Exposure and response analysis of aleglitazar on cardiovascular risk markers and safety outcomes:An analysis of the AleCardio trial

Aims The AleCardio trial aimed to characterize the efficacy and safety of peroxisome proliferator-activated receptor-alpha gamma agonist aleglitazar in patients with type 2 diabetes mellitus and acute coronary syndrome. The trial terminated early because of futility and safety signals. We evaluated whether the safety signals could be attributed to increased exposure to aleglitazar. Materials and Methods The AleCardio trial enrolled 7226 patients to receive aleglitazar 150 mu g or matching placebo on top of standard care. A population pharmacokinetic analysis was conducted in a pharmacokinetic substudy to identify covariates that explained interindividual variability in exposure. Subsequently, the effect of these covariates on surrogate and clinical outcomes was assessed in the full patient population. Results Concomitant administration of clopidogrel was identified as a covariate that influenced the apparent clearance of aleglitazar. Patients using clopidogrel had a mean predicted area under the plasma-concentration-time curve (AUC(0-24)) of 174.7 ng h/mL (SD: +/- 112.9 ng h/mL) versus 142.2 ng h/mL (SD: +/- 92.6 ng h/mL) in patients without clopidogrel. The effect of aleglitazar compared with placebo on HbA1c, haemoglobin, serum creatinine and adiponectin was modified by concomitant clopidogrel use (P for interaction 0.007, 0.002

Alcohol consumption patterns across Europe and adherence to the European guidelines in coronary patients : findings from the ESC-EORP EUROASPIRE V survey

Background and aims: Alcohol consumption is an important risk factor for cardiovascular morbidity and mortality worldwide. The highest levels of alcohol consumption are observed in Europe, where alcohol as contributing cause of coronary heart disease (CHD) is also most significant. We aimed to describe alcohol consumption patterns across European regions and adherence to the current guidelines in patients with a recent CHD event. Methods: The ESC-EORP survey (EUROASPIRE V) has been conducted in 2016-2017 at 131 centers in 27 Eu-ropean countries in 7350 patients with a recent CHD. Median alcohol consumption, as well as the proportion of abstainers and excessive drinkers (i.e. >70 g/week for women and >140 for men, as recommended by the European guidelines on cardiovascular prevention), was calculated for each region. To assess adherence to guidelines, proportions of participants who were advised to reduce excessive alcohol consumption and participants who were incorrectly not advised were calculated per region. Results: Mean age was 64 years (SD: 9.5), 75% were male. Abstention rates were 53% in males and 77% in females, whereas excessive drinking was reported by 9% and 5% of them, respectively. Overall, 57% of the participants were advised to reduce alcohol consumption. In the total population, 3% were incorrectly not advised, however, this percentage differed per region (range: 1%-9%). In regions where alcohol consumption was highest, participants were less often advised to reduce their consumption. Conclusion: In this EUROASPIRE V survey, the majority of CHD patients adhere to the current drinking guidelines, but substantial heterogeneity exists between European regions

Urinary Ethyl Glucuronide as Measure of Alcohol Consumption and Risk of Cardiovascular Disease:A Population-Based Cohort Study

