Background The prognosis of high or markedly low diastolic blood pressure (DBP) with normalized on‐treatment systolic blood pressure on major adverse cardiovascular events (MACEs) is uncertain. This study examined whether treated isolated diastolic hypertension (IDH) and treated isolated low DBP (ILDBP) were associated with MACEs in patients with hypertension. Methods and Results A total of 7582 patients with on‐treatment systolic blood pressure <130 mm Hg from SPRINT (Systolic Blood Pressure Intervention Trial) were categorized on the basis of average DBP: <60 mm Hg (n=1031; treated ILDBP), 60 to 79 mm Hg (n=5432), ≥80 mm Hg (n=1119; treated IDH). MACE risk was estimated using Cox proportional‐hazards models. Among the SPRINT participants, median age was 67.0 years and 64.9% were men. Over a median follow‐up of 3.4 years, 512 patients developed a MACE. The incidence of MACEs was 3.9 cases per 100 person‐years for treated ILDBP, 1.9 cases for DBP 60 to 79 mm Hg, and 1.8 cases for treated IDH. Comparing with DBP 60 to 79 mm Hg, treated ILDBP was associated with an 1.32‐fold MACE risk (hazard ratio [HR], 1.32, 95% CI, 1.05–1.66), whereas treated IDH was not (HR, 1.18 [95% CI, 0.87–1.59]). There was no effect modification by age, sex, atherosclerotic cardiovascular disease risk, or cardiovascular disease history (all P values for interaction >0.05). Conclusions In this secondary analysis of SPRINT, among treated patients with normalized systolic blood pressure, excessively low DBP was associated with an increased MACE risk, while treated IDH was not. Further research is required for treated ILDBP management.

Background and Purpose Oral anticoagulants (OACs) prevent stroke recurrence and vascular embolism in patients with acute ischemic stroke (AIS) and atrial fibrillation (AF). Based on empirical consensus, current guidance recommends a "1-3-6-12 days" rule to resume OACs after AIS. This study investigated the suitability of guideline-recommended timing for OAC initiation. Methods Using data of 12,307 AF patients hospitalized for AIS, for the period 2012 to 2016, in Taiwan's National Health Insurance Research Database, we constructed a sequence of cohorts of OAC users and propensity score-matched nonusers, creating one cohort on each day of OAC initiation for 30 days since admission. Composite outcome included effectiveness (cardiovascular death, ischemic stroke, myocardial infarction, transient ischemic attack, systemic embolism, and venous thromboembolism) and safety (intracranial hemorrhage, gastrointestinal bleeding, and hematuria) outcomes. Comparing with nonusers, we examined the risks in the early OAC use (within 1-3-6-12 days) or guideline-recommended delayed use. Indirect comparison between the early and delayed use was conducted using mixed treatment comparison. Results Across the AIS severity, the risks of composite or effectiveness outcome were lower in OAC users than nonusers, and the risks were similar between the early and delayed use groups. In patients with severe AIS, early OAC use was associated with an increased risk of safety outcome, with a hazard ratio (HR) of 1.67 (confidence interval [CI]: 1 center dot 30-2 center dot 13) compared with nonusers and a HR of 1.44 (CI: 0 center dot 99-2 center dot 09) compared with the delayed use. Conclusion Our study findings support an early OAC initiation in AF patients with mild-to-moderate AIS and a routine delayed use of OACs can be considered in those with severe AIS to avoid a serious bleeding event.

This study aimed to determine the trajectory of diabetic vascular diseases and to investigate the association between vascular diseases and dementia. We included adults aged ≥ 50 years with newly diagnosed type 2 diabetes (n = 173,118) from 2001 to 2005 who were followed-up until December 31, 2013 in the Taiwan’s National Health Insurance Research Database. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) and confidence limits (CLs) for all-cause dementia in relation to the number, types, and occurrence patterns of vascular disease. Within 1 year of diabetes diagnosis, 26.3% of adults developed their first vascular disease. During the 1,864,279 person-years of follow-up, 17,426 adults had all-cause dementia, corresponding to an incidence of 97.9 cases/10,000 person-years in 127,718 adults with at least one vascular disease and 67.5 cases/10,000 person-years in 45,400 adults without vascular diseases. Across all age groups, adults who subsequently developed a vascular disease in two one-year windows since diabetes diagnosis had the highest incidence of all-cause dementia. In comparison with adults without vascular diseases, HR for all-cause dementia was 1.99 (CL: 1.92–2.07) for those with one vascular disease only; 2.04 (CL: 1.98–2.13) for two or more vascular diseases; 3.56 (CL: 3.44–3.70) for stroke only; and 2.06 (CL: 1.99–2.14) for neuropathy alone. Similar associations were also observed with a smaller magnitude for adults with nephropathy, retinopathy, cardiovascular disease, or peripheral arterial disease. Patients with diabetes-related complications, particularly stroke and neuropathy, and those with rapidly developed vascular diseases appeared to have a high risk of dementia.

