Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects

Abstract

Background: Sodium-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.

Methods: Twenty 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.

Results: Oral 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.

Conclusions: Empagliflozin 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.

Keywords: blood volume; natriuresis; sodium-glucose transporter 2 inhibitors.

Figure 1.. Fractional excretion of glucose (FEGlucose) on day 1 (dotted line) and day 14 (solid line) of treatment.

Empa = Empagliflozin.

Figure 2.. Empaglaflolzin increased natiuresis as monotherapy (panel A) and in combination with a loop diuretic (panel B) both with the first dose (top) and after 14 days of therapy (bottom).

FENa: Fractional Excretion of Sodium

Figure 3.. Natriuresis at the Day 1 Visit.

The solid bars represent measured sodium excretion under the 4 different experimental conditions. The thatched area represents the difference in natriuresis between the empagliflozin period and the placebo period. Notably the enhancement during the loop diuretic period is more than 4-fold greater than what is observed during monotherapy, illustrating the synergistic effect between loop diuretics and empagliflozin. Empa: Empagliflozin, Loop: Loop diuretic, FENa: Fractional Excretion of Sodium

Figure 4.. Relationship between natriuresis and metrics of glucosuria.

During the empagliflozin period, there was no association seen between FENa and FE Glucose (Panel A). There was an inverse correlation between both FENa and urinary glucose concentration (Panel B) and glucose excretion (Panel C) over the 6-hour study visits. FE= Fractional Excretion.

Figure 5.. Effects of Empagliflozin on total blood volume and plasma volume.

During the empagliflozin period, patients lost significantly more blood volume (Panel A) and plasma volume (Panel B) than during the placebo period. Empa = Empagliflozin.

Figure 6.. Effects of Empagliflozin on weight and total body water.

During the empagliflozin period, patients lost significantly more weight (Panel A) and Total Body Water (Panel B). Empa = Empagliflozin.