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;) See Editorial on Page 1503 Nonalcoholic fatty liver disease (NAFLD) and its most clinically relevant subset, those with nonalcoholic steatohepatitis (NASH), are a growing health concern throughout the world. The clinical importance of NAFLD is

well established and extends beyond primary liver disease to include higher rates of cardiovascular and other metabolic complications and increased overall mortality.1-4 The ideal Sorafenib mw treatment for NASH has yet to be determined. Obesity and insulin resistance are inextricably linked to NASH, and, therefore, therapies directed at weight reduction and improved insulin sensitivity have been investigated. Lifestyle modification is currently the initial recommendation, but short of recommending diets void of processed sugars and saturated fat,5, 6 the ideal diet is not known. Recently, cross-sectional, self-reported data from a large cohort of well-defined NAFLD patients demonstrated

that only vigorous exercise (≥75 minutes/week) was associated with a decreased likelihood of having NASH.7 Lifestyle modification may be limited in its clinical utility, because patients often cannot maintain either dietary changes or exercise habits. Pharmacotherapy Venetoclax is widely accepted for many chronic medical conditions, and agents that improve hepatic histology would be quite useful. The thiazolinedione (TZD) class of insulin sensitizers have shown variable efficacy in NASH, but are limited find more by side effects, such as weight gain and, possibly, osteopenia and cardiovascular disease.8-11 Although data suggest that up to 47% of patients resolve NASH with pioglitazone, improvement in hepatic fibrosis has shown modest,

if any, improvement with TZD therapy.8-11 In three previous studies with pioglitazone, fibrosis improvement was observed in 29%-46% of patients, but was not significantly different than placebo.8-10 In a previous study with rosiglitazone, 16% of patients showed improved fibrosis and only 3% worsened, compared with 16% and 19%, respectively, for placebo.11 Given the modest effects of TZDs on NASH resolution and fibrosis regression, studies aimed at combination therapies that synergistically improve insulin resistance seemed laudable. Two medications thought to be good candidates for combination included the biguanide, metformin, and the angiotensin receptor blocker (ARB) class of drugs. In addition to the positive benefit of modest weight loss with metformin, data suggest an improvement in serum aminotransferases when used as monotherapy in NASH patients.