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

Diabetes and Carcinoma

Dominique SIMON

Service de Diabétologie – Hôpital de la Pitié – Paris

et INSERM U-780 – Villejuif

[email protected]


Diabetes cancer connections

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

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


Epidemiological data japanese population 2 hr for cancer in diabetic patients

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

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


Epi swedish population 2 rr for cancer top bottom quart

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.)


Epi swedish population 3 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

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

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

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 and carcinoma

Diabetes

Cancer


Diabetes and carcinoma

Diabetes

  • Behavioral factors

  • Diet

  • Physical activity

  • Adiposity

Cancer


Diabetes and carcinoma

Diabetes

  • Metabolic factors

  • Insulin

  • IGF

  • Cytokines, hormones

  • Behavioral factors

  • Diet

  • Physical activity

  • Adiposity

Cancer


Putative mechanisms for cancer diabetes association prostate excluded

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

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

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

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

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

Diabetes after cancer

  • Decreased physical activity

  • Increased sarcopenic adiposity

  • Higher diabetes risk once cancer occurs


Cancer after diabetes

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

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


Diabetes and carcinoma

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


Conclusions

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

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

Physical (In)Activity


Obesity and cancer mortality the cancer prevention study ii

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

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

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

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 cancer1

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

Physical activity and DM

  • Protective for both men and women

  • Overlaps with obesity

  • Improves insulin sensitivity


Physical activity and cancer

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

Liver cancer and diabetes

  • Shared obesity factor

    • Fatty liver

    • Cytokines

    • Cholestasis


Diabetes and carcinoma

Cancer recommendations

DM recommendations

CHD recommendations


Policy opportunities for reversing the obesity epidemic

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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