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Abstract：
UNASSIGNED: Nonalcoholic fatty liver disease (NAFLD) is common among patients with type 2 diabetes mellitus (T2DM) and is associated with increased risk for coronary atherosclerosis and acute cardiovascular (CV) events. We employed the validated, non-invasive Angulo NAFLD fibrosis score (FS) in an intervention study in patients with T2DM and recent acute coronary syndrome (ACS) to determine the association of FS with CV risk and treatment response to apabetalone. Apabetalone is a novel selective inhibitor of the second bromodomain of bromodomain and extra-terminal (BET) proteins, epigenetic regulators of gene expression.
UNASSIGNED: The Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS <-1.455 (F0-F2), -1.455 to 0.675 (indeterminant), and >0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS0-2).
UNASSIGNED: In 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04).
UNASSIGNED: Amongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.
UNASSIGNED: The Phase 3 BETonMACE trial compared apabetalone with placebo in 2,425 patients with T2DM and recent ACS. In this post hoc analysis, we evaluated the impact of apabetalone therapy on CV risk, defined as a composite of major adverse cardiovascular events (MACE: CV death, non-fatal myocardial infarction [MI], or stroke) and hospitalization for heart failure (HHF) in two patient categories of FS that reflect the likelihood of underlying NAFLD. Patients were initially classified into three mutually exclusive categories according to a baseline Angulo FS <-1.455 (F0-F2), -1.455 to 0.675 (indeterminant), and >0.675 (F3-F4), where F0 through F4 connote fibrosis severity none, mild, moderate, severe, and cirrhosis, respectively. The composite of ischemic MACE and HHF in the placebo group was higher in indeterminant and F3-F4 categories compared to the F0-F2 category (17.2% vs 15.0% vs 9.7%). Therefore, for the present analysis, the former two categories were combined into an elevated NAFLD CVD risk group (FS+) that was compared with the F0-F2 group (lower NAFLD risk, FS0-2).
UNASSIGNED: In 73.7% of patients, FS was elevated and consistent with a moderate-to-high likelihood of advanced liver fibrosis (FS+); 26.3% of patients had a lower FS (FS0-2). In the placebo group, FS+ patients had a higher incidence of ischemic MACE and HHF (15.4%) than FS0-2 patients (9.7%). In FS+ patients, addition of apabetalone to standard of care treatment lowered the rate of ischemic MACE compared with placebo (HR = 0.79; 95% CI 0.60-1.05; p=0.10), HHF (HR = 0.53; 95% CI 0.33-0.86; p=0.01), and the composite of ischemic MACE and HHF (HR = 0.76; 95% CI 0.59-0.98; p=0.03). In contrast, there was no apparent benefit of apabetalone in FS0-2 patients (HR 1.24; 95% CI 0.75-2.07; p=0.40; HR 1.12; 95% CI 0.30-4.14; p=0.87; and HR 1.13; 95% CI 0.69-1.86; p=0.62, respectively). Over a median duration of 26.5 months, FS increased from baseline in both treatment groups, but the increase was smaller in patients assigned to apabetalone than to placebo (p=0.04).
UNASSIGNED: Amongst patients with T2DM, recent ACS, and a moderate-to-high likelihood of advanced liver fibrosis, apabetalone was associated with a significantly lower rate of ischemic MACE and HHF and attenuated the increase in hepatic FS over time.
摘要：
未经证实：非酒精性脂肪性肝病(NAFLD)在2型糖尿病(T2DM)患者中很常见，并与冠状动脉粥样硬化和急性心血管事件(CV)风险增加相关。我们采用了经过验证的，一项针对T2DM和近期急性冠脉综合征(ACS)患者的干预研究中的非侵入性AnguloNAFLD纤维化评分(FS),以确定FS与CV风险和阿帕贝酮治疗反应的相关性。Apabetalone是溴结构域和外末端（BET）蛋白的第二个溴结构域的新型选择性抑制剂，基因表达的表观遗传调控因子。
UNASSIGNED：3期BETonMACE试验在2,425例T2DM和近期ACS患者中比较了阿帕贝酮与安慰剂。在这个事后分析中，我们评估了阿帕贝酮治疗对CV风险的影响，定义为主要不良心血管事件的复合(MACE：CV死亡，非致死性心肌梗死[MI]，或卒中）和心力衰竭（HHF）住院的两种患者FS类别，反映了潜在NAFLD的可能性。最初根据基线AnguloFS<-1.455（F0-F2）将患者分为三个相互排斥的类别，-1.455至0.675（不确定因素），>0.675（F3-F4），其中F0至F4表示无纤维化严重程度，温和,中度,严重,和肝硬化，分别。与F0-F2类别相比，安慰剂组中缺血性MACE和HHF的复合物在不确定和F3-F4类别中更高（17.2％vs15.0％vs9.7％）。因此,对于目前的分析，将前两个类别合并为NAFLDCVD风险升高组（FS+），与F0-F2组（较低的NAFLD风险，FS0-2).
未经证实：在73.7%的患者中，FS升高，与晚期肝纤维化（FS+）的中度至高度可能性一致;26.3％的患者具有较低的FS（FS0-2）。在安慰剂组中，FS+患者缺血性MACE和HHF的发生率(15.4%)高于FS0-2患者(9.7%)。在FS+患者中，与安慰剂相比，在标准护理治疗中添加阿帕贝酮可降低缺血性MACE的发生率（HR=0.79;95％CI0.60-1.05;p=0.10），HHF（HR=0.53；95%CI0.33-0.86；p=0.01），以及缺血性MACE和HHF的复合（HR=0.76；95％CI0.59-0.98；p=0.03）。相比之下,阿帕贝酮对FS0-2患者无明显获益(HR1.24;95%CI0.75-2.07;p=0.40;HR1.12;95%CI0.30-4.14;p=0.87;HR1.13;95%CI0.69-1.86;p=0.62).平均持续时间为26.5个月，两个治疗组的FS均从基线增加，但与安慰剂组相比,阿帕贝酮组的增加较小(p=0.04).
未经证实：在T2DM患者中，最近ACS,和晚期肝纤维化的中度到高度的可能性，阿帕贝酮与缺血性MACE和HHF的发生率显著降低相关,并且随着时间的推移减轻了肝脏FS的增加.
UNASSIGNED：3期BETonMACE试验在2,425例T2DM和近期ACS患者中比较了阿帕贝酮与安慰剂。在这个事后分析中，我们评估了阿帕贝酮治疗对CV风险的影响，定义为主要不良心血管事件的复合(MACE：CV死亡，非致死性心肌梗死[MI]，或卒中）和心力衰竭（HHF）住院的两种患者FS类别，反映了潜在NAFLD的可能性。最初根据基线AnguloFS<-1.455（F0-F2）将患者分为三个相互排斥的类别，-1.455至0.675（不确定因素），>0.675（F3-F4），其中F0至F4表示无纤维化严重程度，温和,中度,严重,和肝硬化，分别。与F0-F2类别相比，安慰剂组中缺血性MACE和HHF的复合物在不确定和F3-F4类别中更高（17.2％vs15.0％vs9.7％）。因此,对于目前的分析，将前两个类别合并为NAFLDCVD风险升高组（FS+），与F0-F2组（较低的NAFLD风险，FS0-2).
未经证实：在73.7%的患者中，FS升高，与晚期肝纤维化（FS+）的中度至高度可能性一致;26.3％的患者具有较低的FS（FS0-2）。在安慰剂组中，FS+患者缺血性MACE和HHF的发生率(15.4%)高于FS0-2患者(9.7%)。在FS+患者中，与安慰剂相比，在标准护理治疗中添加阿帕贝酮可降低缺血性MACE的发生率（HR=0.79;95％CI0.60-1.05;p=0.10），HHF（HR=0.53；95%CI0.33-0.86；p=0.01），以及缺血性MACE和HHF的复合（HR=0.76；95％CI0.59-0.98；p=0.03）。相比之下,阿帕贝酮对FS0-2患者无明显获益(HR1.24;95%CI0.75-2.07;p=0.40;HR1.12;95%CI0.30-4.14;p=0.87;HR1.13;95%CI0.69-1.86;p=0.62).平均持续时间为26.5个月，两个治疗组的FS均从基线增加，但与安慰剂组相比,阿帕贝酮组的增加较小(p=0.04).
未经证实：在T2DM患者中，最近ACS,和晚期肝纤维化的中度到高度的可能性，阿帕贝酮与缺血性MACE和HHF的发生率显著降低相关,并且随着时间的推移减轻了肝脏FS的增加.
