OBJECTIVE Nonalcoholic fatty liver disease (NAFLD) is a liver phenotype of type 2 diabetes and obesity. Currently, the efficacy of sodium–glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas in liver pathology and hepatic gene expression profiles for type 2 diabetes with NAFLD are unknown. RESEARCH DESIGN AND METHODS We conducted a 48 week, randomized, open-label, parallel-group trial involving participants with biopsy-confirmed NAFLD. A total of 40 participants were randomly assigned to receive once daily 20 mg tofogliflozin or 0.5 mg glimepiride. The primary outcome was the percentage of participants with at least an improvement in all individual scores for histological categories of steatosis, hepatocellular ballooning, lobular inflammation, and fibrosis by at least 1 point. The secondary end points were the changes in liver enzymes, metabolic markers, and hepatic gene expression profiles. RESULTS Fibrosis scores improved in the tofogliflozin group (60%, P = 0.001), whereas the change from baseline did not differ significantly between the groups (P = 0.172). The histological variables of steatosis (65%, P = 0.001), hepatocellular ballooning (55%, P = 0.002), and lobular inflammation (50%, P = 0.003) were improved in the tofogliflozin group, whereas only hepatocellular ballooning was improved in the glimepiride group (25%, P = 0.025). Hepatic gene expression profiling revealed histology-associated signatures in energy metabolism, inflammation, and fibrosis that were reversed with tofogliflozin. CONCLUSIONS Tofogliflozin and, to a lesser degree, glimepiride led to liver histological and metabolic improvement in participants with type 2 diabetes and NAFLD, with no significant difference between the agents. The hepatic expression of the genes involved in energy metabolism, inflammation, and fibrosis was well correlated with liver histological changes and rescued by tofogliflozin. We need further confirmation through long-term larger-scale clinical trials of SGLT2 inhibitors.

中文翻译：

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Tofogliflozin 和格列美脲对 2 型糖尿病参与者非酒精性脂肪肝的作用比较：一项随机、48 周、开放标签、主动对照试验

目的 非酒精性脂肪性肝病 (NAFLD) 是 2 型糖尿病和肥胖症的肝脏表型。目前，钠-葡萄糖协同转运蛋白 2 (SGLT2) 抑制剂和磺脲类药物在 2 型糖尿病伴 NAFLD 的肝脏病理学和肝脏基因表达谱中的疗效尚不清楚。研究设计和方法 我们进行了一项为期 48 周的随机、开放标签、平行组试验，参与者参与活检证实为 NAFLD。共有 40 名参与者被随机分配接受每日一次 20 mg 托福格列净或 0.5 mg 格列美脲的治疗。主要结果是参与者的百分比，在脂肪变性、肝细胞气球样变、小叶炎症和纤维化等组织学类别的所有个体评分中至少提高了 1 分。次要终点是肝酶的变化，代谢标志物和肝脏基因表达谱。结果 tofogliflozin 组的纤维化评分有所改善（60%，P = 0.001），而与基线的变化在各组之间没有显着差异（P = 0.172）。Tofogliflozin 组的脂肪变性（65%，P = 0.001）、肝细胞气球样变（55%，P = 0.002）和小叶炎症（50%，P = 0.003）的组织学变量得到改善，而仅肝细胞气球样变在格列美脲组（25%，P=0.025）。肝脏基因表达谱揭示了能量代谢、炎症和纤维化的组织学相关特征，而托格列净可逆转这些特征。结论 Tofogliflozin 和较小程度的格列美脲导致 2 型糖尿病和 NAFLD 参与者的肝脏组织学和代谢改善，代理之间没有显着差异。涉及能量代谢、炎症和纤维化的基因在肝脏中的表达与肝脏组织学变化密切相关，并被托格列净挽救。我们需要通过 SGLT2 抑制剂的长期大规模临床试验进一步证实。