非酒精性脂肪性肝炎患者每日一次皮下塞马鲁肽与安慰剂的

StephenW

Efficacy and safety of subcutaneous semaglutide once-daily versus placebo in patients with nonalcoholic steatohepatitis

Semaglutide Resolves NASH in Big Placebo-Controlled Trial

AASLD The Liver Meeting Digital Experience, November 13-16, 2020

Mark Mascolini

Semaglutide, a glucagon-like peptide-1 agonist (GLP-1RA) licensed for treatment of type 2 diabetes, resolved nonalcoholic steatohepatitis (NASH) without worsening fibrosis significantly more often than placebo at all 3 subcutaneous doses used in a 320-person 72-week trial [1]. The medication did not significantly improve fibrosis compared with placebo, but it did improve weight, lipids, and the diabetes metric HbA1c.

Besides lowering glucose, GLP-1RAs have beneficial effect on heart, brain, and pancreas, according to an international team that conducted the semaglutide trial. This 17-country phase 2 double-blind placebo-controlled trial enrolled people with biopsy-confirmed NASH, stage 1 to 3 fibrosis, body mass index above 25 kg/m2 (the overweight threshold), HbA1c at or below 10% and NAFLD Activity Score at or above 4. A hierarchical testing procedure [2] randomized participants to subcutaneous* doses 0.4 mg, 0.2 mg, or 0.1 mg of semaglutide once daily versus placebo for 72 weeks. The primary endpoint was resolution of NASH with no liver fibrosis worsening in people with initial stage 2 or 3 fibrosis.

The trial included 80 people randomized to 0.1 mg of semaglutide, 78 to 0.2 mg, 82 to 0.4 mg, and 80 to placebo [3]. All participants also received counseling on nutrition and physical activity. Age averaged 55 years across the four study group, and 55% to 66.7% across the four groups were women. About 62% in the four study arms had diabetes, and body mass index averaged 35.8 kg/m2. Proportions with stage 1, 2, and 3 fibrosis were 28.1%, 22.5%, and 49.4%.

In the 230 participants with stage 2 or 3 fibrosis, 40.4% receiving 0.1 mg of semaglutide daily (P = 0.01 vs placebo), 35.6% receiving 0.2 mg (P = 0.0359 vs placebo), and 58.9% receiving 0.4 mg (P < 0.0001 vs placebo), compared with 17.2% getting placebo, had resolution of NASH without worsening fibrosis. In an analysis of all randomized participants regardless of fibrosis stage, significantly higher proportions  receiving each dose of semaglutide than placebo had NASH resolution with no fibrosis worsening.

Among participants with stage 2 or 3 fibrosis at baseline, fibrosis did not improve significantly more with any dose of semaglutide than with placebo. Proportions with improved fibrosis were 46.3% with 0.1 mg of semaglutide, 32.1% with 0.2 mg, 42.7% with 0.4 mg, and 31.3% with placebo. Researchers recorded worsening fibrosis in 10% taking 0.1 mg of semaglutide, 7.7% taking 0.2 mg, 4.9% taking 0.4 mg, and 18.8% taking placebo.

Semaglutide yielded dose-dependent 72-week improvements in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and two fibrosis markers (ELF and liver stiffness by FibroScan).

Through 72 weeks in all randomized participants, body weight dropped 4.8% with 0.1 mg of semaglutide, 8.9% with 0.2 mg, 12.5% with 0.4 mg, and 0.6% with placebo (P < 0.05 for all differences from placebo). Over 72 weeks HbA1c fell 0.72% with 0.1 mg of semaglutide, 1.28% with 0.2 mg, 1.22% with 0.4 mg, and 0.04% with placebo (P < 0.05 for all differences from placebo).

Compared with placebo. 0.4 mg of semaglutide yielded a significant gain in “good” HDL cholesterol (P = 0.0064) and significant drops in triglycerides (P < 0.0001), VLDL cholesterol (P < 0.0001), and free fatty acids (P = 0.0029).

Rates of serious adverse events possibly or probably related to study drug were 2.5% with 0.1 mg of semaglutide, 3.8% with 0.2 mg, 2.5% with 0.4 mg, and 1.3% with placebo. Nausea was the most frequent problem, reported in 30% making 0.1 mg of semaglutide, 37.2% taking 0.2 mg, 42% taking 0.4 mg, and 11.3% taking placebo. The researchers believe the overall safety profile of semaglutide is similar to that seen in people with type 2 diabetes, “with no new safety concerns.”

*A tablet formulation of semaglutide is now licensed for type 2 diabetes.

