Gastroenterology & Hepatology, Indiana University School of Medicine, Indianapolis, IN.
Digestive and Liver Diseases, Cedars Sinai Medical Center, Los Angeles, CA.
Hepatology. 2021 Oct;74(4):1809-1824. doi: 10.1002/hep.31843. Epub 2021 Jul 19.
NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH.
A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 μg/mL [0.3] vs. 1.3 μg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27).
Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).
非酒精性脂肪性肝病（NAFLD）的特征是胰岛素抵抗以及脂质和葡萄糖代谢失调。过氧化物酶体增殖物激活受体-α/γ双重激动剂沙格列汀可改善胰岛素敏感性以及血脂和血糖参数。沙格列汀在动物研究中改善了 NASH 组织学。在这项随机对照临床试验中，我们评估了沙格列汀在 NAFLD/NASH 患者中的疗效和安全性。
共纳入了 106 名基线时丙氨酸氨基转移酶（ALT）≥50 U/L且体重指数（BMI）≥25 kg/m²的 NAFLD/NASH 患者，按照 1:1:1:1 的比例随机分为安慰剂组或沙格列汀 1 mg、2 mg 或 4 mg 组，治疗 16 周。主要疗效终点为治疗 16 周时 ALT 水平自基线的变化百分比。通过 MRI 质子密度脂肪分数评估肝脂肪含量（LFC）。与安慰剂组相比，沙格列汀 1 mg、2 mg 和 4 mg 组治疗 16 周时的 ALT 自基线的最小二乘均值百分比变化分别为-25.5%（5.8）、-27.7%（5.9）和-45.8%（5.7），而安慰剂组为 3.4%（5.6）（所有 P 值均<0.001）。与安慰剂相比，沙格列汀 4 mg 可改善 LFC（4.1%[5.9] vs.-19.7%[5.6]）、脂联素（-0.3μg/mL[0.3] vs. 1.3μg/mL[0.3]）、稳态模型评估-胰岛素抵抗（-1.3[1.8] vs.-6.3[1.7]）和三酰甘油（-5.3mg/dL[10.7] vs.-68.7mg/dL[10.3]）（所有 P 值均<0.05）。沙格列汀 4 mg 还可改善脂蛋白颗粒组成和大小，并降低脂毒性脂质种类。沙格列汀耐受性良好。与安慰剂组 0.3kg 的平均体重增加相比，沙格列汀 4 mg 组的平均体重增加为 1.5kg（P=0.27）。
沙格列汀 4 mg 可显著改善 NAFLD/NASH 患者的 ALT、LFC、胰岛素抵抗和致动脉粥样硬化性血脂异常。（临床试验注册号：NCT03061721）。