Empagliflozin, a sodium-glucose cotransport 2 inhibitor, provides A1c reduction by .6-1.0% in large randomized control trials. These trials included adults with type 2 diabetes (T2D) who had baseline A1c 7-10%. The use of empagliflozin in reducing A1c in clinical practice has not been investigated. We constructed a longitudinal cohort of 16391 adults with T2D who initiated empagliflozin from 11/1/2014 to 3/1/2018 in the Veterans Health Administration and followed them until 10/1/2018. We studied 7792 adults (96% men, 73% non-Hispanic white (NHW), 14% black) who had A1c measures at baseline and during follow-up and who did not change their antidiabetic medication regimens (58% with insulin, 36% without insulin). Linear regression estimated absolute A1c change at 6 months, adjusted for age, sex, race/ethnicity, baseline A1c, categorical BMI, kidney function, and concurrent insulin. At baseline, median A1c was 8.5% (12% with A1c ≥10%), median BMI was 33 kg/m2 (25% of adults with BMI 35-40 kg/m2, 18% BMI >40 kg/m2), and 19% with reduced kidney function. Baseline A1c was 8.9% for black adults and 8.5% for NHW adults. The average reduction in A1c was .74% for black adults and .70% for NHW adults. Overall, average adjusted A1c reduction was .71%. Adults with baseline A1c ≥10% had a greater adjusted reduction compared to adults with baseline A1c 7-10% (1.76% vs. .46%, p40 kg/m2 had a greater adjusted reduction compared to normal and overweight adults (.71% and .75%, vs. .46% and .59%, respectively, p 35. This study provides real-world evidence of empagliflozin use and A1c reduction in a large integrated healthcare system. Disclosure P. Chang: None. K. Heberer: None. J. Lee: None. Funding National Institute on Drug Abuse (T32DK007217); U.S. Department of Veterans Affairs

Abstract Introduction The effectiveness of varenicline compared with nicotine replacement therapy (NRT) in achieving smoking cessation in older smokers has not been investigated. This study prospectively compared the effectiveness of varenicline relative to NRT in smokers aged 25–54 years and separately in smokers aged 55 years or older. Methods Among 13 397 smokers participating in the Smoking Cessation Program in Taiwan, 2012–2015, 6336 (19.2%, aged ≥55) received varenicline and 7061 received NRT patch or gum (23.2%, aged ≥55). Participants self-reported smoking behaviors by phone interview after 6 months. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for 7-day, 1-month, and 6-month point-prevalence abstinence. Age-specific models adjusted for sex, education, marital status, smoke-years, nicotine dependence, medical institution, clinic visit number, and duration of medication received. Results Among smokers aged 25–54 years, varenicline users had a greater point-prevalence abstinence than NRT users (e.g., 7-day point-prevalence: 34.0% vs. 23.5%), with adjusted OR ranging from 1.23 (CI: 1.09–1.39; 6-month point-prevalence) to 1.37 (CI: 1.24–1.50; 1-month point-prevalence). Among smokers aged 55 years or older, point-prevalence was similar for varenicline and NRT users (e.g., 7-day point-prevalence: 32.3% vs. 33.1%), and ORs did not suggest that varenicline has greater effectiveness than NRT. Sex and level of nicotine dependence did not modify the age-specific effectiveness of varenicline relative to NRT. Conclusions Varenicline did not offer greater effectiveness in achieving abstinence than NRT for smokers 55 years or older, whereas it was more effective than NRT in smokers aged 25–54 years. These findings highlighted the need for age-specific approaches for effective tobacco control. Implications In this prospective investigation of a national cohort, older smokers (aged ≥55 years) who received varenicline did not have a greater point-prevalence abstinence after 6 months compared with those who used NRT patch or gum. Younger smokers (aged 25–54 years) who received varenicline had a greater likelihood of abstinence than NRT users. Sex and nicotine dependence did not modify the age-specific effectiveness of varenicline relative to NRT patch or gum. Age-appropriate approaches for effective tobacco control are needed.