Background Moderate alcohol consumption has been associated with a lower risk of cardiovascular disease (CVD) and all-cause mortality compared with heavy drinkers and abstainers. To date, studies have relied on self-reported consumption, which may be prone to misclassification. Urinary ethyl glucuronide (EtG) is an alcohol metabolite and validated biomarker for recent alcohol consumption. We aimed to examine and compare the associations of self-reported alcohol consumption and EtG with CVD and all-cause mortality. Methods and Results In 5676 participants of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) study cohort, EtG was measured in 24-hour urine samples and alcohol consumption questionnaires were administered. Participants were followed up for occurrence of first CVD and all-cause mortality. Cox proportional hazards regression models, adjusted for age, sex, and CVD risk factors, were fitted for self-reported consumption, divided into 5 categories: abstention, 1 to 4 units/month (reference), 2 to 7 units/week, 1 to 3 units/day, and ≥4 units/day. Similar models were fitted for EtG, analyzed as both continuous and categorical variables. Follow-up times differed for CVD (8 years; 385 CVD events) and all-cause mortality (14 years; 724 deaths). For both self-reported alcohol consumption and EtG, nonsignificant trends were found toward J-shaped associations between alcohol consumption and CVD, with higher risk in the lowest (hazard ratio for abstention versus 1-4 units/month, 1.42; 95% CI, 1.02-1.98) and highest drinking categories (hazard ratio for ≥4 units/day versus 1-4 units/month, 1.11; 95% CI, 0.68-1.84). Neither self-report nor EtG was associated with all-cause mortality. Conclusions Comparable associations with CVD events and all-cause mortality were found for self-report and EtG. This argues for the validity of self-reported alcohol consumption in epidemiologic research

Adherence to Drinking Guidelines and Reasons for Alcohol Consumption Cessation in the Southern Cone of Latin America – Findings from the CESCAS Study

Introduction: Alcohol consumption is a risk factor for morbidity and mortality globally. Consumption levels in Southern Latin America are among the highest in the world. Objectives: To describe consumption patterns and adherence to guidelines in the general adult population of Southern Latin America, as well as exploration of reasons for alcohol cessation and the advising role of the health worker in this decision. Methods: In 7,520 participants from the Centro de Excelencia en Salud Cardiovascular para el America del Sur (CESCAS) cohort, consumption patterns were described and the proportion excessive drinkers (i.e. >7 units/week for women and >14 for men or binge drinking: >4 (women) or >5 (men) units at a single occasion) was calculated. Former drinkers were asked if they had quit alcohol consumption on the advice of a health worker and/or because of health reasons. Furthermore, among former drinkers, multivariable logistic regression analysis was performed to assess which participant characteristics were independently associated with the chance of quitting consumption on a health worker’s advice. Results: Mean age was 54.8 years (SD = 10.8), 42% was male. Current drinking was reported by 44.6%, excessive drinking by 8.5% of the population. In former drinkers, 23% had quit alcohol consumption because of health reasons, half of them had additionally quit on the advice of a health worker. The majority of former drinkers however had other, unknown, reasons. When alcohol cessation was based on a health worker’s advice, sex, country of residence, educational status and frequency of visiting a physician were independent predictors. Conclusion: In this Southern American population-based sample, most participants adhered to the alcohol consumption guidelines. The advising role of the health worker in quitting alcohol consumption was only modest and the motivation for the majority of former drinkers remains unknown. A more detailed assessment of actual advice rates and exploration of additional reasons for alcohol cessation might be valuable for alcohol policy making.Facultad de Ciencias Médica

Urinary Ethyl Glucuronide Can Be Used as a Biomarker of Habitual Alcohol Consumption in the General Population

BACKGROUND: Alcohol consumption is a frequently studied risk factor for chronic diseases, but many studies are hampered by self-report of alcohol consumption. The urinary metabolite ethyl glucuronide (EtG), reflecting alcohol consumption during the past 72 h, is a promising objective marker, but population data are lacking. OBJECTIVE: The objective of this study was to assess the reliability of EtG as a marker for habitual alcohol consumption compared with self-report and other biomarkers in the general population. METHODS: Among 6211 participants in the Prevention of Renal and Vascular End-Stage Disease (PREVEND) cohort, EtG concentrations were measured in 24-h urine samples. EtG was considered positive when concentrations were ≥100 ng/mL. Habitual alcohol consumption was self-reported by questionnaire (categories: no/almost never, 1-4 units per month, 2-7 units per week, 1-3 units per day or ≥4 units per day). Plasma HDL cholesterol concentration, erythrocyte mean corpuscular volume (MCV), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γ-glutamyltransferase (GGT) were determined as indirect biomarkers of alcohol consumption. Sensitivity, specificity, positive and negative predictive value, and proportions of agreement between reported consumption and EtG were calculated. To test the agreement of EtG concentration and alcohol consumption in categories, linear regression analysis was performed. In addition, the association between EtG concentrations and indirect biomarkers was analyzed. RESULTS: Mean age was 53.7 y, and 52.9% of participants men. Of the self-reported abstainers, 92.3% had an EtG concentration <100 ng/mL. Sensitivity was 66.3%, positive predictive value was 96.3%, and negative predictive value was 47.4%. The proportion of positive agreement was 78.5%, and the proportion of negative agreement was 62.7%. EtG concentrations were linearly associated with higher categories of alcohol consumption (P-trend < 0.001), adjusted for age, sex, and renal function. EtG was positively related to MCV, HDL cholesterol, and GGT but not to AST and ALT concentrations. CONCLUSIONS: This study shows that urinary EtG is in reasonable agreement with self-reported alcohol consumption and therefore can be used as an objective marker of habitual alcohol consumption in the general population

