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Effect of Apabetalone Added to Standard Therapy on Major Adverse Cardiovascular Events in Patients With Recent Acute Coronary Syndrome and Type 2 Diabetes: A Randomized Clinical Trial.
Ray, KK, Nicholls, SJ, Buhr, KA, Ginsberg, HN, Johansson, JO, Kalantar-Zadeh, K, Kulikowski, E, Toth, PP, Wong, N, Sweeney, M, et al
JAMA. 2020;(16):1565-1573
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Abstract
IMPORTANCE Bromodomain and extraterminal proteins are epigenetic regulators of gene transcription. Apabetalone is a selective bromodomain and extraterminal protein inhibitor targeting bromodomain 2 and is hypothesized to have potentially favorable effects on pathways related to atherothrombosis. Pooled phase 2 data suggest favorable effects on clinical outcomes. OBJECTIVE To test whether apabetalone significantly reduces major adverse cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled trial, conducted at 190 sites in 13 countries. Patients with an acute coronary syndrome in the preceding 7 to 90 days, type 2 diabetes, and low high-density lipoprotein cholesterol levels were eligible for enrollment, which started November 11, 2015, and ended July 4, 2018, with end of follow-up on July 3, 2019. INTERVENTIONS Patients were randomized (1:1) to receive apabetalone, 100 mg orally twice daily (n = 1215), or matching placebo (n = 1210) in addition to standard care. MAIN OUTCOMES AND MEASURES The primary outcome was a composite of time to the first occurrence of cardiovascular death, nonfatal myocardial infarction, or stroke. RESULTS Among 2425 patients who were randomized (mean age, 62 years; 618 women [25.6%]), 2320 (95.7%) had full ascertainment of the primary outcome. During a median follow-up of 26.5 months, 274 primary end points occurred: 125 (10.3%) in apabetalone-treated patients and 149 (12.4%) in placebo-treated patients (hazard ratio, 0.82 [95% CI, 0.65-1.04]; P = .11). More patients allocated to apabetalone than placebo discontinued study drug (114 [9.4%] vs 69 [5.7%]) for reasons including elevations of liver enzyme levels (35 [2.9%] vs 11 [0.9%]). CONCLUSIONS AND RELEVANCE Among patients with recent acute coronary syndrome, type 2 diabetes, and low high-density lipoprotein cholesterol levels, the selective bromodomain and extraterminal protein inhibitor apabetalone added to standard therapy did not significantly reduce the risk of major adverse cardiovascular events. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02586155.
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Effect of selective BET protein inhibitor apabetalone on cardiovascular outcomes in patients with acute coronary syndrome and diabetes: Rationale, design, and baseline characteristics of the BETonMACE trial.
Ray, KK, Nicholls, SJ, Ginsberg, HD, Johansson, JO, Kalantar-Zadeh, K, Kulikowski, E, Toth, PP, Wong, N, Cummings, JL, Sweeney, M, et al
American heart journal. 2019;:72-83
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Abstract
After an acute coronary syndrome (ACS), patients with diabetes remain at high risk for additional cardiovascular events despite use of current therapies. Bromodomain and extra-terminal (BET) proteins are epigenetic modulators of inflammation, thrombogenesis, and lipoprotein metabolism implicated in atherothrombosis. The BETonMACE trial tests the hypothesis that treatment with apabetalone, a selective BET protein inhibitor, will improve cardiovascular outcomes in patients with diabetes after an ACS. DESIGN Patients (n = 2425) with ACS in the preceding 7 to 90 days, with type 2 diabetes and low HDL cholesterol (≤40 mg/dl for men, ≤45 mg/dl for women), receiving intensive or maximum-tolerated therapy with atorvastatin or rosuvastatin, were assigned in double-blind fashion to receive apabetalone 100 mg orally twice daily or matching placebo. Baseline characteristics include female sex (25%), myocardial infarction as index ACS event (74%), coronary revascularization for index ACS (80%), treatment with dual anti-platelet therapy (87%) and renin-angiotensin system inhibitors (91%), median LDL cholesterol 65 mg per deciliter, and median HbA1c 7.3%. The primary efficacy measure is time to first occurrence of cardiovascular death, non-fatal myocardial infarction, or stroke. Assumptions include a primary event rate of 7% per annum in the placebo group and median follow-up of 1.5 years. Patients will be followed until at least 250 primary endpoint events have occurred, providing 80% power to detect a 30% reduction in the primary endpoint with apabetalone. SUMMARY BETonMACE will determine whether the addition of the selective BET protein inhibitor apabetalone to contemporary standard of care for ACS reduces cardiovascular morbidity and mortality in patients with type 2 diabetes. Results are expected in 2019.
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CFH and ARMS2 genetic risk determines progression to neovascular age-related macular degeneration after antioxidant and zinc supplementation.
