Empagliflozin in Heart Failure

Abstract

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT-2i's) improve heart failure (HF) 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 SGLT-2i's may help circumvent these limitations. Methods: 20 patients with type-2 diabetes and chronic, stable HF completed a randomized placebo-controlled crossover study of empagliflozin 10mg daily vs. placebo. Patients underwent an intensive 6-hour biospecimen collection and cardio-renal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with repeat of the above protocol. 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 (FENa) increased significantly with empagliflozin monotherapy vs. placebo (FENa 1.2 ± 0.7% vs. 0.7 ± 0.4% p=0.001) and there was a synergistic effect in combination with bumetanide (FENa 5.8 ± 2.5% vs. 3.9 ± 1.9%, p=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208mL, IQR -536 to 153 mL vs -14mL, IQR -282 to 335 mL, p=0.035), and plasma volume (-138mL, IQR -379 to 154mL ± 453 mL, p=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation as change in norepinephrine was superior (p = 0.02) and all other neurohormones similar (p<0.34) during the empagliflozin vs. 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 HF patients and may represent a mechanism contributing to the superior long-term HF outcomes observed with these agents. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT03029760

Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination With Loop Diuretics in Patients With Type 2 Diabetes and Chronic Heart Failure

“…Nevertheless, in the 24-hour urine collections, we also did not find an increase in natriuresis as demonstrated by mmol/L or mmol/d, and although there was a nonsignificant increase in FENa at day 3 caused by empagliflozin, this was absent by week 6. Our data are complementary to those of Griffin et al, 18 and the differences in FENa between our study and that by Griffin et al 18 may reflect the differing time points studied. In the study by Griffin et al, 18 the largest effect of empagliflozin on FENa was beyond 3 hours at day 1, whereas at day 14, the increase in FENa with empagliflozin compared with placebo was attenuated.…”

“…Our data are complementary to those of Griffin et al, 18 and the differences in FENa between our study and that by Griffin et al 18 may reflect the differing time points studied. In the study by Griffin et al, 18 the largest effect of empagliflozin on FENa was beyond 3 hours at day 1, whereas at day 14, the increase in FENa with empagliflozin compared with placebo was attenuated. In a single-blind study, Blau et al 19 found that although canagliflozin caused a significant increase in natriuresis at 24 hours, urine sodium had returned to baseline by 96 hours.…”

“…There was no dietary restriction placed on participants while the 24-hour urine collection was performed, and any variation in glucose control may have modified the urinary responses. The effect of glucosuria from SGLT2 inhibition is well-described in the literature 18 , 20 , 31 and as such we did not measure urine glucose in this study. Given that we demonstrated diuresis in the absence of significant natriuresis, it would have been interesting to identify whether there was an association between glucosuria and 24-hour urine volume.…”

“…Griffin et al 18 recently demonstrated that empagliflozin monotherapy caused a modest natriuresis compared with placebo as measured by the FENa, which was significant at 3 hours after drug administration but not at 1.5 hours. They also reported a synergistic natriuretic effect when empagliflozin was given alongside intravenous loop diuretic.…”

Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients With Type 2 Diabetes and Preserved Kidney Function During Standardized Sodium Intake: Results of the DAPASALT Trial

“…Previous studies of varying designs in healthy volunteers or patients with type 2 diabetes have indeed suggested that SGLT2 inhibitors cause transient increases in 24-h sodium excretion ( 8 – 11 ) along with reductions in plasma and extracellular volume ( 12 , 13 ). Studies in patients with heart failure showed either no change ( 14 ) or a modest increase in sodium excretion in parallel with a reduction in plasma volume ( 15 ). The prior studies were limited by the fact that sodium excretion was estimated from spot urine samples instead of 24-h urine collections, or dietary intake of sodium was not recorded or standardized.…”