Bonora E. Mortality from chronic liver diseases in diabetes. Am J Gastroenterol 2014;109:1020–5. [12] Heuson JC, Legros N, Heimann R. Influence of insulin administration on growth of the 7,12dimethylbenz(a)anthracene-induced mammary carcinoma in intact, oophorectomized, and hypophysectomized rats. Cancer Res 1972;32:233–8. [13] Perry JK, Liu DX, Wu ZS, Zhu T, Lobie PE. Growth hormone and cancer: an update on progress. Curr Opin Endocrinol Diabetes Obes 2013;20:307–13.
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[14] Shimomoto T, Ohmori H, Luo Y, Chihara Y, Denda A, Sasahira T, et al. Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer. Clin Exp Metast 2012;29:915–25. [15] Simon D, Balkau B. Diabetes mellitus, hyperglycaemia and cancer. Diabetes Metab 2010;36:182–91. [16] Bruning PF, Bonfrer JM, van Noord PA, Hart AA, de JongBakker M, Nooijen WJ. Insulin resistance and breast-cancer risk. Int J Cancer 1992;52:511–6. [17] Iwasaki Y, Kambayashi M, Asai M, Yoshida M, Nigawara T, Hashimoto K. High glucose alone, as well as in combination with proinflammatory cytokines, stimulates nuclear factor kappa-B-mediated transcription in hepatocytes in vitro. J Diabetes Complic 2007;21:56–62. [18] Currie CJ, Poole CD, Gale EA. The influence of glucoselowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766–77. [19] Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 2009;32:1620–5.
Contents available at ScienceDirect
Diabetes Research and Clinical Practice jou rnal hom ep ag e: w ww.e l s e v i er . c om/ loca te / d i ab r es
Diabetes and cancer mortality: A multifaceted association Ugo Fedeli b,*, Giacomo Zoppini a, Nicola Gennaro b, Mario Saugo b a
Section of Endocrinology and Metabolism, Department of Medicine, Azienda Ospedaliera Universitaria Integrata, University of Verona, Verona, Italy b SER – Regional Epidemiological Department, Veneto Region, Italy
article info
abstract
Article history:
In a large cohort of subjects with diabetes cancer mortality increased by 30%, possibly due to
Received 26 June 2014
lower survival, reverse causality, and an etiologic role of diabetes in cancer. A two-fold
Received in revised form
increased mortality from liver and pancreatic cancer was confirmed in both genders
27 August 2014
irrespective of follow-up period or disease duration. # 2014 Elsevier Ireland Ltd. All rights reserved.
Accepted 15 September 2014 Available online 5 October 2014 Keywords: Diabetes Cancer risk Mortality
1.
Introduction
Evidence from the literature indicates an increased risk of cancer mortality from colorectal, breast, endometrium, kidney, liver and pancreas cancer among persons with diabetes [1–8]. It is, nevertheless, still unclear whether diabetes should be considered an independent risk factor for these neoplasms. To explain the increased cancer mortality among diabetic patients three main mechanisms can be hypothesized: 1. Diabetes is a well-recognized prognostic factor for cancer patients. One of the most widely applied comorbidity scores including diabetes, the Charlson index [9], was validated from survival data of women with breast cancer: patients with cancer carry a higher mortality risk if affected also by diabetes. 2. A new onset of diabetes is often considered by clinicians a marker of occult cancer, or of progression of a known
disease (reverse causality: diabetes is a consequence of cancer). For example, there is debate as to whether diabetes increases the risk of pancreatic cancer, or if the onset of diabetes is due to a pre-clinical cancer [10]. 3. Diabetes is etiologically associated with specific cancer sites: diabetes can be a cause of cancer, or a common etiologic pathway could lead to both diabetes and cancer (e.g., through overweight). Aim of the study was to explore these hypotheses in a large cohort of diabetic patients.
2.
Methods
Mortality was investigated in diabetic patients identified from the regional archive of subjects exempt from medical charges due to diabetes in the Veneto Region (North-Eastern Italy).
* Corresponding author at: SER – Epidemiological Department, Veneto Region, Passaggio Gaudenzio 1, 35131 Padova, PD, Italy. Tel.: +39 049 8778251; fax: +39 049 8778235. E-mail address: [email protected] (U. Fedeli). http://dx.doi.org/10.1016/j.diabres.2014.09.027 0168-8227/# 2014 Elsevier Ireland Ltd. All rights reserved.
