Rosiglitazone Versus Rosiglitazone and Metformin Versus Rosiglitazone and Losartan in the Treatment of Nonalcoholic Steatohepatitis in Humans: A 12-Month Randomized, Prospective, Open-Label Trial

Medication combinations that improve the efficacy of thiazolidinediones or ameliorate weight-gain side effects of therapy represent an attractive potential treatment for (NASH). The aim of this randomized, open-label trial was to assess the efficacy of rosiglitazone and metformin in combination versus rosiglitazone and losartan, compared to rosiglitazone alone, after 48 weeks of therapy. A total of 137 subjects with biopsy-proven NASH were enrolled and randomly assigned to receive either 4 mg twice-daily of rosiglitazone, 4 mg of rosiglitazone and 500 mg of metformin twice-daily, or 4 mg of rosiglitazone twice-daily and 50 mg of losartan once-daily for 48 weeks. Patients were screened for other etiologies of chronic liver disease, including daily alcohol intake in excess of 20 g. Repeat liver biopsy was performed after 48 weeks of therapy and reviewed in a blinded fashion by a single expert hepatopathologist. The primary aim of the study was to assess for differences between treatment groups in the improvement of steatosis, hepatocellular inflammation, and fibrosis. In total, 108 subjects completed the trial. Primary outcome revealed no significant difference between treatment groups in all histologic parameters (steatosis, P 5 0.137; hepatocellular inflammation, P = 0.320; fibrosis, P = 0.229). Overall improvement in steatosis, hepatocellular inflammation, ballooning degeneration, and fibrosis was observed (P <= 0.001). Serum aminotransferases were reduced in all three groups (P < 0.001 within treatment, P > 0.05 between groups). Metformin did not significantly mitigate weight gain (P = 0.051). Conclusions: Forty-eight weeks of combination therapy with rosiglitazone and metformin or rosiglitazone and losartan confers no greater benefit than rosiglitazone alone with respect to histopathology. (HEPATOLOGY 2011;54:1631-1639)