ABSTRACT 27-Hydroxycholesterol (27HC) is a purported, novel endogenous SERM. In animal models, 27HC has an anti-estrogen effect in bone, and 17β-estradiol mitigates this effect. 27HC in relation to fracture risk has not been investigated in humans. Depending on the level of bioavailable 17β-estradiol (bioE2), 27HC may increase fracture risk in postmenopausal women and modify the fracture risk reduction from menopausal hormone therapy (MHT). To test these a priori hypotheses, we conducted a nested case-cohort study of 868 postmenopausal women within the Women's Health Initiative Hormone Therapy (WHI-HT) trials. The WHI-HT tested conjugated equine estrogens versus placebo and separately conjugated equine estrogens plus progestin versus placebo. Fracture cases were 442 women who had an adjudicated incident hip or clinical vertebral fracture during the WHI-HT follow-up. The subcohort included 430 women randomly selected at WHI-HT baseline, four of whom had a subsequent fracture. Of the 868 women, 266 cases and 219 non-cases were assigned to the placebo arms. Cox models estimated hazard ratios for incident fracture in relation to pre-randomization circulating levels of 27HC and 27HC/bioE2 molar ratio. Models adjusted for age, race/ethnicity, total cholesterol, bioE2, sex hormone-binding globulin, 25-hydroxyvitamin D, diabetes, osteoporosis, prior MHT use, BMI, falls history, and prior fracture. In women assigned to placebo arms, those in the middle and the highest tertiles of 27HC/bioE2 had an up to 1.9-fold (95% confidence intervals, 1.25 to 2.99) greater risk of fracture than women in the lowest tertile. In women assigned to MHT arms, fracture risk increased with continuous 27HC/bioE2 levels but not with categorical levels. 27HC levels alone were not associated with fracture risk. 27HC and 27HC/bioE2 did not modify the fracture risk reduction from MHT. In postmenopausal women, circulating levels of 27HC relative to bioE2 may identify those at increased risk of fracture. © 2018 American Society for Bone and Mineral Research.

Context: Cardiometabolic conditions increase in midlife, but early customized prevention strategies are not established for such women. Objective: To characterize and identify factors longitudinally related to constellations of cardiometabolic risk components in multiracial/ethnic women in midlife. Design: We conducted a prospective, longitudinal, multiethnic cohort study of 3003 midlife women undergoing menopausal transition (MT). Metabolic syndrome (MetS) was defined as having at least three of five components: high fasting triglyceride (hTG) level, low high-density lipoprotein cholesterol (lHDL-C) level, high fasting plasma glucose (hGluc) level, large waist circumference (abdominal obesity; Ob), and hypertension (HTN). We described the patterns of constellations and estimated hazard ratios (HRs) for constellations at (i) incident MetS and (ii) recovery from MetS, using multivariable-adjusted Cox regression. Setting: Seven US sites. Participants: In all, 1412 non-Hispanic white, 851 black, 272 Japanese, 237 Hispanic, and 231 Chinese women. Exposures: Race/ethnicity, lifestyle factors, and MT stage. Main Outcomes Measures: Cardiometabolic constellations, incident MetS, and MetS recovery. Results: Central obesity was the most frequent component. Having no components was the most frequent (31%) baseline constellation. Physical activity (HR = 1.68; 95% CI: 1.06, 2.68) and lower caloric intake (HR = 0.96; 95% CI: 0.93, 0.99 per 100 cal/d) were associated with recovery from MetS. Ob/hTG/lHDL-C (18%), Ob/HTN/lHDL-C (16%), and Ob/HTN/hGluc (14%) were frequent incident constellations. Physically active women had 26% to 62% lower hazards of incident MetS than inactive women. Conclusions: Modifiable lifestyle behaviors were related to recovery from MetS and decreased risk of the most frequent MetS constellations in midlife women.

