Body fluid regulation via chronic inhibition of sodium–glucose cotransporter-2 in patients with heart failure: a post hoc analysis of the CANDLE trial

Fujiki, Shinya; Tanaka, Atsushi; Imai, Takumi; Shimabukuro, Michio; Uehara, Hiroki; Nakamura, Ikuko; Matsunaga, Kazuo; Kashimura, Takeshi; Minamino, Tohru; Inomata, Takayuki; Node, Koichi

doi:10.1007/s00392-022-02049-4

Cited by 9 publications

(8 citation statements)

References 33 publications

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“…On the basis of a comprehensive review, we identified 15 studies that evaluated the effect of SGLT2 inhibitors on plasma volume (Table 2). 64,[72][73][74]78,[98][99][100][101][102][103][104][105][106][107][108][109] Unfortunately, most studies estimated changes in plasma volume using the Kaplan-Hakim and Strauss formulae, which cannot be applied to the evaluation of changes produced by SGLT2 inhibitors. Four reports 64,72,74,109 used indicator dilution methods, and of these, 3 were double blind and placebo controlled.…”

Section: Effect Of Sglt2 Inhibitors On Plasma and Blood Volume In Cli...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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Section: Effect Of Sglt2 Inhibitors On Plasma and Blood Volume In Cli...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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“…It has been demonstrated that patients with CHF have myocardial interstitial oedema, which causes systolic and diastolic cardiac dysfunction and increased stiffness of the left ventricle [ 30 ]. Opposite to loop diuretics, which lead besides reduction of interstitial fluid, simultaneously to a reduction of intravascular volume, SGLT2 inhibitors reduce selectively interstitial fluid with only a minimal change in blood volume [ 31 , 32 ]. Such a decrease in myocardial oedema may contribute to the improved prognosis observed in patients with CHF started on SGLT2 inhibitors.…”

Section: Discussionmentioning

confidence: 99%

The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial

et al. 2022

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Introduction Sodium-glucose co-transporter 2 (SGLT2) inhibitors have cardiovascular protective properties in addition to the metabolic effects and represent a cornerstone of treating patients with chronic heart failure (CHF). We hypothesised that empagliflozin reduces tissue sodium content in patients with CHF. Methods In a double-blind, randomised (2:1), placebo-controlled, parallel-group, clinical trial, 74 patients with NYHA class II–III CHF and an ejection fraction of 49% or less received empagliflozin 10 mg once daily or placebo for 3 months. In each patient, tissue sodium content of the lower leg was assessed non-invasively by sodium-MRI (23Na-MRI) at baseline, after 1 and 3 months of treatment. Results After 1 and 3 months treatment with empagliflozin (n = 48), a significant decrease in skin sodium content was observed (1 month: 22.8 ± 6.1 vs. 21.6 ± 6.0 AU, p = 0.039; 3 months: 22.9 ± 6.1 vs. 21.6 ± 6.1 AU, p = 0.013), while there was no change in muscle sodium and muscle water content. In direct comparison, the change in skin sodium content between baseline and 3 months was − 1.3 ± 3.5 AU in the empagliflozin group versus 0.6 ± 3.5 AU in the placebo group (p for between-group difference = 0.022). No significant difference regarding change in muscle sodium and in muscle water content was observed after 3 months treatment between the two groups. Conclusion This trial showed a significant decrease in skin sodium content after 1 and 3 months of treatment with empagliflozin. The decrease in skin sodium content may reflect a decrease in subclinical micro-oedema or/and in non-osmotic bound tissue sodium, both reported to impair left ventricular function. Trial registration number NCT03128528 (http://www.clinicaltrials.gov). Trial registration date 25th April 2017.

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“…Estimations of fluid volumes were performed at baseline and at 24 weeks after treatment using the following formulas and clinical variables 18–20 . The ePV at baseline was calculated using the Kaplan‐Hakim formula, 21

ePV = (1 - haematocrit) \times (a + [b \times body weight (kg)]) .

where a = 1530 in men and 864 in women, and b = 41 in men and 47.9 in women.…”

Section: Methodsmentioning

confidence: 99%

“…Estimations of fluid volumes were performed at baseline and at 24 weeks after treatment using the following formulas and clinical variables. [18][19][20] The ePV at baseline was calculated using the Kaplan-Hakim formula, 21 ePV…”

Section: Estimated Fluid Volume Calculationmentioning

confidence: 99%

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post‐hoc analysis of the PROCEED trial

Maruhashi,

Tanaka,

Takahashi

et al. 2024

Diabetes Obesity Metabolism

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AimsTo analyse the changes in erythropoietic and estimated fluid volume parameters after the initiation of ipragliflozin, a sodium‐glucose co‐transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD).MethodsThis was a post‐hoc analysis of the PROCEED trial, which evaluated the effect of 24‐week ipragliflozin treatment on endothelial dysfunction in patients with T2DM and CKD. We evaluated the changes in erythropoietic and estimated fluid volume parameters from baseline to 24 weeks post‐treatment in 53 patients who received ipragliflozin (ipragliflozin group) and 55 patients with T2DM and CKD without sodium‐glucose co‐transporter 2 inhibitors (control group), a full analysis set of the PROCEED trial.ResultsThe increases in haemoglobin [estimated group difference, 0.5 g/dl; 95% confidence interval (CI), 0.3‐0.8; p < .001], haematocrit (estimated group difference, 2.2%; 95% CI, 1.3‐3.1; p < .001) and erythropoietin (estimated log‐transformed group difference, 0.1; 95% CI, 0.01‐0.3; p = .036) were significantly greater in the ipragliflozin group than those in the control group. Ipragliflozin treatment was significantly associated with an increase in erythropoietin, independent of the corresponding change in haemoglobin (β = 0.253, p < .001) or haematocrit (β = 0.278, p < .001). Reductions in estimated plasma volume (estimated group difference, −7.94%; 95% CI, −11.6 to −4.26%; p < .001) and estimated extracellular volume (estimated group difference, −181.6 ml; 95% CI, −275.7 to −87.48 ml; p < .001) were significantly greater in the ipragliflozin group than those in the control group.ConclusionsErythropoiesis was enhanced and estimated fluid volumes were reduced by ipragliflozin in patients with T2DM and CKD.Clinical trialPROCEED trial (registration number: jRCTs071190054).

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Body fluid regulation via chronic inhibition of sodium–glucose cotransporter-2 in patients with heart failure: a post hoc analysis of the CANDLE trial

Cited by 9 publications

References 33 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

The SGLT2 inhibitor empagliflozin reduces tissue sodium content in patients with chronic heart failure: results from a placebo-controlled randomised trial

Erythropoiesis and estimated fluid volume regulation following initiation of ipragliflozin treatment in patients with type 2 diabetes mellitus and chronic kidney disease: A post‐hoc analysis of the PROCEED trial

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