SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism

Packer, Milton

doi:10.1038/s41569-022-00824-4

Cited by 69 publications

(99 citation statements)

References 278 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the cardioprotective effects of SGLT2 inhibitors represent a direct beneficial effect to reduce cardiomyocyte stress and injury, which is independent of the binding to SGLT2 in the heart or the presence or actions of these drugs on SGLT2 in the proximal renal tubule. 3–5 Nevertheless, any durable changes in the volume set point produced by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular cardiac effects of these drugs to mediate their benefits on the clinical course of heart failure.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

2023

Self Cite

View full text Add to dashboard Cite

SGLT2 (sodium-glucose cotransporter 2) inhibitors interfere with the reabsorption of glucose and sodium in the early proximal renal tubule, but the magnitude and duration of any ensuing natriuretic or diuretic effect are the result of an interplay between the degree of upregulation of SGLT2 and sodium-hydrogen exchanger 3, the extent to which downstream compensatory tubular mechanisms are activated, and (potentially) the volume set point in individual patients. A comprehensive review and synthesis of available studies reveals several renal response patterns with substantial variation across studies and clinical settings. However, the common observation is an absence of a large acute or chronic diuresis or natriuresis with these agents, either when given alone or combined with other diuretics. This limited response results from the fact that renal compensation to these drugs is rapid and nearly complete within a few days or weeks, preventing progressive volume losses. Nevertheless, the finding that fractional excretion of glucose and lithium (the latter being a marker of proximal sodium reabsorption) persists during long-term treatment with SGLT2 inhibitors indicates that pharmacological tolerance to the effects of these drugs at the level of the proximal tubule does not meaningfully occur. This persistent proximal tubular effect of SGLT2 inhibitors can be hypothesized to produce a durable improvement in the internal set point for volume homeostasis, which may become clinically important during times of fluid expansion. However, it is difficult to know whether a treatment-related change in the volume set point actually occurs or contributes to the effect of these drugs to reduce the risk of major heart failure events. SGLT2 inhibitors exert cardioprotective effects by a direct effect on cardiomyocytes that is independent of the presence of or binding to SGLT2 or the actions of these drugs on the proximal renal tubule. Nevertheless, changes in the volume set point mediated by SGLT2 inhibitors might potentially act cooperatively with the direct favorable molecular and cellular effects of these drugs on cardiomyocytes to mediate their benefits on the development and clinical course of heart failure.

show abstract

Section: Discussionmentioning

confidence: 99%

“…2 Second, SGLT2 inhibitors act directly on the heart to induce nutrient deprivation signaling and promote autophagy, which reduces oxidative and endoplasmic reticulum stress and enhances cellular function and viability. 3,4…”

mentioning

confidence: 99%

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

2023

Self Cite

View full text Add to dashboard Cite

show abstract

“…We showed that CO 2 levels were significantly negatively correlated with B‐type natriuretic peptide ( r = −0.28, P < 0.001) and positively correlated with the estimated glomerular filtration rate ( r = 0.20, P = 0.001) and left ventricular ejection fraction ( r = 0.13, P < 0.001) 2 . Indeed, as suggested by Guarnaccia et al, hypocapnia could also form a vicious circle with lower circulating oxygen in the progression of AHF 3 . This could cause a persistent lack of myocardial energy and deterioration of haemodynamics, ultimately leading to multi‐organ damage, including kidney damage.…”

mentioning

confidence: 77%

Sodium‐glucose transporter 2 inhibitors may improve the prognosis of acute heart failure by correcting hypocapnia

Tang

Miao

2023

ESC Heart Failure

View full text Add to dashboard Cite

“…We report that empagliflozin significantly and coordinately induces the expression of the genes for nutrient sensors, AMPKa1 and NAMPT, and their downstream target PGC-1a in skeletal muscle in normal mice under ad libitum feeding. Increasing numbers of studies showed that SGLT2i increased the activation of these mediators of mitochondrial metabolism in a variety of experimental models such as diabetic mice, high-fat dietinduced obese mice, Dahl-sensitive rats, cultured cardiomyocytes exposed to lipopolysaccharide, doxorubicin or angiotensin II (see reviews 4,35 ). In addition, it is well established that AMPKa1, NAMPT, and PGC-1a form a molecular network that plays an important role in cellular energy homeostasis in skeletal muscle 36 .…”

Section: Discussionmentioning

confidence: 99%

Empagliflozin induces the transcriptional program for nutrient homeostasis in skeletal muscle in normal mice

Kawakami

Matsui

et al. 2023

Preprint

View full text Add to dashboard Cite

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve heart failure (HF) outcomes across a range of patient characteristics. A hypothesis that SGLT2i induce metabolic change similar to fasting has recently been proposed to explain their profound clinical benefits. However, it remains unclear whether SGLT2i primarily induce this change in physiological settings. Here, we demonstrate that empagliflozin administration under ad libitum feeding did not cause weight loss but did increase transcripts of the key nutrient sensors, AMP-activated protein kinase (AMPK) and nicotinamide phosphoribosyltransferase (NAMPT), and the master regulator of mitochondrial gene expression, PGC-1a, in quadriceps muscle in healthy mice. Expression of these genes correlated with that of PPARa and PPARd target genes related to mitochondrial metabolism and oxidative stress response, and also correlated with serum ketone body b-hydroxybutyrate. These results were not observed in the heart. Collectively, this study revealed that empagliflozin activates transcriptional programs critical for sensing and adaptation to nutrient availability intrinsic to skeletal muscle rather than the heart even in normocaloric condition. As activation of PGC-1a is sufficient for metabolic switch from fatigable, glycolytic metabolism toward fatigue-resistant, oxidative mechanism in skeletal muscle myofibers, our findings may partly explain the improvement of exercise tolerance in patients with HF receiving empagliflozin.

show abstract

SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism

Cited by 69 publications

References 278 publications

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

Critical Analysis of the Effects of SGLT2 Inhibitors on Renal Tubular Sodium, Water and Chloride Homeostasis and Their Role in Influencing Heart Failure Outcomes

Sodium‐glucose transporter 2 inhibitors may improve the prognosis of acute heart failure by correcting hypocapnia

Empagliflozin induces the transcriptional program for nutrient homeostasis in skeletal muscle in normal mice

Contact Info

Product

Resources

About