Mara Z. Vitolins

Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials.

IMPORTANCE Menopausal hormone therapy continues in clinical use but questions remain regarding its risks and benefits for chronic disease prevention. OBJECTIVE To report a comprehensive, integrated overview of findings from the 2 Womens Health Initiative (WHI) hormone therapy trials with extended postintervention follow-up. DESIGN, SETTING, AND PARTICIPANTS A total of 27,347 postmenopausal women aged 50 to 79 years were enrolled at 40 US centers. INTERVENTIONS Women with an intact uterus received conjugated equine estrogens (CEE; 0.625 mg/d) plus medroxyprogesterone acetate (MPA; 2.5 mg/d) (n = 8506) or placebo (n = 8102). Women with prior hysterectomy received CEE alone (0.625 mg/d) (n = 5310) or placebo (n = 5429). The intervention lasted a median of 5.6 years in CEE plus MPA trial and 7.2 years in CEE alone trial with 13 years of cumulative follow-up until September 30, 2010. MAIN OUTCOMES AND MEASURES Primary efficacy and safety outcomes were coronary heart disease (CHD) and invasive breast cancer, respectively. A global index also included stroke, pulmonary embolism, colorectal cancer, endometrial cancer, hip fracture, and death. RESULTS During the CEE plus MPA intervention phase, the numbers of CHD cases were 196 for CEE plus MPA vs 159 for placebo (hazard ratio [HR], 1.18; 95% CI, 0.95-1.45) and 206 vs 155, respectively, for invasive breast cancer (HR, 1.24; 95% CI, 1.01-1.53). Other risks included increased stroke, pulmonary embolism, dementia (in women aged ≥65 years), gallbladder disease, and urinary incontinence; benefits included decreased hip fractures, diabetes, and vasomotor symptoms. Most risks and benefits dissipated postintervention, although some elevation in breast cancer risk persisted during cumulative follow-up (434 cases for CEE plus MPA vs 323 for placebo; HR, 1.28 [95% CI, 1.11-1.48]). The risks and benefits were more balanced during the CEE alone intervention with 204 CHD cases for CEE alone vs 222 cases for placebo (HR, 0.94; 95% CI, 0.78-1.14) and 104 vs 135, respectively, for invasive breast cancer (HR, 0.79; 95% CI, 0.61-1.02); cumulatively, there were 168 vs 216, respectively, cases of breast cancer diagnosed (HR, 0.79; 95% CI, 0.65-0.97). Results for other outcomes were similar to CEE plus MPA. Neither regimen affected all-cause mortality. For CEE alone, younger women (aged 50-59 years) had more favorable results for all-cause mortality, myocardial infarction, and the global index (nominal P < .05 for trend by age). Absolute risks of adverse events (measured by the global index) per 10,000 women annually taking CEE plus MPA ranged from 12 excess cases for ages of 50-59 years to 38 for ages of 70-79 years; for women taking CEE alone, from 19 fewer cases for ages of 50-59 years to 51 excess cases for ages of 70-79 years. Quality-of-life outcomes had mixed results in both trials. CONCLUSIONS AND RELEVANCE Menopausal hormone therapy has a complex pattern of risks and benefits. Findings from the intervention and extended postintervention follow-up of the 2 WHI hormone therapy trials do not support use of this therapy for chronic disease prevention, although it is appropriate for symptom management in some women. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000611.

One-year weight losses in the Look AHEAD study: factors associated with success.

This report provides a further analysis of the first year weight losses in the Look AHEAD (Action for Health in Diabetes) study and identifies factors associated with success. Participants were a total of 5,145 men and women with type 2 diabetes who were recruited at 16 sites and randomly assigned to an intensive lifestyle intervention (ILI) or a control condition, Diabetes Support and Education (DSE). During year 1, participants in ILI received comprehensive diet and physical activity counseling in a total of 42 group and individual sessions, compared with three educational sessions for DSE participants. As reported previously, at the end of the year, ILI participants lost 8.6% of initial weight, compared to 0.7% for DSE (P < 0.001). Within the ILI group, all racial/ethnic groups achieved clinically significant weight losses (>5.5%), although there were significant differences among groups. For the year, ILI participants attended an average of 35.4 treatment sessions and reported exercising a mean of 136.6 min/week and consuming a total of 360.9 meal replacement products. Greater self‐reported physical activity was the strongest correlate of weight loss, followed by treatment attendance and consumption of meal replacements. The use of orlistat, during the second half of the year, increased weight loss only marginally in those ILI participants who had lost <5% of initial weight during the first 6 months and chose to take the medication thereafter as a toolbox option. The lifestyle intervention was clinically effective in all subsets of an ethnically and demographically diverse population.

Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer

BACKGROUND Although some observational studies have associated higher calcium intake and especially higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk, no randomized trial has evaluated these relationships. METHODS Postmenopausal women (N = 36 282) who were enrolled in a Womens Health Initiative clinical trial were randomly assigned to 1000 mg of elemental calcium with 400 IU of vitamin D(3) daily or placebo for a mean of 7.0 years to determine the effects of supplement use on incidence of hip fracture. Mammograms and breast exams were serially conducted. Invasive breast cancer was a secondary outcome. Baseline serum 25-hydroxyvitamin D levels were assessed in a nested case-control study of 1067 case patients and 1067 control subjects. A Cox proportional hazards model was used to estimate the risk of breast cancer associated with random assignment to calcium with vitamin D(3). Associations between 25-hydroxyvitamin D serum levels and total vitamin D intake, body mass index (BMI), recreational physical activity, and breast cancer risks were evaluated using logistic regression models. Statistical tests were two-sided. RESULTS Invasive breast cancer incidence was similar in the two groups (528 supplement vs 546 placebo; hazard ratio = 0.96; 95% confidence interval = 0.85 to 1.09). In the nested case-control study, no effect of supplement group assignment on breast cancer risk was seen. Baseline 25-hydroxyvitamin D levels were modestly correlated with total vitamin D intake (diet and supplements) (r = 0.19, P < .001) and were higher among women with lower BMI and higher recreational physical activity (both P < .001). Baseline 25-hydroxyvitamin D levels were not associated with breast cancer risk in analyses that were adjusted for BMI and physical activity (P(trend) = .20). CONCLUSIONS Calcium and vitamin D supplementation did not reduce invasive breast cancer incidence in postmenopausal women. In addition, 25-hydroxyvitamin D levels were not associated with subsequent breast cancer risk. These findings do not support a relationship between total vitamin D intake and 25-hydroxyvitamin D levels with breast cancer risk.

Four-year weight losses in the Look AHEAD study: factors associated with long-term success.

This report provides a further analysis of the year 4 weight losses in the Look AHEAD (Action for Health in Diabetes) study and identifies factors associated with long‐term success. A total of 5,145 overweight/obese men and women with type 2 diabetes were randomly assigned to an intensive lifestyle intervention (ILI) or a usual care group, referred to as Diabetes Support and Education (DSE). ILI participants were provided approximately weekly group or individual treatment in year 1; continued but less frequent contact was provided in years 2–4. DSE participants received three group educational sessions in all years. As reported previously, at year 4, ILI participants lost an average of 4.7% of initial weight, compared with 1.1% for DSE (P < 0.0001). More ILI than DSE participants lost ≥5% (46% vs. 25%, P < 0.0001) and ≥10% (23% vs. 10%, P < 0.0001) of initial weight. Within the ILI, achievement of both the 5% and 10% categorical weight losses at year 4 was strongly related to meeting these goals at year 1. A total of 887 participants in ILI lost ≥10% at year 1, of whom 374 (42.2%) achieved this loss at year 4. Participants who maintained the loss, compared with those who did not, attended more treatment sessions and reported more favorable physical activity and food intake at year 4. These results provide critical evidence that a comprehensive lifestyle intervention can induce clinically significant weight loss (i.e., ≥5%) in overweight/obese participants with type 2 diabetes and maintain this loss in more than 45% of patients at 4 years.

