Dietary Modification Trial Research Articles

Another treatment gap: Restarting secondary prevention medications: The Women's Health Initiative

Women's long-term patterns of evidence-based preventive medication utilization following a coronary heart disease (CHD) diagnosis have not been sufficiently studied. Postmenopausal women 50-79 years were eligible for randomization in the Women's Health Initiative's (WHI) hormone trials if they met inclusion and exclusion criteria and were >80% adherent during a placebo-lead-in period and in the dietary modification trial if they were willing to follow a 20% fat diet. Those with adjudicated myocardial infarction or coronary revascularization after the baseline visit were included in the analysis (n=2627). Baseline visits occurred between 1993 and 1998, then annually until the trials ended in 2002 through 2005; medication inventories were obtained at baseline and years 1, 3, 6 and 9. Utilization at the first WHI visit following a CHD diagnosis increased over time for statins (49% to 72%; p<0.0001), beta-blockers (49% to 62%; p=0.003), and angiotensin-converting enzyme inhibitors/angiotensin-II receptor blockers (ACEI/ARBs ) [26 to 43%; p<0.0001]. Aspirin use remained stable at 76% (p=0.09). Once women reported using a statin, aspirin, or beta-blocker, 84-89% reported use at 1 or more subsequent visits, with slightly lower rates for ACEI/ARBS (76%). Statin, aspirin, beta-blocker, or ACEI/ARB use was reported at 2 or more consecutive visits by 57%, 66%, 48%, and 28% respectively. These drugs were initiated or resumed at a later visit by 24%, 17%, 15%, and 17%, respectively, and were never used during the period of follow-up by 19%, 10%, 33%, and 49% respectively. Efforts to improve secondary prevention medication utilization should target both drug initiation and restarting drugs in patients who have discontinued them.

Vasomotor Symptoms, Adoption of a Low-Fat Dietary Pattern, and Risk of Invasive Breast Cancer: A Secondary Analysis of the Women's Health Initiative Randomized Controlled Dietary Modification Trial

To assess whether the effect of a low-fat dietary pattern on breast cancer incidence varied by report of baseline vasomotor symptoms. Postmenopausal women age 50 to 79 years enrolled onto the Women's Health Initiative (WHI) Dietary Modification trial from 1993 to 1998 were randomly assigned to a low-fat dietary intervention (n = 19,541) or comparison (n = 29,294). Presence of vasomotor symptoms at baseline was ascertained from a 34-item self-report symptom inventory. Women were queried semi-annually for a new diagnosis of breast cancer. Each case report was verified by medical record and pathology report review by centrally trained WHI physician adjudicators. Among participants who reported hot flashes (HFs) at baseline (n = 3,375), those assigned to the low-fat diet had a breast cancer rate of 0.27 compared with their counterparts in the control group who had a rate of 0.41 (hazard ratio [HR] = 0.65; 95% CI, 0.42 to 1.01). Among women reporting no HFs (n = 45,160), the breast cancer rate was 0.42 in those assigned to the low-fat diet compared with 0.46 in the control group (HR = 0.93; 95% CI, 0.84 to 1.03; P for interaction = .12 by HF status). Furthermore, the dietary benefits observed seemed to be specific to estrogen receptor (ER) -positive/progesterone receptor (PR) -positive tumors (ER positive/PR positive v other, P for risk = .03). Although women with and without HFs differed with regard to breast cancer risk factors, the effect of the diet intervention on breast cancer incidence by HF status was consistent across risk factor strata. The results of this trial, which are hypothesis generating, suggest that HFs may identify a subgroup of postmenopausal women whose risk of invasive breast cancer might be reduced with the adoption of a low-fat eating pattern.

Low-fat, increased fruit, vegetable, and grain dietary pattern, fractures, and bone mineral density: the Women’s Health Initiative Dietary Modification Trial

