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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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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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Acetaminophen protein adduct formation following low-dose acetaminophen exposure: comparison of immediate-release vs extended-release formulations.
James, LP, Chiew, A, Abdel-Rahman, SM, Letzig, L, Graudins, A, Day, P, Roberts, D
European journal of clinical pharmacology. 2013;(4):851-7
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PURPOSE Acetaminophen (APAP) protein adducts are a biomarker of APAP metabolism, reflecting oxidation of APAP and generation of the reactive metabolite N-acetyl-p-benzoquinone imine. High levels of adducts correspond to liver toxicity in patients with APAP-related acute liver failure. Adduct formation following low-dose exposure to APAP has not been well studied. APAP protein adducts were measured in blood samples collected from fasted individuals who participated in a crossover study of APAP (80 mg/kg) comparing extended release (ER) and immediate release (IR) formulations. METHODS Adducts were quantified in all postdose blood samples using a validated high-performance liquid chromatography electrochemical detection (HPLC-EC) assay. RESULTS Comparison of pharmacokinetic parameters for adducts did not reveal significant differences between ER and IR formulations, with one exception. Formation rates for adducts were faster for IR than the ER formulation (0.420 ± 0.157 vs. 0.203 ± 0.080 1/h), respectively. Maximum plasma concentrations (Cmax) of adducts for IR and ER were 0.108 (±0.020) and 0.100 (±0.028) nmol/ml serum, respectively, and were two orders of magnitude lower than adduct levels previously reported in adults with acute liver failure secondary to APAP. CONCLUSIONS APAP protein adducts are rapidly formed following nontoxic ingestion of APAP at levels significantly lower than those associated with acute liver failure.
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Associations of the FTO rs9939609 and the MC4R rs17782313 polymorphisms with type 2 diabetes are modulated by diet, being higher when adherence to the Mediterranean diet pattern is low.
Ortega-Azorín, C, Sorlí, JV, Asensio, EM, Coltell, O, Martínez-González, MÁ, Salas-Salvadó, J, Covas, MI, Arós, F, Lapetra, J, Serra-Majem, L, et al
Cardiovascular diabetology. 2012;:137
Abstract
BACKGROUND Although the fat mass and obesity (FTO) and melanocortin-4 receptor (MC4R) genes have been consistently associated with obesity risk, the association between the obesity-risk alleles with type 2 diabetes is still controversial. In some recent meta-analyses in which significant results have been reported, the associations disappeared after adjustment for body mass index (BMI). However gene-diet interactions with dietary patterns have not been investigated. Our main aim was to analyze whether these associations are modulated by the level of adherence to the Mediterranean Diet (MedDiet). METHODS Case-control study in 7,052 high cardiovascular risk subjects (3,430 type 2 diabetes cases and 3,622 non-diabetic subjects) with no differences in BMI. Diet was assessed by validated questionnaires. FTO-rs9939609 and MC4R-rs17782313 were determined. An aggregate genetic score was calculated to test additive effects. Gene-diet interactions were analyzed. RESULTS Neither of the polymorphisms was associated with type 2 diabetes in the whole population. However, we found consistent gene-diet interactions with adherence to the MedDiet both for the FTO-rs9939609 (P-interaction=0.039), the MC4R-rs17782313 (P-interaction=0.009) and for their aggregate score (P-interaction=0.006). When adherence to the MedDiet was low, carriers of the variant alleles had higher type 2 diabetes risk (OR=1.21, 95%CI: 1.03-1.40; P=0.019 for FTO-rs9939609 and OR=1.17, 95%CI:1.01-1.36; P=0.035 for MC4R-rs17782313) than wild-type subjects. However, when adherence to the MedDiet was high, these associations disappeared (OR=0.97, 95%CI: 0.85-1.16; P=0.673 for FTO-rs9939609 and OR=0.89, 95%CI:0.78-1.02; P=0.097 for MC4R-rs17782313). These gene-diet interactions remained significant even after adjustment for BMI. As MedDiet is rich in folate, we also specifically examined folate intake and detected statistically significant interaction effects on fasting plasma glucose concentrations in non-diabetic subjects. However these findings should be interpreted with caution because folate intake may simply reflect a healthy dietary pattern. CONCLUSIONS These novel results suggest that the association of the FTO-rs9939609 and the MC4R-rs17782313 polymorphisms with type 2 diabetes depends on diet and that a high adherence to the MedDiet counteracts the genetic predisposition.
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Effects of male hypogonadism on regional adipose tissue fatty acid storage and lipogenic proteins.
Santosa, S, Jensen, MD
PloS one. 2012;(2):e31473
Abstract
Testosterone has long been known to affect body fat distribution, although the underlying mechanisms remain elusive. We investigated the effects of chronic hypogonadism in men on adipose tissue fatty acid (FA) storage and FA storage factors. Twelve men with chronic hypogonadism and 13 control men matched for age and body composition: 1) underwent measures of body composition with dual energy x-ray absorptiometry and an abdominal CT scan; 2) consumed an experimental meal containing [(3)H]triolein to determine the fate of meal FA (biopsy-measured adipose storage vs. oxidation); 3) received infusions of [U-(13)C]palmitate and [1-(14)C]palmitate to measure rates of direct free (F)FA storage (adipose biopsies). Adipose tissue lipoprotein lipase, acyl-CoA synthetase (ACS), and diacylglycerol acetyl-transferase (DGAT) activities, as well as, CD36 content were measured to understand the mechanism by which alterations in fat storage occur in response to testosterone deficiency. Results of the study showed that hypogonadal men stored a greater proportion of both dietary FA and FFA in lower body subcutaneous fat than did eugonadal men (both p<0.05). Femoral adipose tissue ACS activity was significantly greater in hypogonadal than eugonadal men, whereas CD36 and DGAT were not different between the two groups. The relationships between these proteins and FA storage varied somewhat between the two groups. We conclude that chronic effects of testosterone deficiency has effects on leg adipose tissue ACS activity which may relate to greater lower body FA storage. These results provide further insight into the role of androgens in body fat distribution and adipose tissue metabolism in humans.