Convergent Mechanisms of Metabolism-Based Therapeutics in MASH: Mechanistic Review of SGLT2 Inhibitors and GLP-1 Receptor Agonists

Metabolic dysfunction-associated steatohepatitis (MASH) is a multifaceted disorder with an unmet need for effective pharmacotherapies. The emergence of two classes of anti-diabetic agents, SGLT2 inhibitors and GLP-1 receptor agonists, are now widely acknowledged as frontrunners of therapeutic options for MASH, and they have both also been shown to have durable, actionable anti-fibrotic biology. They also appear to engage disparate primary mechanisms of action, raising new questions about their commonality behind therapeutic efficacy. In this review, we propose an integrated hypothesis that places AMP-activated protein kinase (AMPK) as the master convergent node for MASH therapeutics. We suggest that the two drug classes act through discrete upstream pathways to activate AMPK. Both SGLT2 inhibitors and GLP-1 receptor agonists activate AMPK, but SGLT2 inhibitors appear to preferentially engage an LKB1-dependent energy crisis to upregulate AMPK, while GLP-1 receptor agonists engage a CaMKKβ-dependent hormonal signal. While still exerting the same ultimate reach of activating AMPK, their differential activation of AMPK results in differential downstream effects; SGLT2 inhibitors engage cell-intrinsic stress responses such as inflammation and autophagy, whereas GLP-1 receptor agonists primarily regulate systemic and cellular lipid metabolism. Furthermore, we detail the unique, cell-type selective, and epigenetic mechanisms of SGLT2 upregulation in the fibrotic liver which eclectically provide molecular mechanistic rational for the SGLT2 inhibitors' direct hepatic action pathways. Once again, our integrated model resolves unanswered paradoxes for each drug class, but also creates a strong mechanistic rationale for the application of precision medicine and rational synergies of combination therapies for MASH.