Background: The effects of dietary changes on osteoporosis, low bone density, and frequent falls are unestablished.Objective: We assessed the effect of the Women’s Health Initiative Dietary Modification low-fat and increased fruit, vegetable, and grain intervention on incident hip, total, and site-specific fractures and self-reported falls, and, in a subset, on bone mineral density (BMD).Design: Postmenopausal women (n = 48,835) aged 50–79 y (18.6% of minority race-ethnicity) were randomly assigned to receive the Dietary Modification intervention (40%, n = 19,541) (daily goal: ≤20% of energy as fat, ≥5 servings of vegetables and fruit, and ≥6 servings of grains) or to a comparison group that received no dietary changes (60%; n = 29,294).Results: After a mean 8.1 y of follow-up, 215 women in the intervention group and 285 women in the comparison group (annualized rate: 0.14% and 0.12%, respectively) experienced a hip fracture (hazard ratio: 1.12; 95% CI: 0.94, 1.34; P = 0.21). The intervention group (n = 5423; annualized rate: 3.44%) had a lower rate of reporting ≥2 falls than did the comparison group (n = 8695; annualized rate: 3.67%) (HR: 0.92; 95% CI: 0.89, 0.96; P < 0.01). There was a significant interaction according to hormone therapy use; those in the comparison group receiving hormone therapy had the lowest incidence of hip fracture. In a subset of 3951 women, hip BMD at years 3, 6, and 9 was 0.4–0.5% lower in the intervention group than in the comparison group (P = 0.003).Conclusions: A low-fat and increased fruit, vegetable, and grain diet intervention modestly reduced the risk of multiple falls and slightly lowered hip BMD but did not change the risk of osteoporotic fractures. This trial was registered at clinicaltrials.gov as NCT00000611.

Biomarker-calibrated energy and protein consumption and increased cancer risk among postmenopausal women.

The authors previously reported equations, derived from the Nutrient Biomarker Study within the Women's Health Initiative, that produce calibrated estimates of energy, protein, and percentage of energy from protein consumption from corresponding food frequency questionnaire estimates and data on other factors, such as body mass index, age, and ethnicity. Here, these equations were applied to yield calibrated consumption estimates for 21,711 women enrolled in the Women's Health Initiative dietary modification trial comparison group and 59,105 women enrolled in the observational study. These estimates were related prospectively to total and site-specific invasive cancer incidence (1993-2005). In combined cohort analyses that do not control for body mass, uncalibrated energy was not associated with total cancer incidence or site-specific cancer incidence for most sites, whereas biomarker-calibrated energy was positively associated with total cancer (hazard ratio = 1.18, 95% confidence interval: 1.10, 1.27, for 20% consumption increase), as well as with breast, colon, endometrial, and kidney cancer (respective hazard ratios of 1.24, 1.35, 1.83, and 1.47). Calibrated protein was weakly associated, and calibrated percentage of energy from protein was inversely associated, with total cancer. Calibrated energy and body mass index associations were highly interdependent. Implications for the interpretation of nutritional epidemiology studies are described.

Multivitamin use and risk of cancer and cardiovascular disease in the Women's Health Initiative cohorts.

Millions of postmenopausal women use multivitamins, often believing that supplements prevent chronic diseases such as cancer and cardiovascular disease (CVD). Therefore, we decided to examine associations between multivitamin use and risk of cancer, CVD, and mortality in postmenopausal women. The study included 161 808 participants from the Women's Health Initiative clinical trials (N = 68 132 in 3 overlapping trials of hormone therapy, dietary modification, and calcium and vitamin D supplements) or an observational study (N = 93 676). Detailed data were collected on multivitamin use at baseline and follow-up time points. Study enrollment occurred between 1993 and 1998; the women were followed up for a median of 8.0 years in the clinical trials and 7.9 years in the observational study. Disease end points were collected through 2005. We documented cancers of the breast (invasive), colon/rectum, endometrium, kidney, bladder, stomach, ovary, and lung; CVD (myocardial infarction, stroke, and venous thromboembolism); and total mortality. A total of 41.5% of the participants used multivitamins. After a median of 8.0 years of follow-up in the clinical trial cohort and 7.9 years in the observational study cohort, 9619 cases of breast, colorectal, endometrial, renal, bladder, stomach, lung, or ovarian cancer; 8751 CVD events; and 9865 deaths were reported. Multivariate-adjusted analyses revealed no association of multivitamin use with risk of cancer (hazard ratio [HR], 0.98, and 95% confidence interval [CI], 0.91-1.05 for breast cancer; HR, 0.99, and 95% CI, 0.88-1.11 for colorectal cancer; HR, 1.05, and 95% CI, 0.90-1.21 for endometrial cancer; HR, 1.0, and 95% CI, 0.88-1.13 for lung cancer; and HR, 1.07, and 95% CI, 0.88-1.29 for ovarian cancer); CVD (HR, 0.96, and 95% CI, 0.89-1.03 for myocardial infarction; HR, 0.99, and 95% CI, 0.91-1.07 for stroke; and HR, 1.05, and 95% CI, 0.85-1.29 for venous thromboembolism); or mortality (HR, 1.02, and 95% CI, 0.97-1.07). After a median follow-up of 8.0 and 7.9 years in the clinical trial and observational study cohorts, respectively, the Women's Health Initiative study provided convincing evidence that multivitamin use has little or no influence on the risk of common cancers, CVD, or total mortality in postmenopausal women.

