1. Diabetes in Postmenopausal Women The Women’s Health Initiative
Barbara V. Howard, PhD
Senior Scientist, MedStar Health Research Institute
Professor of Medicine, Georgetown University School of Medicine

2. Women’s Health Initiative
48,835
36,282
3 Controlled Trials
27,347
Hormone Therapy Trials
Calcium/Vitamin D Trial
Dietary Modification Trial:
Breast & Colorectal Cancers (Coronary Heart Disease 2 endpoint)
Overlapping participation in the clinical trials offers a cost-efficient design.
Women invited to participate in HRT and DM after meeting eligibility criteria and providing informed consent.
93,676
1 Observational Study
Observational Study
161,808 women total

3. Diabetes Prevalence and Incidence by Ethicity
ASIAN
BLACK
HISPANIC
WHITE
Total baseline
4188
14595
6447
133,452
Prevalence (%)
5.92
12.16
7.23
3.34
adjusted OR (CI)
2.4 ( )
2.6( )
1.8( ) 1
Total followup
3940
12,830
6009
128,998
Incidence/100py
1.13
1.87
1.67
0.82
adjusted HR (CI)
1.86
1.55
Ma et al 2012, Diabetes Care 35:1-9

4. Hormone Therapy and Diabetes

5. Profile of the E+P Trial Participants for the Analysis of Diabetes Outcome
Initiated screening (N = 373,092)
Provided consent and reported no hysterectomy (N = 18,845)
Randomized (N = 16,608)
Estrogen +Progestin
(N = 8,506)
Placebo
(N = 8,102)
No Diabetes
(N = 8014)
5.6 yrs avg followup
No Diabetes
(N = 7627)
5.6 yrs avg followup

6. Development of DM in Group treated with E+ P Compared to Placebo
Margolis et al Diabetologia 2004: 47:

7. E+P and Incidence of DM RR (vs placebo) 0.79, CI: 0.67,0.93
Adjusted for 7 endpoints CI: 0.63,0.99
Sensitivity analysis by adherent participants RR 0.67, CI: 0.54,0.82
Adjustment for BMI, waist, and ageRR 0.77, CI: 0.64, 0.93
No interactions by age, race, obesity
E+P is associated with small but significant decreases in fasting glucose and insulin and a decrease in HOMA-IR at one year of followup

8. Effect of Estrogen alone vs Placebo on DM Incidence
Solid: E; Dotted: placebo HR 0.88 ( )
Bonds et al JCEM 2006: 91:

9. Implications Small DM decrease does not outweigh other risks
Probably reflects the androgenic milieu associated with insulin resistance
Should lead to future development of preventive strategies

10. Diet and Diabetes

11. WHI Dietary Modification Trial
48,835 randomized to
WHI DM Trial
Intervention (40%): Low-fat Dietary Pattern
19,541
Comparison (60%): Usual Dietary Pattern 29,294
2005
N=1,165 (6%) excluded from analysis for prevalent diabetes
N=1,783 (6%) excluded from analysis for prevalent diabetes
N=27,511 analyzed
N=18,376 analyzed
To test the effect of a low-fat dietary pattern on breast and colorectal cancers and heart disease in postmenopausal women.
~90% retention in both intervention and comparison

12. WHI DM Trial Dietary Goals
Comparison
Not asked to make changes
Given USDA Dietary Guidelines for Americans 1990 or 1995
Intervention
20% energy from fat
≥ 5 fruit/vegetable servings daily
≥ 6 grain servings daily
Achieved –
11% reduction in fat yr 1, 8% at end
All types of fat equally reduced
F/V reduced one serving and grains ½ serving
Wt diff 2 kg first year , 0.5kg at end

13. Risk of Treated Diabetes in the WHI Dietary Modification Trial
N=3,341 cases
7.1% intervention
7.4% comparison
Tinker et al 2008; Arch Intern Med:

14. Low Fat Diet and Diabetes
A low-fat diet alone did not result in a decreased risk of developing treated diabetes mellitus among generally healthy postmenopausal women.
In subgroup analyses, women reporting the greatest decreases in total fat intake showed a decreased risk of diabetes. However, the decreased risk may have been related to the ad libitum low-fat diet and consequent weight loss experienced among participants in the intervention group.
A low-fat dietary pattern may be a useful adjunct approach for weight loss in lifestyle interventions to prevent diabetes.