e87
diabetes research and clinical practice 106 (2014) e86–e89
Table 1 – Standardized mortality ratios (SMR) with 95% confidence intervals (CI) in a cohort of 167,621 diabetic patients followed-up for three years: analysis of the underlying cause of death. Cause of death (ICD-10 codes)
Males
All causes All neoplasms (C00-D48) All malignant neoplasms (C00-C97) Malignant neoplasms of Lip, oral cavity and pharynx (C00-C14) Esophagus (C15) Stomach (C16) Colon, rectum and anus (C18-C21) Liver and intrahepatic bile ducts (C22) Pancreas (C25) Larynx (C32) Trachea, bronchus and lung (C33-C34) Melanoma of skin (C43) Female breast (C50) Uterus (C53-C55) Ovary (C56) Prostate (C61) Kidney and renal pelvis (C64-C65) Bladder (C67) Central nervous system (C70-C72) Non-Hodgkin’s lymphoma (C82-C85) Multiple myeloma (C90) Leukemia (C91-C95)
n
SMR (CI)
n
SMR (CI)
9866 3425 3300
1.49 (1.46–1.52) 1.30 (1.26–1.34) 1.31 (1.26–1.35)
7268 1893 1810
1.53 (1.49–1.56) 1.32 (1.26–1.38) 1.33 (1.27–1.39)
76 57 151 328 486 343 46 812 24
1.26 0.91 1.14 1.22 2.40 2.16 0.99 1.15 0.97
(0.99–1.58) (0.69–1.18) (0.96–1.33) (1.09–1.36) (2.19–2.62) (1.93–2.40) (0.73–1.33) (1.08–1.24) (0.62–1.44)
174 71 101 47 77 43 83
1.02 1.12 1.10 1.03 1.22 0.98 1.05
(0.88–1.19) (0.88–1.42) (0.90–1.34) (0.75–1.37) (0.96–1.52) (0.71–1.32) (0.83–1.30)
Details have been previously published [11]. Briefly, records of patients aged 30–89 years registered with diabetes in December 2007 were anonymized and linked with the archive of causes of death. Subjects were followed from January 1, 2008 either until death, 90 years of age, or December 31, 2010, whichever came first. The archive did not include the date of diagnosis, but that of diabetes registration. This date could follow the diagnosis by several years, but allowed us to identify a sub-cohort of subjects (registered before 2001) with at least seven years of diabetes duration at the beginning of the follow-up. Standardized Mortality Ratios (SMR) with 95% confidence intervals based on the Poisson distribution were the ratios between cancer deaths observed in the cohort, and those expected according to age-gender-specific regional mortality rates. SMRs were assessed for the whole cohort, and for the sub-cohort with longer disease duration. Furthermore, SMRs were computed separately for each year of follow-up.
3.
15 21 78 188 140 237 1 201 12 268 73 65
0.93 1.39 1.25 1.13 1.86 1.95 0.40 1.13 1.00 1.32 1.65 1.10
(0.52–1.53) (0.86–2.12) (0.99–1.56) (0.98–1.31) (1.56–2.19) (1.71–2.22) (0.01–2.21) (0.98–1.30) (0.52–1.75) (1.17–1.49) (1.30–2.08) (0.85–1.40)
33 22 26 51 40 61
1.25 1.13 0.93 1.13 1.28 1.30
(0.86–1.76) (0.71–1.71) (0.61–1.37) (0.84–1.49) (0.91–1.74) (0.99–1.67)
Results
167,621 subjects with diabetes (54.6% men) were identified in December 2007 and through follow-up 17,134 deaths (10.2% of the cohort) were recorded. Malignant neoplasms accounted for 29.8% of deaths. Both genders experienced a more than 30% increased risk of dying from malignant neoplasms overall, and a two-fold increased risk of dying from liver and pancreatic cancers (Table 1). Mortality from colorectal and lung cancer in males, and from breast and uterus cancer in females was significantly higher than that expected from regional rates. The increased mortality risk from liver and pancreatic cancer did not decline through follow-up, while the excess risk of mortality from other-site cancers combined decreased from 26% to 9% (Fig. 1).
2,5
2,25 2,13
SMR
Females
2,13 2,13 1,82
1,64
1,6
1,58
1,16
1,09
1,26 1 2nd Year of follow-up
1st Liver
Pancreas
Other malignant
3rd Non-malignant
Fig. 1 – Standardized mortality ratios (SMR, logarithmic scale) for selected cancer sites in a cohort of 167,621 diabetic patients, by year since the beginning of follow-up.
e88
diabetes research and clinical practice 106 (2014) e86–e89
Table 2 – Standardized mortality ratios (SMR) with 95% Confidence intervals (CI) in the whole cohort (1st year of follow-up excluded) and in the sub-cohort of patients (n = 74,392) with at least seven years of length of disease. Males (M) and females (F) combined. Cause of death
SMR (CI) Whole cohort (1st year of follow-up excluded)
All non-malignant causes (M + F) Liver and intrahepatic bile ducts (M + F) Pancreas (M + F) Malignant neoplasms, liver/pancreas excluded (M + F) Trachea, bronchus and lung (M + F) Colon, rectum and anus (M + F) Female breast (F) Uterus (F)
Mortality risks did not show major changes when early mortality was accounted for by excluding the 1st year of follow-up, or when analyses were restricted to the sub-cohort (n = 74,392) with at least 7 years of diabetes duration. Except for lung cancer, the increased risks found for liver, pancreatic, colorectal, female breast, and uterus cancers remained statistically significant (Table 2).
4.