Vavvas, DG, Small, KW, Awh, CC, Zanke, BW, Tibshirani, RJ, Kustra, R
Proceedings of the National Academy of Sciences of the United States of America. 2018;(4):E696-E704
Abstract
We evaluated the influence of an antioxidant and zinc nutritional supplement [the Age-Related Eye Disease Study (AREDS) formulation] on delaying or preventing progression to neovascular AMD (NV) in persons with age-related macular degeneration (AMD). AREDS subjects (n = 802) with category 3 or 4 AMD at baseline who had been treated with placebo or the AREDS formulation were evaluated for differences in the risk of progression to NV as a function of complement factor H (CFH) and age-related maculopathy susceptibility 2 (ARMS2) genotype groups. We used published genetic grouping: a two-SNP haplotype risk-calling algorithm to assess CFH, and either the single SNP rs10490924 or 372_815del443ins54 to mark ARMS2 risk. Progression risk was determined using the Cox proportional hazard model. Genetics-treatment interaction on NV risk was assessed using a multiiterative bootstrap validation analysis. We identified strong interaction of genetics with AREDS formulation treatment on the development of NV. Individuals with high CFH and no ARMS2 risk alleles and taking the AREDS formulation had increased progression to NV compared with placebo. Those with low CFH risk and high ARMS2 risk had decreased progression risk. Analysis of CFH and ARMS2 genotype groups from a validation dataset reinforces this conclusion. Bootstrapping analysis confirms the presence of a genetics-treatment interaction and suggests that individual treatment response to the AREDS formulation is largely determined by genetics. The AREDS formulation modifies the risk of progression to NV based on individual genetics. Its use should be based on patient-specific genotype.
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The effects of high and low doses of folic acid on oxidation of protein levels during pregnancy: a randomized double-blind clinical trial.
Shiralizadeh, J, Barmaki, H, Haiaty, S, Faridvand, Y, Mostafazadeh, M, Mokarizadeh, N, Kamrani, A, Isazadeh, A, Maroufi, NF
Hormone molecular biology and clinical investigation. 2017;(3)
Abstract
Objective Oxidants include important active molecules which are created in the body and attack biological molecules especially lipids, carbohydrates, nucleic acids and proteins, and cause oxidation and various diseases in the body. Antioxidants existing in the body help to avoid the incidence of these injuries. Pregnant women are among those where oxidation of biological molecules may do irreparable damage to them and their embryos. So, the purpose of this study was to review the effect of folic acid with both high (5 mg/day) and low (0.5 mg/day) doses on the changes of oxidative protein in reducing plasma homocystein concentration during pregnancy. Materials and methods Forty-five pregnant women participated in this study. They were divided into two groups: group 1 included 23 women who received 5 mg/day folic acid and group 2 included 23 women who took 0.5 mg/day folic acid before pregnancy till the 36th week pregnancy. We measured the biochemical variables in the serum of pregnant women at the beginning and at the end of the study. Results Folic acid reduced plasma homocytein in both low and high dose groups (p = 0.035, p = 0.012, respectively). Also, the results showed that folic acid prescription led to reduce plasma level of carbonyl groups in both low and high dose groups (p = 0.01, p = 0.03, respectively). Furthermore, the results showed that there is no significant difference between two groups and folic acid affects both groups equally. Conclusion It is possible that folic acid administration can reduce plasma homocysteine and carbonyl levels during pregnancy in dose independent manner.
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Formoterol, a highly β2-selective agonist, induces gender-dimorphic whole body leucine metabolism in humans.
Lee, P, Birzniece, V, Umpleby, AM, Poljak, A, Ho, KK
Metabolism: clinical and experimental. 2015;(4):506-12
Abstract
OBJECTIVE Formoterol is a β(2)-selective agonist that enhances protein anabolism in rodents. Whether formoterol imparts anabolic benefits in humans is unknown. The objective of the study was to investigate the effects of formoterol on whole body protein rates of turnover, oxidative loss and synthesis. DESIGN Open label intervention study. PATIENTS Fifteen healthy adults (8 men). MEASUREMENTS Volunteers were treated with oral formoterol 160 μg/day for one week. Changes in leucine turnover (LRa; index of protein breakdown), oxidation (Lox; irreversible protein loss) and incorporation into protein (LIP; index of protein synthesis) were assessed using the whole body 1-[(13)C]leucine turnover technique before/after treatment. RESULTS LRa, Lox and LIP correlated significantly with lean body mass (LBM). LRa, adjusted for LBM was significantly higher (P<0.05, 160±6 vs 109±3 μmol/min) in men but not fractional Lox and LIP (expressed as a proportion of LRa). Formoterol reduced LRa (-9±4%) in men but stimulated LRa (9±3%) in women. Formoterol significantly reduced (P<0.05) fractional Lox, an effect greater in women (-4±1 vs -1±1 %). It stimulated fractional LIP in women (∆4±1%, P<0.05) but not in men (∆1±1%). Formoterol induced an absolute anabolic effect that was greater in women (30 vs 8%). Heart rate, systolic and diastolic blood pressures were unaffected. CONCLUSION In a therapeutic dose, formoterol stimulates protein anabolism in humans. It induced gender-dimorphic effects on protein turnover and on the partitioning of amino acids from oxidative loss toward protein synthesis, effects that are greater in women than in men. Formoterol holds promise as a treatment for sarcopenia.
