Non-alcoholic fatty liver disease in type 2 diabetes: Emerging evidence of benefit of peroxisome proliferator-activated receptors agonists and incretin-based therapies

Abstract

Nonalcoholic fatty liver disease (NAFLD) is a global epidemic, affecting more than half of the people living with type 2 diabetes (T2D). The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other, which significantly increases the hepatic as well as extrahepatic complications. Until recently, there was no approved pharmacological treatment for NAFLD/ nonalcoholic steatohepatitits (NASH). However, there is evidence that drugs used for diabetes may have beneficial effects on NAFLD. Insulin sensitizers acting through peroxisome proliferator-activated receptor (PPAR) modulation act on multiple levels of NAFLD pathogenesis. Pioglitazone (PPARγ agonist) and saroglitazar (PPARα/γ agonist) are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D, although data on biopsy-proven NASH are lacking with the latter. Initial data on elafibanor (PPAR α/δ agonist) and Lanifibranor (pan PPAR agonist) are promising. On the other hand, incretin therapies based on glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RA) and dual- and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties. GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual- and triple-agonists are required. Furthermore, the long-term safety of these therapies in NAFLD needs to be established. Collaborative efforts among healthcare providers such as primary care doctors, hepatologists, and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.

Keywords: Non-alcoholic fatty liver disease; Type 2 diabetes; Evidence; PPAR agonists; Incretin-based therapies

Core Tip: Co-existence of non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) synergistically act to increase the risk of adverse hepatic and extra hepatic outcomes. T2DM is an established risk factor for NAFLD progression to NASH, advanced fibrosis or cirrhosis. Timely intervention in these populations could have a significant effect on liver- related outcomes. Newer dual and pan-PPAR agonists show promising results in patients with NAFLD/NASH and T2DM. Incretin-based therapy for the treatment of NAFLD is currently being explored. With better understanding of the complex interaction between T2DM and NAFLD, PPAR agonists and incretin-based therapies are likely to provide more effective approach of NAFLD management in T2DM.