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Effects of empagliflozin on renal sodium and glucose handling in patients with acute heart failure.

ABSTRACT:

Aims

Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF.

Methods and results

This study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 ± 12 vs. -2 ± 12 mL/min/1.73 m² ; P = 0.009), which recovered within 30 days.

Conclusion

In patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.

SUBMITTER: Boorsma EM

PROVIDER: S-EPMC8048437 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsImpairment of vascular function contributes to the progression of chronic heart failure (HF) by increasing the afterload. Treatment with selective sodium-glucose cotransporter 2 (SGLT2) inhibitors improves the prognosis of HF, but the precise mechanisms remain unclear. The aim of this study was to analyse the effect of empagliflozin on vascular function in patients with HF.Methods and resultsIn an investigator initiated, double-blind, randomized, placebo-controlled, parallel-group, clinical study, patients with HF NYHA II-III and an ejection fraction of 49% or less were randomized 2:1 to receive empagliflozin 10 mg once daily or placebo for 3 months. A total of 74 patients (15% female), aged 66 ± 9 years, with a mean ejection fraction of 39 ± 8% and a median NTproBNP of 558 pg/mL (IQR 219-1051 pg/mL), were included. Vascular parameters such as central systolic blood pressure (cSBP), central pulse pressure (cPP), forward (FPH), and reflected pressure pulse height (RPH) decreased under resting conditions after 1 and 3 months (1 month: cSBP -6.4 ± 8.3 mmHg, P < 0.001, cPP -3.0 ± 6.6 mmHg, P = 0.004, FPH -2.5 ± 4.5 mmHg, P = 0.001, RPH -1.6 ± 3.0 mmHg, P = 0.001; 3 months: cSBP -4.6 ± 8.4 mmHg, P = 0.001, cPP -3.1 ± 4.8 mmHg, P < 0.001, FPH -1.7 ± 3.7 mmHg, P = 0.004, RPH -1.4 ± 2.5 mmHg, P = 0.001) in patients treated with empagliflozin (n = 45). In accordance, cSBP and cPP decreased in patients with empagliflozin treatment under 24 h ambulatory conditions after 1 and 3 months (1 month: cSBP -4.8 ± 10.1 mmHg, P = 0.003, cPP -2.0 ± 5.7 mmHg, P = 0.026; 3 months: cSBP -4.7 ± 9.0 mmHg, P = 0.002, cPP -2.1 ± 6.4 mmHg, P = 0.044). In the placebo group, there was no significant change after 1 and 3 months. The decrease in cSBP under resting conditions (-5.7 ± 2.4 mmHg, P = 0.019) after 1 month and in cSBP (-6.0 ± 2.6, P = 0.027) as well as in pulse wave velocity (-0.5 ± 0.2 m/s, P = 0.021) under 24 h ambulatory conditions after 3 months was greater in the empagliflozin group than in the placebo group.ConclusionsWe found an improvement of vascular function after treatment with empagliflozin that indicates decreased afterload of the left ventricle and may contribute to the beneficial effects of SGLT2 inhibition in HF.

Project description:BackgroundSodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.MethodsTwenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.ResultsOral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (P<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; P=0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; P=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; P=0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; P=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (P=0.02) and all other neurohormones were similar (P<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (P=0.20) or renal dysfunction (P>0.11 for all biomarkers), whereas both serum magnesium (P<0.001) and uric acid levels (P=0.008) improved.ConclusionsEmpagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.