Autophagy is a lysosome-dependent intracellular degradative pathway, which mediates the cellular adaptation to nutrient and
oxygen depletion as well as to oxidative and endoplasmic reticulum stress. The molecular mechanisms that stimulate autophagy include the activation of energy deprivation sensors, sirtuin-1 (
SIRT1) and
adenosine monophosphate-activated
protein kinase (AMPK). These
enzymes not only promote organellar integrity directly, but they also enhance autophagic flux, which leads to the removal of dysfunctional mitochondria and peroxisomes.
Type 2 diabetes is characterized by suppression of
SIRT1 and AMPK signaling as well as an impairment of autophagy; these derangements contribute to an increase in oxidative stress and the development of
cardiomyopathy.
Antihyperglycemic drugs that signal through
insulin may further suppress autophagy and worsen
heart failure. In contrast,
metformin and
SGLT2 inhibitors activate
SIRT1 and/or AMPK and promote autophagic flux to varying degrees in cardiomyocytes, which may explain their benefits in experimental
cardiomyopathy. However,
metformin and
SGLT2 inhibitors differ meaningfully in the molecular mechanisms that underlie their effects on the heart. Whereas
metformin primarily acts as an agonist of AMPK,
SGLT2 inhibitors induce a fasting-like state that is accompanied by ketogenesis, a
biomarker of enhanced
SIRT1 signaling. Preferential
SIRT1 activation may also explain the ability of
SGLT2 inhibitors to stimulate erythropoiesis and reduce
uric acid (a
biomarker of oxidative stress)-effects that are not seen with
metformin. Changes in both hematocrit and serum
urate are the most important predictors of the ability of
SGLT2 inhibitors to reduce the risk of cardiovascular death and hospitalization for
heart failure in large-scale trials.
Metformin and
SGLT2 inhibitors may also differ in their ability to mitigate diabetes-related increases in intracellular
sodium concentration and its adverse effects on mitochondrial functional integrity. Differences in the actions of
SGLT2 inhibitors and
metformin may reflect the distinctive molecular pathways that explain differences in the cardioprotective effects of these drugs.