Vitamin Supplements and Cancer Prevention: Where Do Randomized Controlled Trials Stand?

Vitamin Supplements and Cancer Prevention: Where Do Randomized Controlled Trials Stand?

Should lifestyle modifications be promoted to prevent breast cancer?

Should lifestyle modifications be promoted to prevent breast cancer?

Abstract CN06-02: Fitness versus fatness in breast cancer risk and prognosis

Abstract CN06-02: Fitness versus fatness in breast cancer risk and prognosis

Current Concepts in Diet and Prostate Cancer

Increasing evidence suggests that diet influences the initiation and progression of prostate cancer. Herein, we review associations of specific foods and nutrients with prostate cancer, summarizing important and clinically relevant emerging data on this complex topic. Foods and nutrients associated with a decreased risk of prostate cancer include lycopene, soy, cruciferous vegetables, vitamin E and selenium. Although prospective clinical trials of dietary supplements and dietary modification to prevent or control prostate cancer are underway, definitive clinical evidence is currently lacking.

Low-Fat Dietary Pattern and Risk of Benign Proliferative Breast Disease: A Randomized, Controlled Dietary Modification Trial

Modifiable factors, including diet, might alter breast cancer risk. We used the Women's Health Initiative Dietary Modification trial to test the effect of the intervention on risk of benign proliferative breast disease, a condition associated with increased risk of, and considered to be on the pathway to, invasive breast cancer. The Women's Health Initiative Dietary Modification trial was a randomized, controlled, primary prevention trial conducted in 40 U.S. clinical centers from 1993 to 2005. A total of 48,835 postmenopausal women, ages 50 to 79 years, without prior breast cancer, were enrolled. Participants were randomly assigned to the dietary modification intervention group or to the comparison group. The intervention was designed to reduce total dietary fat intake to 20% of total energy intake, and to increase fruit and vegetable intake to > or =5 servings/d and intake of grain products to > or =6 servings/d, but resulted in smaller, albeit significant, changes in practice. Participants had biennial mammograms and regular clinical breast exams. We identified women who reported breast biopsies free of cancer, obtained the histologic sections, and subjected them to standardized central review. During follow-up (average, 7.7 years), 570 incident cases of benign proliferative breast disease were ascertained in the intervention group and 793 in the comparison group. The hazard ratio for the association between dietary modification and benign proliferative breast disease was 1.09 (95% confidence interval, 0.98-1.23). Risk varied by levels of baseline total vitamin D intake but it varied little by levels of other baseline variables. These results suggest that a modest reduction in fat intake and increase in fruit, vegetable, and grain intake do not alter the risk of benign proliferative breast disease.

Calcium, Vitamin D Supplementation, and Physical Function in the Women's Health Initiative

Objectives The Women's Health Initiative (WHI) randomized trial of calcium/vitamin D supplementation found reduced bone loss with active treatment compared to placebo. Now we examine whether the treatment affected self-reported physical functioning and objective measures of physical functioning. Design A randomized, double-blind, placebo-controlled trial of 1,000 mg calcium carbonate plus 400 IU vitamin D 3 per day or matching placebo pills. Subjects/setting The study included 33,067 women (50 to 79 years old) at 40 US study centers. Main outcome measures Physical functioning was assessed by questionnaire at enrollment in WHI, 1 year prior to calcium/vitamin D trial randomization and at study close-out (average follow-up 7.1 years). Objective physical performance and self-reported exercise measures were collected at WHI baseline (1 year prior to calcium/vitamin D enrollment) and 2 years and 4 years after calcium/vitamin D trial enrollment in a subsample (n=3,137). Statistical analyses performed Calcium/vitamin D effects were tested in unadjusted and interaction linear models for each of the physical function measures. Covariates were baseline total calcium intake, fracture risk score, treatment arm in the hormone therapy and dietary modification trials (ie, active drug or placebo, low-fat diet intervention or usual diet, respectively) and age. Results Neither intention to treat nor high adherence analyses produced substantial effects of calcium/vitamin D compared to placebo on physical functioning or performance. The interaction analyses also did not result in differences because of calcium/vitamin D. Conclusions As the first long-term randomized trial to examine the effectiveness of calcium and vitamin D in protecting against decline of physical functioning in older women, the results did not support benefit.

