eAppendix

Page

The E3N cohort…………………………………..…………………………………………………….2

eFigure 1. Type 2 diabetes case ascertainment in the E3N cohort……………………………...4

eTable 1. Anatomical Therapeutic Chemical Classification System (ATC) codes used for

identification of diabetes cases in the E3N cohort………………….…………………………..….5

eFigure 2. Hazard Ratios of All-Cause Mortality by Body-Mass Index (Panel A),

excluding Women with Chronic Disease (Panel B), and additionally excluding Women Who

Had Never Smoked (Panel C)………………………………………………………………………..6

eTable 2. Age-adjusted characteristics of 88,373 French Women from the E3N Cohort Study

by Body-Mass Index Categories at Baseline in 1990………………………………..…………….9

eTable 3. Hazard Ratios of All-Cause Mortality by Body-Mass Index at the Time

of Diabetes Diagnosis……………………………………………………………………………….10

eTable 4. Hazard Ratios of All-Cause Mortality by Body-Mass Index categories in 1993 Stratified by Diabetes………………………………………………………………………………...11

eTable 5. Hazard Ratios of All-Cause Mortality by Waist Circumference in 1994

Stratified by Diabetes……..……………………………………………………………………….…12

The E3N cohort

The E3N cohort study, the French component of the European Prospective Investigation into Cancer and Nutrition (EPIC),1 includes 98,995 women born between 1925 and 1950 and affiliated to a health insurance plan that covers mostly teachers and their spouses.2 All participants signed an informed consent letter in compliance with the French National Commission for Computerized Data and Individual Freedom (CNIL). Participants were mailed questionnaires in 1990, 1992, 1993, 1994, 1997, 2000, 2002 and 2005. The 1990 questionnaire collected information on weight, height, marital status, education, menopausal status and menopause hormone therapy use, physical activity, smoking status, treated hypertension, cardiovascular disease (stroke, myocardial infarction and angina) and cancer. In 1993, we included a previously validated dietary questionnaire3 to assess habitual diet, and in 1994, we asked participants to provide information on waist circumference. The average proportion of responses to each questionnaire was 83%, and to date vital status is unknown for only 740 (0.75%) participants. We calculated BMI as self-reported weight (kg) in 1990 divided by self-reported height squared (m2). Reporting errors in weight and height are common4 and may result in bias5. Therefore, we assessed the validity of self-reported weight and height relative to measured weight and height among 152 E3N participants living in Paris. Self-reports of weight,height and BMI were highly correlated with actual measurements made by trained personnel (r=0.94 for weight, r=0.89 for height and r=0.92 for BMI) 6. The mean self-reported weight was 61.9 kg (SD±10.4) and the measured weight 61.7 kg (SD±10.4); while for height the self-reported and the measured were 161.4 cm (SD±6.4) and161.0 cm (SD±6.1), respectively. For BMI, means were 23.81(SD±3.8) for self-reports and 23.79(SD±3.8) for measured. We estimated weekly metabolic equivalents from responses to questions on moderate and vigorous physical activity.7

The ascertainment of diabetes in E3N has been described elsewhere.8 Briefly, we identified potential cases of type 2 diabetes through self-report in the questionnaires up to 2008 and through ATC (Anatomical Therapeutic Chemical Classification System) drug codes [eAppendix Table 1] from a drug reimbursement database provided by the health insurance plan that includes 98% of participants.9 All potential cases received a supplementary questionnaire that assessed diagnosis date, symptoms, fasting or random glucose concentrations at diagnosis, current therapy, and the most recent values for fasting glucose and Hb1Ac. Women were confirmed as having type 2 diabetes if they (i) self-reported a diagnosis and either had ≥1 reimbursement claim for diabetic medications or met the WHO criteria for diabetes on the supplementary questionnaires, or (ii) were identified through the claims database and either had the diagnosis confirmed by the supplementary questionnaire or, if they did not respond to the questionnaire, had ≥2 claims for diabetic medications. Date of type 2 diabetes diagnosis was ascertained through self-report in the questionnaires up to 30 June 2007.  If no date was available we attributed the date diagnosis to January 1st of the year of diagnosis reported in the supplementary diabetes questionnaire. For individuals who were identified through the claims database the date for the first reimbursement was used as the date of diabetes diagnosis.  Further detail on case confirmation is provided in the eAppendix Figure 1. Deaths were identified through regularly updated reports from the health insurance plan, a postal service response stating that the recipient was deceased and from next-of-kin, and cause of death was determined by searching the French Death Index (CépiDc).

