Abstract：
Patients with advanced fibrosis due to nonalcoholic steatohepatitis (NASH) are at high risk of morbidity and mortality. We previously found that a combination of the farnesoid X receptor agonist cilofexor (CILO) and the acetyl-CoA carboxylase inhibitor firsocostat (FIR) improved liver histology and biomarkers in NASH with advanced fibrosis but was associated with hypertriglyceridemia. We evaluated the safety and efficacy of icosapent ethyl (Vascepa) and fenofibrate to mitigate triglyceride elevations in patients with NASH treated with CILO and FIR.
Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n = 33) or fenofibrate 145 mg daily (n = 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored.
All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were -12 mg/dL (IQR, -33 to 7 mg/dL; P = .09) vs -32 mg/dL (IQR, -76 to 6 mg/dL; P = .012) and at 6 weeks were +41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs -2 mg/dL (IQR, -42 to 54 mg/dL; P = .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL).
In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition.
gov, Number: NCT02781584.
Patients with NASH with elevated triglycerides (≥150 and <500 mg/dL) were randomized to Vascepa 2 g twice daily (n = 33) or fenofibrate 145 mg daily (n = 33) for 2 weeks, followed by the addition of CILO 30 mg and FIR 20 mg daily for 6 weeks. Safety, lipids, and liver biochemistry were monitored.
All treatments were well-tolerated; most treatment-emergent adverse events were Grade 1 to 2 severity, and there were no discontinuations due to adverse events. At baseline, median (interquartile range [IQR]) triglycerides were similar in the Vascepa and fenofibrate groups (median, 177 [IQR, 154-205] vs 190 [IQR, 144-258] mg/dL, respectively). Median changes from baseline in triglycerides for Vascepa vs fenofibrate after 2 weeks of pretreatment were -12 mg/dL (IQR, -33 to 7 mg/dL; P = .09) vs -32 mg/dL (IQR, -76 to 6 mg/dL; P = .012) and at 6 weeks were +41 mg/dL (IQR, 16-103 mg/dL; P < .001) vs -2 mg/dL (IQR, -42 to 54 mg/dL; P = .92). In patients with baseline triglycerides <250 mg/dL, fenofibrate was more effective vs Vascepa in mitigating triglyceride increases after 6 weeks of combination treatment (+6 vs +39 mg/dL); similar trends were observed in patients with baseline triglycerides ≥250 mg/d (-61 vs +99 mg/dL).
In patients with NASH with hypertriglyceridemia treated with CILO and FIR, fenofibrate was safe and effectively mitigated increases in triglycerides associated with acetyl-CoA carboxylase inhibition.
gov, Number: NCT02781584.
摘要：
目的：非酒精性脂肪性肝炎（NASH）导致的晚期纤维化患者的发病率和死亡率都很高。我们先前发现，法尼醇X受体激动剂cilofexor（CILO）和乙酰辅酶A羧化酶抑制剂firsocostat（FIR）的组合可改善NASH晚期纤维化的肝组织学和生物标志物，但与高甘油三酯血症有关。我们评估了二十碳五烯酸乙酯（Vascepa）和非诺贝特减轻CILO和FIR治疗NASH患者甘油三酯升高的安全性和有效性。
方法：将甘油三酯升高（≥150和<500mg/dL）的NASH患者随机分为Vascepa2g，每天两次（n=33）或非诺贝特145mg，持续2周。然后每天添加CILO30mg和FIR20mg，持续6周。安全,脂质，和肝脏生化监测。
结果：所有治疗均耐受良好；大多数治疗引起的不良事件严重程度为1至2级，并且没有因不良事件而停药.在基线,Vascepa和非诺贝特组的甘油三酯中位数（四分位距[IQR]）相似（中位数，177[IQR,154-205]vs190[IQR，144-258]mg/dL，分别)。预处理2周后，Vascepa与非诺贝特的甘油三酯相对于基线的中位数变化为-12mg/dL（IQR，-33至7mg/dL；P=.09）与-32mg/dL（IQR，-76至6mg/dL；P=.012)，6周时为+41mg/dL(IQR，16-103mg/dL；P<.001）与-2mg/dL（IQR，-42至54毫克/分升；P=.92）。在基线甘油三酯<250mg/dL的患者中，联合治疗6周后,非诺贝特在缓解甘油三酯升高方面比Vascepa更有效(+6vs+39mg/dL);基线甘油三酯≥250mg/d的患者中观察到类似趋势(-61vs+99mg/dL).
结论：在用CILO和FIR治疗的高甘油三酯血症NASH患者中，非诺贝特是安全的，有效地减轻了与乙酰辅酶A羧化酶抑制相关的甘油三酯的增加。
结果：政府，编号：NCT02781584。
方法：将甘油三酯升高（≥150和<500mg/dL）的NASH患者随机分为Vascepa2g，每天两次（n=33）或非诺贝特145mg，持续2周。然后每天添加CILO30mg和FIR20mg，持续6周。安全,脂质，和肝脏生化监测。
结果：所有治疗均耐受良好；大多数治疗引起的不良事件严重程度为1至2级，并且没有因不良事件而停药.在基线,Vascepa和非诺贝特组的甘油三酯中位数（四分位距[IQR]）相似（中位数，177[IQR,154-205]vs190[IQR，144-258]mg/dL，分别)。预处理2周后，Vascepa与非诺贝特的甘油三酯相对于基线的中位数变化为-12mg/dL（IQR，-33至7mg/dL；P=.09）与-32mg/dL（IQR，-76至6mg/dL；P=.012)，6周时为+41mg/dL(IQR，16-103mg/dL；P<.001）与-2mg/dL（IQR，-42至54毫克/分升；P=.92）。在基线甘油三酯<250mg/dL的患者中，联合治疗6周后,非诺贝特在缓解甘油三酯升高方面比Vascepa更有效(+6vs+39mg/dL);基线甘油三酯≥250mg/d的患者中观察到类似趋势(-61vs+99mg/dL).
结论：在用CILO和FIR治疗的高甘油三酯血症NASH患者中，非诺贝特是安全的，有效地减轻了与乙酰辅酶A羧化酶抑制相关的甘油三酯的增加。
结果：政府，编号：NCT02781584。
