Income variability and incident cardiovascular disease in diabetes: a population-based cohort study.

BACKGROUND AND AIMS: Longitudinal change in income is crucial in explaining cardiovascular health inequalities. However, there is limited evidence for cardiovascular disease (CVD) risk associated with income dynamics over time among individuals with type 2 diabetes (T2D). METHODS: Using a nationally representative sample from the Korean National Health Insurance Service database, 1 528 108 adults aged 30-64 with T2D and no history of CVD were included from 2009 to 2012 (mean follow-up of 7.3 years). Using monthly health insurance premium information, income levels were assessed annually for the baseline year and the four preceding years. Income variability was defined as the intraindividual standard deviation of the percent change in income over 5 years. The primary outcome was a composite event of incident fatal and nonfatal CVD (myocardial infarction, heart failure, and stroke) using insurance claims. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated after adjusting for potential confounders. RESULTS: High-income variability was associated with increased CVD risk (HRhighest vs. lowest quartile 1.25, 95% CI 1.22-1.27; Ptrend < .001). Individuals who experienced an income decline (4 years ago vs. baseline) had increased CVD risk, which was particularly notable when the income decreased to the lowest level (i.e. Medical Aid beneficiaries), regardless of their initial income status. Sustained low income (i.e. lowest income quartile) over 5 years was associated with increased CVD risk (HRn = 5 years vs. n = 0 years 1.38, 95% CI 1.35-1.41; Ptrend < .0001), whereas sustained high income (i.e. highest income quartile) was associated with decreased CVD risk (HRn = 5 years vs. n = 0 years 0.71, 95% CI 0.70-0.72; Ptrend < .0001). Sensitivity analyses, exploring potential mediators, such as lifestyle-related factors and obesity, supported the main results. CONCLUSIONS: Higher income variability, income declines, and sustained low income were associated with increased CVD risk. Our findings highlight the need to better understand the mechanisms by which income dynamics impact CVD risk among individuals with T2D.

Association between physical activity changes and risk of incident ischemic stroke following cancer diagnosis: A nationwide retrospective cohort study.

BACKGROUND: Physical inactivity is prevalent after cancer treatment, which could increase ischemic stroke risk in cancer survivors. This study investigated the association between physical activity change from pre- to post-diagnosis and ischemic stroke risk among cancer survivors. METHODS: Using data from the Korean National Health Insurance Service database, 269,943 cancer survivors (mean [SD] age, 56.3 [12.1] years; 45.7% male) with no history of cardiovascular disease were evaluated based on changes in physical activity from pre- to post-diagnosis. Using the Fine-Gray model, subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs) for ischemic stroke risk were calculated, considering death as a competing risk. RESULTS: After cancer diagnosis, 62.0% remained inactive, 10.1% remained active, 16.6% became active, and 11.4% became inactive. During a mean (SD) follow-up of 4.1 (2.0) years, being active both pre- and post-diagnosis was associated with a 15% decreased risk of ischemic stroke (sHR, 0.85; 95% CI, 0.75-0.96), compared with those who remained inactive. Cancer survivors who became active and inactive post-diagnosis showed a 16% and 11% lower ischemic stroke risk (sHR, 0.84; 95% CI, 0.75-0.93; sHR, 0.89; 95% CI, 0.79-0.99), respectively, than those who remained inactive. Analysis by the primary cancer site did not substantially differ from the main findings. CONCLUSIONS: Physical activity is associated with reduced ischemic stroke risk among cancer survivors. The potential benefits of physical activity are not limited to individuals who were physically active before cancer diagnosis, thus preventive strategies against ischemic stroke should emphasize physical activity throughout the cancer journey.

Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors.

BACKGROUND: The risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. This study aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment. METHODS: Using data from the Korean Health Insurance Service database (2010-2017), 113,232 women newly diagnosed with breast cancer (aged ≥ 18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n = 566,160) (mean[SD] follow-up, 5.1[2.1] years). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities. RESULTS: BCS had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger BCS (age < 40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older BCS, especially those aged > 65 years. Use of anthracyclines was associated with increased AF risk among BCS (sHR 1.57; 95% CI 1.28-1.92), which was more robust in younger BCS (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤ 50 years). CONCLUSIONS: Our findings suggest that younger BCS had an elevated risk of incident AF, regardless of the length of follow-up. Use of anthracyclines may be associated with increased mid-to-long-term AF risk among BCS.

