Emerging advances in the pharmacologic treatment of nonalcoholic steatohepatitis and related cirrhosis

The prevalence of nonalcoholic fatty liver disease (NAFLD) is rapidly growing throughout the world. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, is likely to become the leading cause of cirrhosis and etiology for liver transplantation in future decades in the Western World. Most patients with NAFLD have some components of metabolic syndrome, including obesity, insulin resistance, dyslipidemia, and hypertension. NAFLD encompasses a wide spectrum of liver damage, ranging from simple steatosis to NASH, that can progress to advanced liver disease, as well as hepatocellular carcinoma. Unfortunately, the options for the pharmacological treatment of NASH are still very limited. Nonetheless, several classes of therapies have shown promise, and are currently being evaluated in large phase 2b and phase 3 trials, creating some hope that selected agents will be approved in the coming years. As NASH is a heterogeneous disease, multiple mechanistic pathways are being targeted to achieve optimal treatment response. Combination therapy is also on the horizon, where 2 or more drugs targeting different mechanistic pathways are being used to boost the clinical response. In this review, we first present the current concept of the pathophysiology of NASH, focusing on the pathways currently targeted in clinical trials. We then present the pharmacological agents that are being evaluated in phase IIb of clinical development and beyond, using histological outcomes, and finally we present preliminary results from the combination trials that have already been initiated.