Diabetes and carcinoma
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Diabetes and Carcinoma. Dominique SIMON Service de Diabétologie – Hôpital de la Pitié – Paris et INSERM U-780 – Villejuif [email protected] Diabetes – Cancer connections. Diabetes/high BG level and cancer mortality/incidence : epidemiological data

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Diabetes and Carcinoma

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Diabetes and Carcinoma

Dominique SIMON

Service de Diabétologie – Hôpital de la Pitié – Paris

et INSERM U-780 – Villejuif

[email protected]


Diabetes – Cancer connections

  • Diabetes/high BG level and cancer mortality/incidence :

    • epidemiological data

    • putative mechanisms/diabetes treatment

  • Pancreatic cancer and diabetes

  • Influence of cancer on diabetes and vice versa


Epidemiological data Japanese population (1)

  • 97,771 Japanese subjects (47.3% males)

  • 40-69 yrs old ; age = 51.6±7.9 yrs at baseline in 1990-4

  • Average follow-up : 10.7 yrs (up to 31 December 2003)

  • Diabetic patients: 6.7% in males ; 3.1% in females

  • 6,462 cases of newly diagnosed cancer (3,907 in males and 2,555 in females)

    Inoue M et al. Arch Intern Med 2006; 166 : 1871-7


MEN

All sites : 1.27 (1.14-1.42)

Liver : 2.24 (1.64-3.04)

Pancreas : 1.85 (1.07-3.20)

Kidney : 1.92 (1.06-3.46)

Colon : 1.36 (1.00-1.85)

Stomach:1.23 (0.98-1.54)

Prostate: 0.82 (0.51-1.33)

All HR adjusted for age, BMI, tobacco, alcohol and vegetables consumption, physical activity

WOMEN

All sites : 1.21 (0.99-1.47)

Stomach : 1.61 (1.02-2.54)

Liver : 1.94 (1.00-1.85)

Ovary: 2.42 (0.96-6.09)

Pancreas: 1.33 (0.53-3.31)

Breast: 0.83 (0.44-1.57)

Inoue M et al. Arch Intern Med 2006; 166 : 1871-7

Epidemiological data Japanese population (2)HR for Cancer in diabetic patients


Epidemiological data Swedish population (1)

  • 64,597 Swedish non diabetic subjects (48.5% males)

  • 40-60 yrs old ; age=46.1±9.8 yrs at baseline since 1985

  • Average follow-up : 8.3±3.6 yrs

  • FPG and 2-h PG measured : 5.4±1.0 and 6.6±1.7 mM

  • FPG : normal=87%; IFG=10.5%; diabetes=2.5%

  • 2-h PG : normal=93%; IGT=6%; diabetes=1%

  • 2,478 cases of newly diagnosed cancer (46.5% in males)

  • RR for top quartile vs bottom quartile of FPG and 2-h PG

    Stattin P et al. Diabetes Care 2007; 30 : 561-7


MEN(all sites)

FPG : 1.08 (0.92-1.27) ptrend= 0.25

2-h PG : 0.98 (0.84-1.16) ptrend= 0.99

After exclusion of prostate cancer :

FPG : 1.12 (0.92-1.36) ptrend= 0.16

2-h PG : 1.17 (0.95-1.45) ptrend= 0.095

RR unchanged after adjustment for BMI and tobacco consumpt.

WOMEN (all sites)

FPG : 1.26 (1.09-1.47) ptrend< 0.001

2-h PG : 1.31 (1.12-1.52) ptrend< 0.001

After correction for random variation PG :

FPG : 1.75 (1.32-2.36) ptrend< 0.001

2-h PG : 1.63 (1.26-2.18) ptrend< 0.001

Stattin P et al. Diabetes Care 2007; 30 : 561-7

Epi Swedish population (2)RR for Cancer (top/bottom quart.)


FPG

Pancreas : 2.49 (1.23-5.45) ptrend= 0.006

Mal. melan. : 2.16 (1.14-4.35) ptrend= 0.01

Ur. tract : 1.69 (0.95-3.16) ptrend= 0.049

Endometr. : 1.86 (1.09-3.31) ptrend= 0.019

Prostate : 0.96 (0.74-1.26) ptrend= 0.71

RR unchanged after adjustment for BMI and tobacco consumption

2-h PG

Pancreas : 0.91 (0.47-1.78) ptrend= 0.91

M. mel. : 1.65 (0.89-3.17) ptrend= 0.09

Ur. tract : 1.18 (0.65-2.17) ptrend= 0.78

Endom. : 1.82 (1.07-3.23) ptrend= 0.03

Prostate : 0.79 (0.61-1.02) ptrend= 0.07

Stattin P et al. Diabetes Care 2007; 30 : 561-7

Epi Swedish population (3)RR for Cancer (top/bottom quart.)