15. Diabetes and Energy Intake
 Uncalibrated energy intake was slightly associated with diabetes risk. Biomarker-calibrated energy intake was highly associated with risk of diabetes.
 Body mass, as BMI, as an indicator of energy balance, appeared to mediate the association of biomarker-calibrated energy with diabetes risk.
 Results were similar among racial and ethnic groups, although the sample sizes were small with wide confidence intervals in all but the white group.
 Research continues with uncalibrated and biomarker-calibrated measures of dietary intake and activity expenditure.
Tinker et al Am J Clin Nutr 94:

16. Diabetes and Dairy Intake
Median servings/day: 1.5, 0.8 for low-fat, and 0.4 for high-fat. Yogurt consumption low (median, ½ per week; 38% reported rarely or never ). Women with the highest consumption were more likely to be : white, have a higher income and education, not smoke, have no family history of diabetes, use hormone therapy, have a slightly lower BMI, and be more active.

17. Diabetes and Dairy Intake
Quintiles of intake
First
Second
Third
Fourth
Fifth
p trend# n
18,037
15,915
16,024
16,050
16,047
Diabetes cases, n (%)
1,078 (6.0)
842 (5.3)
714 (4.4)
644 (4.0)
668 (4.2)
Age, ethnicity, energy*
1.00 (reference)
0.86 (0.78, 0.95)
0.75 ( )
0.68 ( )
0.70 ( )
<0.0001
Multivariable model†
0.97 ( )
0.63 ( )
0.48 ( )
0.60 ( )
0.0006
Multivariable model† + dietary glycemic load + dietary total fat + dietary total fiber + total magnesium
0.96 ( )
0.65 ( )
0.50 ( )
0.65 ( )
0.003
Margolis et al ; J Nutr. 141:

18. Conclusions
A diet high in low-fat dairy products may lower diabetes risk in postmenopausal women. Further research is needed
High yogurt consumption was also associated with a decreased risk of diabetes. This inverse relationship was more pronounced in women with a higher body mass index (BMI).
There was no association between high-fat dairy consumption and diabetes risk.

19. Ca/Vit D and Diabetes

20. Calcium/Vitamin D Trial and DM Incidence
68,132 WHI CT Participants
1000 mg elemental calcium as calcium carbonate & IU vitamin D3
Divided dose; with meals
Avg FU 7.0 yrs
31,850 Ineligible or Not Interested
36,282 Randomized
CaD
Placebo
(N = 18,176)
(N = 18,106)
Close-Out
(N=16,936)
Close-Out
(N=16,815)

21. Cumulative incidence of diabetes by calcium/vitamin D treatment assignment
DeBoer et al. 2008; Diabetes Care. 31:701-7.

22. 25(OH) Vitamin D Levels and Incident Type 2 Diabetes
5262 women, mean age 66, followed 7.3 yrs from nested case control studies of fractures or cancer
Serum 25(OH) vitamin D measured
Incidence of DM by self report or taking DM medications
Robinson et al. 2011; D Care 34:

23. Lack of Association of VitD and DM
LINEAR TREND
CONTINUOUS
25 (OH)D model
p value
OR (CI)
Age, ethnicity
0.107
0.98 (.94,1.02)
+Geog, time of year and trial
0.98 (0.94,1.02)
+ smoke, alcohol, education, BMI, waist, PA, HT use, HT, hx of CVD
0.956
1.01 (0.98,1.05)
+ vitamin use, skin CA, CVD, F/V, SAT, protein, fiber, Ca, Mg GL
0.643
1.00 (0.96,1.05)
NO interaction by BMI, race or CVD status

24. Other Risk Factors

26. Determinants of Racial/Ethnic Disparities in incident Diabetes
Hispanics
Asians
Healthy Weight (66%)
Diet (15%)
Physical Activity (22%)
Whites
Blacks
Healthy Weight (55%)
Diet (15%)
Healthy Weight (64%)
Diet (30%)
Physical Activity (29%)
Healthy Weight (66%)
Physical Activity(7%)
Physical Activity(7%)

27. Smoking and Risk of Diabetes
SMOKING STATUS
T2D CASES (N)
ADJUSTED HR (95% CI) *
Never Smoker
7727
REF
Former Smoker
6188
1.00 (0.97 – 1.04)
Current Smoker
1161
1.28 (1.20 – 1.36)
* Cox proportional hazards models adjusted for age, race/ethnicity, education, BMI, waist circumference, alcohol, physical activity, hypertension and hypercholesterolemia.
Luo et al. 2012, Arch Int Med 172:438-40