Association between healthy dietary patterns and markers of oxidative stress in the Sister Study.

PURPOSE: We assessed the cross-sectional association between healthy dietary patterns [alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] and urinary biomarkers of oxidative stress. METHODS: Between 2003 and 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35 to 74 (non-Hispanic White, 83.7%). Data were analyzed for 844 premenopausal and 454 postmenopausal women who had urine samples analyzed for F2-isoprostanes and non-missing covariate data. Food frequency questionnaire responses were used to calculate dietary pattern scores. Concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were measured in urine samples by GC/MS for premenopausal women and LC/MS for postmenopausal women. Multivariable linear regression models were used to estimate associations between aMED, DASH, aHEI, and HEI-2015 and urinary F2-isoprostanes by menopausal status. Effect modification by sociodemographic, lifestyle, and clinical characteristics was also evaluated. RESULTS: Among premenopausal women, the four dietary indices were inversely associated with 8-iso-PGF2α (aMED ßQ4vsQ1: - 0.17, 95% CI - 0.27, - 0.08; DASH ßQ4vsQ1: - 0.18, 95% CI - 0.28, - 0.08; aHEI ßQ4vsQ1: - 0.20, 95% CI - 0.30, - 0.10; HEI-2015 ßQ4vsQ1: - 0.19, 95% CI - 0.29, - 0.10). In contrast, inverse associations with 8-iso-PGF2α-M were found for the continuous aMED, aHEI, and HEI-2015. Associations between dietary indices and 8-iso-PGF2α were generally stronger among younger women, women with lower income, and women with higher BMI. Similar results were observed among postmenopausal women, though only the continuous DASH and aHEI models were statistically significant. CONCLUSION: Healthy dietary patterns were associated with lower levels of oxidative stress.

Synergistic association between underweight and type 2 diabetes on the development of laryngeal cancer: a national population-based retrospective cohort study.

BACKGROUND: Although cigarette smoking is the most significant risk factor for laryngeal cancer, other risk factors might also be associated with the development of laryngeal cancer. We investigated whether underweight and type 2 diabetes are associated with laryngeal cancer in a Korean population. METHODS: A total of 9,957,059 participants (≥20 years) without prior history of cancer who underwent a National Health Insurance Service health checkup in 2009 were followed up until December 31, 2018. Newly diagnosed laryngeal cancer was identified using claim data, and underweight was defined as body mass index (BMI) < 18.5 kg/m2. A Cox proportional-hazards models with multivariable adjustment were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs). RESULTS: During the median follow-up period of 8.3 years, 3504 cases of laryngeal cancer occurred. Underweight was associated with increased risk of laryngeal cancer after adjusting for potential confounders (HR: 1.43, 95% CI: 1.22-1.69) compared to those who were not underweight. Underweight and type 2 diabetes were synergistically associated with higher risk of laryngeal cancer (HR: 2.33, 95% CI: 1.54-3.51), compared to those without either condition. This relationship was stronger in those with an age < 65 years (HR: 3.33, 95% CI: 1.88-5.87) and alcohol consumption (HR: 2.72, 95% CI: 1.64-4.53). CONCLUSIONS: These results suggest that underweight may be a significant risk factor for laryngeal cancer and that underweight and type 2 diabetes might synergistically increase the risk of laryngeal cancer.

Association of dietary and plasma carotenoids with urinary F2-isoprostanes.

PURPOSE: Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations between carotenoids and biomarkers of oxidative stress or inflammation. METHODS: From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35-74. Post-menopausal participants (n = 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of ß-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were also measured. Since the biomarker 8-iso-PGF2α can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF2α to prostaglandin F2α ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations. RESULTS: Total plasma carotenoids were inversely associated with 8-iso-PGF2α-M concentrations (P for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and ß-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF2α; Phighest vs. lowest quartile = 0.04 and P for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF2α, suggesting an additional anti-inflammatory effect. Supplemental ß-carotene was inversely associated with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF2α. Dietary carotenoids were not associated with either biomarker. CONCLUSION: Plasma carotenoids and supplemental ß-carotene were associated with lower concentrations of 8-iso-PGF2α metabolite. Plasma carotenoids associations may reflect antioxidant effects.