Validity and Reproducibility of a Food Frequency Interview in a Multi-Cultural Epidemiologic Study

PURPOSE: There is limited support for the validity and reproducibility of dietary assessment in culturally diverse populations. The goal of this study was to evaluate the comparative validity and reproducibility of a Food Frequency Questionnaire (FFQ) used in the observational, multi-cultural Insulin Resistance Atherosclerosis Study (IRAS). METHODS: Women (n = 186) were approximately equally distributed by ethnicity from one urban center (African Americans and non-Hispanic whites) and one rural center (Hispanics and non-Hispanic whites). The IRAS FFQ was modified from the National Cancer Institute Health Habits and History Questionnaire to include ethnic and regional foods. Validity was assessed by comparing dietary values, including supplements, obtained from the FFQ to the average intake estimated from a series of 8 24-hour dietary recalls collected by telephone over the same 1-year period. Reproducibility was assessed among women who reported no change in their usual diet (n = 133) by comparing data from the original IRAS FFQ (in-person) with the FFQ administered for the validity study (two to four years later, by telephone). RESULTS: Correlation coefficients for validity were statistically significant for most nutrients (mean r = 0.62 urban non-Hispanic white, 0.61 rural non-Hispanic whites, 0.50 African American, 0.41 Hispanic) and did not differ among subgroups of obesity or diabetes status. The median correlation coefficient for the total sample was 0.49. Correlations were lower for women with less than 12 years of education (mean r = 0.30; median r = 0.25). The lower correlations among Hispanics was largely explained by the lower educational attainment in that sample. For reproducibility, the mean correlation for nutrients evaluated was r = 0.62 (median r = 0.63) and did not differ for subgroups. CONCLUSIONS: Although educational attainment must be considered, the IRAS FFQ appears to be reasonably valid and reliable in a diverse cohort.

Deteriorating dietary habits among adults with hypertension: DASH dietary accordance, NHANES 1988-1994 and 1999-2004.

BACKGROUND Although the DASH (Dietary Approaches to Stop Hypertension trial) diet is among the therapeutic lifestyle changes recommended for individuals with hypertension (HTN), accordance with the DASH diet is not known. METHODS Using data from the National Health and Nutrition Examination Survey (NHANES) from the 1988-1994 and 1999-2004 periods, DASH accordance among individuals with self-reported HTN was estimated based on 9 nutrient targets (fat, saturated fat, protein, cholesterol, fiber, magnesium, calcium, sodium, and potassium) (score range, 0-9). Using data from 1999-2004, we compared the DASH score among demographic groups in age- and energy-adjusted models and modeled the odds of a DASH-accordant dietary pattern (>or=4.5) using multivariable logistic regression. The DASH score, DASH accordance, and percentage of participants achieving individual targets were compared with estimates from NHANES 1988-1994 data. RESULTS Based on 4386 participants with known HTN in the recent survey period (1999-2004), the mean (SE) DASH score, after adjustment for age and energy intake, was 2.92 (0.05), with 19.4% (1.2%) classified as DASH accordant. In multivariable logistic regression models, DASH accordance was associated with older age, nonblack ethnicity, higher education, and known diabetes mellitus. Accordance with DASH was 7.3% lower in the recent survey period compared with NHANES 1988-1994 (26.7% [1.1%]) (P < .001), reflecting fewer patients with HTN meeting nutrient targets for total fat, fiber, and magnesium. CONCLUSION The dietary profile of adults with HTN in the United States has a low accordance with the DASH dietary pattern, and the dietary quality of adults with HTN has deteriorated since the introduction of the DASH diet, suggesting that secular trends have minimized the impact of the DASH message.

Measuring Adherence to Behavioral and Medical Interventions

Measuring adherence to medical and behavioral interventions is important to clinicians and researchers since inadequate adherence can reduce the effectiveness of an intervention. Unfortunately, there is no gold standard for measuring adherence across health behaviors. Adherence needs to be defined situationally with parameters of acceptable adherence carefully delineated and appropriate to the health behavior being studied. Additionally, measurement methods must be valid, reliable, and sensitive to change; this paper reviews these criteria. Methods used to measure adherence to dietary interventions include 24-hour recalls, food diaries, and food frequency questionnaires. Direct and indirect calorimetry, doubly labeled water, and a variety of self-report methods can be used to measure adherence in physical activity interventions. Adherence to pharmacological interventions is assessed using self-report methods, biochemical measures, medication counts, and the automated pharmacy database review strategy. The strengths and weaknesses of these methods for measuring adherence to dietary, physical activity, and pharmacological interventions are reviewed. Control Clin Trials 2000;21:188S-194S

