Empagliflozin Exhibits Therapeutic Effect in Preclinical Model of Liver Disease (NASH)

Abstract

Nonalcoholic steatohepatitis (NASH) and diabetes are common conditions that coexist and drive adverse outcomes. Empagliflozin (empa), a sodium-glucose co-transporter-2 inhibitor (SGLT2i), has achieved a 38% reduction in the cardiovascular (CV) and all-cause mortality in type 2 diabetes patients with high CV risks. In preclinical models, SGLT2 inhibitors have been reported to increase insulin sensitivity, decrease body weight and reduce markers of oxidative stress and inflammation in tissues. Therefore, we investigated the effect of empa in a mouse model of NASH and hyperglycemia. Neonatal male mice (2 days after birth) were injected subcutaneously with streptozotocin and then were fed with a HFD from 4 weeks of age. Then from 6 to 8 weeks of age, mice were treated by oral gavage with vehicle, empa (10 mg/kg) in comparison to telmisartan (telmi, 15 mg/kg) as positive control. A group of mice, under normal diet and without STZ injection were used also as normal controls. NAS, (Histological NAFLD Scoring) evaluating fat deposition, inflammation and ballooning as well as mRNA expression for inflammation markers were performed. Blood glucose level was significantly increased in the vehicle group (525 mg/dL,) compared to the normal group (50 mg/dL). Empa significantly decreased the blood glucose (261 mg/dL) while telmi did not (429.4 mg/dL). NAS was significantly increased in the vehicle (4.1) compared to the normal control (0.0) groups and significantly decreased in telmi (1.4) and empa (1.4 ± 1.0) groups compared to the vehicle group. Telmi but also empa reduced collagen deposition and ameliorated the fat deposition. This was accompanied by a significant reduction of hepatic TNFα mRNA (1.7, 2.8 for telmi and empa, respectively compared to vehicle group (5.7). These features may qualify empagliflozin for the therapy of NASH and raise interest to evaluate further the potential of the combination of these two approved drugs, with different modes of action in the treatment of liver diseases. Disclosure E. Mayoux: None. T. Klein: Employee; Self; Boehringer Ingelheim GmbH. M. Mark: Employee; Self; Boehringer Ingelheim GmbH.