For the current analysis, from 98,995 E3N participants we excluded women with prevalent diabetes or without a date of diagnosis (n=898), without valid BMI information or with a BMI < 18.5 (n=6,221) and those who were lost to follow-up after baseline or without a date of death (n=3,503). Therefore our analysis was based on 88,373 women who were followed to death or to June 30, 2007, whichever occurred earlier.

4

eFigure 1. Type 2 diabetes case ascertainment in the E3N cohort.

eTable 1. Anatomical Therapeutic Chemical Classification System (ATC) codes used for identification of diabetes cases in the E3N cohort

ATC code

Name

ATC code

Name

A10BF01

acarbose

A10BA02

metformin

A10BF02

miglitol

A10BD03

metformin/rosiglitazone

A10BB01

glibenclamide

A10BD07

metformin/sitagliptin

A10BB03

tolbutamide

A10BD05

metformin/pioglitazone 

A10BB04

glibornuride

A10BD02

metformin/sulfonamides

A10BB06

carbutamide

A10BD08

metformin/vildagliptin

A10BB07

glipizide

A10BH01

sitagliptin

A10BB09

gliclazide

A10BH02

vildagliptin

A10BB12

glimepiride

A10BH03

saxagliptin

A10BG02

rosiglitazone

A10BX02

repaglinide

A10BG03

pioglitazone

A10BX04

exenatide

A10BX06

benfluorex

A10BX07

liraglutide

eFigure 2. Hazard Ratios for All-Cause Mortality According to Body-Mass Index (Panel A), excluding Women with Chronic Disease (Panel B), and additionally excluding Women Who Had Ever Smoked (Panel C).

Hazard ratios were adjusted for age, marital status, highest level of educational level attainment, menopausal status and hormone replacement therapy use, physical activity, treated hypertension, smoking status (never, past and current), cardiovascular disease (stroke, myocardial infarction and angina) and cancer.

I bars denote 95 percent confidence intervals. P for trend: Panel A <0.0001; Panel B <0.0001; Panel C <0.0001.

eTable 2. Age-adjusted characteristics of 88,373 French Women from the E3N Cohort Study by Body-Mass Index Categories at Baseline in 1990

BMI (kg/m²)

 Characteristic

18.5-22.4 

22.5-24.9 

 25.0-27.4

27.5-29.9 

≥30

No. Participants

49,127

23,372

9,620

3,586

2,668

Living with a partner

82.4

83.5

82.6

81.1

78.0

College education

38.3

32.3

27.2

24.6

23.9

Smoking

Current

15.9

13.3

12.4

12.8

13.0

Past

31.2

30.6

30.8

31.6

31.9

Never

52.9

56.0

56.9

55.6

55.1

Mean physical activity, METs

41.5

42.1

41.7

39.9

38.9

Current use of MHT

15.0

18.2

16.8

14.9

10.7

Treated hypertension

5.8

9.4

13.8

18.8

26.2

Cancer diagnosis

4.4

4.9

5.8

5.4

5.8

Cardiovascular disease diagnosis

0.8

1.1

1.7

2.2

2.3

Values are in percent unless noted. MHT: Menopause hormone therapy.

eTable 3. Hazard Ratios of All-Cause Mortality According to Body-Mass Index at the Time of Diabetes Diagnosis

BMI

Deaths

Age-Adjusted

(95% CI)

Multivariate-Adjusted

(95% CI)

All

18.5-22.4

7

1.13 (0.45-2.88)

1.15 (0.45-2.96)

22.5-24.9

12

1.00

1.00

25.0-27.4

15

0.90 (0.42-1.93)

0.88 (0.41-1.90)

27.5-29.9

9

0.64 (0.27-1.51)

0.64 (0.27-1.52)

≥30

11

0.50 (0.22-1.17)

0.53 (0.23-1.23)

P for Trend

0.04

0.07

Excluding women with chronic disease

18.5-22.4

6

1.16 (0.42-3.19)

1.22 (0.44-3.40)