One-Year Results of a Community-Based Translation of the Diabetes Prevention Program Healthy-Living Partnerships to Prevent Diabetes (HELP PD) Project

OBJECTIVE Although the Diabetes Prevention Program (DPP) and the Finnish Diabetes Prevention Study (FDPS) demonstrated that weight loss from lifestyle change reduces type 2 diabetes incidence in patients with prediabetes, the translation into community settings has been difficult. The objective of this study is to report the first-year results of a community-based translation of the DPP lifestyle weight loss (LWL) intervention on fasting glucose, insulin resistance, and adiposity. RESEARCH DESIGN AND METHODS We randomly assigned 301 overweight and obese volunteers (BMI 25–40 kg/m2) with fasting blood glucose values between 95 and 125 mg/dL to a group-based translation of the DPP LWL intervention administered through a diabetes education program (DEP) and delivered by community health workers (CHWs) or to an enhanced usual-care condition. CHWs were volunteers with well-controlled type 2 diabetes. A total of 42.5% of participants were male, mean age was 57.9 years, 26% were of a race/ethnicity other than white, and 80% reported having an education beyond high school. The primary outcome is mean fasting glucose over 12 months of follow-up, adjusting for baseline glucose. RESULTS Compared with usual-care participants, LWL intervention participants experienced significantly greater decreases in blood glucose (−4.3 vs. −0.4 mg/dL; P < 0.001), insulin (−6.5 vs. −2.7 μU/mL; P < 0.001), homeostasis model assessment of insulin resistance (−1.9 vs. −0.8; P < 0.001), weight (−7.1 vs. −1.4 kg; P < 0.001), BMI (−2.1 vs. −0.3 kg/m2; P < 0.001), and waist circumference (−5.9 vs. −0.8 cm; P < 0.001). CONCLUSIONS This translation of the DPP intervention conducted in community settings, administered through a DEP, and delivered by CHWs holds great promise for the prevention of diabetes by significantly decreasing glucose, insulin, and adiposity.

Reproductive History and Oral Contraceptive Use in Relation to Risk of Triple-Negative Breast Cancer

BACKGROUND Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers. METHODS Using data from 155,723 women enrolled in the Womens Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs). RESULTS Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10,000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10,000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype. CONCLUSION The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further confirmation because the biological mechanisms underlying these differences are uncertain.

Diabetes, Metformin, and Breast Cancer in Postmenopausal Women

PURPOSE Emerging evidence suggests that metformin may reduce breast cancer incidence, but reports are mixed and few provide information on tumor characteristics. Therefore, we assessed associations among diabetes, metformin use, and breast cancer in postmenopausal women participating in Womens Health Initiative clinical trials. PATIENTS AND METHODS In all, 68,019 postmenopausal women, including 3,401 with diabetes at study entry, were observed over a mean of 11.8 years with 3,273 invasive breast cancers diagnosed. Diabetes incidence status was collected throughout follow-up, with medication information collected at baseline and years 1, 3, 6, and 9. Breast cancers were confirmed by review of central medical records and pathology reports. Cox proportional hazards regression, adjusted for breast cancer risk factors, compared breast cancer incidence in women with diabetes who were metformin users or nonusers with breast cancer incidence in women without diabetes. RESULTS Compared with that in women without diabetes, breast cancer incidence in women with diabetes differed by diabetes medication type (P = .04). Women with diabetes receiving medications other than metformin had a slightly higher incidence of breast cancer (hazard ratio [HR], 1.16; 95% CI, 0.93 to 1.45), and women with diabetes who were given metformin had lower breast cancer incidence (HR, 0.75; 95% CI, 0.57 to 0.99). The association was observed for cancers positive for both estrogen receptor and progesterone receptor and those that were negative for human epidermal growth factor receptor 2. CONCLUSION Metformin use in postmenopausal women with diabetes was associated with lower incidence of invasive breast cancer. These results can inform future studies evaluating metformin use in breast cancer management and prevention.