Associations of general obesity and central obesity with the risk of hepatocellular carcinoma in a Korean population: A national population-based cohort study.

Numerous previous studies have shown an association between general obesity and hepatocellular carcinoma (HCC). However, relatively few reports on the association of central obesity and HCC are available in Asian populations. Therefore, we investigated the association between WC representing central obesity and the risk of HCC in addition to BMI representing general obesity and the risk of HCC in Korea. A total of 10 505 818 participants who received the National Health Insurance Service (NHIS) health checkups in 2009 were screened for study eligibility, and 26 979 cases of HCC occurred during the 7.3 years of mean follow-up. General obesity increased the risk of HCC with hazard ratios (HRs) of 1.14 (95% CI, 1.11-1.18) for BMI 25.0-<30.0 kg/m2 and 1.52 (95% CI, 1.43-1.61) for BMI ≥30 kg/m2 compared to those whose BMI is within the normal range. Central obesity was also associated with a higher risk of HCC. For the participants with a WC ≥105 cm in men and WC ≥100 cm in women, the risk of HCC was higher than that of the reference group (HR = 1.69, 95% CI, 1.54-1.85). The HRs were 1.13 (95% CI, 1.07-1.19) for nonobese participants with central obesity, and 1.34 (95% CI, 1.30-1.38) for obese participants with central obesity compared to those without both conditions. Our findings suggest that the risk of HCC increases even more when general obesity is combined with central obesity. Moreover, central obesity is associated with the risk of HCC, regardless of general obesity.

Dietary inflammatory potential, oxidative balance score, and risk of breast cancer: Findings from the Sister Study.

Diet, inflammation, and oxidative stress may be important in breast carcinogenesis, but evidence on the role of the inflammatory and prooxidative potential of dietary patterns is limited. Energy adjusted-Dietary Inflammatory Index (E-DII™) and dietary oxidative balance score (D-OBS) were calculated for 43 563 Sister Study cohort participants who completed a Block 1998 food frequency questionnaire at enrollment in 2003-2009 and satisfied eligibility criteria. D-OBS was validated using measured F2 -isoprostanes and metabolites. High E-DII score and low D-OBS represent a more proinflammatory and prooxidant diet, respectively, and associations of quartiles of each index with breast cancer (BC) risk were estimated using multivariable Cox proportional hazards regression. There were 2619 BCs diagnosed at least 1 year after enrollment (mean follow-up 8.4 years). There was no overall association between E-DII and BC risk, whereas there was a suggestive inverse association for the highest vs lowest quartile of D-OBS (HR 0.92 [95% CI, 0.81-1.03]). The highest quartile of E-DII was associated with risk of triple-negative BC (HR 1.53 [95% CI, 0.99-2.35]). When the two indices were combined, a proinflammatory/prooxidant diet (highest tertile of E-DII and lowest tertile of D-OBS) was associated with increased risk for all BC (HR 1.13 [95% CI, 1.00-1.27]) and for triple-negative BC (1.72 [95% CI, 1.10-2.70]), compared to an antiinflammatory/antioxidant diet (lowest tertile of E-DII and highest tertile of D-OBS). Diets with increased inflammatory potential and reduced oxidative balance were positively associated with overall and triple-negative BC.

Making sense of associations between type 2 diabetes, metformin, and breast cancer risk.

The relationship between type 2 diabetes (T2D), metformin, and breast cancer is complex. T2D may increase risk, but metformin used as first-line treatment of T2D may decrease breast cancer risk. This comment explores efforts to disentangle effects of T2D and metformin use on breast cancer risk in a prospective study.

Obesity and breast cancer risk for pre- and postmenopausal women among over 6 million Korean women.

