NASH (nonalcoholic steatohepatitis), diabetes, and macrovascular disease: multiple chronic conditions and a potential treatment at the metabolic root

ABSTRACT

Introduction: NASH and type 2 diabetes (T2D) are clinical definitions that overlap and result from metabolic dysfunction caused by over-nutrition relative to metabolic need. This volume details drug development programs aimed at specific NASH pathology with a focus on liver outcomes; this commentary suggests a metabolic approach that should not be overlooked based on a new understanding of insulin sensitizers.

Areas covered: The overlap of NASH and T2D with respect to metabolic syndrome is discussed in the context of new understandings of insulin sensitizers. Adverse clinical outcomes in subjects with advanced NAFLD (e.g. NASH) and advanced metabolic dysfunction (e.g., T2D) are primarily due to cardiovascular issues. Clinical evidence suggests that insulin resistance and hyperinsulinemia predict adverse cardiovascular outcomes. NALFD/NASH significantly contributes to insulin resistance and hyperinsulinemia. A new insulin sensitizer that targets the newly identified mitochondrial pyruvate carrier could provide an approach.

Expert opinion: A metabolic approach is needed for the treatment of NASH. Clinical studies are underway to determine whether a new insulin sensitizer that targets pyruvate metabolism can impact NASH, T2D, and cardiovascular disease. A broader view of metabolic disease may provide a more assessable way to track therapeutic benefit.

KEYWORDS:

• NASH
• NAFLD
• type 2 diabetes
• MPC
• insulin sensitizers
• MSDC-0602K

Article Highlights

• NASH is a metabolic-based constellation of multiple organ pathology that overlaps with type 2 diabetes, pre-diabetes and cardiovascular disease.

• NAFLD/NASH and pre-diabetes/diabetes are related disorders with metabolic dysfunction driven by overnutrition with a consequence of insulin resistance and hyperinsulinemia.

• Adverse clinical outcomes in subjects with advanced NAFLD (e.g. NASH) and advanced metabolic dysfunction (e.g., T2D) are primarily attributed to cardiovascular issues.

• While there are compounds with many mechanisms in development as potential treatments for NASH, it would be useful to have approaches that impact the metabolic dysfunction produced by overnutrition, especially since this appears to be a root cause of the spectrum of disease that includes type 2 diabetes and NASH as its most severe manifestations.

• Clinical studies are underway to determine whether a new insulin sensitizer that targets pyruvate metabolism can impact NASH, T2D, and cardiovascular disease.

This box summarizes the key points contained in the article.

Declaration of interest

J Colca is CSO and Founder of Cirius Therapeutics and Metabolic Solutions Development Company, USA, which were involved in the discovery and development of the agent MSDC-0602K. The author has 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.

Additional information

Funding

This paper was not funded.