Diabetes in Postmenopausal Women The Women’s Health Initiative whi

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

2. Women’s Health Initiative 27,347 36,282 3 Controlled Trials 48,835 93,676 1 Observational Study Hormone Therapy Trials Calcium/Vitamin D Trial Dietary Modification Trial: Breast & Colorectal Cancers (Coronary Heart Disease 2 endpoint) Observational Study 161,808 women total

3. Diabetes Prevalence and Incidence by Ethicity Ma et al 2012, Diabetes Care 35:1-9

4. Hormone Therapy and Diabetes

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

6. Development of DM in Group treated with E+ P Compared to Placebo Margolis et al Diabetologia 2004: 47:1175-87

7. 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 E+P and Incidence of DM

8. Effect of Estrogen alone vs Placebo on DM Incidence Solid: E; Dotted: placebo HR 0.88 (.77-1.01) Bonds et al JCEM 2006: 91:3404-10

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. 48,835 randomized to WHI DM Trial 1993-1998 Intervention (40%): Low-fat Dietary Pattern 19,541 Comparison (60%):Usual Dietary Pattern 29,294 N=1,783 (6%) excluded from analysis for prevalent diabetes N=1,165 (6%) excluded from analysis for prevalent diabetes 2005 N=27,511 analyzed N=18,376 analyzed WHI Dietary Modification Trial To test the effect of a low-fat dietary pattern on breast and colorectal cancers and heart disease in postmenopausal women.

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:1500-11.

14. 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. Low Fat Diet and 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 2011. Am J Clin Nutr 94:1600-6.

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 Margolis et al. 2011; J Nutr. 141:1969-74

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 & 400 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: 628-34

23. Lack of Association of VitD and DM NO interaction by BMI, race or CVD status

24. Other Risk Factors

26. Determinants of Racial/Ethnic Disparities in incident Diabetes Whites Blacks Hispanics Asians Physical Activity(7%) Physical Activity(7%)

27. Smoking and Risk of Diabetes * 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 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: 1898-1904 • Hepatocyte Growth Factor and DM risk • Rajpathak et al 2010; Diabetes Care 33:2013-5

31. SHBG and Risk of Diabetes Chen et al, 2012. Clin Chem 58:10

32. Telomere Length and DM Risk You et al, 2012. Diabetes

33. Enormous Potential for Genetic Studies • Calpain-10 Gene and DM risk • Liu et al 2007, Hum Mol Genet 16:2960-71 • 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: 1812-20 • FTO polymorphisms – obesity but not DM risk • Liu et al 2008, Obesity 16:2472-80 • 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, 2012 J Clin Oncol 30:2844-52

36. Metformin and Breast CA 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. 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 -2.66-0.1) 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 0.57-0.99) Conclusions

38. Diabetes and Statin Use

39. Diabetes and Statin Use Culver et al 2012; Arch Intern Med;172:144-152.

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