PURPOSE: To examine the association between obesity measured by body mass index (BMI) and waist circumference (WC) according to menopausal status in Korean women. METHODS: We identified 6,467,388 women, using the Korean National Health Insurance System Cohort. Cox-proportional hazard models were used to generate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for breast cancer risk in relation to BMI and WC. RESULTS: In postmenopausal women, the risk of breast cancer increased with BMI. Compared to women with a BMI of 18.5-23 kg/m two, the risk of invasive breast cancer was lower in patients with BMI < 18.5 (aHR 0.82, 95% CI 0.75-0.89), while it increased linearly in those with BMI 23-25 (1.11, 1.08-1.14), BMI 25-30 (1.28, 1.25-1.32), and BMI ≥ 30 (1.54,1.47-1.62). In contrast, the risk of breast cancer decreased with BMI in premenopausal women. Compared to women with a BMI of 18.5-23, the risk of IBC was similar in those with a BMI < 18.5 (1.02, 0.94-1.11) and BMI 23-25 (1.01, 0.97-1.05), but was significantly lower in those with a BMI 25-30 (0.95, 0.91-0.98) and BMI ≥ 30 (0.90, 0.82-0.98). A relative increase with BMI was less profound for carcinoma in situ in postmenopausal women, and a relative decrease was more profound in premenopausal women. An analysis using WC showed almost identical results. CONCLUSIONS: There was a positive relationship between obesity and breast cancer in postmenopausal women, and an inverse association in premenopausal women.

Relationship between diet quality scores and the risk of frailty and mortality in adults across a wide age spectrum.

BACKGROUND: Beyond intakes of total energy and individual nutrient, eating patterns may influence health, and thereby the risk of adverse outcomes. How different diet measures relate to frailty-a general measure of increased vulnerability to unfavorable health outcomes-and mortality risk, and how this might vary across the life course, is not known. We investigated the associations of five dietary indices (Nutrition Index (NI), the energy-density Dietary Inflammatory Index (E-DII™), Healthy Eating Index-2015 (HEI-2015), Mediterranean Diet Score (MDS), and Dietary Approaches to Stop Hypertension (DASH)) with frailty and mortality. METHODS: We included 15,249 participants aged ≥ 20 years from the 2007-2012 cohorts of the National Health and Nutrition Examination Survey (NHANES). The NI combined 31 nutrition-related deficits. The E-DII is a literature-derived dietary index associated with inflammation. The HEI-2015 assesses adherence to the Dietary Guidelines of Americans. The MDS represents adherence to the traditional Mediterranean diet. DASH combines macronutrients and micronutrients to prevent hypertension. Frailty was evaluated using a 36-item frailty index. Mortality status was ascertained up to December 31, 2015. RESULTS: Participants' mean age was 47.2 ± 16.7 years and 51.7% were women. After adjusting for age, sex, race, educational level, marital and employment status, smoking, BMI, and study cohort, higher NI and E-DII scores and lower HEI-2015, MDS, and DASH scores were individually significantly associated with frailty. All dietary scores were significantly associated with 8-year mortality risk after adjusting for basic covariates and frailty: NI (hazard ratio per 0.1 point, 1.15, 95%CI 1.10-1.21), E-DII (per 1 point, 1.05, 1.01-1.08), HEI-2015 (per 10 points, 0.93, 0.89-0.97), MDS (per 1 point, 0.94, 0.90-0.97), and DASH (per 1 point, 0.96, 0.93-0.99). The associations of E-DII, HEI-2015, and MDS scores with 8-year mortality risk persisted after additionally adjusting for NI. CONCLUSIONS: NI, E-DII, HEI-2015, MDS, and DASH scores are associated with frailty and 8-year mortality risk in adults across all ages. Nevertheless, their mechanisms and sensitivity to predict health outcomes may differ. Nutrition scores have the potential to include measures of both consumption and laboratory and physical measures of exposure.

Association between meat consumption and risk of breast cancer: Findings from the Sister Study.

