Miyake Teruki, Yoshida Osamu, Matsuura Bunzo, Furukawa Shinya, Hirooka Masashi, Abe Masanori, Tokumoto Yoshio, Koizumi Yohei, Watanabe Takao, Takeshita Eiji, Sunago Kotaro, Yukimoto Atsushi, Watanabe Kyoko, Miyazaki Masumi, Kanzaki Sayaka, Nakaguchi Hironobu, Koizumu Mitsuhito, Yamamoto Yasunori, Kumagi Teru, Hiasa Yoichi
Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, 791-0295, Japan.
Department of Lifestyle-Related Medicine and Endocrinology, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime, Japan.
Diabetes Ther. 2022 May;13(5):1083-1096. doi: 10.1007/s13300-022-01239-7. Epub 2022 Mar 21.
Untreated nonalcoholic fatty liver may progress to nonalcoholic steatohepatitis (NASH) and cirrhosis and induce hepatocellular carcinoma and liver failure. Type 2 diabetes mellitus (T2DM), often complicated with nonalcoholic fatty liver disease (NAFLD), is a driver of NAFLD progression. Thus, efficacious treatment strategies for patients with coexisting NAFLD and T2DM are important for preventing NAFLD progression. Although previous studies have demonstrated that either sodium-glucose transporter 2 inhibitors (SGLT2is) or glucagon-like peptide 1 receptor agonists (GLP-1 RAs) benefit NASH patients with T2DM, the rate of NASH resolution has not sufficiently improved. Therefore, we developed a protocol for a randomized controlled trial to examine whether the addition of an SGLT2i to the treatment regimen of patients receving a GLP-1 RA (combination therapy), within the therapeutic dose range for T2DM, increases the rate of NASH resolution in patients with coexisting NASH and T2DM.
This open-label, randomized, parallel-group study commenced in June 2021, will conclude recruitment in May 2023, and will end by March 2025. Sixty patients with NASH complicated by T2DM are enrolled at the Ehime University Hospital in Toon, Japan. Participants will be randomized into: (1) an intervention group receiving combination therapy with the SGLT2i luseogliflozin 2.5 mg, once daily (Taisho Pharmaceutical, Tokyo, Japan) and the GLP-1 RA semaglutide 0.5 mg, once per week (Novonordisk, Copenhagen, Denmark); and (2) a control group receiving monotherapy with the GLP-1 analog semaglutide. The primary endpoints, which will be ascertained by liver biopsy, are: (1) NASH resolution rate from baseline without worsening of liver fibrosis after 52 weeks of intervention; (2) rate of improvement from baseline of at least 1 point in the NAFLD activity score without worsening of liver fibrosis after 52 weeks of intervention; and (3) rate of improvement from baseline of at least one fibrosis stage without worsening of NASH after 52 weeks of intervention.
University Hospital Medical Information Network Clinical Trial Registry (UMIN-CTR) number: UMIN000045003. Japan Registry of Clinical Trials registration number: jRCTs061210009.
未经治疗的非酒精性脂肪肝可能进展为非酒精性脂肪性肝炎（NASH）和肝硬化，并引发肝细胞癌和肝衰竭。2型糖尿病（T2DM）常并发非酒精性脂肪肝病（NAFLD），是NAFLD进展的一个驱动因素。因此，针对同时患有NAFLD和T2DM的患者的有效治疗策略对于预防NAFLD进展很重要。尽管先前的研究表明，钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）或胰高血糖素样肽1受体激动剂（GLP-1 RAs）对患有T2DM的NASH患者有益，但NASH缓解率并未得到充分改善。因此，我们制定了一项随机对照试验方案，以研究在T2DM治疗剂量范围内，在接受GLP-1 RA治疗的患者（联合治疗）的治疗方案中添加SGLT2i是否能提高同时患有NASH和T2DM的患者的NASH缓解率。
这项开放标签、随机、平行组研究于2021年6月开始，将于2023年5月结束招募，并将于2025年3月结束。日本东荣市爱媛大学医院招募了60例并发T2DM的NASH患者。参与者将被随机分为：（1）干预组，接受SGLT2i鲁格列净2.5毫克每日一次（日本东京大正制药）和GLP-1 RA司美格鲁肽0.5毫克每周一次（丹麦哥本哈根诺和诺德）的联合治疗；（2）对照组，接受GLP-1类似物司美格鲁肽单药治疗。主要终点将通过肝活检确定，包括：（1）干预52周后，NASH缓解率从基线开始且肝纤维化无恶化；（2）干预52周后，NAFLD活动评分从基线至少改善1分且肝纤维化无恶化；（3）干预52周后，至少一个纤维化阶段从基线改善且NASH无恶化。
大学医院医学信息网络临床试验注册中心（UMIN-CTR）编号：UMIN000045003。日本临床试验注册编号：jRCTs061210009。