22.5-24.9

10

1.00

1.00

25.0-27.4

10

0.73 (0.30-1.76)

0.73 (0.30-1.75)

27.5-29.9

7

0.59 (0.22-1.55)

0.58 (0.22-1.54)

≥30

9

0.47 (0.19-1.16)

0.47 (0.19-1.18)

P for Trend

0.05

0.05

Excluding women with chronic disease and smokers

18.5-22.4

5

1.49 (0.46-4.90)

1.80 (0.55-6.03)

22.5-24.9

6

1.00

1.00

25.0-27.4

7

0.79 (0.27-2.36)

0.85 (0.28-2.54)

27.5-29.9

3

0.42 (0.11-1.68)

0.45 (0.11-1.83)

≥30

4

0.36 (0.10-1.28)

0.34 (0.10-1.24)

P for Trend

0.02

0.02

CI: Confidence interval. Hazard ratios were adjusted for age, marital status, highest level of educational level attainment, menopausal status and hormone replacement therapy use, physical activity, treated hypertension, smoking status (never, past and current), cardiovascular disease (stroke, myocardial infarction and angina) and cancer.

13

eTable 4. Hazard Ratios of All-Cause Mortality According to Body-Mass Index categories in 1993 Stratified by Diabetes

No diabetes

Diabetes

BMI

Deaths

Age-Adjusted (95% CI)

Multivariate-Adjusted

(95% CI)

Deaths

Age-Adjusted (95% CI)

Multivariate-Adjusted (95% CI)

All (n=65,285)

18.5-22.4

951

0.93 (0.84-1.03)

0.96 (0.86-1.06)

5

0.90 (0.31-2.64)

0.95 (0.31-2.94)

22.5-24.9

630

1.00

1.00

10

1.00

1.00

25.0-27.4

371

1.28 (1.13-1.46)

1.23 (1.08-1.40)

7

0.61 (0.23-1.61)

0.64 (0.23-1.79)

27.5-29.9

135

1.27 (1.06-1.53)

1.20 (1.00-1.45)

4

0.56 (0.18-1.79)

0.64 (0.19-2.12)

≥30

120

1.74 (1.43-2.11)

1.55 (1.27-1.89)

5

0.48 (0.16-1.39)

0.55 (0.18-1.73)

P for Trend

<0.0001

<0.0001

0.15

0.28

Excluding women with chronic disease (n=60,474)

18.5-22.4

709

0.87 (0.78-0.98)

0.89 (0.79-0.99)

4

0.82 (0.25-2.65)

0.88 (0.26-3.01)

22.5-24.9

495

1.00

1.00

9

1.00

1.00

25.0-27.4

272

1.21 (1.05-1.41)

1.18 (1.02-1.37)

5

0.50 (0.17-1.50)

0.58 (0.19-1.81)

27.5-29.9

102

1.24 (1.00-1.53)

1.18 (0.95-1.46)

3

0.50 (0.13-1.83)

0.56 (0.15-2.13)

≥30

81

1.51 (1.20-1.91)

1.36 (1.07-1.73)

4

0.43 (0.13-1.38)

0.47 (0.14-1.61)

P for Trend

<0.0001

<0.0001

0.16

0.22

Excluding women with chronic disease and smokers (n=32,547)

18.5-22.4

383

0.84 (0.72-0.98)

0.85 (0.73-1.00)

2

0.74 (0.14-3.80)

0.93 (0.16-5.30)

22.5-24.9

290

1.00

1.00

5

1.00

1.00

25.0-27.4

152

1.15 (0.94-1.40)

1.12 (0.92-1.37)

4

0.65 (0.18-2.43)

0.83 (0.21-3.31)

27.5-29.9

58

1.20 (0.90-1.59)

1.16 (0.87-1.53)

1

0.60 (0.04-2.58)

0.40 (0.04-3.68)

≥30

43

1.52 (1.11-2.10)

1.39 (1.01-1.92)

3

0.39 (0.08-2.00)

0.47 (0.08-2.67)

P for Trend

<0.0001

<0.0001

0.24

0.32

CI: Confidence interval. Hazard ratios were adjusted for age, marital status, highest level of educational level attainment, menopausal status and hormone replacement therapy use, physical activity, treated hypertension, smoking status (never, past and current), cardiovascular disease (stroke, myocardial infarction and angina) and cancer, energy intake, processed red meat intake, fruits and vegetables , alcohol and coffee.

