Background. Nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, comprises a
spectrum of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is associated with an
increased risk of hepatocellular carcinoma (HCC) and cardiometabolic disease. Insulin resistance (IR) is the underlying pathogenic
mechanism for NAFLD, the presence of which in turn, is a strong predictor for the development of metabolic disorders. Hence, therapy
of NAFLD with insulin-sensitizing drugs (ISDs) should ideally improve the key hepatic histological changes (steatosis, inflammation and
fibrosis), but should also reduce cardiometabolic and cancer risk.
Objectives. In this review, the rationale for the use of ISDs and the evidence for their efficacy are detailed. In particular, the mechanism
of action, potential for use, limitations and untoward effects of metformin and thiazolidinediones are systematically reviewed. Further,
we discuss novel ISDs that may have potential clinical utility in NAFLD.
Results and Conclusion. Despite the theoretical prediction that ISDs might have beneficial effects on disease outcomes, evidence that
ISDs are able to alter the natural history of NAFLD are presently not available. The exploration of novel strategies exploiting “nonconventional”
ISDs is encouraged.