Meat consumption has been postulated to increase the risk of breast cancer, but this association has not been consistently seen. We examined the association between consumption of different types of meat, meat mutagens and incident invasive breast cancer. Information on consumption of different meat categories and meat cooking practice behaviors was obtained from 42,012 Sister Study participants who completed a Block 1998 Food Frequency Questionnaire at enrollment (2003-2009) and satisfied eligibility criteria. Exposure to meat type and meat mutagens was calculated, and associations with invasive breast cancer risk were estimated using multivariable Cox proportional hazards regression. During follow-up (mean, 7.6 years), 1,536 invasive breast cancers were diagnosed at least 1 year after enrollment. Increasing consumption of red meat was associated with increased risk of invasive breast cancer (HRhighest vs. lowest quartile :1.23, 95% CI: 1.02-1.48, ptrend = 0.01). Conversely, increasing consumption of poultry was associated with decreased invasive breast cancer risk (HR highest vs. lowest quartile : 0.85; 95% CI: 0.72-1.00; ptrend = 0.03). In a substitution model with combined red meat and poultry consumption held constant, substituting poultry for red meat was associated with decreased invasive breast cancer risk (HR highest vs. lowest quartile of poultry consumption: 0.72, 95% CI: 0.58-0.89). No associations were observed for cooking practices, estimated heterocyclic amines or heme iron from red meat consumption with breast cancer risk. Red meat consumption may increase the risk of invasive breast cancer, whereas poultry consumption may be associated with reduced risk. Substituting poultry for red meat could reduce breast cancer risk.

Day-to-day regularity in breakfast consumption is associated with weight status in a prospective cohort of women.

BACKGROUND: Evidence suggests that regular eating patterns (i.e., consistent day-to-day frequency and timing of consumption) may be favorable with respect to weight status, and breakfast may be a particularly important meal for weight maintenance. We examined the relationship between regular breakfast consumption habits and weight status among women. MATERIALS AND METHODS: Modified Poisson regression models examined day-to-day regularity in breakfast consumption among 46,037 women in the prospective Sister Study cohort in relation to weight status. Cross-sectional outcomes included overweight (body mass index (BMI) ≥ 25.0 kg/m2) and obesity (BMI ≥ 30.0 kg/m2); waist circumference (WC) ≥ 88 cm; and waist-to-hip ratio (WHR) ≥ 0.85. Self-reported weight 5 years post-baseline was used to calculate 5 kg weight gain and incident overweight and obesity using BMI. RESULTS: Compared to women who reported eating breakfast 3 to 4 days/week (irregular breakfast eaters), women who ate breakfast 7 days/week were between 11% to 17% less likely to be obese as measured by WHR (prevalence ratio (PR): 0.89; 95%CI: 0.85, 0.94), WC (PR: 0.85; 95%CI: 0.82, 0.88), and BMI (PR: 0.83; 95%CI: 0.79, 0.87) after multivariable adjustment. Women who never ate breakfast were between 11% to 22% less likely to be obese as measured by WHR (PR: 0.89; 95%CI: 0.83, 0.96), WC (PR: 0.82; 95%CI: 0.78, 0.87), and BMI (PR: 0.78; 95%CI: 0.72, 0.84) compared to irregular breakfast eaters. Prospective analyses showed a 21% and 28% lower risk of 5-year incident obesity among participants who always (relative risk (RR): 0.79; 95%CI: 0.70, 0.90) or never (RR: 0.72; 95%CI: 0.59, 0.87) ate breakfast, respectively, compared to those who ate breakfast 3 to 4 days/week. No association was observed for incident 5 kg weight gain. CONCLUSIONS: Results suggest that a regular breakfast consumption habit, comprising eating breakfast every day or never, may be important for maintaining a healthy weight.

Exposure-weighted scoring for metabolic syndrome and the risk of myocardial infarction and stroke: a nationwide population-based study.

