The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet

Scholtes, Rosalie A.; Muskiet, Marcel H.A.; Baar, Michiel J. B. van; Hesp, Anne C.; Greasley, Peter J.; Hammarstedt, Ann; Karlsson, Cecilia; Hallow, K. Melissa; Danser, A.H. Jan; Heerspink, Hiddo J L; Raalte, Daniël H. van

doi:10.1016/j.ekir.2022.02.023

Cited by 13 publications

(15 citation statements)

References 41 publications

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“…50 The activation of these counterregulatory mechanisms may explain why the initial natriuretic and osmotic diuretic response to SGLT2 inhibitors is not sustained. [81][82][83] Accordingly, we observed no meaningful decrease in NT-proBNP in the current study, a finding consistent with our earlier observations based on a conventional ELISA assay. 84 Our findings should be considered in light of certain strengths and limitations.…”

Section: Promotion Of Renal Tubular Integrity and Regenerationsupporting

confidence: 92%

Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme

Zannad

Ferreira

Butler

et al. 2022

European Heart Journal

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Background Sodium glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. Aims To explore the effect of empagliflozin on circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics. Methods Over 1250 circulating proteins were measured at baseline, week 12 and week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs placebo), which were then linked to demonstrated biological actions in the heart and kidneys. Results At week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e., their levels were changed by ≥10% with a false discovery rate < 1% (empagliflozin vs placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to week 52 were generally concordant with the changes from baseline to week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at week 52, but not at week 12. The most common biological action of differentially-expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially-expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption. Conclusions Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signaling and transmembrane sodium transport.

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Section: Promotion Of Renal Tubular Integrity and Regenerationsupporting

confidence: 92%

Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme

Zannad

Ferreira

Butler

et al. 2022

European Heart Journal

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“…However, after 5 to 7 days, although fractional lithium excretion was maintained and glycosuria persisted, the drugs had no significant effect on total urinary sodium excretion or volume. Several studies 37,39,40,44,46,72 have noted a decrease in free water clearance, accompanied by vasopressin activation; such an antiaquaretic counterregulatory response may be particularly likely in patients with diabetes. 83…”

Section: Evaluation Of Sodium and Water Excretion In Clinical Studies...mentioning

confidence: 96%

“…As noted earlier, after SGLT2 inhibition, the reabsorption of sodium and chloride is enhanced in downstream nephron sites 20,33 as a result of upregulation of vasopressin, uromodulin, aldosterone, and α-ketoglutarate. 20,28,32,36–38,44–46 Increases in aldosterone may in part explain the effect of SGLT2 inhibitors to mitigate the risk of hyperkalemia (without inducing hypokalemia) in patients with diabetes or heart failure. 47,48…”

Section: Effects Of Sglt2 Inhibition In the Proximal Renal Tubule And...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

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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.

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“…In this setting, SGLT2 inhibition exerts a short-term osmotic diuretic effect with little increase in urinary sodium excretion, 22,23 suggesting that any increase in urine volume is related to augmented glucose (and not sodium) excretion. However, early increases in urinary water excretion are not sustained because of the activation of adaptive mechanisms that decrease free water clearance, 24 explaining why longterm SGLT2 inhibition does not change serum sodium concentration. 25 Additional lines of evidence raise further doubts that a sustained diuretic effect can account for the benefits of SGLT2 inhibitors in HF.…”

Section: Potential Benefits Of Sglt2 Inhibitors Acting As Osmotic Diu...mentioning

confidence: 99%

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

2022

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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.

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The Adaptive Renal Response for Volume Homeostasis During 2 Weeks of Dapagliflozin Treatment in People With Type 2 Diabetes and Preserved Renal Function on a Sodium-Controlled Diet

Cited by 13 publications

References 41 publications

Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme

Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme

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

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