SGLT2 Inhibitor Versus Sulfonylurea on Type 2 Diabetes With NAFLD
- Conditions
- Non-alcoholic Fatty Liver Disease
- Interventions
- Registration Number
- NCT02649465
- Lead Sponsor
- Kanazawa University
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description SGLT2 inhibitor Tofogliflozin N=20 SGLT2 inhibitor dosage (Tofogliflozin): a dose of 20mg once daily for 48 weeks. Sulfonylurea Glimepiride N=20 Sulfonylurea (Glimepiride): an initial dose of 0.5 mg once daily for 48 weeks.
- Primary Outcome Measures
Name Time Method The improvement in histologic features of NAFLD 48 weeks
- Secondary Outcome Measures
Name Time Method Change from baseline in lipid profile 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 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 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
Trial Locations
- Locations (1)
Kanazawa University Graduate School of Medical Sciences
🇯🇵Kanazawa, Ishikawa, Japan