Tobita Hiroshi, Sato Shuichi, Miyake Tatsuya, Ishihara Shunji, Kinoshita Yoshikazu
Department of Gastroenterology and Hepatology, Shimane University Faculty of Medicine, Izumo, Japan.
Curr Ther Res Clin Exp. 2017 Jul 8;87:13-19. doi: 10.1016/j.curtheres.2017.07.002. eCollection 2017.
Nonalcoholic steatohepatitis (NASH) is an active form of nonalcoholic fatty liver disease. Risk factors for NASH include type 2 diabetes mellitus (T2DM) and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitors used to treat T2DM prevent glucose reabsorption in the kidney and increase glucose urinary excretion. Dapagliflozin is a potent, selective SGLT2 inhibitor that reduces hyperglycemia in patients with T2DM and has been demonstrated to reduce some complications associated with NASH in rodent models.
To assess the efficacy and safety profile of dapagliflozin for the treatment of NASH-associated with T2DM.
In this single-arm, nonrandomized, open-label study, 16 patients with percutaneous liver biopsy-confirmed NASH and T2DM were enrolled to be prescribed dapagliflozin 5 mg/d for 24 weeks. Of these, 11 patients were evaluable. Patients with chronic liver disease other than NASH were excluded. Body composition, laboratory variables related to liver tests and metabolism, and glucose homeostasis were assessed at baseline and periodically during the study. Changes from baseline were evaluated with the Wilcoxon signed-rank test.
Administration of dapagliflozin for 24 weeks was associated with significant decreases in body mass index ( < 0.01), waist circumference ( < 0.01), and waist-to-hip ratio ( < 0.01). Changes in body composition were driven by reductions in body fat mass ( < 0.01) and percent body fat ( < 0.01), without changes in lean mass or total body water. Liver tests (ie, serum concentrations of aspartate aminotransferase, alanine aminotransferase, ferritin, and type IV collagen 7S) also significantly improved during the study. Insulin concentrations decreased ( < 0.01 by Week 24) in combination with significant reductions in fasting plasma glucose ( < 0.01) and glycated hemoglobin ( < 0.01) levels and increases in adiponectin ( < 0.01) levels from Week 4 onward.
Dapagliflozin was associated with improvements in body composition, most likely a reduction in visceral fat, which occurred together with improvements in liver tests and metabolic variables in patients with NASH-associated with T2DM. UMIN Clinical Trial Registry identifier: UMIN000023574.
非酒精性脂肪性肝炎（NASH）是非酒精性脂肪肝病的一种活跃形式。NASH的风险因素包括2型糖尿病（T2DM）和肥胖。用于治疗T2DM的钠-葡萄糖协同转运蛋白2（SGLT2）抑制剂可防止肾脏对葡萄糖的重吸收并增加尿糖排泄。达格列净是一种强效、选择性SGLT2抑制剂，可降低T2DM患者的高血糖，并已在啮齿动物模型中证明可减少与NASH相关的一些并发症。
评估达格列净治疗与T2DM相关的NASH的疗效和安全性。
在这项单臂、非随机、开放标签研究中，纳入16例经皮肝活检确诊为NASH且患有T2DM的患者，给予达格列净5mg/d，持续24周。其中11例患者可进行评估。排除患有NASH以外的慢性肝病患者。在基线和研究期间定期评估身体成分、与肝功能和代谢相关的实验室指标以及葡萄糖稳态。采用Wilcoxon符号秩检验评估与基线相比的变化。
服用达格列净24周与体重指数显著降低（<0.01）、腰围显著降低（<0.01）和腰臀比显著降低（<0.01）相关。身体成分的变化是由体脂量减少（<0.01）和体脂百分比降低（<0.01）驱动的，瘦体重或总体水无变化。在研究期间，肝功能指标（即血清天冬氨酸氨基转移酶、丙氨酸氨基转移酶、铁蛋白和IV型胶原7S的浓度）也显著改善。胰岛素浓度降低（第24周时<0.01），同时空腹血糖显著降低（<0.01）、糖化血红蛋白水平显著降低（<0.01），从第4周起脂联素水平升高（<0.01）。
达格列净与身体成分改善相关，最可能是内脏脂肪减少，同时伴有与T2DM相关的NASH患者肝功能指标和代谢变量的改善。UMIN临床试验注册编号：UMIN000023574。
