Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis

Abstract

SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate–activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator–activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.

The Neurohormonal Overactivity Syndrome in Heart Failure

“…At the molecular level, SGLT-2i lead to transcriptional reprogramming of cardiomyocytes that closely resembles that observed during nutrient deprivation. This alteration in signaling triggers the housekeeping pathway of autophagy, which clears the cytosol of threatening cytosolic constituents that cause cellular stress, thereby decreasing the risk of cardiomyopathy development [ 42 ]. Remarkably, similar alterations in cellular signaling and autophagic flux have also been observed in neurohormonal inhibitors.…”

Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors

“…SGLT2 inhibition-mediated glycosuria increases the net urinary caloric loss to approximately 200–300 kcal/day, promoting a fasting-like metabolic program including free fatty acid oxidation, glucogenesis, and ketogenesis, which is triggered by activation of AMP-activated protein kinase (AMPK) [ 3 – 5 , 14 , 49 ]. AMPK activates PGC-1α in SIRT1, a NAD+-dependent protein deacetylase, -dependent and -independent mechanisms, whereas it inhibits mTORC1 activity, compensating for the state of energy depletion [ 5 , 49 ]. In addition, activation of the AMPK/PGC-1α pathway and inhibition of mTORC1 activity by SGLT2 inhibition has been shown to attenuate mitochondrial dysfunction, oxidative stress, and inflammation, where they promote autophagy [ 5 , 49 ].…”

“…AMPK activates PGC-1α in SIRT1, a NAD+-dependent protein deacetylase, -dependent and -independent mechanisms, whereas it inhibits mTORC1 activity, compensating for the state of energy depletion [ 5 , 49 ]. In addition, activation of the AMPK/PGC-1α pathway and inhibition of mTORC1 activity by SGLT2 inhibition has been shown to attenuate mitochondrial dysfunction, oxidative stress, and inflammation, where they promote autophagy [ 5 , 49 ]. Intriguingly, BAIBA is released to circulation through a PGC-1α-dependent mechanism in myocytes, which is a mechanism of exercise-induced increase in circulating BAIBA [ 38 ].…”

“…Intriguingly, BAIBA is released to circulation through a PGC-1α-dependent mechanism in myocytes, which is a mechanism of exercise-induced increase in circulating BAIBA [ 38 ]. There are several experimental studies showing enhancement in PGC-1α activity by treatment with an SGLT2i in the muscle and liver [ 49 , 50 ], though there was a contradicted observation [ 51 ]. Collectively, the results indicate that an SGLT2i may serve as an exercise mimetic in addition to functioning as a starvation mimetic via PGC-1α-mediated increase in circulating BAIBA.…”

Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors

“…Decreases in readouts for the mTORC1 pathway were observed throughout nephron segments, effectively uncoupling these changes from solute transport ( 18 ). Importantly, SGLT2 inhibition engenders relative cell starvation ( Figure 1B ), as opposed to a nutrient overload state, which may occur in a variety of cell types by non–SGLT2 receptor mechanisms ( 20 ). Within cardiac myocytes, empagliflozin can bind and block GLUT1 and GLUT4 intracellularly, thus reducing glucose transport into cells ( 21 ).…”