Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
Efficacy and Safety of the Farnesoid X Receptor Agonist Obeticholic Acid in Patients With Type 2 Diabetes and Nonalcoholic Fatty Liver Disease
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DOI：
10.1053/j.gastro.2013.05.042
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发表时间：
2013-09-01
期刊：
影响因子：
29.4
通讯作者：
Shapiro, David
中科院分区：
文献类型：
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作者：
Mudaliar, Sunder;Henry, Robert R.;Shapiro, David
背景与目的：奥贝胆酸（OCA；INT-747，6α-乙基-鹅去氧胆酸）是主要人胆汁酸鹅去氧胆酸的半合成衍生物，法尼醇 X 受体是调节葡萄糖和脂质代谢的核激素受体的天然激动剂。在动物模型中，OCA 可降低胰岛素抵抗和肝脂肪变性。方法：我们进行了一项双盲、安慰剂对照、概念验证研究，以评估 OCA 对非酒精性脂肪肝病和 2 型糖尿病患者胰岛素敏感性的影响。患者被随机分配到安慰剂组 (n = 23)、25 mg OCA (n = 20) 或 50 mg OCA (n = 21) 组，每日一次，持续 6 周。在 6 周治疗期之前和之后，使用 2 阶段高胰岛素正常血糖胰岛素钳夹测量胰岛素敏感性。我们还测量了肝酶、脂质分析物、成纤维细胞生长因子 19、7 α-羟基-4-胆固醇-3-酮（BA 前体）、内源性胆汁酸和肝纤维化标志物的水平。结果：当患者接受低剂量胰岛素输注时，25 mg OCA 治疗组的胰岛素敏感性较基线增加 28.0% (P = .019)，50 mg OCA 治疗组的胰岛素敏感性较基线增加 20.1% (P = .060)。联合 OCA 组的胰岛素敏感性增加了 24.5% (P = .011)，而安慰剂组则降低了 5.5%。在接受高剂量胰岛素输注的患者中观察到类似的模式。 OCA组的γ-谷氨酰转移酶和丙氨酸氨基转移酶水平显着降低，并且体重减轻与剂量相关。他们的血清低密度脂蛋白胆固醇和成纤维细胞生长因子 19 水平也升高，与 7-α-羟基-4-胆固醇-3-一和内源性胆汁酸水平降低相关，表明法尼醇 X 受体被激活。 25 mg OCA 治疗组的肝纤维化标志物显着下降。各组之间的不良经历相似。结论：在这项 2 期试验中，2 型糖尿病和非酒精性脂肪肝患者服用 25 或 50 mg OCA 6 周耐受性良好，可提高胰岛素敏感性，并减少肝脏炎症和纤维化标志物。需要进行更长时间和更大规模的研究。 ClinicalTrials.gov，编号：NCT00501592。
BACKGROUND & AIMS: Obeticholic acid (OCA; INT-747, 6 alpha-ethyl-chenodeoxycholic acid) is a semisynthetic derivative of the primary human bile acid chenodeoxycholic acid, the natural agonist of the farnesoid X receptor, which is a nuclear hormone receptor that regulates glucose and lipid metabolism. In animal models, OCA decreases insulin resistance and hepatic steatosis. METHODS: We performed a double-blind, placebocontrolled, proof-of-concept study to evaluate the effects of OCA on insulin sensitivity in patients with nonalcoholic fatty liver disease and type 2 diabetes mellitus. Patients were randomly assigned to groups given placebo (n = 23), 25 mg OCA (n = 20), or 50 mg OCA (n = 21) once daily for 6 weeks. A 2-stage hyperinsulinemiceuglycemic insulin clamp was used to measure insulin sensitivity before and after the 6-week treatment period. We also measured levels of liver enzymes, lipid analytes, fibroblast growth factor 19, 7 alpha-hydroxy-4-cholesten-3-one (a BA precursor), endogenous bile acids, and markers of liver fibrosis. RESULTS: When patients were given a low-dose insulin infusion, insulin sensitivity increased by 28.0% from baseline in the group treated with 25 mg OCA (P = .019) and 20.1% from baseline in the group treated with 50 mg OCA (P = .060). Insulin sensitivity increased by 24.5% (P = .011) in combined OCA groups, whereas it decreased by 5.5% in the placebo group. A similar pattern was observed in patients given a high-dose insulin infusion. The OCA groups had significant reductions in levels of gamma-glutamyltransferase and alanine aminotransferase and dose-related weight loss. They also had increased serum levels of low-density lipoprotein cholesterol and fibroblast growth factor 19, associated with decreased levels of 7 alpha-hydroxy-4-cholesten-3-one and endogenous bile acids, indicating activation of farnesoid X receptor. Markers of liver fibrosis decreased significantly in the group treated with 25 mg OCA. Adverse experiences were similar among groups. CONCLUSIONS: In this phase 2 trial, administration of 25 or 50 mg OCA for 6 weeks was well tolerated, increased insulin sensitivity, and reduced markers of liver inflammation and fibrosis in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Longer and larger studies are warranted. ClinicalTrials.gov, Number: NCT00501592.