Diabetes and Carcinoma

Dominique SIMON

Service de Diabétologie – Hôpital de la Pitié – Paris

et INSERM U-780 – Villejuif

dominique.simon@psl.aphp.fr

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

Epidemiological data Japanese population (2)

HR for Cancer in diabetic patientsMEN

• 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 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 (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

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 BMI Jee 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, smoking Rapp 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

Behavioral factorsDietPhysical activityAdiposity

Diabetes

Cancer

Behavioral factorsDietPhysical activityAdiposity

Diabetes

Cancer

Metabolic factorsInsulinIGFCytokines, hormones

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 = 0.005 Huxley 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 : 561-7 2-Jee SH et al. JAMA 2005; 293: 194-202

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

Type 1 (n=1210)

Type 2 (n=1780)

Diabetes 44.1 15.3 Cardiopathy 30.3 48.8

. ischaemic 24.8 38.0 Accidents 6.2 1.4 Suicide 2.8 0.1 Nephropathy 2.8 0.9 Cancer 2.8 9.9 Stroke 2.1 9.5 Pneumopathy 1.4 3.1 Hepatopathy 1.4 0.8

Moss SE et al. Am J Public Health 1991 ; 81 : 1158-62

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 ActivityWHO 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 men1.62 ( 95% CI = 1.40 – 1.87) in women

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

Cancer Mortality and BMI, Men

0 1 2 3 4 5 6 7

Relative Risk and 95% CI

All Cancers (> 40)

Non-Hodgkin’s lymphoma (> 35)

All other cancers (> 30)

Kidney (> 35)

Multiple myeloma (> 35)

Gall bladder (> 30)

Colon &Rectum (> 35)

Esophageal (> 30)

Pancreas (> 35)

Liver (> 35)

Prostate (> 35)

Stomach (> 35)

4.5

2.6*

1.9

1.9*

1.8

1.8

1.7*

1.5

1.5

1.3

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

1.7

1.7

Cancer Mortality and BMI, women

0 1 2 3 4 5 6 7 8 9 10 11

Relative Risk and 95% CI

Ovarian (> 35)

All Cancers (> 40)

Non-Hodgkin’s lymphoma (> 35)

All other cancers (> 40)

Kidney (> 40)

Multiple myeloma (> 35)

Gall bladder (> 30)

Colon &Rectum (> 40)

Esophageal (> 30)

Uterus (> 40)

Pancreas (> 40)

Liver (> 35)

Breast (> 40)

Cervix (> 35)

6.3

4.8

3.2

2.8

2.6*

2.5*

2.1

2.1

2.0

1.9*

1.71.5

1.5

1.4

* RR for women who never smoked E. 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 diabetesindependent 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 recommendationsDM 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