Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial

Jensen, Jørgen Steen; Omar, Massar; Kistorp, Caroline; Tuxen, Christian; Gustafsson, Ida; Køber, Lars; Gustafsson, Finn; Faber, Jens; Malik, Mariam Elmegaard; Fosbøl, Emil Loldrup; Bruun, Niels Eske; Forman, Julie Lyng; Jensen, Lars Thorbjørn; Møller, Jacob Eifer; Schou, Morten

doi:10.1016/s2213-8587(20)30382-x

Cited by 85 publications

(88 citation statements)

References 30 publications

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“…Although the present study cannot clarify the effects of SGLT2 inhibitors on heart failure (HF), it was reported that SGLT2 inhibitors are useful in managing HF, 11 suggesting the importance of SGLT2 inhibitor-induced changes in ePV. 5 The potential importance of interstitial fluid changes to improve HF symptoms may be a feature that distinguishes SGLT2 inhibitors from other diuretics. 1 A significant increase in eGFR over 52 weeks was observed.…”

Section: Discussionmentioning

confidence: 99%

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Association of estimated plasma volume and weight loss after long‐term administration and subsequent discontinuation of the sodium‐glucose cotransporter‐2 inhibitor tofogliflozin

Matsubayashi

Yoshida

Suganami

et al. 2021

Diabetes Obesity Metabolism

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Sodium-glucose cotransporter-2 inhibitors (SGLT2) are drugs that have been reported to have several effects through the regulation of plasma volume, for example, antihypertensive effects. This study aimed to clarify the impact of long-term administration and subsequent discontinuation of the SGLT2 inhibitor tofogliflozin on estimated plasma volume (ePV), brain natriuretic peptide (BNP) and the relationship between changes in ePV, BNP and body weight (BW). Data from 157 participants with type 2 diabetes receiving tofogliflozin monotherapy in a phase 3 study were analysed.Changes in variables or correlations among them during a 52-week administration and a 2-week post-treatment period were investigated. Percent change in ePV was calculated using the Strauss formula. Significant decreases in BW, ePV and ln-transformed BNP (ln-BNP) were noted by week 52. %ΔBW was not significantly correlated with %ΔePV and Δln-BNP, while %ΔePV was significantly correlated with Δln-BNP. Two weeks after discontinuation of tofogliflozin, BW, ePV and ln-BNP were significantly increased. %ΔBW was significantly correlated with %ΔePV and Δln-BNP. Furthermore, ePV and BNP were significantly higher than baseline levels.

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Section: Discussionmentioning

confidence: 99%

“…4 However, the validity of using ePV as an index of PV changes due to SGLT2 inhibitors (especially short-term changes) was not fully established, 4 but there is no other PV index that can be easily calculated in routine clinical practice. Since previous studies related to SGLT2 inhibitors used ePV, 5,6 we used ePV in the present study.…”

Section: Introductionmentioning

confidence: 99%

Association of estimated plasma volume and weight loss after long‐term administration and subsequent discontinuation of the sodium‐glucose cotransporter‐2 inhibitor tofogliflozin

Matsubayashi

Yoshida

Suganami

et al. 2021

Diabetes Obesity Metabolism

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“…min/1.73 m². The results showed that empagliflozin reduced estimated extracellular volume, estimated plasma volume, and measured GFR after 12 weeks, implying that fluid volume changes might be an important mechanism underlying the beneficial clinical effects of SGLT2i (165). However, the recent Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial (VERTIS CV) reported no significant benefit of ertugliflozin for the renal composite outcomes (death from renal causes, renal replacement therapy, or D-Scr) (166).…”

Section: Mechanismsmentioning

confidence: 99%

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

et al. 2021

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Over decades, substantial progress has been achieved in understanding the pathogenesis of proteinuria in diabetic kidney disease (DKD), biomarkers for DKD screening, diagnosis, and prognosis, as well as novel hypoglycemia agents in clinical trials, thereby rendering more attention focused on the role of renal tubules in DKD. Previous studies have demonstrated that morphological and functional changes in renal tubules are highly involved in the occurrence and development of DKD. Novel tubular biomarkers have shown some clinical importance. However, there are many challenges to transition into personalized diagnosis and guidance for individual therapy in clinical practice. Large-scale clinical trials suggested the clinical relevance of increased proximal reabsorption and hyperfiltration by sodium-glucose cotransporter-2 (SGLT2) to improve renal outcomes in patients with diabetes, further promoting the emergence of renal tubulocentric research. Therefore, this review summarized the recent progress in the pathophysiology associated with involved mechanisms of renal tubules, potential tubular biomarkers with clinical application, and renal tubular factors in DKD management. The mechanism of kidney protection and impressive results from clinical trials of SGLT2 inhibitors were summarized and discussed, offering a comprehensive update on therapeutic strategies targeting renal tubules.

