Pleiotropic Effects and Safety of Sodium Glucose Co-transporter 2 Inhibitor Versus Sulfonylurea in Patients With Type 2 Diabetes and Non-alcoholic Fatty Liver
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 1
- 主要终点
- The improvement in histologic features of NAFLD
研究概览
简要总结
The clinicopathological analyses revealed that reduction in HbA1c and use of insulin independently contribute to the reduction in liver fibrosis scores during the histological course of NAFLD development. These findings led us to hypothesize that glycemic control and insulin ameliorate or protect against the histological progression of liver fibrosis in patients with NAFLD.
In the present study, we investigated the efficacy of SGLT2 inhibitor tofogliflozin and sulfonylurea glimepiride, which lower glucose levels similarly with reduction and elevation in circulating insulin levels, respectively, in NAFLD patients with type 2 diabetes for 48 weeks by examining liver histology, as well as hepatic enzymes, metabolic markers, and hepatic gene expression profiles.
详细描述
Nonalcoholic fatty liver disease (NAFLD), ranging from simple fatty liver to nonalcoholic steatohepatitis (NASH), is a liver phenotype of metabolic disorders, such as diabetes, obesity, and metabolic syndrome. NAFLD and type 2 diabetes share epidemiological and pathophysiological features. Specifically, hyperglycemia is closely associated with liver fibrosis, which is associated with liver cirrhosis, hepatocellular carcinoma, and prognosis in patients with NASH.
To date, some anti-diabetic agents have been tested in patients with NAFLD. The guidelines in the Asian Pacific, European, and American association recommended the administration of PPAR gamma agonist (pioglitazone) and glucagon-like peptide receptor agonists (GLP1RA) for the treatment of diabetes with NAFLD/NASH. However, there are concerns about adverse effects such as weight gain, edema, fractures, and carcinogenesis in pioglitazone or gastrointestinal adverse effects and medication burden as an injection in GLP1 RA. In addition, because all of these anti-diabetic agents significantly reduced glycemic levels compared with placebo, liver histological improvement may be theoretically attributable to glucose reduction itself.
Both sodium-glucose cotransporter 2 (SGLT2) inhibitors and sulfonylureas are chosen as the second-line therapy when glycemic control cannot be achieved with metformin or as the first-line therapy when metformin is contraindicated or not tolerated. In animal models of NAFLD/NASH, SGLT2 inhibitors protect against steatosis, inflammation, and fibrosis. Previous clinical trials have demonstrated that SGLT2 inhibitors exert protective effects on liver enzymes and liver steatosis in patients with NAFLD/NASH. However, these studies lack a control group or histological examination, which precludes meaningful conclusions since the natural course of the disease or tight glycemic control may ameliorate liver histology in some patients with NAFLD. Sulfonylureas are still reliable and potent antidiabetic agents in insulinopenic patients with type 2 diabetes and therefore are used as the second-line therapy, especially when the cost is a significant issue. Besides, sulfonylureas reduce glucose and elevate weight, which may render positive and negative effects, respectively, on liver pathology in NAFLD/NASH. In the phase 3 trial, canagliflozin was non-inferior to glimepiride for reduction of HbA1c at 52 weeks. However, the differences between SGLT2 inhibitors and sulfonylureas on NAFLD patients with type 2 diabetes under similar glucose reduction remain uncertain.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 20 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- 未提供
排除标准
- 未提供
研究组 & 干预措施
SGLT2 inhibitor
N=20 SGLT2 inhibitor dosage (Tofogliflozin): a dose of 20mg once daily for 48 weeks.
干预措施: Tofogliflozin (Drug)
Sulfonylurea
N=20 Sulfonylurea (Glimepiride): an initial dose of 0.5 mg once daily for 48 weeks.
干预措施: Glimepiride (Drug)
结局指标
主要结局
The improvement in histologic features of NAFLD
时间窗: 48 weeks
次要结局
- Change from baseline in liver enzymes(48 weeks)
- Change from baseline in body composition(48 weeks)
- Change from baseline in fasting plasma glucose level and glucose metabolism assessed with arginine tolerance test(48 weeks)
- Changes from baseline in organ-specific insulin sensitivity and glucagon response during a euglycemic hyperinsulinemic clamp study(48 weeks)
- Change from baseline in lipid profile(48 weeks)
- Change from baseline in renal function and electrolyte balances(48 weeks)
- Change from baseline in oxidative stress(48 weeks)
- Change from baseline in cytokine (TNF-alpha, leptin, adiponectin) levels(48 weeks)
- Change from baseline in hepatokine (Selenoprotein P, LECT2) levels(48 weeks)
- Change from baseline in organ-specific fat accumulation(48 weeks)
- Change from baseline in oxidative and non-oxidative glucose disposal(48 weeks)
- Change from baseline in respiratory quotients(48 weeks)
- Change from baseline in energy expenditure(48 weeks)
- Change from baseline in autonomic nerve function.(48 weeks)
- Changes from baseline in minerals and bone metabolism(48 weeks)
- Changes from baseline in endothelial functions(48 weeks)
- Changes from baseline in fatty acids profiles(48 weeks)
- Factors associated with the changes in autonomic nerve function, organ-specific fat accumulation, and glucagon response.(48 weeks)
- Changes from baseline in gene expression profiles in the liver and blood cells(48 weeks)
- Changes from baseline in microRNAs and exosome contents(48 weeks)
- Epigenomic changes from baseline in genes of the liver and blood cells(48 weeks)
研究者
Toshinari Takamura, MD, PhD
Department of Disease Control and Homeostasis
Kanazawa University