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

Hormone Therapy Trials

Calcium/Vitamin D Trial

Dietary Modification Trial:Breast & Colorectal Cancers (Coronary Heart Disease 2 endpoint)

Observational Study93,676

1 O

bserv

ati

on

al

Stu

dy

48,835

36,282

3 C

on

trolled

Tri

als

27,347

161,808 women total

Women’s Health Initiative

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 (2.1-2.8) 2.6(2.4-2.75) 1.8(1.6-2.0) 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 1.67 1

Ma et al 2012, Diabetes Care 35:1-9

Hormone Therapy and Diabetes

Profile of the E+P Trial Participants for the Analysis of Diabetes Outcome

Provided consent and reportedno hysterectomy (N = 18,845)

Initiated screening (N = 373,092)

Randomized (N = 16,608)

No Diabetes (N = 8014)

5.6 yrs avg followup

Estrogen +Progestin(N = 8,506)

No Diabetes(N = 7627)

5.6 yrs avg followup

Placebo(N = 8,102)

Development of DM in Group treated with E+ P Compared to Placebo

Margolis et al Diabetologia 2004: 47:1175-87

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

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

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

Diet and Diabetes

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.

48,835 randomized to WHI DM Trial

Intervention (40%): Low-fat Dietary Pattern19,541

Comparison (60%):Usual Dietary Pattern 29,294

1993-1998

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

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

Diabetes

0.0

0.0

20

.04

0.0

60

.08

0.1

0

0 1 2 3 4 5 6 7 8 9

Time (years)

Cum

ulat

ive

Haz

ard

InterventionComparison

Intervention:Events 86 102 139 138 172 173 167 134 122 53N at risk18376 18135 17882 17567 17257 16925 16517 14311 9504 4707

Comparison:Events 153 183 232 210 236 245 291 245 143 81N at risk27511 27079 26685 26253 25822 25321 24865 21434 14130 6987

HR = 0.96 (95% CI, 0.90-1.03) P-value = 0.25

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.

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.

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.

Diabetes and Dairy IntakeMedian 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.

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 (0.68-0.83)

0.68 (0.61-0.75)

0.70 (0.64-0.77)

<0.0001

Multivariable model† 1.00 (reference)

0.97 (0.68-1.38)

0.63 (0.43-0.93)

0.48 (0.32-0.73)

0.60 (0.41-0.89)

0.0006

Multivariable model† + dietary glycemic load + dietary total fat + dietary total fiber + total magnesium

1.00 (reference)

0.96 (0.69-1.41)

0.65 (0.44-0.97)

0.50 (0.33-0.76)

0.65 (0.44-0.96)

0.003

Diabetes and Dairy Intake

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

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.

Ca/Vit D and Diabetes

Calcium/Vitamin D Trial and DM Incidence

68,132 WHI CT Participants

31,850 Ineligible or Not Interested

CaD

(N = 18,176)

Placebo

(N = 18,106)

36,282 Randomized

Close-Out

(N=16,936)

Close-Out

(N=16,815)

•1000 mg elemental calcium

as calcium carbonate & 400 IU vitamin D3

•Divided dose; with meals•Avg FU 7.0 yrs

Cumulative incidence of diabetes by calcium/vitamin D treatment assignment

DeBoer et al. 2008; Diabetes Care. 31:701-7.

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

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 0.107 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

Other Risk Factors

Determinants of Racial/Ethnic Disparities in incident Diabetes

Whites Blacks

Physical Activity(7%)

Hispanics Asians

Physical Activity(7%)

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)

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

SMOKING STATUS ADJUSTED HR (95% CI) WEIGHT GAIN <5 KG

ADJUSTED HR (95% CI) WEIGHT GAIN >5 KG

Never Smokers REF 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)

Three year risk of diabetes – smoking status and weight changes

P for interaction = 0.02

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

Conclusions

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

SHBG and Risk of Diabetes

Chen et al, 2012. Clin Chem 58:10

Telomere Length and DM Risk

You et al, 2012. Diabetes

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

Medication Use

Metformin Therapy and Breast CA

Chlebowski, et al, 2012 J Clin Oncol 30:2844-52

Metformin and Breast CA DIABETES (OTHER

MEDICATION)DIABETES (METFORMIN)

N (Ann %) HR (95% CI)

N (Ann %) HR (95% CI) P-value

Invasive BC

12.9 (0.47)

1.16 (0.93- 1.45)

104 (0.40)

0.75 (0.57-0.99)

.04

ER+/PR+ 78 (0.29)

1.08 (0.81-1.48)

59 (0.23)

0.64 (0.45-0.92)

.04

ER+/PR- 17 (0.062)

1.27 (0.68-2.37)

14 (0.054)

1.14 (0.58-2.23)

.72

ER-/PR- 18 (0.066)

1.78 (1.05-3.07)

14 (0.054)

0.68 (0.24-1.59)

.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

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 -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)

Diabetes and Statin Use

Diabetes and Statin Use

Culver et al 2012; Arch Intern Med;172:144-152.

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