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“…This article summarizes the results of the cardiovascular outcome trials carried out with empagliflozin, [1][2][3] and analyzes the EMPA-REG mediation sub-analysis results, 14 EMPA-HEART, 15 and EMPIRE-HF, and substudies. [16][17][18][19] Also, "EMPA-PIG" 20 and EMPA-TROPISM, 21 which outline the intrinsic myocardial mechanisms associated with clinical benefit in HFrEF in higher mammals 20 and especially in humans in-vivo. [15][16][17][18][19]21 Figure 1: Hazard ratios are illustrated with their lower and upper limits of the confidence interval for the incidence of 3-MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in cardiovascular outcome trials with empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin in a ASCVD population.…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18][19] Also, "EMPA-PIG" 20 and EMPA-TROPISM, 21 which outline the intrinsic myocardial mechanisms associated with clinical benefit in HFrEF in higher mammals 20 and especially in humans in-vivo. [15][16][17][18][19]21 Figure 1: Hazard ratios are illustrated with their lower and upper limits of the confidence interval for the incidence of 3-MACE (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) in cardiovascular outcome trials with empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin in a ASCVD population. A protective effect is observed against the 3-MACE with empagliflozin and canagliflozin, not so for dapagliflozin and ertugliflozin, which showed a noninferior or safety result.…”

Section: Introductionmentioning

confidence: 99%

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

Enrique¹,

Castillo-Núñez

Gilberto

2021

MRAJ

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Sodium-glucose cotransporter 2 inhibitors (SGLT2i) like empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, and sotagliflozin (both a sodium-glucose cotransporter 1 inhibitor [SGLT1i] and SGLT2i), are drugs that inhibit the action of sodium-glucose cotransporters in the proximal renal tubule and/or the intestine. Therefore, causing natriuresis, glucosuria, and reduced intestinal glucose absorption. Besides this mechanism of action, which determines glycemia reduction, there are multiple extra-glycemic mechanisms in extensive research in humans in-vivo, which, beyond in-vitro or experimental studies, is dissecting the mechanisms explaining the initially unanticipated and ultimately incredibly significant and welcomed cardiac and nephroprotective results of these drugs. This article centers on the cardioprotective effects of empagliflozin, namely, a reduction of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure, among others. These effects were demonstrated in the EMPA-REG and EMPEROR-Reduced clinical outcome trials, which will be initially summarized to later frame them in the results of the mechanistic trials EMPA-HEART, EMPIRE-HF (including sub-studies), EMPA-TROPISM, and “EMPA-PIG.” The mechanistic trials showed favorable changes in the left ventricular mass index, left ventricular end-systolic and end-diastolic volumes, extracellular and intravascular volumes, glomerular filtration rate, myocardial remodeling, among others. These were investigator-initiated studies to go beyond in-vitro and experimental evidence. The results and analysis allow us to understand myocardial energy remodeling as an intrinsic myocardial mechanism that underlies anatomical, functional, and neurohormonal myocardial remodeling. Together with other systemic actions, predominantly renal (not discussed in this article), contribute significantly to this drug's clinical benefit.

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Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial

Cited by 85 publications

References 30 publications

Association of estimated plasma volume and weight loss after long‐term administration and subsequent discontinuation of the sodium‐glucose cotransporter‐2 inhibitor tofogliflozin

Association of estimated plasma volume and weight loss after long‐term administration and subsequent discontinuation of the sodium‐glucose cotransporter‐2 inhibitor tofogliflozin

Current Challenges and Future Perspectives of Renal Tubular Dysfunction in Diabetic Kidney Disease

Empagliflozin, Beyond Glucose Reduction. The Unanticipated and Welcomed Cardioprotective Results. Switching the Heart at Four Levels: Energetic, Anatomical, Functional, and Neuro-Hormonal

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