Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
Effects of dapagliflozin and n-3 carboxylic acids on non-alcoholic fatty liver disease in people with type 2 diabetes: a double-blind randomised placebo-controlled study.
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DOI：
10.1007/s00125-018-4675-2
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发表时间：
2018-09
期刊：
影响因子：
8.2
通讯作者：
Oscarsson J
中科院分区：
文献类型：
--
作者：
Eriksson JW;Lundkvist P;Jansson PA;Johansson L;Kvarnström M;Moris L;Miliotis T;Forsberg GB;Risérus U;Lind L;Oscarsson J
EFFECT-II研究旨在研究达格列净和omega-3 （n-3）羧酸（OM-3CA）单独或联合对2型糖尿病和非酒精性脂肪性肝病（NAFLD）患者肝脏脂肪含量的影响。这项随机安慰剂对照双盲平行组研究在瑞典大学医院的五个临床研究中心进行，84名2型糖尿病和NAFLD患者通过集中随机系统按1:1:1:1随机分配到四种治疗方法，所有参与者以及参与研究进行和分析的研究者和工作人员对治疗方法都是盲的。每组接受以下口服剂量之一：10 mg达格列净（n = 21）， 4 g OM-3CA (n = 20)，两者联合（n = 22）或安慰剂（n = 21）。主要终点是通过MRI评估肝脏脂肪含量（质子密度脂肪分数[PDFF]），此外，在基线和治疗12周后（试验完成）评估肝脏总体积、葡萄糖和脂质代谢标志物以及肝细胞损伤和氧化应激。参与者平均年龄为65.5岁（SD 5.9）， BMI为31.2 kg/m2(3.5)，肝脏PDFF为18%（9.3）。所有积极治疗均显著降低肝脏PDFF，相对变化：OM-3CA， - 15%；dapagliflozin,−13%;OM-3CA + dapagliflozin,−21%。与安慰剂相比，只有联合治疗降低了肝脏PDFF （p = 0.046）和肝总脂肪体积（相对变化，- 24%,p = 0.037）。积极治疗组PNPLA3 I148M多态性与肝脏PDFF变化存在交互作用（p = 0.03）。达格列净单药治疗，而不是与OM-3CA联合治疗，降低了肝细胞损伤生物标志物的水平，包括丙氨酸转氨酶、天冬氨酸转氨酶、γ-谷氨酰转移酶（γ-GT）、细胞角蛋白（CK） 18-M30和CK 18-M65和血浆成纤维细胞生长因子21 （FGF21）。γ-GT的变化与肝脏PDFF的变化相关（ρ = 0.53, p = 0.02）。单独使用达格列净和联合使用OM-3CA可改善血糖控制，降低体重和腹部脂肪体积。脂肪酸氧化应激生物标志物不受治疗影响。与以前的研究相比，这些治疗没有新的或意想不到的不良事件。达格列净和OM-3CA联合治疗可显著降低肝脏脂肪含量。达格列净单药治疗降低了所有测量的肝细胞损伤生物标志物和FGF21，提示NAFLD的疾病改善作用。该研究由阿斯利康公司资助。本文的在线版本（10.1007/s00125-018-4675-2）包含同行评审但未经编辑的补充材料，授权用户可使用。
The EFFECT-II study aimed to investigate the effects of dapagliflozin and omega-3 (n-3) carboxylic acids (OM-3CA), individually or combined, on liver fat content in individuals with type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). This randomised placebo-controlled double-blind parallel-group study was performed at five clinical research centres at university hospitals in Sweden. 84 participants with type 2 diabetes and NAFLD were randomly assigned 1:1:1:1 to four treatments by a centralised randomisation system, and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. Each group received oral doses of one of the following: 10 mg dapagliflozin (n = 21), 4 g OM-3CA (n = 20), a combination of both (n = 22) or placebo (n = 21). The primary endpoint was liver fat content assessed by MRI (proton density fat fraction [PDFF]) and, in addition, total liver volume and markers of glucose and lipid metabolism as well as of hepatocyte injury and oxidative stress were assessed at baseline and after 12 weeks of treatment (completion of the trial). Participants had a mean age of 65.5 years (SD 5.9), BMI 31.2 kg/m2 (3.5) and liver PDFF 18% (9.3). All active treatments significantly reduced liver PDFF from baseline, relative changes: OM-3CA, −15%; dapagliflozin, −13%; OM-3CA + dapagliflozin, −21%. Only the combination treatment reduced liver PDFF (p = 0.046) and total liver fat volume (relative change, −24%, p = 0.037) in comparison with placebo. There was an interaction between the PNPLA3 I148M polymorphism and change in liver PDFF in the active treatment groups (p = 0.03). Dapagliflozin monotherapy, but not the combination with OM-3CA, reduced the levels of hepatocyte injury biomarkers, including alanine aminotransferase, aspartate aminotransferase, γ-glutamyl transferase (γ-GT), cytokeratin (CK) 18-M30 and CK 18-M65 and plasma fibroblast growth factor 21 (FGF21). Changes in γ-GT correlated with changes in liver PDFF (ρ = 0.53, p = 0.02). Dapagliflozin alone and in combination with OM-3CA improved glucose control and reduced body weight and abdominal fat volumes. Fatty acid oxidative stress biomarkers were not affected by treatments. There were no new or unexpected adverse events compared with previous studies with these treatments. Combined treatment with dapagliflozin and OM-3CA significantly reduced liver fat content. Dapagliflozin monotherapy reduced all measured hepatocyte injury biomarkers and FGF21, suggesting a disease-modifying effect in NAFLD. ClinicalTrials.gov NCT02279407 The study was funded by AstraZeneca. The online version of this article (10.1007/s00125-018-4675-2) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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