There are no US Food and Drug Administration–approved therapies at present for NASH. However, there are dozens of agents that are currently in trials that are being delivered principally as monotherapies. 

It is important to note that NASH is a heterogeneous disorder with many different subpopulations and presentations that limit our ability to lump this disorder into a one-size-fits-all approach. In this regard, the approach to enrolling patients in clinical trials can be tailored, and this, at some level, may be contributing to some of the disappointing results that we have seen to date. We should consider accurately phenotyping patients with NASH so that, in clinical trials, the investigational treatment’s mechanism of action is a good match with the patient’s NASH phenotype and relevant drivers.

Regarding the monotherapy trials, there are many different agents and mechanisms that are being studied, including farnesoid X receptor agonists and peroxisome proliferator-activated receptor (PPAR) agonists targeting a variety of different receptors, including PPARα, PPARδ, and PPARγ, and then a series of agonists of fibroblast growth factor 19 (FGF19) and FGF21, all of which have an impact on de novo hepatic lipogenesis. These trials have had variable results with regard to the reduction of hepatic steatosis and hepatic fibrosis. Other mechanisms of action that are being evaluated in clinical trials include thyroid hormone receptor β agonists, which work on altering the metabolic rate in the liver, as well as agents that directly block lipogenesis, including acetyl-CoA carboxylase inhibitors. 

In addition, the glucagon-like peptide 1 agonists and the sodium-glucose cotransporter-2 inhibitors are already approved for the management of diabetes. Given their mechanisms of action, the use of these agents actually results in predictable weight loss, which is reliably associated with improvements in liver fat and NASH histology. This is an approach that may be sensible for our patients with type 2 diabetes and NASH.

In thinking about potential treatments for NASH, customizing therapies to our specific patient population may be the most effective strategy. There have been some promising results associated with some of the aforementioned classes, and there may be a role for combination therapies. For instance, coupling an agent with a mechanism that produces hepatic steatosis reduction with another agent with an antifibrotic mechanism  may be effective for patients with more advanced NASH fibrosis. 

Current strategies need to be informed by a deeper understanding of the underlying drivers and mechanisms that operate in individual patients and a given population. We must determine how to better apply the myriad of treatments that are in development to a more suitable and specific population rather than being disappointed by suboptimal results when we apply these treatments broadly to a large group of patients with a mixture of NASH phenotypes.