Management of nonalcoholic fatty liver disease: Lessons learned from type 2 diabetes

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of insulin resistance, which is the hallmark of type 2 diabetes (T2D). NAFLD is a known risk factor for developing T2D and has a very high prevalence in those with existing T2D. The diabetes spectrum includes several conditions from prediabetes to T2D to insulin‐dependent diabetes leading to macrovascular and microvascular complications. Similarly, NAFLD has a histologic spectrum that ranges from the relatively benign nonalcoholic fatty liver to the aggressive form of nonalcoholic steatohepatitis with or without liver fibrosis to nonalcoholic steatohepatitis‐cirrhosis leading to end‐stage liver disease. The management of T2D has witnessed significant changes over the past few decades with multiple new drug classes entering the treatment algorithm. Unfortunately, there are no U.S. Food and Drug Administration‐approved medications to treat NAFLD, and guidelines for the management of NAFLD are less established. However, the field of drug development in NAFLD has witnessed a revolution over the past 5 years with the establishment of a regulatory pathway for Food and Drug Administration approval; this has generated substantial interest from pharmaceutical companies. Several diabetes medications have been studied as potential treatments for NAFLD with promising results; moreover, drugs that target specific pathways that play a role in NAFLD development and progression are being developed at a rapid pace. Given the similarities between NAFLD and T2D in terms of pathogenesis, underlying risk factors, and disease spectrum, lessons learned from optimizing treatment for T2D can be extrapolated to the management of NAFLD. The aim of this review is to use the founding principles of the comprehensive type 2 diabetes management algorithm to optimize the management of NAFLD. (Hepatology Communications 2018;2:778‐785)

HOMA‐IR: An independent predictor of advanced liver fibrosis in nondiabetic non‐alcoholic fatty liver disease

“…Unfortunately, there are no US Food and Drug Administration‐approved medications to treat NAFLD, and guidelines for the management of NAFLD are less well established. In this context, improving IR may be beneficial for anti‐fibrotic treatment, even among the patients with nondiabetic NAFLD …”

Looking Into the Crystal Ball: Predicting the Future Challenges of Fibrotic NASH Treatment

“…However, one question will be whether switching to another agent is sufficient for continuation of improvement. This is largely unknown at this point, but lessons from diabetes have taught us that an add‐on strategy might be the best approach . The initial management of individuals with new‐onset T2D typically starts with lifestyle modifications and metformin monotherapy, but when this approach fails to achieve the glycemic target, combination therapy with another agent is usually started (dual therapy) .…”

“…This is largely unknown at this point, but lessons from diabetes have taught us that an add-on strategy might be the best approach. (8) The initial management of individuals with new-onset T2D typically starts with lifestyle modifications and metformin monotherapy, but when this approach fails to achieve the glycemic target, combination therapy with another agent is usually started (dual therapy). (31) If the hemoglobin A1c (A1C) target is not achieved after 3 months of dual therapy, a third agent could be added as part of triple therapy.…”

“…In addition, the AURORA phase III trial is enrolling patients with NASH fibrosis to be treated with cenicriviroc, a chemokine receptor type 2 and type 5 dual inhibitor with antifibrotic efficacy. Other compounds have shown efficacy at different levels of disease development and progression, including those with metabolic, anti‐inflammatory, and antifibrotic effects providing a robust pipeline for drug development …”

“…Other compounds have shown efficacy at different levels of disease development and progression, including those with metabolic, anti-inflammatory, and antifibrotic effects providing a robust pipeline for drug development. (8,9) For patients to qualify for these medications, they will most likely need to have stage 3 or 4 fibrosis, and the primary treatment endpoint will be improvement of fibrosis by at least one stage. However, several challenges are likely to arise immediately after US Food and Drug Administration (FDA) approval of medications intended to treat fibrosis, including choosing the best approach for identifying patients with NASH-associated advanced fibrosis, the duration of treatment, methods to assess response to treatment, and finally, decision-making tools to determine futility and the need to add on or switch treatments, especially when additional medications become available.…”