BACKGROUND: Metabolic syndrome (MetS) status changes over time, but few studies have investigated the relationship between the extent or duration of exposure to MetS and the risk of cardiovascular disease (CVD). We investigated the cumulative effects of MetS and its components on the risk of myocardial infarction (MI) and stroke. METHODS: From the Korean National Health Insurance database, 2,644,851 people who received annual health examinations from 2010 to 2013 were recruited. Exposure-weighted scores for MetS during this 4-year period were calculated in two ways: cumulative number of MetS diagnoses (MetS exposure score, range: 0-4) and the composite of its five components (MetS component exposure score, range: 0-20). The multivariable Cox proportional-hazards model was used to assess CVD risk according to the exposure-weighted scores for MetS. RESULTS: MetS was identified at least once in 37.6% and persistent MetS in 8.2% of subjects. During the follow-up (median, 4.4 years), 10,522 cases of MI (0.4%) and 10,524 cases of stoke (0.4%) occurred. The risk of MI and stroke increased gradually with increasing exposure scores of MetS and its components (each P for trend < 0.0001). The hazard ratio [(HR) (95% CI)] of MI and stroke were 5.27 (4.20-6.62) and 3.90 (3.09-4.93), respectively, in those with a score of 20 compared with those with a MetS component exposure score of 0. People fulfilling only two MetS components out of 20 already had 22% increased risk of MI, and those with three MetS components had 24% increased risk of stroke. These associations were consistent in the subgroup and sensitivity analyses. CONCLUSIONS: A dose-response relationship between the cumulative exposure to metabolic disturbances and incident MI or stroke was evident. Even minimal exposure to MetS components was sufficient to increase the risk of CVD significantly, highlighting the importance of intensive risk management for the prevention of CVD.

Associations of Variability in Blood Pressure, Glucose and Cholesterol Concentrations, and Body Mass Index With Mortality and Cardiovascular Outcomes in the General Population.

BACKGROUND: Variability in metabolic parameters, such as fasting blood glucose and cholesterol concentrations, blood pressure, and body weight can affect health outcomes. We investigated whether variability in these metabolic parameters has additive effects on the risk of mortality and cardiovascular outcomes in the general population. METHODS: Using nationally representative data from the Korean National Health Insurance System, 6 748 773 people who were free of diabetes mellitus, hypertension, and dyslipidemia and who underwent ≥3 health examinations from 2005 to 2012 were followed to the end of 2015. Variability in fasting blood glucose and total cholesterol concentrations, systolic blood pressure, and body mass index was measured using the coefficient of variation, SD, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability. Participants were classified numerically according to the number of high-variability parameters (eg, a score of 4 indicated high variability in all 4 metabolic parameters). Cox proportional hazards models adjusting for age, sex, smoking, alcohol, regular exercise, income, and baseline levels of fasting blood glucose, systolic blood pressure, total cholesterol, and body mass index were used. RESULTS: There were 54 785 deaths (0.8%), 22 498 cases of stroke (0.3%), and 21 452 myocardial infarctions (0.3%) during a median follow-up of 5.5 years. High variability in each metabolic parameter was associated with a higher risk for all-cause mortality, myocardial infarction, and stroke. Furthermore, the risk of outcomes increased significantly with the number of high-variability metabolic parameters. In the multivariable-adjusted model comparing a score of 0 versus 4, the hazard ratios (95% CIs) were 2.27 (2.13-2.42) for all-cause mortality, 1.43 (1.25-1.64) for myocardial infarction, and 1.41 (1.25-1.60) for stroke. Similar results were obtained when modeling the variability using the SD, variability independent of the mean, and average real variability, and in various sensitivity analyses. CONCLUSIONS: High variability of fasting blood glucose and total cholesterol levels, systolic blood pressure, and body mass index was an independent predictor of mortality and cardiovascular events. There was a graded association between the number of high-variability parameters and cardiovascular outcomes.

Higher diet-dependent acid load is associated with risk of breast cancer: Findings from the sister study.