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Effect of exercise combined with dietary intervention on obese children and adolescents associated with the FTO rs9939609 polymorphism.
Zou, ZC, -J Mao, L, Shi, YY, Chen, JH, Wang, LS, Cai, W
European review for medical and pharmacological sciences. 2015;(23):4569-75
Abstract
OBJECTIVE Aim of this study was to investigate the association of the FTO rs9939609 polymorphism with the effects of the exercise and dietary intervention on obese adolescents and children in China. PATIENTS AND METHODS Total 138 chinese children and adolescents (77 males and 61 females, aged 10-18 years) were recruited in the 2012 summer camp in Shanghai. Dietary and exercise intervention was performed for four weeks. Obesity related parameters were detected by the physical examination before and after four-week's intervention. Genotyping of the FTO rs9939609 was performed by using a TaqMan SNP Genotyping Assay. SPSS 19.0 were used to do the statistical analysis. RESULTS Finally, 135 campers were investigated in this study. The AA, AT and TT genotype frequencies of rs9939609 were 5.2%, 33.3% and 61.5%, respectively. The BMI in individuals with the genotype AA (or AT) was significantly higher compared with their with TT genotype (p = 0.044). The levels of body mass index (BMI), insulin (INS), total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), red blood cell (RBC), Hemoglobin (HB) and hematocrit (HCT) in campers were significantly declined by the combined intervention (p < 0.05). Moreover, the levels of TC, low-density lipoprotein (LDL), RBC, HB, and HCT in the camper with genotype AA (or AT) were significantly decreased by the combined intervention compared with the camper with genotype TT (p < 0.05). CONCLUSIONS The effects of exercise combined with dietary intervention on obesity were associated with the FTO rs9939609 polymorphism in chinese adolescents and children.
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The FTO genotype as a useful predictor of body weight maintenance: initial data from a 5-year follow-up study.
Matsuo, T, Nakata, Y, Hotta, K, Tanaka, K
Metabolism: clinical and experimental. 2014;(7):912-7
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OBJECTIVE We examined associations between the fat-mass and obesity-associated (FTO) gene (rs9939609) and any weight change over a 5-year period following a 14-week lifestyle intervention among middle-aged Japanese women. MATERIALS/METHODS One hundred twenty-eight Japanese women (BMI >25 kg/m²) participated in a 14-week weight loss intervention between 2004 and 2006. Of the participants, 62 consented to the 5-year follow-up measurement session. Of these women, 47 women who achieved a weight loss of at least 10% from their baseline values during the 14-week intervention were included in the analysis. Body weight, body fat, abdominal fat assessed by CT scans, and metabolic risk factors (i.e., blood pressure, lipids, and glucose) were measured at baseline, post-intervention, and at the 5-year follow-up. RESULTS During the 5-year non-intervention period, increases in body weight, fat mass, total abdominal fat, and subcutaneous abdominal fat were significantly greater in subjects with the homozygous minor allele (AA genotype, n=4; 8.5%) than in those with the homozygous major allele (TT genotype, n=31; 66.0%) or heterozygous allele (TA genotype, n=12; 25.5%). In multiple regression analyses, the variation in rs9939609 was a significant and independent predictor (P<0.001) for regaining weight during the 5-year follow-up. CONCLUSIONS Our data suggest that Japanese women with the risk allele (AA) of rs9939609 may have more difficulty preventing fat gain from reoccurring after weight loss intervention than women with the other genotypes.
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Daily protein intake and patient outcomes in severe acute kidney injury: findings of the randomized evaluation of normal versus augmented level of replacement therapy (RENAL) trial.
