Anti-diabetic drugs and NASH: from current options to promising perspectives

ABSTRACT

Introduction: Accumulating evidence supports a bidirectional association between nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D). There is a clinical challenge to consider pharmaceutical strategies targeting the metabolic dysfunction common to NASH and T2D pathogenesis.

Areas covered: By using PubMed, we performed a literature search to review the potential beneficial effect of anti-diabetic and metabolic investigational drugs on NASH.

Expert opinion: Since insulin resistance is central in the pathophysiology of both T2D and NASH, there is an urgent need for new insulin sensitizers. Peroxisome proliferator-activated receptor (PPAR) agonists, especially PPARγ and pan-PPARs agonists, have shown some beneficial effects on both NASH and liver fibrosis, but their routine use should be limited by their safety profile. Incretin-based therapies, including glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and the polyagonists (GLP-1, GIP, glucagon) under development are the most promising anti-diabetic drugs for NASH treatment, mainly due to their action on body weight loss. Preliminary, preclinical and early phase studies suggest that SGLT2 inhibitors and fibroblast growth factor (FGF)19 and FGF21-based therapies are promising targets for NASH and T2D treatment. The common weakness for all of these drugs is their limited effect on liver fibrosis, potentially due to short-term trial design.

KEYWORDS:

• NAFLD
• liver steatosis
• insulin resistance
• T2D
• diabetes
• glucagon-like peptide 1
• incretins
• PPAR
• SGLT2 inhibitor
• polyagonists
• NASH
• nonalcoholic steatohepatitis

Article highlights

• There are still no approved treatments specifically for NAFLD or NASH.

• There is a bidirectional relationship between NAFLD and T2D

• PPARγ agonists improve insulin resistance and promotes NASH resolution but their clinical use is limited by their safety profile

• GLP-1 RAs and peptide-based polyagonists decrease liver steatosis and potentially liver fibrosis mainly by promoting massive weight loss

• The potential effect of SGLT2 inhibitors on NAFLD/NASH in patients with T2D needs to be confirmed in dedicated trials

• FGF21analogs decrease liver fat content rather than glucose parameters

• The action on NAFLD/NASH should be a selection criterion for anti-diabetic drugs in a personalized management of T2D.

Declaration of interest

B Cariou reports grants and personal fees from Amgen, Regeneron, and Sanofi, and personal fees from Abbott, Akcea, AstraZeneca, Bristol Myers Squibb, Genfit, Gilead, Eli Lilly and Company, Merck (MSD), and Novo Nordisk. J Boursier reports grant from Inventiva, grants and personal fees from Echosens, Intercept, and Siemens, and personal fees from Bristol Myers Squibb, Gilead, Eli Lilly, and Pfizer. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose