Relation of statin use with non-melanoma skin cancer: prospective results from the Women\u27s Health Initiative.

BACKGROUND: The relationship between statin use and non-melanoma skin cancer (NMSC) is unclear with conflicting findings in literature. Data from the Women\u27s Health Initiative (WHI) Observational Study and WHI Clinical Trial were used to investigate the prospective relationship between statin use and NMSC in non-Hispanic white (NHW) postmenopausal women. METHODS: The WHI study enrolled women aged 50-79 years at 40 US centres. Among 133 541 NHW participants, 118 357 with no cancer history at baseline and complete medication/covariate data comprised the analytic cohort. The association of statin use (baseline, overall as a time-varying variable, duration, type, potency, lipophilicity) and NMSC incidence was determined using random-effects logistic regression models. RESULTS: Over a mean of 10.5 years of follow-up, we identified 11 555 NMSC cases. Compared with participants with no statin use, use of any statin at baseline was associated with significantly increased NMSC incidence (adjusted odds ratio (ORadj) 1.21; 95% confidence interval (CI): 1.07-1.35)). In particular, lovastatin (OR 1.52; 95% CI: 1.08-2.16), simvastatin (OR 1.38; 95% CI: 1.12-1.69), and lipophilic statins (OR 1.39; 95% CI: 1.18-1.64) were associated with higher NMSC risk. Low and high, but not medium, potency statins were associated with higher NMSC risk. No significant effect modification of the statin-NMSC relationship was found for age, BMI, smoking, solar irradiation, vitamin D use, and skin cancer history. CONCLUSIONS: Use of statins, particularly lipophilic statins, was associated with increased NMSC risk in postmenopausal white women in the WHI cohort. The lack of duration-effect relationship points to possible residual confounding. Additional prospective research should further investigate this relationship.British Journal of Cancer advance online publication, 7 January 2016; doi:10.1038/bjc.2015.376 www.bjcancer.com

Associations of social determinants of health with life expectancy and future health risks among individuals with type 2 diabetes: two nationwide cohort studies in the UK and USA

Background: Social determinants of health (SDHs) are the primary drivers of preventable health inequities, and the associations between SDHs and health outcomes among individuals with type 2 diabetes remain unclear. This study aimed to estimate the associations of combined SDHs with life expectancy and future health risks among adults with type 2 diabetes from the UK and USA. Methods: In an analysis of two nationwide cohort studies, adults with type 2 diabetes were identified from the UK Biobank from March 13, 2006, to Oct 1, 2010 (adults aged 37–73 years) and the US National Health and Nutrition Examination Survey (NHANES) from 1999 to 2018 (adults aged ≥20 years). Participants with type 2 diabetes at baseline were included in our analysis. Participants without information on SDHs or follow-up were excluded. The UK Biobank assessed 17 SDHs and the US NHANES assessed ten SDHs, with each SDH dichotomised into advantaged and disadvantaged levels. The combined score of SDHs were calculated as the sum of the weighted scores for each SDH. Participants were then categorised into tertiles (favourable, medium, and unfavourable SDH groups). Primary outcomes were life expectancy and mortality in both cohorts, and incidences of cardiovascular disease, diabetes-related microvascular disease, dementia, and cancer in the UK Biobank. Outcomes were obtained from disease registries up until Dec 31, 2021, in the UK Biobank and Dec 31, 2019, in the US NHANES cohorts. Findings: We included 17 321 participants from the UK Biobank cohort (median age 61·0 years [IQR 56·0–65·0]; 6028 [34·8%] women and 11 293 [65·2%] men) and 7885 participants from the NHANES cohort (mean age 59·2 years [95% CI 58·7–59·6]; 3835 [49·1%, weighted] women and 4050 [50·9%, weighted] men) in our analysis. In the UK Biobank, 3235 deaths (median follow-up 12·3 years [IQR 11·5–13·2]), 3010 incident cardiovascular disease (12·1 years [10·8–13·0]), 1997 diabetes-related microvascular disease (8·0 years [7·1–8·9]), 773 dementia (12·6 years [11·8–13·5]), and 2259 cancer cases (11·3 years [10·4–12·2]) were documented; and the US NHANES documented 2278 deaths during a median follow-up of 7·0 years (3·7–11·2). After multivariable adjustment, compared with the favourable SDH group, the hazard ratio was 1·33 (95% CI 1·21–1·46) in the medium SDH group and 1·89 (1·72–2·07) in the unfavourable SDH group in the UK Biobank cohort; 1·51 (1·34–1·70) in the medium SDH group and 2·02 (1·75–2·33) in the unfavourable SDH group in the US NHANES cohort for all-cause mortality; 1·13 (1·04–1·24) in the medium SDH group and 1·40 (1·27–1·53) in the unfavourable SDH group for incident cardiovascular disease; 1·13 (1·01–1·27) in the medium SDH group and 1·41 (1·26–1·59) in the unfavourable SDH group for incident diabetes-related microvascular disease; 1·35 (1·11–1·64) in the medium SDH group and 1·76 (1·46–2·13) in the unfavourable SDH group for incident dementia; and 1·02 (0·92–1·13) in the medium SDH group and 1·17 (1·05–1·30) in the unfavourable SDH group for incident cancer in the UK Biobank cohort (ptrend<0·010 for each category). At the age of 45 years, the mean life expectancy of participants was 1·6 years (0·6–2·3) shorter in the medium SDH group and 4·4 years (3·3–5·4) shorter in the unfavourable SDH group than in the favourable SDH group in the UK Biobank. In the US NHAHES cohort, the life expectancy was 1·7 years (0·6–2·7) shorter in the medium SDH group and 3·0 years (1·8–4·3) shorter in the unfavourable SDH group, compared with the favourable group. Interpretation: Combined unfavourable SDHs were associated with a greater loss of life expectancy and higher risks of developing future adverse health outcomes among adults with type 2 diabetes. These associations were similar across two nationwide cohorts from varied social contexts, and were largely consistent across populations with different demographic, lifestyle, and clinical features. Thus, assessing the combined SDHs of individuals with type 2 diabetes might be a promising approach to incorporate into diabetes care to identify socially vulnerable groups and reduce disease burden. Funding: The National Natural Science Foundation of China, the National Key R&D Program of China, and the Fundamental Research Funds for the Central Universities

Dietary Glutamine and Glutamate in Relation to Cardiovascular Disease Incidence and Mortality in the United States Men and Women with Diabetes Mellitus

Background:Evidence regarding the potential health effects of dietary amino acids glutamine and glutamate among individuals with type 2 diabetes (T2D) is limited. Objectives: The aim was to examine dietary glutamine and glutamate in relation to subsequent risk of cardiovascular disease (CVD) and mortality among individuals with T2D.Methods: We prospectively followed 15,040 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1980–2014 and Health Professionals Follow-Up Study: 1986–2018). Diet was repeatedly assessed using validated food frequency questionnaires every 2–4 y. Associations of energy-adjusted glutamine and glutamate intake, as well as their ratio, with CVD risk and mortality, were assessed using Cox proportional-hazards models with adjustments for demographics, dietary and lifestyle factors, and medical history. Results: During 196,955 and 225,371 person-years of follow-up in participants with T2D, there were 2927 incident CVD cases and 4898 deaths, respectively. Higher intake of glutamine was associated with lower risk of CVD incidence, CVD mortality, and total mortality: comparing extreme quintiles, the hazard ratios (HRs) (95% confidence intervals [CIs]) were 0.88 (0.77, 0.99), 0.78 (0.65, 0.92), and 0.84 (0.76, 0.92), respectively (all P-trend &lt; 0.05). In contrast, higher intake of glutamate was associated with a higher risk of CVD incidence, CVD mortality, and total mortality; the HRs were 1.30 (1.15, 1.46), 1.46 (1.24, 1.72), and 1.20 (1.09, 1.32), respectively (all P-trend &lt; 0.05). Furthermore, comparing extreme quintiles, a higher dietary glutamine-to-glutamate ratio was associated with a lower risk of CVD incidence (0.84 [0.75, 0.95]), CVD mortality (0.66 [0.57, 0.77]), and total mortality (0.82 [0.75, 0.90]). In addition, compared with participants with stable or decreased consumption of glutamine-to-glutamate ratio from prediabetes to postdiabetes diagnosis, those who increased the ratio had a 17% (5%, 27%) lower CVD mortality. Conclusions: In adults with T2D, dietary glutamine was associated with a lower risk of CVD incidence and mortality, whereas the opposite was observed for glutamate intake.</p

Dietary Glutamine and Glutamate in Relation to Cardiovascular Disease Incidence and Mortality in the United States Men and Women with Diabetes Mellitus

Background:Evidence regarding the potential health effects of dietary amino acids glutamine and glutamate among individuals with type 2 diabetes (T2D) is limited. Objectives: The aim was to examine dietary glutamine and glutamate in relation to subsequent risk of cardiovascular disease (CVD) and mortality among individuals with T2D.Methods: We prospectively followed 15,040 men and women with T2D at baseline or diagnosed during follow-up (Nurses' Health Study: 1980–2014 and Health Professionals Follow-Up Study: 1986–2018). Diet was repeatedly assessed using validated food frequency questionnaires every 2–4 y. Associations of energy-adjusted glutamine and glutamate intake, as well as their ratio, with CVD risk and mortality, were assessed using Cox proportional-hazards models with adjustments for demographics, dietary and lifestyle factors, and medical history. Results: During 196,955 and 225,371 person-years of follow-up in participants with T2D, there were 2927 incident CVD cases and 4898 deaths, respectively. Higher intake of glutamine was associated with lower risk of CVD incidence, CVD mortality, and total mortality: comparing extreme quintiles, the hazard ratios (HRs) (95% confidence intervals [CIs]) were 0.88 (0.77, 0.99), 0.78 (0.65, 0.92), and 0.84 (0.76, 0.92), respectively (all P-trend &lt; 0.05). In contrast, higher intake of glutamate was associated with a higher risk of CVD incidence, CVD mortality, and total mortality; the HRs were 1.30 (1.15, 1.46), 1.46 (1.24, 1.72), and 1.20 (1.09, 1.32), respectively (all P-trend &lt; 0.05). Furthermore, comparing extreme quintiles, a higher dietary glutamine-to-glutamate ratio was associated with a lower risk of CVD incidence (0.84 [0.75, 0.95]), CVD mortality (0.66 [0.57, 0.77]), and total mortality (0.82 [0.75, 0.90]). In addition, compared with participants with stable or decreased consumption of glutamine-to-glutamate ratio from prediabetes to postdiabetes diagnosis, those who increased the ratio had a 17% (5%, 27%) lower CVD mortality. Conclusions: In adults with T2D, dietary glutamine was associated with a lower risk of CVD incidence and mortality, whereas the opposite was observed for glutamate intake.</p

Effects of moderate/vigorous activity on 3-year body composition changes in postmenopausal women: a target trial emulation.

Background and Objective Postmenopausal women tend to experience significant changes in body composition, particularly abdominal adipose tissue (AAT) deposition patterns, which are hypothesized to be critical factors influencing future cardiometabolic disease risk. Physical activity has a demonstrable effect on body composition and overall health. However, there is little evidence for how different intensities and durations of physical activity over a sustained period of time influence AAT patterns and other measures of body composition in postmenopausal women. We emulated a target trial of physical activity interventions, including the 2018 Physical Activity Guidelines for Americans recommendations, on 3-year changes in AAT and body composition. Methods We analyzed observational data from 4,451 postmenopausal women aged 50-79 years in the Women's Health Initiative (WHI) to emulate a three-year target trial of adhering to increasing minutes of moderate (at least 15, 30, 75, 150, 300 minutes/week) and vigorous (at least 15, 30, 75, 150 minutes/week) physical activity aligned with the physical activity guidelines. All participants had repeated whole body Dual X-Ray Absorptiometry (DXA) scans with derived abdominal visceral (VAT) and subcutaneous adipose tissue (SAT). The measured differences in average levels of VAT, SAT, and other body composition measures determined at end of follow-up were estimated with the parametric-g formula. Results Over 3 years, interventions of increasing minutes of moderate activity would result in dose-dependent reductions in abdominal VAT, SAT, and overall body fat, and increases in lean soft tissue, with the greatest estimated benefit at the 2018 physical activity guideline recommendation of 150 mins/wk or more. Compared to no intervention, if all participants had adhered to at least 150 mins/wk of moderate physical activity, they would have 16.8 cm2 lower VAT (95% CI -23.1, -10.4), 26.8 cm2 lower SAT (95% CI -36.3, -17.3), 1.3% lower total body fat% (95% CI -1.8, -0.7), 1.2 % higher total lean soft tissue% (95% CI 0.7, 1.8), and 2.6 kg lower total bodyweight (95% CI -3.6, -1.5). We saw similar patterns in our vigorous-intensity activity interventions - if all participants adhered to at least 150 mins/wk, they would have experienced 6.7 cm2 lower VAT (95% CI -17.7, 4.3), 13.3 cm2 lower SAT (95% CI -28.8, 2.1), 1.0 % lower total body fat percent (95% CI -2.0, 0.0 ), % higher total lean soft tissue percent (95% CI) and a 0.9 kg lower total bodyweight (95% CI -2.7, 0.8). Conclusion This hypothetical emulated intervention indicated that postmenopausal women who adhere to physical activity guideline recommendations would experience beneficial changes in abdominal VAT, SAT, and overall body composition over 3 years. The study results underscore the imperative to explore further how physical activity may serve as a potential determinant of body composition

An analysis of the association between statin use and risk of endometrial and ovarian cancers in the Women\u27s Health Initiative

© 2018 Background: Statins have anti proliferative activity in vitro against endometrial and ovarian cancer and can affect levels of reproductive hormones. We analyzed data from the Women\u27s Health Initiative (WHI) to assess whether statins are associated with risk of endometrial and ovarian cancer. Methods: The WHI study included 161,808 postmenopausal women in which incident cases of endometrial (n = 1377) and ovarian cancer (n = 763) were identified over an average of 10.8 (SD + 3.3) years. Information on statin use and risk factors was collected at baseline and follow-up. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the association of statin use and risk of endometrial and ovarian cancer. All statistical tests were two-sided. Results: Statins were used at baseline by 7.5% women and by up to 25% at year nine. The multivariable adjusted HR for risk of endometrial cancer for baseline statin use was 0.74, 95% C.I. 0.59–0.94 and for ovarian cancer was 1.15, 95% C.I. 0.89–1.50. In time-dependent models, statins were not associated with endometrial cancer (HR 0.91, 95% C.I. 0.76–1.08) however there was an increased risk of ovarian cancer (HR 1.30, 95% CI 1.04–1.62), largely attributed to the effect of the hydrophilic statin, pravastatin (1.89, 95% CI 1.24–2.88). Conclusions: There was a reduction in risk of endometrial cancer among statin users at baseline but not in time-dependent models. Pravastatin use was associated with an increased risk of ovarian cancer. Analyses of larger numbers of cases are needed to evaluate these findings

Urinary concentrations of phthalate biomarkers and weight change among postmenopausal women: a prospective cohort study

Abstract Background Some phthalates are endocrine disrupting chemicals used as plasticizers in consumer products, and have been associated with obesity in cross-sectional studies, yet prospective evaluations of weight change are lacking. Our objective was to evaluate associations between phthalate biomarker concentrations and weight and weight change among postmenopausal women. Methods We performed cross-sectional (N = 997) and longitudinal analyses (N = 660) among postmenopausal Women’s Health Initiative participants. We measured 13 phthalate metabolites and creatinine in spot urine samples provided at baseline. Participants’ weight and height measured at in-person clinic visits at baseline, year 3, and year 6 were used to calculate body mass index (BMI). We fit multivariable multinomial logistic regression models to explore cross-sectional associations between each phthalate biomarker and baseline BMI category. We evaluated longitudinal associations between each biomarker and weight change using mixed effects linear regression models. Results In cross-sectional analyses, urinary concentrations of some biomarkers were positively associated with obesity prevalence (e.g. sum of di (2-ethylhexyl) phthalate metabolites [ΣDEHP] 4th vs 1st quartile OR = 3.29, 95% CI 1.80–6.03 [p trend< 0.001] vs normal). In longitudinal analyses, positive trends with weight gain between baseline and year 3 were observed for mono-(2-ethyl-5-oxohexyl) phthalate, monoethyl phthalate (MEP), mono-hydroxybutyl phthalate, and mono-hydroxyisobutyl phthalate (e.g. + 2.32 kg [95% CI 0.93–3.72] for 4th vs 1st quartile of MEP; p trend < 0.001). No statistically significant associations were observed between biomarkers and weight gain over 6 years. Conclusions Certain phthalates may contribute to short-term weight gain among postmenopausal women

Prospective association of vitamin D concentrations with mortality in postmenopausal women: Results from the Women\u27s Health Initiative (WHI)

Background: Prospective epidemiologic data on the association between vitamin D and all-cause and cause-specific mortality are limited. Objective: This study aimed to determine whether 25-hydroxyvitamin D [25(OH)D] concentrations were prospectively and independently associated with cardiovascular disease (CVD), cancer, and all-cause mortality in postmenopausal women. Design: A substudy in 2429 postmenopausal women within the Women\u27s Health Initiative (WHI) with measured baseline 25(OH) D concentrations were followed for 10 y for death from CVD, cancer, and all-cause mortality. Proportional hazards models were performed to evaluate quartiles of month-adjusted 25(OH)D concentrations, with adjustment for potential confounders. Sequential model building and analysis for multiplicative interaction were performed to evaluate the effects of central adiposity on the association of low 25(OH)D with all-cause mortality. Results: Of the 2429 women, 224 deaths occurred, with 79 deaths from CVD and 62 deaths from cancer. Multivariate-adjusted HRs that compared quartiles 1 (lowest) to 4 (highest) of 25(OH)D for all-cause mortality (HR: 1.25; 95% CI: 0.80, 1.95), CVD mortality (HR: 1.27; 95% CI: 0.81, 1.99), and cancer mortality (HR: 1.39; 95% CI: 0.88, 2.19) were not significant. There was a potential interaction (P = 0.08) between abdominal obesity and low 25(OH)D concentrations that showed an increased risk of the lowest quartile of 25(OH)D concentrations (HR: 1.85; 95% CI: 1.00, 3.44) with increased mortality in women with a normal waist circumference but no increased risk in women with abdominal obesity (HR: 0.96; 95% CI: 0.52, 1.76). Conclusion: Body fat distribution may play an important role in the modulation of the effect of low vitamin D concentrations on health. This trial was registered at clinicaltrials.gov as NCT 00000611. © 2011 American Society for Nutrition

Healthy lifestyle and risk of incident heart failure with preserved and reduced ejection fraction among post-menopausal women: The Women\u27s Health Initiative study

© 2020 Elsevier Inc. We examined associations of diet, physical activity, cigarette smoking, and body mass index (BMI), separately and as a cumulative lifestyle score, with incident hospitalized HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). This analysis included 40,095 postmenopausal women in the Women\u27s Health Initiative clinical trial and observational studies, aged 50–79 years and without self-reported HF at baseline. A healthy lifestyle score (HLS) was developed, in which women received 1 point for each healthy lifestyle. A weighted HLS was also created to examine the independent magnitude of each of the lifestyle factors in HF subtypes. Trained adjudicators determined cases of incident hospitalized HF, HFpEF, HFrEF through March 2018. Multiple variable Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up period of 14.5 years, 659 incident HFrEF and 1276 HFpEF cases were documented. Across unweighted HLS of 0 (referent), 1, 2, 3, and 4, multivariable adjusted HRs (95% CI) for HFrEF were 1.00, 0.52 (0.38, 0.71), 0.40 (0.29, 0.56), 0.33 (0.23, 0.48), and 0.33 (0.19, 0.56) (P-trend = 0.03) and for HFpEF were 1.00, 0.47 (0.37, 0.59), 0.39 (0.30, 0.49), 0.26 (0.20, 0.34), and 0.23 (0.15, 0.35) (P-trend \u3c 0.001). Results were similar for the weighted HLS. Our findings suggest that following a healthy lifestyle pattern is associated with lower risks of HFpEF and HFrEF among postmenopausal women

The association of walking pace and incident heart failure and subtypes among postmenopausal women

BACKGROUND: To investigate the association between walking pace and the risk of heart failure (HF) and HF sub-types. METHODS: We examined associations of self-reported walking pace with risk of incident HF and HF subtypes of preserved (HFpEF) and reduced (HFrEF) ejection fractions, among 25,183 postmenopausal women, ages 50-79 years. At enrollment into the Women\u27s Health Initiative cohort in 1993-1998, this subset of women was free of HF, cancer, or the inability to walk one block, with self-reported information on walking pace and walking duration. Multivariable Cox regression was used to examine associations of walking pace (casual \u3c2 mph [referent], average 2-3 mph, and fast \u3e3 mph) with incident HF. We also examined the joint association of walking pace and duration with incident HF. RESULTS: There were 1455 incident adjudicated acute decompensated HF hospitalization cases during a median of 16.9 years of follow-up. There was a strong inverse association between walking pace and overall risk of HF (HR = 0.73, 95% CI [0.65, 0.83] for average vs. casual walking; HR = 0.66, 95%CI [0.56, 0.78] for fast vs. casual walking). There were similar associations of walking pace with HFpEF (HR = 0.73, 95%CI [0.62, 0.86] average vs. casual; HR = 0.63, 95%CI [0.50, 0.80] for fast vs. casual) and with HFrEF (HR = 0.72, 95%CI [0.57, 0.91] for average vs. casual; HR = 0.74, 95%CI [0.54, 0.99] for fast vs. casual). The risk of HF associated with fast walking with less than 1 h/week walking duration was comparable with the risk of HF among casual and average walkers with more than 2 h/week walking duration. CONCLUSION: Walking pace was inversely associated with risks of overall HF, HFpEF, and HFrEF in postmenopausal women. Whether interventions to increase the walking pace in older adults will reduce HF risk and whether fast pace will compensate for the short duration of walking warrants further study