Bellomo, R, Cass, A, Cole, L, Finfer, S, Gallagher, M, Lee, J, Lo, S, McArthur, C, McGuinness, S, Norton, R, et al
Blood purification. 2014;(4):325-34
Abstract
BACKGROUND AND AIMS We aimed to examine the association between daily protein intake (DPI) and outcomes in patients from the Randomized Evaluation of Normal versus Augmented Level (RENAL) trial. METHODS We analyzed the association between DPI and clinical outcomes using multivariable logistic regression, Cox proportional hazards models and time-adjusted analysis. RESULTS During ICU stay, mean DPI was 37.6 g/day among survivors and 37.7 g/day among nonsurvivors (p = 0.96; DPI of 0.5 g/kg/day). Only 159 (10.9%) of the patients received a mean DPI of >1 g/kg. Patients with a DPI above the median had a 43.1% mortality compared with 46.1% for a DPI below the median (p = 0.25). On multivariate analysis, a lower DPI was not associated with increased odds ratios for 90-day mortality or any secondary outcomes. Cox proportional hazards models and time-adjusted analysis confirmed these findings. CONCLUSIONS In the RENAL study, mean DPI was low. Within the confines of such low DPI, greater amounts of DPI were not independently associated with improved clinical outcomes. Video Journal Club "Cappuccino with Claudio Ronco" at www.karger.com/?doi=363175.
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FTO gene: association to weight regain after lifestyle intervention in overweight children.
Reinehr, T, Wolters, B, Roth, CL, Hinney, A
Hormone research in paediatrics. 2014;(6):391-6
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OBJECTIVE Polymorphisms in intron 1 of the 'fat mass and obesity-associated' (FTO) gene are associated with weight status. We hypothesized that the risk allele at a polymorphism in intron 1 of FTO is associated with weight regain after end of lifestyle intervention. METHODS We longitudinally analyzed the changes of weight status as BMI-SDS in 346 unrelated overweight children (mean age 10.6 ± 2.6 years, 45% male, mean BMI-SDS 2.39 ± 0.49) both at the end of a 1-year lifestyle intervention and 1 year after the end of this intervention. We genotyped the obesity risk SNP rs9939609 at FTO by ARMS-PCR. RESULTS The children reduced their BMI-SDS (-0.29 ± 0.33; p < 0.001) during intervention and increased their BMI-SDS between the end of intervention and 1 year later (+0.10 ± 0.41; p < 0.001). The obesity risk allele at FTO SNP rs9939609 was not associated with BMI-SDS reduction during the lifestyle intervention (p = 0.622), but with weight regain 1 year after end of the intervention in multiple linear regression analyses adjusted for age, sex, pubertal stage, and baseline BMI-SDS (Bonferroni corrected p = 0.002). CONCLUSIONS The obesity risk allele at a polymorphism in intron 1 of FTO was associated with weight regain 1 year after a 1-year lifestyle intervention.
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FTO T/A and peroxisome proliferator-activated receptor-γ Pro12Ala polymorphisms but not ApoA1 -75 are associated with better response to lifestyle intervention in Brazilians at high cardiometabolic risk.
Curti, ML, Rogero, MM, Baltar, VT, Barros, CR, Siqueira-Catania, A, Ferreira, SR
Metabolic syndrome and related disorders. 2013;(3):169-76
Abstract
BACKGROUND The role of obesity-related polymorphisms on weight loss and inflammatory responses to interventions is unclear. We investigated associations of certain polymorphisms with response to a lifestyle intervention. METHODS This 9-month intervention on diet and physical activity included 180 Brazilians at high cardiometabolic risk, genotyped for the fat mass and obesity-associated (FTO) T/A, peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala, and ApoA1 -75G/A polymorphisms. Changes in metabolic and inflammatory variables were analyzed according to these polymorphisms. RESULTS The intervention resulted in lower energy intake and higher physical activity. Anthropometric measurements, 2-hr plasma glucose, insulin, high-density lipoprotein cholesterol (HDL-C), and apolipoprotein B (ApoB) improved significantly for the total sample, and these benefits were similar among genotypes. Only variant allele carriers of FTO T/A decreased fasting plasma glucose after intervention (99.9±1.3 to 95.6±1.4 mg/dL, P=0.021). Mean blood pressure reduced after intervention in variant allele carriers of the PPARγ Pro12Ala (109.4±2.1 to 101.3±2.1 mmHg, P<0.001). Improvement in lipid variables was not significant after adjustment for medication. Only the reference genotype of PPARγ Pro12Ala increased apolipoprotein A1 (ApoA1) after intervention (134.3±2.4 to 140.6±2.3 mg/dL, P<0.001). Only variant allele carriers of FTO reduced C-reactive protein (CRP) concentration (0.366±0.031 to 0.286±0.029 mg/dL, P=0.023). CONCLUSION In Brazilian individuals, the FTO T/A polymorphism induces a favorable impact on inflammatory status and glucose metabolism. The reference genotype of PPARγ Pro12Ala seems to favor a better lipid profile, while the variant allele decreases blood pressure. Our data did not support benefits of the variant allele of ApoA1 -75G/A polymorphism. Further studies are needed to direct lifestyle intervention to subsets of individuals at cardiometabolic risk.