Type 2 Diabetes (T2D) increases the risk of cardiovascular diseases (CVD). However, limited studies demonstrated the risk of CVD related to anti-diabetes medications in adults with T2D and with advanced chronic kidney disease (CKD). This study aimed to compare the risk of CVD and all-cause mortality in adults with T2D and with advanced CKD who received sulfonylurea, dipeptidyl peptidase-4 (DPP-4), thiazolidinedione, α-glucosidase inhibitor or glinide. We prospectively studied adults with T2D who used erythropoietin, as an indicator for advanced CKD, from January 1, 2009 to December 31, 2012, in Taiwan’s National Health Insurance Research Database. Follow-up ended on December 31, 2013. We identified 5,415 adults with T2D who received prescriptions of single anti-diabetes medication within 90 days of the first EPO prescription, excluding those with coronary heart disease, stroke, amputation, heart failure, or dialysis in 30 days before the prescription of anti-diabetes medication. The composite primary outcome included CVD (coronary heart disease, stroke, amputation, heart failure) and all-cause mortality. Cox regression estimated hazard ratio with adjustment for age, gender, T2D duration, CVD, Comorbid condition, Antidiabetic medication, Antihypertensive medication, antiplatelet and Statin use . After 1:4 ration propensity score matching, 302 sulfonylurea users, 23 thiazolidinedione users, 61 DPP-4 users and 37 α-glucosidase inhibitor users were matched to 663, 41, 105 and 72 glinide users, respectively. These 2589 matched samples (mean age, 64.5 years; T2D duration, 8.4 years) contributed to an average of 8.5 months (SD=9.8) of follow-up. Multivariable-adjusted hazard ratio for the primary outcome were 0.89 (p=0.11) comparing sulfonylurea with glinide, 0.57 (p=0.17) comparing thiazolidinedione with glinide, 1.17 (p=0.42) for DPP-4 versus glinide, and 1.10 (p=0.68) for α-glucosidase inhibitor versus glinide. In adults with T2D and with advance CKD, sulfonylurea, thiazolidinedione, DPP-4 and α-glucosidase inhibitor seemed to not increase the risk of CVD as compared with glinides.

Purpose: Osteoblasts and their precursors support hematopoiesis in the bone marrow. We hypothesized that declines in Hgb levels are associated with bone mineral density (BMD). Methods: The Cardiovascular Health Study is a prospective longitudinal study that enrolled 5888 community-dwelling adults aged > 65 years and measured hemoglobin twice, in 1989-90 and 1992-93, as well as BMD by dual-energy X-ray absorptiometry (DXA) in 1994-95. In a subset of 1513 men and women with a Hgb in 1992-93 and BMD, we used linear regression to estimate associations of Hgb (per standard deviation (SD)) with total hip (TH), lumbar spine (LS) and total body (TB) BMD, and used Poisson regression to estimate associations of anemia (in 1992-93; Hgb < 13 g/dL in men; < 12 g/dL in women) with "low BMD" defined as T-score less than -1 at the TH. In 1277 participants with Hgb measured on average 2.9 years apart and BMD, we used linear regression to estimate the associations of annualized change in Hgb with TH, LS and TB BMD. All models included age, sex, study-site, race, smoking, alcohol use, weight, height, steroid use, physical activity score, self-reported health, previous cardiovascular disease and prior anti-fracture medication use. Results: No significant association was observed between Hgb, measured a mean 2.2 years prior to BMD, and BMD at the TH and LS in men (TH beta = -0.60 [x 10(-2)g/cm(2) per 1.1 g/dL Hgb], 95% CI: -1.88 to 0.68; LS beta = -1.69, 95% CI: -3.83 to 0.45) or women (TH beta = - 0.49 [x 10(-2) g/cm(2) per 1.3 g/dL Hgb], 95% CI: -1.57 to 0.59; LS beta = -0.40, 95% CI: -2.57 to 1.76). Anemia was not observed to be significantly associated with low BMD in men (RR = 0.99, 95% CI: 0.72-1.40) nor women (RR = 0.98, 95% CI: 0.82-1.17). The mean change in Hgb was a loss of 0.06 g/dL/year (SD = 0.32). Change in Hgb was not observed to be significantly associated with BMD in men (TH beta = -0.55[x 10(-2) g/cm(2) per 1 g/dL annualized Hgb change], 95% CI: -4.28 to 3.19; LS beta = 0.63, 95% CI: -5.38 to 6.65) or women (TH beta = 0.92, 95% CI: -1.96 to 3.79; LS beta = -1.77, 95% CI: -7.52 to 3.98). No significant association was observed between anemia and low bone density by T-score in men and women. Conclusions: These findings support neither the hypothesis that low Hgb prior to bone density or decreases in Hgb are associated with bone density in older community-dwelling adults nor the use of Hgb level as a case-finding tool to prompt BMD measurement.