Other epidemiological data (1) Korean study

  • 1,298,385 subjects (63.9% males)

  • Age = 46.9±11.5 yrs with 9.4 yrs of follow-up

  • 53,833 incident cancers (70.1% in males)

  • HR* in top (≥ 7.8 mM) vs bottom (<5.0 mM) FPG in men and women respectively :

  • all cancers incidence = 1.22 (1.16-1.27) and 1.15 (1.01-1.25)

  • all cancers mortality = 1.29 (1.22-1.37) and 1.23 (1.09-1.39)

  • pancreatic cancer death = 1.91 (1.52-2.41) and 2.05 (1.43-2.93)

  • liver cancer death = 1.57 (1.40-1.76) and 1.33 (1.01-1.81)

  • colon cancer death = 1.31 (1.03-1.67) (only in men)

    *unchanged with adjustment for BMIJee SH et al. JAMA 2005; 293: 194-202


Other epidemiological data (2)Austrian study

  • 140,813 subjects (45.2% males)

  • Age = 43±15 yrs with 8.4±3.8 yrs of follow-up

  • 5,212 cases of cancer

  • HR* in top (≥ 7.0 mM) vs reference (4.2-5.2 mM) FPG :

    - for all cancers incidence = 1.20 (1.03-1.39) in men and 1.28 (1.08-1.53) in women

    - for liver cancer = 3.56 (1.58-8.02) in combined sexes

    - for gallbladder and bile duct cancer incidence = 3.35 (1.16-9.70) in combined sexes

    *adjusted for age, BMI, smokingRapp K et al. Diabetologia 2006; 49: 945-52


Association of diabetes/high B G level and risk of cancer

  • Increased risk (~ +20%) of all cancers incidence and mortality in diabetic patients and non diabetic subjects with higher glucose level

  • Increased risk of digestive cancers (pancreas, liver, stomach, colon) in diabetic patients and non diabetic subjects with higher glucose level

  • Decreased risk of prostate cancer in diabetic patients [meta-analysis : HR = 0.91 (0.87-0.95)*]

    *Bonovas S et al. Diabetologia 2004; 47: 1071-8


Diabetes

Cancer


Diabetes

  • Behavioral factors

  • Diet

  • Physical activity

  • Adiposity

Cancer


Diabetes

  • Metabolic factors

  • Insulin

  • IGF

  • Cytokines, hormones

  • Behavioral factors

  • Diet

  • Physical activity

  • Adiposity

Cancer


Putative mechanisms for cancer- diabetes association (prostate excluded)

  • Both reflects common exposure (diet high in fats and energy, low in fibers; low level of physical exercise)

  • Reduced insulin sensitivity with compensatory hyperinsulinemia and elevated levels of IGF-1 stimulation of cell proliferation

  • Insulin activates IGF-1 receptor, known to have growth-promoting effects

  • Excess insulin down-regulates the level of IGF-BP1 increase in the IGF-1 availability to the IGF-1 receptor


Putative role of diabetes treatment in the development of cancer – Saskatchewan Health database(1)

  • Population-based cohort study ~ 1,000,000 subjects

  • Compared cancer-related mortality according to new treatment by OAD or insulin in type 2 diabetic patients

  • Cancer mortality over 5.4±1.9 yrs of follow-up :

  • 4.9% in sulfonylurea monotherapy users

  • 3.5% in metformin users (3.3% in monotherapy)

  • 5.8% in insulin users (vs 3.6% without insulin)

  • HR for cancer death in SU vs metformine = 1.3 (1.1-1.6) and insulin vs no insulin = 1.9 (1.5-2.4)

    Bowker SL et al. Diabetes Care 2006; 29: 254-8


Putative role of diabetes treatment in the development of cancer (2)

  • Limitations of the Saskatchewan study1 :

  • observational data and clinicians’ prescibing could be affected by cancer

  • no information on glycaemic control, BMI, smoking status…

  • no information on cancer incidence

  • DARTS pilot observational study2 :

  • case-control study using a population-based databases on 314,127 subjects including 11,876 T2D patients 923 K

  • adjusted*  for any exposure to metformine = 0.77 (0.64-0.92)

  • dose-response relationship HR for this effect

  • reduction of cancer risk with metformine via AMPK/LKB1 ?

  • limitations : observational; influence of K on clinicians’prescribing ?

    1Bowker SL et al. Diabetes Care 2006; 29: 254-8 2Evans JMM et al. BMJ 2005; 330: 1304-5 *adjusted for BMI,BP, smoking


Putative mechanisms for prostate cancer- diabetes association

  • Reduced insulin response in diabetic patients ?

  • Commun factor increasing the risk of diabetes and decreasing the risk of prostate cancer : obesity inducing a decrease in androgens level ?

  • rather good evidence from animal models

  • low testosterone level in diabetic and obese patients


T2 diabetes and pancreatic cancer

  • Meta-analysis of 36 (17 case-control and 19 prospective) studies by Huxley

  •  = 1.82 (1.66-1.99)

  • Influence of diabetes duration on  : 2.1 (1.9-2.3) if < 5 yrs vs 1.5 (1.3-1.8) if ≥ 5 yrs*

  • Reverse causality in part : diabetes can be an early manifestation of pancreatic cancer

  • No evidence to screen for pancreas K in Diab.