Dietary factors that contribute to chronic low-grade metabolic acidosis have been linked to breast cancer risk, but to date no epidemiologic study has examined diet-dependent acid load and breast cancer. We used data from 43,570 Sister Study participants who completed a validated food frequency questionnaire at enrollment (2003-2009) and satisfied eligibility criteria. The Potential Renal Acid Load (PRAL) score was used to estimate diet-dependent acid load. Higher scores reflect greater consumption of protein and phosphorus, and lower consumption of potassium, calcium and magnesium. The association between PRAL and breast cancer was evaluated using multivariable Cox proportional hazards regression. We identified 1,614 invasive breast cancers diagnosed at least 1 year after enrollment (mean follow-up, 7.6 years). The highest PRAL quartile, reflecting greater acid-forming potential, was associated with increased risk of breast cancer (HRhighest vs. lowest quartile : 1.21 [95% CI, 1.04-1.41], ptrend = 0.04). The association was more pronounced for estrogen receptor (ER)-negative (HRhighest vs. lowest quartile : 1.67 [95% CI, 1.07-2.61], ptrend = 0.03) and triple-negative breast cancer (HRhighest vs. lowest quartile : 2.20 [95% CI, 1.23-3.95], ptrend = 0.02). Negative PRAL scores, representing consumption of alkaline diets, were associated with decreased risk of ER-negative and triple-negative breast cancer, compared to a PRAL score of 0 representing neutral pH. Higher diet-dependent acid load may be a risk factor for breast cancer while alkaline diets may be protective. Since PRAL scores are positively correlated with meat consumption and negatively correlated with fruit and vegetable intake, results also suggest that diets high in fruits and vegetables and low in meat may be protective against hormone receptor negative breast cancer.

Severe hypoglycemia and the risk of cardiovascular disease and mortality in type 2 diabetes: a nationwide population-based cohort study.

BACKGROUND: We investigated the association regarding severe hypoglycemia episodes with cardiovascular disease risk and all-cause mortality in patients with type 2 diabetes. METHODS: Baseline and follow-up data (n = 1,568,097) from patients with type 2 diabetes were retrieved from the National Health Insurance System database (covering the entire Korean population). Type 2 diabetes, severe hypoglycemia, and major comorbidities were identified using International Classification of Diseases 10 codes and medication information. Individuals who were classified as type 2 diabetes in the year of 2009 were screened, and we counted severe hypoglycemia episodes from 2007 to 2009. The primary outcome was newly developed myocardial infarction (MI), stroke, heart failure, or all-cause mortality. Participants were followed from the baseline index date to the date of death or until December 31, 2015. RESULTS: In total, 19,660 (1.2%) patients developed at least one severe hypoglycemia event during the period from 2007 to 2009. Mean follow-up was 5.7 years. After adjustment for confounding factors, the hazard ratio (HR) of MI significantly and sequentially increased: 0 vs. 1 episode, HR 1.56, 95% CI 1.46-1.64; 0 vs. 2 episodes, HR 1.86, 95% CI 1.61-2.15; 0 vs. 3 or more episodes, HR 1.86, 95% CI 1.48-2.35, P for trend < 0.001. Similar findings were noted regarding the relationship of severe hypoglycemia episodes with stroke, heart failure, and all-cause mortality. Risks for all outcomes were highest within 1 year from the index date and showed decreasing trends with follow-up. Sensitivity analyses of the data from the subgroup population and 797,544 subjects who received a national health examination did not change the significance of the main findings. CONCLUSION: Among adult Korean patients with type 2 diabetes, a severe hypoglycemia episode is associated with increased risk for cardiovascular outcomes and all-cause mortality. Significant results from dose-response, temporal, and sensitivity analyses may suggest the possibility of direct causality between severe hypoglycemia and cardiovascular outcomes and mortality.

Changes in cardiovascular disease risk and risk factors among women with and without breast cancer.

BACKGROUND: Cardiovascular disease (CVD) risk is an important health concern among survivors of breast cancer. However, few studies to date have examined whether trajectories of CVD risk and major risk factors are worse among women with a breast cancer diagnosis compared with those without. METHODS: Changes in weight, body mass index, waist circumference, systolic blood pressure, and 10-year CVD risk were compared between women with (813 women) and without (1049 women) an incident breast cancer diagnosis while they were enrolled in the National Institute of Environmental Health Sciences Sister Study cohort. Blood pressure and adiposity measures were collected by trained examiners at an enrollment visit (≥1 year before breast cancer diagnosis) and a second home visit 4 to 11 years later (≥1 year after breast cancer diagnosis). The non-laboratory-based Framingham risk score, a measure of 10-year general CVD risk, was calculated at both the enrollment and second visits. All analyses were stratified by menopausal status at the time of enrollment. RESULTS: Women who were premenopausal at the time of enrollment experienced moderate increases in weight, waist circumference, systolic blood pressure, and CVD risk over the study period. Those who were postmenopausal at the time of enrollment demonstrated little change in weight, but were found to have increases in waist circumference, systolic blood pressure, and CVD risk. In both groups, changes over time did not differ significantly according to breast cancer status. Neither chemotherapy nor endocrine therapy were found to be associated with greater increases in CVD risk or risk factors. CONCLUSIONS: In the current study cohort, changes over time in CVD risk, adiposity measures, and blood pressure were similar between women who developed an incident breast cancer and those who did not.