Reporting on the Women's Health Initiative Dietary Modification Trials: Did the Media Make the Grade?

Reporting on the Women's Health Initiative Dietary Modification Trials: Did the Media Make the Grade?

Use of Recovery Biomarkers to Calibrate Nutrient Consumption Self-Reports in the Women's Health Initiative

Underreporting of energy consumption by self-report is well-recognized, but previous studies using recovery biomarkers have not been sufficiently large to establish whether participant characteristics predict misreporting. In 2004-2005, 544 participants in the Women's Health Initiative Dietary Modification Trial completed a doubly labeled water protocol (energy biomarker), 24-hour urine collection (protein biomarker), and self-reports of diet (assessed by food frequency questionnaire (FFQ)), exercise, and lifestyle habits; 111 women repeated all procedures after 6 months. Using linear regression, the authors estimated associations of participant characteristics with misreporting, defined as the extent to which the log ratio (self-reported FFQ/nutritional biomarker) was less than zero. Intervention women in the trial underreported energy intake by 32% (vs. 27% in the comparison arm) and protein intake by 15% (vs. 10%). Younger women had more underreporting of energy (p = 0.02) and protein (p = 0.001), while increasing body mass index predicted increased underreporting of energy and overreporting of percentage of energy derived from protein (p = 0.001 and p = 0.004, respectively). Blacks and Hispanics underreported more than did Caucasians. Correlations of initial measures with repeat measures (n = 111) were 0.72, 0.70, 0.46, and 0.64 for biomarker energy, FFQ energy, biomarker protein, and FFQ protein, respectively. Recovery biomarker data were used in regression equations to calibrate self-reports; the potential application of these equations to disease risk modeling is presented. The authors confirm the existence of systematic bias in dietary self-reports and provide methods of correcting for measurement error.

Low-Fat Dietary Pattern and Risk of Colorectal Cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Low-Fat Dietary Pattern and Risk of Colorectal Cancer: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Lessons from hormone replacement therapy trials for primary prevention of cardiovascular disease

Coronary heart disease in women is a common cause of morbidity and mortality, particularly after menopause. It was thought that estrogen and progesterone protected women from coronary heart disease. The recommendations of the recent Women's Health Initiative, however, are that hormone replacement therapy should not be used for primary prevention of coronary heart disease in women. Here, we have made a comprehensive review of major studies and comment on the validity of this recommendation. We have also analyzed the importance of dietary modification in primary prevention. In addition, we have delineated the important predictors of cardiovascular disease in women from prior observational and clinical studies. Recent major studies, including the Women's Health Initiative (WHI) and Heart and Estrogen/Progestin Replacement Study (HERS), studied the role of hormone replacement therapy in protecting women from coronary heart disease. These studies showed no significant reduction in coronary heart disease events. In addition, the dietary modification component of the Women's Health Initiative did not show any significant reduction in the incidence of coronary heart disease. It can be summarized that hormone replacement is not generally recommended in postmenopausal women for primary prevention of coronary heart disease. Although the dietary modification trials did not show any significant reduction in the incidence of coronary heart disease, it is currently recommended to continue using a heart-healthy diet.

Predictors of Dietary Change and Maintenance in the Women’s Health Initiative Dietary Modification Trial

Objective To identify predictors of dietary change to and maintenance of a low-fat eating pattern (<20% energy from fat, ≥5 servings fruits/vegetables daily, and ≥6 servings grains daily) among a cohort of postmenopausal women. Candidate predictors included intrapersonal, interpersonal, intervention program characteristics, and clinical center. Design Longitudinal study within the Women’s Health Initiative Dietary Modification Trial. Dietary change was evaluated after 1 year of participation in the Women’s Health Initiative Dietary Modification Trial, and dietary maintenance after 3 years. Subjects Postmenopausal women aged 50 to 79 years at baseline who were randomized to the intervention arm of the Women’s Health Initiative Dietary Modification Trial (n=19,541). Statistical analysis Univariate and multivariate linear regression analysis was performed and associations evaluated between candidate predictors and each of the three dietary goals: percent energy from fat, fruit/vegetable servings, and grain servings. Results Year 1 (change) predictors of percent energy from fat ( P<0.005) included being younger (β=2.12; 70 to 79 years vs 50 to 59 years), more educated (β=–.69; college vs high school), more optimistic (β=–.07), attending more sessions (β=–.69), and submitting more self-monitoring records (β=–.74). At year 3 (maintenance), the predictors of percent energy from fat ( P<0.005) included attending more sessions (β=–.65) and submitting more self-monitoring scores (β=–.71). The analytic model predicted 22% of the variance in fat intake at year 1 and 27% at year 3 ( P<0.01). Conclusions The strongest predictors of dietary change and maintenance were attending intervention sessions and self-monitoring dietary intake. Novel was the finding that optimism predicted dietary change.