28. Three year risk of diabetes – smoking status and weight changes
ADJUSTED HR (95% CI) WEIGHT GAIN <5 KG
ADJUSTED HR (95% CI) WEIGHT GAIN >5 KG
Never Smokers
REF
Former Smokers
1.00 (0.96 – 1.05)
0.96 (0.86 – 1.07)
Continuing Smokers
1.16 (1.04 – 1.29)
1.32 (1.06 – 1.64)
New Quitters
1.17 (0.98 – 1.41)
1.67 (1.36 – 2.05)
P for interaction = 0.02

29. Conclusions
Compared to never smoking, smoking cessation in post-menopausal women is associated with a 40% increased risk of T2D (higher than the 20% increased risk of continuing to smoke)
Both substantial weight gain (>5 kg) and the residual effects of high cumulative smoking exposure (>20 pack-year) contribute to post- cessation T2D risk
T2D risk decreases to that of a non-smoker about 10 years after quitting despite adverse effects of weight gain

30. Novel Biomarkers CRP, IL-6 and TNFalpha as predictors of DM
Liu et al 2007; Arch Int Med 167:176-85
Endothelial Adhesion Molecules as predictors of DM
Liu et al 2007; Diabetes 56:
Hepatocyte Growth Factor and DM risk
Rajpathak et al 2010; Diabetes Care 33:2013-5

31. SHBG and Risk of Diabetes
Chen et al, Clin Chem 58:10

32. Telomere Length and DM Risk
You et al, Diabetes

33. Enormous Potential for Genetic Studies
Calpain-10 Gene and DM risk
Liu et al 2007, Hum Mol Genet 16:
UCP2-UCP3 cluster and DM risk
Liu et al 2008, Diabetes 57:1101-7
FABP4 variants and DM risk
Liu et al 2010, Obesity 18:
FTO polymorphisms – obesity but not DM risk
Liu et al 2008, Obesity 16:
DM risk variants across populations PAGE
Haiman et al 2012, Arch Int Med 172:438-40

34. Medication Use

35. Metformin Therapy and Breast CA
Chlebowski, et al, J Clin Oncol 30:

36. Metformin and Breast CA
DIABETES (OTHER MEDICATION)
DIABETES (METFORMIN)
N (Ann %)
HR (95% CI)
HR (95% CI)
P- value
Invasive BC
(0.47)
( )
(0.40)
( )
.04
ER+/PR+
(0.29)
( )
(0.23)
( )
ER+/PR-
(0.062)
( )
(0.054)
( )
.72
ER-/PR-
(0.066)
( )
(0.054)
( )
.06
adjusted for age, first degree relative with breast cancer, benign breast disease, age at menarche, age at menopause, parity, age at first birth, education, number of months breast fed, smoking, alcohol consumption, BMI, physical activity, duration of E-alone use, duration of E+P use, bilateral oophorectomy, mammogram within two years of baseline , hormone therapy trial randomization, dietary trial randomization or OS enrollment, enrollment into WHI extension, and race/ethnicity

37. Conclusions
Metformin use was associated with lower rates of invasive breast cancer except ER+/PR-
Metformin use was associated with lower rates of HR + but not HR- cases
Metformin use was associated with weight loss (mean 1.4 kg for baseline to year 1, 95% CI ) compared to use of other diabetes medication or women without diabetes (P=0.02)
Adjustment for weight loss didn’t change association of metformin to breast cancer (HR 0.75; 95% CI )

38. Diabetes and Statin Use

39. Diabetes and Statin Use
Culver et al 2012; Arch Intern Med;172:

40. Overall Conclusions
The WHI dataset provides a wealth of opportunities to study physiologic, behavioral and genetic determinants of diabetes in a multiethnic cohort.
The results of the 3 trials suggest that Ca and Vitamin D play little role in DM, and that lower fat diets coupled with weight loss can be a preventive strategy . The small protective effects of hormones point to mechanistic directions that may yield future prevention strategies
Observational analyses demonstrate the importance of lifestyle – diet , physical activity and smoking in the development of diabetes in PM women, and show that the inflammatory process is a key component in the development of diabetes
Future genetic studies can explore gene-environment interactions