Alcohol consumption patterns across Europe and adherence to the European guidelines in coronary patients: Findings from the ESC-EORP EUROASPIRE V survey

Background and aims: Alcohol consumption is an important risk factor for cardiovascular morbidity and mortality worldwide. The highest levels of alcohol consumption are observed in Europe, where alcohol as contributing cause of coronary heart disease (CHD) is also most significant. We aimed to describe alcohol consumption patterns across European regions and adherence to the current guidelines in patients with a recent CHD event. Methods: The ESC-EORP survey (EUROASPIRE V) has been conducted in 2016–2017 at 131 centers in 27 European countries in 7350 patients with a recent CHD. Median alcohol consumption, as well as the proportion of abstainers and excessive drinkers (i.e. >70 g/week for women and >140 for men, as recommended by the European guidelines on cardiovascular prevention), was calculated for each region. To assess adherence to guidelines, proportions of participants who were advised to reduce excessive alcohol consumption and participants who were incorrectly not advised were calculated per region. Results: Mean age was 64 years (SD: 9.5), 75% were male. Abstention rates were 53% in males and 77% in females, whereas excessive drinking was reported by 9% and 5% of them, respectively. Overall, 57% of the participants were advised to reduce alcohol consumption. In the total population, 3% were incorrectly not advised, however, this percentage differed per region (range: 1%–9%). In regions where alcohol consumption was highest, participants were less often advised to reduce their consumption. Conclusion: In this EUROASPIRE V survey, the majority of CHD patients adhere to the current drinking guidelines, but substantial heterogeneity exists between European regions

Effects of mood inductions by meal ambiance and moderate alcohol consumption on endocannabinoids and N-acylethanolamines in humans: a randomized crossover trial.

BackgroundThe endocannabinoid system is suggested to play a regulatory role in mood. However, the response of circulating endocannabinoids (ECs) to mood changes has never been tested in humans. In the present study, we examined the effects of mood changes induced by ambiance and moderate alcohol consumption on plasma ECs 2-arachidonoylglycerol (2-AG), anandamide (AEA), and some N-acylethanolamine (NAE) congeners in humans.MethodsHealthy women (n = 28) participated in a randomized cross-over study. They consumed sparkling white wine (340 mL; 30 g alcohol) or alcohol-free sparkling white wine (340 mL; ResultsPlasma concentrations of palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) increased after 30 min in the unpleasant ambiance, while they decreased in the pleasant ambiance. Changes in ECs and their NAE congeners correlated with mood states, such as happiness and fatigue, but in the pleasant ambiance without alcohol only. ECs and their NAE congeners were correlated with serum free fatty acids and cortisol.ConclusionThis is the first human study to demonstrate that plasma NAEs are responsive to an unpleasant meal ambiance. Furthermore, associations between mood states and ECs and their NAE congeners were observed.Trial registrationClinicaltrials.gov NCT01426022

The biphasic effects of moderate alcohol consumption with a meal on ambiance-induced mood and autonomic nervous system balance: a randomized crossover trial.

