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The principal molecular stimulus to gluconeogenesis and ketogenesis is activation of SIRT1 (sirtuin-1) and its downstream mediators: PGC-1\u03b1 (proliferator-activated receptor gamma coactivator 1-alpha) and FGF21 (fibroblast growth factor 21). These three nutrient deprivation sensors exert striking cardioprotective effects in a broad range of experimental models. This benefit appears to be related to their actions to alleviate oxidative stress and promote autophagy\u2014a lysosome-dependent degradative pathway that disposes of dysfunctional organelles that are major sources of cellular injury. Nutrient deprivation sensors are suppressed in states of perceived energy surplus (ie, type 2 diabetes mellitus and chronic heart failure), but SGLT2 inhibitors activate SIRT1\/PGC-1\u03b1\/FGF21 signaling and promote autophagy. This effect may be related to their action to trigger the perception of a system-wide decrease in environmental nutrients, but SGLT2 inhibitors may also upregulate SIRT1, PGC-1\u03b1, and FGF21 by a direct effect on the heart. Interestingly, metformin-induced stimulation of AMP-activated protein kinase (a nutrient deprivation sensor that does not promote ketogenesis) has not been shown to reduce heart failure events in clinical trials. 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