* p = 0.005Huxley R et al. Br J Cancer 2005; 92: 2076-83


Diabetes after cancer

  • Decreased physical activity

  • Increased sarcopenic adiposity

  • Higher diabetes risk once cancer occurs


Cancer after diabetes

  • Higher morbidity with Rx

  • Higher mortality

  • Higher recurrence (breast)

  • Worsening of diabetes control as an alert signal for cancer


Impact of PG level on cancer risk

  • Swedish study1:

    - absolute risk of any cancer over 20 yrs in a woman in the bottom vs top quartile of FPG : 7% and 9% respectively (7% and 11% after correction for random FPG variation)

    - fraction of all cancers attributable to a high level of PG : 5% (95% CI = 2-8%) for FPG and 4% (1-8%) for 2h-PG [10% (7-15%) and 9% (6-15%) after correction]

  • Korean study2 : 802/20,566 cancer deaths in men and 46/5907 in women estimated to be attributable to “high” FPG level (≥ 90 mg/dl)

    1-Stattin P et al. Diabetes Care 2007; 30 : 561-72-Jee SH et al. JAMA 2005; 293: 194-202


Causes of deaths (%)in diabetic patients - Wisconsin Study


Conclusions

  • Moderate increase (~ +25%) of cancer risk in diabetic patients, mainly digestive cancers

  • To reduce cardiovascular complications remains the priority in diabetic patients

  • Obesity is a common risk factor for diabetes and cardiovascular disease but also, directly, for cancer

  • To prevent obesity is the major Public Health concern at the present time


Obesity, Physical Activity

WHO estimates 20% of cancers caused by obesity, lack of physical activity

International Agency for Research on Cancer, 2003


Physical (In)Activity


Obesity and cancer mortality The Cancer Prevention Study II

  • Prospective study begun in 1982 in the US

  • 404,576 men and 495, 477 women ≥ 30 yrs

  • 16 yrs of follow-up

  • Mean age = 57 yrs at enrollment

  • 216,000 deaths including 57,145 deaths from cancer (32,303 in men)

  • RR all cancer mortality in subjects with BMI ≥ 40 kg/m2 vs those with 18.5 < BMI < 24.9 kg/m2 :

    • 1.52 ( 95% CI = 1.13 – 2.05) in men

    • 1.62 ( 95% CI = 1.40 – 1.87) in women

      E. E. Calle et al. NEJM 2003; 348: 1625-38


Cancer Mortality and BMI, Men

1.3

Prostate (> 35)

1.5

1.5

Non-Hodgkin’s lymphoma (> 35)

All Cancers (> 40)

1.7*

All other cancers (> 30)

1.7

Kidney (> 35)

1.7

1.8

Multiple myeloma (> 35)

Gall bladder (> 30)

1.8

Colon &Rectum (> 35)

Esophageal (> 30)

1.9*

1.9

Stomach (> 35)

2.6*

Pancreas (> 35)

4.5

Liver (> 35)

Relative Risk and 95% CI

* RR for men who never smokedE. E. Calle et al. NEJM 2003; 348: 1625-38


Cancer Mortality and BMI, women

1.4

1.5

Colon &Rectum (> 40)

1.5

Multiple myeloma (> 35)

Ovarian (> 35)

1.7

1.9*

Liver (> 35)

2.0

All Cancers (> 40)

2.1

Non-Hodgkin’s lymphoma (> 35)

2.1

Breast (> 40)

2.5*

Gall bladder (> 30)

2.6*

All other cancers (> 40)

2.8

Esophageal (> 30)

3.2

Pancreas (> 40)

4.8

Cervix (> 35)

6.3

Kidney (> 40)

Uterus (> 40)

Relative Risk and 95% CI

* RR for women who never smokedE. E. Calle et al. NEJM 2003; 348: 1625-38


Obesity and cancer

  • Major risk factor - both men and women

  • Post menopausal breast

  • Endometrial

  • Colorectal

  • Esophageal

  • Liver

  • Renal

  • Prostate (advanced disease at higher obesity levels)


Obesity and cancer

  • Major risk factor - both men and women

  • Post menopausal breast

  • Endometrial

  • Colorectal

  • Esophageal

  • Liver

  • Renal

  • Prostate (advanced disease at higher obesity levels)

Associations with diabetes

independent of obesity


Physical activity and DM

  • Protective for both men and women

  • Overlaps with obesity

  • Improves insulin sensitivity


Physical activity and cancer

  • Protective for both men and women

  • Overlaps with obesity

  • Apparent independent benefits for breast and colon cancer


Liver cancer and diabetes

  • Shared obesity factor

    • Fatty liver

    • Cytokines

    • Cholestasis


Cancer recommendations

DM recommendations

CHD recommendations


Policy opportunities for reversing the obesity epidemic

  • Convergence of evidence for cancer, heart disease, diabetes

    - Though the fear of single diseases may be more motivating than fear of collective diseases

  • Collaboration across disease- specific governmental and NGO groups

    • ACS, AHA, ADA partnership


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