BACKGROUND: The pre-drinking mood state has been indicated to be an important factor in the mood effects of alcohol. However, for moderate alcohol consumption there are no controlled studies showing this association. Also, the mood effects of consuming alcohol combined with food are largely unknown. The aim of this study was to investigate the effects of moderate alcohol combined with a meal on ambiance-induced mood states. Furthermore effects on autonomic nervous system activity were measured to explore physiological mechanisms that may be involved in changes of mood state. METHODS: In a crossover design 28 women (age 18-45 y, BMI 18.5-27 kg/m2) were randomly allocated to 4 conditions in which they received 3 glasses of sparkling white wine (30 g alcohol) or alcohol-free sparkling white wine while having dinner in a room with either a pleasant or unpleasant created ambiance. Subjects filled out questionnaires (B-BAES, POMS and postprandial wellness questionnaire) at different times. Skin conductance and heart rate variability were measured continuously. RESULTS: Moderate alcohol consumption increased happiness scores in the unpleasant, but not in the pleasant ambiance. Alcohol consumption increased happiness and stimulation feelings within 1 hour and increased sedative feelings and sleepiness for 2.5 hour. Skin conductance was increased after alcohol within 1 hour and was related to happiness and stimulation scores. Heart rate variability was decreased after alcohol for 2 hours and was related to mental alertness. CONCLUSION: Mood inductions and autonomic nervous system parameters may be useful to evaluate mood changes by nutritional interventions. Moderate alcohol consumption elevates happiness scores in an unpleasant ambiance. However, drinking alcohol during a pleasant mood results in an equally positive mood state. TRIAL REGISTRATION: Clinicaltrials.gov NCT01426022

Effect of red wine consumption on biomarkers of oxidative stress

Aims: To evaluate the effect of acute and chronic consumption of red wine or de-alcoholized red wine with a similar antioxidant capacity on plasma total antioxidant capacity (TEAC), nuclear factor-κB (NF-κB) activity and F2-isoprostanes (8-iso-PGF2α) in healthy men. Methods: Nineteen healthy men with an increased waist circumference (≥94 cm) and a body mass index above 25 kg/m2 participated in a randomized, controlled crossover design trial. They daily consumed 450 ml of red wine (four drinks; 41.4 g alcohol) or 450 ml of de-alcoholized red wine during dinner for 4 weeks each. On the last day of each treatment period, blood was collected before and 1 h after a standardized dinner with red wine or de-alcoholized red wine and also 24-h urine was collected. Results: Absolute TEAC levels were higher 1 h after dinner with red wine compared with dinner with de-alcoholized red wine (1.3 versus 1.1 mmol Trolox equivalents/l; P = 0.03). Consumption of dinner together with de-alcoholized red wine acutely stimulated NF-κB activity in peripheral blood mononuclear cells (0.4-0.7 HeLa equivalents/2.5 μg protein; P = 0.006), whereas this increase was completely suppressed when the dinner was combined with red wine. A chronic increase in urinary 8-iso-PGF2α after 4 weeks of red wine consumption compared with de-alcoholized red wine consumption (157 pg/mg creatinine and 141 pg/mg creatinine, respectively, P = 0.006) was also observed. Conclusions: Consumption of a moderate dose of red wine can acutely increase plasma TEAC and suppress NF-κB activation induced by a meal. Controversially, 4 weeks of red wine consumption compared with de-alcoholized red wine consumption increases the oxidative lipid damage marker 8-iso-PGF2α

Correlations between changes in mood and endocannabinoids and <i>N</i>-acylethanolamines in a pleasant ambiance without alcohol.

<p>A) 2-arachidonoylglycerol (2-AG), B) anandamide (AEA), C) palmitoylethanolamide (PEA), D) docosahexaenoylethanolamide (DHEA), E) oleoylethanolamide (OEA), and F) stearoylethanolamide (SEA). The figure shows spearman rank correlations with ranked values on both axes of the panels. n = 16.</p