Relation of demographic factors, menstrual history, reproduction and medication use to sex hormone levels in postmenopausal women

In postmenopausal women, levels of estrogens, androgens, and perhaps prolactin have been related to risk of breast and other hormonal cancers in women. However, the determinants of these hormone concentrations have not been firmly established. Associations among various demographic, menstrual, and reproductive factors, medication use and endogenous sex hormone concentrations (estradiol, free estradiol, estrone, estrone sulfate, testosterone, free testosterone, sex hormone binding globulin, androstenedione, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), dihydrotestosterone, and prolactin) were evaluated in a cross-sectional analysis from a simple random sample of 274 postmenopausal women selected from the Women's Health Initiative Dietary Modification Trial. In multiple regression analyses on log-transformed hormones, the concentrations of DHEA, and DHEAS were negatively and statistically significantly associated with age (both beta=-0.03, P<0.001, respectively). Estradiol, estrone, DHEA, and free testosterone concentrations were higher in African-American than in non-Hispanic White women, but after multivariate adjustment the associations were statistically significant only for free testosterone (beta=0.38, P=0.01). Women who had a history of bilateral oophorectomy had a mean 35% lower testosterone concentration compared with women with at least one ovary remaining (beta=-0.43, P=0.002), and lower free testosterone (beta=-0.42, P=0.04) after multivariate adjustment. Women who reported regular use of NSAIDs had higher DHEA concentrations (beta=0.20, P=0.04) and lower prolactin concentrations (beta=-0.18, P=0.02) compared with non-users. These results suggest that while age, oophorectomy status, and NSAID use may be associated with selected sex hormone concentrations, few menstrual or reproductive factors affect endogenous sex hormones in the postmenopausal period.

Low-Fat Dietary Pattern and Risk of Cardiovascular Disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Low-Fat Dietary Pattern and Risk of Cardiovascular Disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Exercise and biomarkers for cancer prevention studies.

The International Agency for Research on Cancer estimates that 25% of cancer cases worldwide are caused by overweight or obesity and a sedentary lifestyle. These lifestyle patterns may increase cancer risk by several mechanisms including increased estrogens and testosterone, hyperinsulinemia and insulin resistance, increased inflammation, and depressed immune function. Several randomized clinical trials have shown that physical activity and diet interventions can change biomarkers of cancer risk. In a controlled physical activity trial, we found decreases in serum estrogen, testosterone, and insulin in overweight, sedentary postmenopausal women with a 1-y exercise program consisting of moderate-intensity aerobic exercise, 45 min/d, 5 d/wk. In another controlled trial in middle-aged to older persons, we found that a 1-y exercise intervention of 60 min/d, 6 d/wk, reduced colon crypt cell proliferation in men who adhered closely to the program. Only 1 trial, the Women's Health Initiative Dietary Modification Trial, has published results of a dietary intervention on breast cancer incidence and reported a statistically nonsignificant 9% reduction in invasive breast cancer incidence in postmenopausal women following a low-fat dietary pattern for 8-12 y. Other trials under way are testing effects of weight loss, physical activity, and dietary patterns on other cancer biomarkers. The NCI-funded Transdisciplinary Research on Energetics and Cancer centers are exploring novel research into mechanisms linking energy balance with cancer risk and prevention. The worldwide trends toward increasing overweight and obesity and decreasing physical activity may lead to an increased incidence of several cancers unless other means of risk reduction counteract these effects. Thus, adoption of lifestyle changes by individuals and populations may have a large impact on the future incidence of cancer.

Low-Fat Dietary Pattern and Risk of Cardiovascular Disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial

Low-Fat Dietary Pattern and Risk of Cardiovascular Disease: The Women's Health Initiative Randomized Controlled Dietary Modification Trial