Sodium-Glucose Cotransporter-2 Inhibition Exacerbates Hepatic Encephalopathy in Biliary Cirrhotic Rats

Abstract

In liver cirrhosis, hepatic inflammation and abundant portal-systemic collaterals are indicated for the development of hepatic encephalopathy. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a type of anti-diabetic agent, which exert pleiotropic and anti-inflammatory effects. Diabetes and chronic liver disease often coexist but the influence of SGLT-2 inhibition on liver cirrhosis and hepatic encephalopathy remains unknown. This study investigated the effect of SGLT-2 inhibition on cirrhotic rats. Biliary cirrhosis was induced in Sprague-Dawley rats via common bile duct ligation. A total of 2-weeks treatment with the SGLT-2 inhibitor, empagliflozin 30 mg/kg/day, was applied. The motor activities, hemodynamics, biochemistry parameters, plasma levels of vascular endothelial growth factor (VEGF) and the severity of portal-systemic collateral shunts were measured. The hepatic histopathology and protein expressions were examined. We found that empagliflozin treatment did not affect hemodynamics, liver biochemistry or blood glucose levels in cirrhotic rats. Empagliflozin did not affect hepatic inflammation and fibrosis. The protein expression of factors related to liver injury were not influenced by empagliflozin.However, empagliflozin decreased motor activities in cirrhotic rats and increased portal-systemic collateral shunts and VEGF plasma levels. In summary, SGLT-2 inhibition by empagliflozin did not ameliorate portal hypertension and hepatic This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward.

Progress in the Study of the Hepatoprotective Effect of SGLT2i on NAFLD Patients with T2DM

“…Therefore, in view of the development of hepatic encephalopathy, patients with cirrhosis should be cautious about using empagliflozin. [41] Animal trials have shown that SGLT-2i has the risk of aggravating hepatic encephalopathy, and SGLT-2i is not necessarily a safe and effective hypoglycemic drug for T2MD patients with advanced NAFLD progression to cirrhosis complicated with hepatic encephalopathy. In a meta-analysis, it was noted that SGLT-2 inhibitors reduced hospitalizations for heart failure more than GLP-1 receptor agonists.…”