OBJECTIVE:To evaluate factors associated with incident self-reported vaginal dryness and the consequences of this symptom across the menopausal transition in a multiracial/ethnic cohort of community-dwelling women.METHODS:We analyzed questionnaire and biomarker data from baseline and 13 approximately annual visits over 17 years (1996-2013) from 2,435 participants in the Study of Women's Health Across the Nation, a prospective cohort study. We used discrete-time Cox proportional-hazards regression to identify predictors of incident vaginal dryness and to evaluate vaginal dryness as a predictor of pain during intercourse and changes in sexual intercourse frequency.RESULTS:The prevalence of vaginal dryness increased from 19.4% among all women at baseline (ages 42-53 years) to 34.0% at the 13th visit (ages 57-69 years). Advancing menopausal stage, surgical menopause, anxiety, and being married were positively associated with developing vaginal dryness, regardless of partnered sexual activity. For women not using hormone therapy, higher concurrent levels of endogenous estradiol were inversely associated (multivariable-adjusted hazard ratio: 0.94 per 0.5 standard deviation increase, 95% confidence interval: 0.91-0.98). Concurrent testosterone levels, concurrent dehydroepiandrosterone sulfate levels, and longitudinal change in any reproductive hormone were not associated with developing vaginal dryness. Both vaginal dryness and lubricant use were associated with subsequent reporting of pain during intercourse, but not with a decline in intercourse frequency.CONCLUSION:In these longitudinal analyses, our data support many clinical observations about the relationship between vaginal dryness, menopause, and pain during intercourse, and suggest that reporting of vaginal dryness is not related to androgen level or sexual intercourse frequency.

OBJECTIVE High triglyceride (TG) levels and low HDL cholesterol (HDL-C) levels are risk factors for cardiovascular disease. It is unclear whether this relationship depends on glycemic dysregulation, sex, or LDL cholesterol (LDL-C) level. RESEARCH DESIGN AND METHODS We studied 3,216 participants (40% men, 41% with diabetes) who were free of cardiovascular disease at baseline in a community-based, prospective cohort of American Indians (median follow-up 17.7 years). Cox models estimated hazard ratios (HRs) and 95% CIs for incident ischemic stroke and coronary heart disease (CHD) in relation to combined TG and HDL-C status, where a fasting TG level ≥150 mg/dL was “high” and a fasting HDL-C level <40 mg/dL for men (<50 mg/dL for women) was “low.” Models included age, sex, BMI, smoking, diabetes, fasting LDL-C level, antihypertensive medications, physical activity, estimated glomerular filtration rate, and urinary albumin-to-creatinine ratio. RESULTS Participants with high TG and low HDL levels had a 1.32-fold greater HR (95% CI 1.06–1.64) for CHD than those with normal TG and normal HDL levels. It was observed in participants with diabetes, but not in those without diabetes, that high TG plus low HDL levels were associated with a 1.54-fold greater HR (95% CI 1.15–2.06) for CHD (P value for interaction = 0.003) and a 2.13-fold greater HR (95% CI 1.06–4.29) for stroke (P value for interaction = 0.060). High TG and low HDL level was associated with CHD risk in participants with an LDL-C level of ≥130 mg/dL, but this was not observed in those participants with lower LDL-C levels. Sex did not appear to modify these associations. CONCLUSIONS Adults with both high TG and low HDL-C, particularly those with diabetes, have increased risks of incident CHD and stroke. In particular, those with an LDL-C level ≥130 mg/dL may have an increased risk of incident stroke.

Objectives: This study investigated the prevalence and correlates of electronic cigarettes (e-cigarettes) use in Taiwan.Design and setting: We studied a nationally representative random sample in the 2015 Taiwan Adult Smoking Behavior Survey.Participants: This study included 26 021 participants aged 15 years or older (51% women, 79% nonsmokers, 16% aged 15-24 years), after excluding 31 persons (0.1%) who had missing information on e-cigarette use.Primary outcome measures: The prevalence of ever having used e-cigarettes was calculated in the overall sample and by smoking status (current, former and never) or age (15-24, 25-44 and >= 45 years). We performed multivariable log-binomial regression to assess correlates of ever having used e-cigarettes among all participants and separately for subgroups by smoking status and age.Results: Approximately 3% of all participants had ever used e-cigarettes. The prevalence of ever having used e-cigarettes was high in current smokers (14%) and people aged 18-24 years (7%). E-cigarette use was particularly common in people aged 15-24 years who were current (49-52%) or former (22-39%) smokers. Ever having used e-cigarettes was positively associated with tobacco smoking (adjusted prevalence ratio (aPR): 21.5, 95% CI 15.4 to 29.8, current smokers; aPR: 8.3, 95% CI 15.2 to 13.1, former smokers), younger age and high socioeconomic status. Age remained a significant factor of ever having used e-cigarettes across smoking status groups. Among non-smokers, men had a 2.4-fold (95% CI 1.5 to 3.8) greater prevalence of e-cigarette use than women.Conclusions: E-cigarette use was uncommon in the general population in Taiwan, but prevalence was high among smokers and young people. This study highlights challenges that e-cigarettes pose to tobacco control, which warrant high priority action by policymakers and public health professionals. E-cigarette regulations should focus on young people.