Discussion
The present data confirm increased mortality in diabetic patients from multiple cancer sites: liver, pancreas, colonrectum, breast, and uterus. Different possible biologic pathways leading to cancer risk in diabetes have been proposed: hyperinsulinemia, which promotes cancer growth directly [12] or through the effect of insulin-like growth factor-1 [13]; hyperglycemia, reported to promote tumor cell proliferation and metastasis in type 2 diabetes [14–16]; the permanent proinflammatory condition that characterize diabetes especially under poor metabolic control [17]. The report has both limits and strengths to explore different mechanisms underlying the association between diabetes and cancer. Among limits, the short follow-up restricted analyses on the temporal association between diabetes and cancer. Moreover, since follow-up was based on mortality and not incidence data, it is difficult to disentangle an association due to lower survival of cancer patients with diabetes, or to an increased cancer incidence in diabetic subjects. To complicate the scenario, another recently introduced issue is the influence of different anti-diabetic drugs on cancer risk [18,19], but we could not explore this issue because data on treatment were lacking. Among strengths, the study is based on a large number of observed cancer deaths. For some cancer site – including liver and pancreas – with poor survival, mortality is a proxy of incidence, and available data allowed exploration of initial time trends in cancer risk through the follow-up period. Moreover, a sub-cohort of patients with long disease duration was available to confirm mortality figures. In view of the above the main findings were: (1) a two-fold increased mortality for liver and pancreatic cancer in both genders, irrespective of follow-up period or disease duration. Due to the low survival for these cancer
1.59 2.32 1.98 1.13 1.10 1.13 1.25 1.71
(1.56–1.63) (2.10–2.55) (1.78–2.19) (1.08–1.17) (1.02–1.19) (1.02–1.26) (1.06–1.45) (1.27–2.26)
Diagnosed before 2001 1.82 2.32 1.78 1.13 1.07 1.17 1.26 1.57
(1.78–1.87) (2.06–2.59) (1.56–2.02) (1.08–1.19) (0.97–1.18) (1.03–1.33) (1.04–1.50) (1.08–2.20)
sites, mortality approximates incidence and the findings suggest a causal role of diabetes. Additional studies are warranted to investigate a potential modifying effect of different anti-diabetic drugs. (2) a 15% excess risk of mortality for other cancers combined. Although decreasing through the follow-up period, the risk did not return to unity at the end of follow-up, nor in the subcohort with longer disease duration. This could be due to a lower survival of cancer patients with diabetes, or to a causal association with specific tumor sites, as colon-rectum or female reproductive system. These latter associations need to be further examined with cancer incidence data.
Conflict of interest The authors declare that they have no conflict of interest.
references
[1] Buysschaert M, Sadikot S. Diabetes and cancer: a 2013 synopsis. Diabetes Metab Syndr: Clin Res Rev 2013;7:247–50. [2] Shikata K, Ninomiya T, Kiyohara Y. Diabetes mellitus and cancer risk: review of the epidemiological evidence. Cancer Sci 2013;104:9–14. [3] De Bruijn KM, Arends LR, Hansen BE, Leeflang S, Ruiter R, van Eijck CH. Systematic review and meta-analysis of the association between diabetes mellitus and incidence and mortality in breast and colorectal cancer. Br J Surg 2013;100:1421–9. [4] McAuliffe JC, Christein JD. Type 2 diabetes mellitus and pancreatic cancer. Surg Clin N Am 2013;93:619–27. [5] Walker JJ, Brewster DH, Colhoun HM, Fischbacher CM, Lindsay RS, Wild SH, Scottish Diabetes Research Network (SDRN) Epidemiology Group. Cause-specific mortality in Scottish patients with colorectal cancer with and without type 2 diabetes (2000–2007). Diabetologia 2013;56:1531–41. [6] Grote VA, Becker S, Kaaks R. Diabetes mellitus type 2 – an independent risk factor for cancer. Exp Clin Endocrinol Diabetes 2010;118:4–8. [7] Verlato G, Zoppini G, Bonora E, Muggeo M. Mortality from site-specific malignancies in type 2 diabetic patients from Verona. Diabetes Care 2003;26:1047–51.
diabetes research and clinical practice 106 (2014) e86–e89
[8] Giovannucci E, Harlan DM, Archer MC, Bergenstal RM, Gapstur SM, Habel LA, et al. Diabetes and cancer: a consensus report. Diabetes Care 2010;33:1674–85. [9] 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. [10] Liao KF, Lai SW, Li CI, Chen WC. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol 2012;27:709–13. [11] Zoppini G, Fedeli U, Gennaro N, Saugo M, Targher G, Bonora E. Mortality from chronic liver diseases in diabetes. Am J Gastroenterol 2014;109:1020–5. [12] Heuson JC, Legros N, Heimann R. Influence of insulin administration on growth of the 7,12dimethylbenz(a)anthracene-induced mammary carcinoma in intact, oophorectomized, and hypophysectomized rats. Cancer Res 1972;32:233–8. [13] Perry JK, Liu DX, Wu ZS, Zhu T, Lobie PE. Growth hormone and cancer: an update on progress. Curr Opin Endocrinol Diabetes Obes 2013;20:307–13.
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