eTable 5. Hazard Ratios of All-Cause Mortality According to Waist Circunference in 1994 Stratified by Diabetes

No diabetes

Diabetes

Waist circumference

Deaths

Age-Adjusted (95% CI)

Multivariate-Adjusted (95% CI)

Deaths

Age-Adjusted (95 %CI)

Multivariate-Adjusted (95% CI)

All (n=62,198)

<90 cm

1650

1.00

1.00

14

1.00

1.00

≥90 cm

300

1.78 (1.57-2.02)

1.58 (1.39-1.80)

13

1.12 (0.53-2.39)

1.12 (0.51-2.48)

Excluding women with chronic disease (n=57,154)

<90 cm

1238

1.00

1.00

11

1.00

1.00

≥90 cm

210

1.73 (1.49-2.00)

1.58 (1.36-1.84)

10

1.15 (0.49-2.70)

1.12 (0.47-2.72)

Excluding women with chronic disease and smokers (n=30,911)

<90 cm

687

1.00

1.00

7

1.00

1.00

≥90 cm

111

1.63 (1.33-2.00)

1.50 (1.22-1.85)

4

0.79 (0.23-2.71)

0.82 (0.23-2.94)

CI: Confidence interval. Hazard ratios were adjusted for age, marital status, highest level of educational level attainment, menopausal status and hormone replacement therapy use, physical activity, treated hypertension, smoking status (never, past and current), cardiovascular disease (stroke, myocardial infarction and angina) and cancer.

1.Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, Fahey M, Charrondiere UR, Hemon B, Casagrande C, Vignat J, Overvad K, Tjonneland A, Clavel-Chapelon F, Thiebaut A, Wahrendorf J, Boeing H, Trichopoulos D, Trichopoulou A, Vineis P, Palli D, Bueno-De-Mesquita HB, Peeters PH, Lund E, Engeset D, Gonzalez CA, Barricarte A, Berglund G, Hallmans G, Day NE, Key TJ, Kaaks R, Saracci R. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 2002;5(6B):1113-24.

2.Tehard B, Lahmann PH, Riboli E, Clavel-Chapelon F. Anthropometry, breast cancer and menopausal status: use of repeated measurements over 10 years of follow-up-results of the French E3N women's cohort study. Int J Cancer 2004;111(2):264-9.

3.van Liere MJ, Lucas F, Clavel F, Slimani N, Villeminot S. Relative validity and reproducibility of a French dietary history questionnaire. Int J Epidemiol 1997;26 Suppl 1:S128-36.

4.Spencer EA, Appleby PN, Davey GK, Key TJ. Validity of self-reported height and weight in 4808 EPIC-Oxford participants. Public Health Nutr 2002;5(4):561-5.

5.Chiolero A, Peytremann-Bridevaux I, Paccaud F. Associations between obesity and health conditions may be overestimated if self-reported body mass index is used. Obes Rev 2007;8(4):373-4.

6.Tehard B, van Liere MJ, Com Nougue C, Clavel-Chapelon F. Anthropometric measurements and body silhouette of women: validity and perception. J Am Diet Assoc 2002;102(12):1779-84.

7.Tehard B, Friedenreich CM, Oppert JM, Clavel-Chapelon F. Effect of physical activity on women at increased risk of breast cancer: results from the E3N cohort study. Cancer Epidemiol Biomarkers Prev 2006;15(1):57-64.

8.de Lauzon-Guillain B, Fournier A, Fabre A, Simon N, Mesrine S, Boutron-Ruault MC, Balkau B, Clavel-Chapelon F. Menopausal hormone therapy and new-onset diabetes in the French Etude Epidemiologique de Femmes de la Mutuelle Generale de l'Education Nationale (E3N) cohort. Diabetologia 2009;52(10):2092-100.

9.Clavel-Chapelon F, van Liere MJ, Giubout C, Niravong MY, Goulard H, Le Corre C, Hoang LA, Amoyel J, Auquier A, Duquesnel E. E3N, a French cohort study on cancer risk factors. E3N Group. Etude Epidemiologique aupres de femmes de l'Education Nationale. Eur J Cancer Prev 1997;6(5):473-8.