Progression of cardiovascular autonomic neuropathy and cardiovascular disease in type 2 diabetes.

BACKGROUND: To examine whether the progression rate of cardiovascular autonomic neuropathy (CAN) stage is an independent predictive factor for cardiovascular disease (CVD) in type 2 diabetes. METHODS: Standardized cardiovascular autonomic reflex tests (CARTs) using traditional Ewing method were performed at baseline. The follow-up CARTs was recommended once every two years. We estimated the primary CVD endpoint, defined as coronary artery disease and ischemic stroke. The association between the progression rate of CAN stage and CVD was examined using time-dependent Cox proportional hazard models. RESULTS: At baseline, 578 patients completed follow-up CARTs; the cohort comprised 329 women (56.9%) with a mean age of 58.3 ± 10.3 years and a mean diabetes duration of 10.1 ± 6.2 years. One hundred and seventy-six patients (30.4%) developed CAN progression between baseline and follow-up CARTs. In the multivariable Cox proportional hazards regression analysis, patients with CAN progression demonstrated a 3.32 times higher risk (95% confidence interval, CI 1.81-6.14, P < 0.001) of CVD than those without CAN progression. Patients who experienced CAN progression from the normal to definite stage had the greatest risk of CVD compared to other patients (hazard ratio 4.91, 95% CI 2.05-11.77, P for trend = 0.001). CONCLUSIONS: CAN stage progression was associated with an increased risk of CVD in this type 2 diabetes cohort. Patients with rapid CAN progression had the greatest risk of CVD. Thus, regular screening and risk management of CAN progression is necessary to prevent CVD.

Dietary Glycemic Index and Glycemic Load Are Positively Associated with Oxidative Stress among Premenopausal Women.

Background: Diets with a high glycemic index (GI) and glycemic load (GL) have been hypothesized to increase oxidative stress, but the limited human studies are inconsistent. Objective: The aim of this cross-sectional study was to investigate associations between dietary GI, GL, and carbohydrate intake and oxidative stress, as measured by F2-isoprostanes (F2-IsoPs). Methods: Concentrations of F2-IsoP and its metabolite (15-F2t-IsoP-M) were measured in urine samples collected at enrollment from 866 premenopausal women (aged 35-54 y) participating in the Sister Study. Total carbohydrate intake and dietary GI and GL were assessed using a validated food frequency questionnaire. Urinary F2-IsoP and 15-F2t-IsoP-M concentrations were compared across quintiles of carbohydrate intake, GI, and GL using multivariable linear regression models. Results: Urinary F2-IsoP concentrations were positively associated with dietary GI (P-trend = 0.023), and both F2-IsoP and 15-F2t-IsoP-M concentrations were positively associated with GL (F2-IsoP: P-trend < 0.001; 15-F2t-IsoP-M: P-trend < 0.001) and total carbohydrate intake (F2-IsoP: P-trend = 0.012; 15-F2t-IsoP-M: P-trend < 0.001). Stratified analyses suggested that a positive association between GI and urinary 15-F2t-IsoP-M concentrations was present among women with a body mass index [BMI (in kg/m2)] ≥30.0, but not among those with a BMI of <25.0 or 25.0-29.9 (P-interaction = 0.01). Conclusions: Our cross-sectional analyses in a sample of premenopausal women support hypothesized relations between high dietary GI and GL and oxidative stress, as assessed by urinary F2-IsoP and 15-F2t-IsoP-M concentrations. Given potential associations between oxidative stress and the development of cardiovascular disease and type 2 diabetes, our findings may have important implications for reducing chronic disease risk.