A Phase 2, Randomized Controlled Trial of Berberine Ursodeoxycholate (BUDCA) in Patients with Presumed Non-Alcoholic Steatohepatitis (NASH) and Type 2 Diabetes

Background & Aims: Non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and diabetes and may lead to progressive liver disease although current treatment options are limited. Berberine ursodeoxycholate is an ionic salt of berberine and ursodeoxycholic acid, representing a new molecular entity that offers the possibility of combination therapy for NASH in a single treatment. Methods: A prospective, randomized, double-blind, placebo-controlled trial of two doses of berberine ursodeoxycholate administered orally was conducted in a cohort of 100 subjects with fatty liver disease and diabetes. Treatment was for 18 weeks and endpoints measured included reduction in liver fat content measured by MRI proton density fat fraction, improvement in glycemic control, changes in liver-associated enzymes, safety and tolerability. Results: Subjects that received 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content compared to placebo (mean absolute decrease -4.8% vs. -2.0% [p=0.011], mean relative decrease -24.1 vs -8.3% [p=0.016]). Also, compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in serum alanine aminotransferase and gamma glutamyl transferase activities. Serum lipid levels decreased modestly during therapy. The higher dose of berberine ursodeoxycholate was associated with an average weight loss (LS Mean) of -3.5kg compared to only -1.1kg with placebo (p=0.012). Diarrhea and abdominal discomfort were the most frequently reported adverse events.  Conclusions:  Berberine ursodeoxycholate is single molecule with a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and data from this phase 2 randomized controlled trial supportr its further development as a treatment for NASH with diabetes.