Beyond ketosis: the search for the mechanism underlying SGLT2-inhibitor benefit continues

Despite the impressive clinical benefits and widespread adoption of sodium glucose cotransporter 2 inhibitors (SGLT2i) to treat all classes of heart failure, their cardiovascular mechanisms of action are poorly understood. Proposed mechanisms range broadly and include enhanced ketogenesis, where the mild ketosis associated with SGLT2i use is presumed to be beneficial. However, in this issue of the JCI, carefully conducted metabolic flux studies by Goedeke et al. comparing the effects of SGLT2i and exogenous ketones suggest differential effects. Thus, the mechanisms of action for SGLT2i are likely pleiotropic, and further work is needed to fully understand their beneficial effects.