References
1. Newsome PN, Buchholtz K, Cusi K, et al. Efficacy and safety of subcutaneous semaglutide once-daily versus placebo in patients with nonalcoholic steatohepatitis. AASLD The Liver Meeting Digital Experience, November 13-16, 2020. Abstract 10.
2. ClinicalTrials.gov. Investigation of efficacy and safety of three dose levels of subcutaneous semaglutide once daily versus placebo in subjects with non-alcoholic steatohepatitis. ClinicalTrials.gov identifier NCT02970942.
3. Bretz F, Xun X. Introduction to multiplicity in clinical trials. Novartis. http://www2.cscc.unc.edu/impact7/system/files/Bretz_Slides.pdf

StephenW

非酒精性脂肪性肝炎患者每日一次皮下塞马鲁肽与安慰剂的疗效和安全性

Semaglutide在大型安慰剂对照试验中解决NASH

AASLD肝脏会议数字体验，2020年11月13日至16日

马克·马斯科利尼

Semaglutide是一种许可用于治疗2型糖尿病的胰高血糖素样肽1激动剂（GLP-1RA），在3人皮下注射的3种皮下剂量（320人使用）中，与非安慰剂相比，其解决的非酒精性脂肪性肝炎（NASH）的发生率没有安慰剂显着增加。每周试用[1]。与安慰剂相比，这种药物不能显着改善纤维化，但可以改善体重，血脂和糖尿病指标HbA1c。

根据进行semaglutide试验的国际研究小组称，除了降低葡萄糖外，GLP-1RA对心脏，大脑和胰腺也有有益作用。这项17国2期双盲安慰剂对照试验纳入了经活检证实为NASH，1至3期纤维化，体重指数高于25 kg / m2（超重阈值），HbA1c等于或低于10％以及NAFLD活动的患者得分等于或高于4。分级测试程序[2]随机将参与者皮下注射剂量为0.4 mg，0.2 mg或0.1 mg的Semaglutide与安慰剂相比，每天一次，持续72周。主要终点是NASH的缓解，最初2或3期纤维化患者无肝纤维化恶化。

该试验包括80人随机分配至0.1 mg司马鲁肽，78至0.2 mg，82至0.4 mg和80至安慰剂[3]。所有参与者还接受了有关营养和体育锻炼的咨询。在四个研究组中，平均年龄为55岁，在四个组中，女性为55％至66.7％。在四个研究组中，约有62％患有糖尿病，体重指数平均为35.8 kg / m2。具有1、2和3期纤维化的比例分别为28.1％，22.5％和49.4％。

在患有2或3期纤维化的230名参与者中，有40.4％的人每天接受0.1 mg的司马鲁肽治疗（P = 0.01 vs安慰剂），35.6％的人接受0.2 mg（P = 0.0359 vs安慰剂）和58.9％的患者接受0.4 mg（P <0.0001与安慰剂相比，有17.2％的人服用了安慰剂，但NASH的缓解却没有使纤维化恶化。在对所有随机参与者的分析中，无论其纤维化程度如何，接受安慰剂的每个剂量的Semaglutide比例均显着高于安慰剂组，其NASH分辨率无纤维化恶化。

在基线时患有2或3期纤维化的参与者中，任何剂量的semaglutide的纤维化没有比安慰剂明显改善更多。改善纤维化的比例分别为：0.1 mg司马鲁肽46.3％，32.1％0.2mg，42.7％0.4mg和安慰剂31.3％。研究人员记录到10％的人服用0.1毫克的semaglutide，7.7％的服用0.2毫克，4.9％的服用0.4毫克和18.8％的服用安慰剂，使纤维化恶化。

Semaglutide可在72周内剂量依赖性地改善丙氨酸氨基转移酶（ALT），天冬氨酸氨基转移酶（AST），γ-谷氨酰转移酶（GGT）和两种纤维化标记物（通过FibroScan获得的ELF和肝硬度）。

在所有随机参与者的72周内，使用Semaglutide的0.1 mg，使用0.2 mg的8.9％，使用0.4 mg的12.5％，使用安慰剂的0.6％降低了体重（对于所有与安慰剂的差异，P <0.05）。在72周内，使用0.1 mg semaglutide的HbA1c下降0.72％，使用0.2 mg的HbA1c下降1.2％，使用0.4 mg的1.22％，使用安慰剂的0.04％（与安慰剂的所有差异均P <0.05）。

与安慰剂相比。 0.4 mg的semaglutide可显着增加“好”的HDL胆固醇（P = 0.0064），并显着降低甘油三酸酯（P <0.0001），VLDL胆固醇（P <0.0001）和游离脂肪酸（P = 0.0029）。

可能或可能与研究药物相关的严重不良事件发生率分别为：0.1 mg semaglutide占2.5％，0.2 mg占3.8％，0.4 mg占2.5％，安慰剂占1.3％。恶心是最常见的问题，据报道有30％的人服用0.1 mg的Semaglutide，37.2％的服用0.2 mg，42％的服用0.4 mg和11.3％的服用安慰剂。研究人员认为，semaglutide的总体安全性与2型糖尿病患者相似，“无需担心新的安全性”。

*塞马鲁肽的片剂现已获得2型糖尿病的许可。

参考文献
1. Newsome PN，Buchholtz K，Cusi K等。非酒精性脂肪性肝炎患者每日一次皮下塞马鲁肽与安慰剂的疗效和安全性比较。 AASLD肝脏会议数字体验，2020年11月13日至16日。摘要10。
2. ClinicalTrials.gov。在非酒精性脂肪性肝炎患者中，与安慰剂相比，每日一次皮下注射semaglutide三种剂量水平的疗效和安全性研究。 ClinicalTrials.gov标识符NCT02970942。
3. Bretz F，XunX。临床试验中的多样性介绍。诺华http://www2.cscc.unc.edu/impact7/system/files/Bretz_Slides.pdf