Table 1 Effect of SGLT2 Inhibitors on Urinary Sodium Excretion and Objective Evidence of Congestion in Randomized Controlled Trials of Patients With Heart Failure
Study | Patient Population | Baseline Natriuretic Peptides | Study Design | Study Drugs | Major Findings |
|---|---|---|---|---|---|
Small Short-Term Mechanistic Studies (n < 100) | |||||
Griffin et al. [17] | 20 patients, euvolemic heart failure, diabetes and resistant to loop diuretics | NT-proBNP ≈400 pg/ml | Double-blind, randomized, placebo-controlled crossover trial | Empagliflozin 10 mg/day vs. placebo, each for 14 days | SGLT2i increased fractional sodium excretion after 1 and 14 days. Decrease in body weight and blood volume at 14 days, but no change in NT-proBNP. |
Kolwelter et al. [18] | 74 patients with stable euvolemic heart failure | NT-proBNP ≈450 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day vs. placebo for 3 months | SGLT2i increased urinary volume but not urinary sodium excretion at 1 month. No between-group differences in urinary volume, urinary sodium excretion or NT-proBNP after 3 months. No effect on extracellular water at 1 or 3 months. |
RECEDE-CHF [19] | 23 patients with diabetes and stable heart failure | NT-proBNP ≈2400 pg/ml | Double-blind, randomized, placebo-controlled, crossover trial | Empagliflozin 25 mg/day vs. placebo, each given for 6 weeks | SGLT2i increased urinary volume after 3 days and 6 weeks due to increase in free water clearance. No short-term or long-term changes in 24-hour urinary sodium excretion. No change in NT-proBNP after 3 days or 6 weeks. Weight loss at week 6, but not after 3 days. |
EMPAG-HF [20] | 60 patients, hospitalized for worsening heart failure | NT-proBNP ≈3400 pg/ml | Double-blind, randomized, placebo-controlled, parallel-group trial | Empagliflozin 25 mg/day vs. placebo for 5 days | SGLT2i increased urine volume over 5 days, but no effect on spot urinary sodium concentration or fractional sodium excretion. Decrease in NT-proBNP but not in body weight after 5 days. |
79 patients, hospitalized for worsening heart failure | NT-proBNP 5200 pg/ml | Double-blind, randomized, placebo-controlled, parallel-group trial | Empagliflozin 10Â mg/day or placebo for 30 days | SGLT2i increased urine volume, but no effect on fractional sodium excretion, spot urinary sodium concentration, NT-proBNP, dyspnea score or body weight after 4 days. | |
Tamaki et al. [23] | 59 patients with diabetes, hospitalized for worsening heart failure | NT-proBNP 3200 pg/ml | Open-label randomized parallel-group trial | Empagliflozin 10Â mg/day vs. other diabetic therapy for 7 days | SGLT2i increased urinary volume and urinary sodium excretion at 24Â h; no assessments at day 7. No change in body weight after 1 or 7 days. Lower NT-proBNP at day 7. |
Yeoh et al. [24] | 61 patients hospitalized for worsening heart failure and fluid retention, diuretic resistant | NT-proBNP ≈4000 pg/ml | Open-label, randomized, parallel-group trial | Dapagliflozin 10 mg/day vs. metolazone 5–10 mg/day for 3 days | No change in spot urinary sodium concentration with SGLT2i during 3 days. Less natriuresis, lower loop diuretic efficiency and less weight loss with SGLT2i than metolazone. No between-group difference in interstitial lung fluid. |
Multicenter Efficacy Endpoint Trials (Typically n > 100) of 12 Weeks Duration | |||||
EMPIRE- | 190 patients with stable heart failure, reduced EF | NT-proBNP ≈600 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day or placebo for 12 weeks | No between-group differences in NT-proBNP, daily activity or KCCQ. In 70 patients, no between-group difference in pulmonary capillary wedge pressure at rest or exercise after 12 weeks. Total blood volume reduced by only 1%. |
PRESERVED-EF [33] | 324 patients with heart failure, preserved EF | NT-proBNP ≈700 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Dapagliflozin 10 mg/day vs. placebo, for 12 weeks. | SGLT2i improved KCCQ and 6-minute walk distance, without change in NT-proBNP. Body weight decreased by ≈0.8 kg after 12 weeks. |
EMBRACE-HF [34] | 65 patients with stable heart failure | NT-proBNP ≈800 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day vs. placebo, for 12 weeks | Pulmonary arterial diastolic pressure was ≈1–2 mm Hg lower in the SGLT2i group, which persisted even when drug withdrawn for 1 week. No between-group differences in 6-minute walk distance, KCCQ or NT-proBNP at 12 weeks |
CHIEF-HF [35] | 448 patients with stable heart failure | Not performed | Double-blind, randomized, placebo-controlled parallel-group trial | Canagliflozin 100Â m/day vs. placebo, for 12 weeks | SGLT2i improved KCCQ scores at 12 weeks. No assessments of congestion or cardiac filling pressures were performed. |
EMPERIAL-Preserved [36] | 315 patients with stable heart failure, preserved EF | NT-proBNP ≈900 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day vs. placebo, for 12 weeks | No between-group difference in 6-minute walk distance, dyspnea score, KCCQ scores, clinical congestion score or NT-proBNP at 12 weeks. |
263 patients with stable heart failure | NT-proBNP ≈1100 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Dapagliflozin 10 mg/day vs. placebo, for 12 weeks. | SGLT2i improved KCCQ scores at 12 weeks, but did not have an effect on NT-proBNP at 6 or 12 weeks. In subgroup of 85 patients, no change in lung fluid volume at 12 weeks vs. placebo | |
EMPERIAL-Reduced [36] | 312 patients with stable heart failure, reduced EF | NT-proBNP ≈1500 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day vs. placebo, for 12 weeks | No between-group difference in 6-minute walk distance, and no effect on dyspnea score or NT-proBNP at 12 weeks. Nominally significant between-group difference in KCCQ and clinical congestion score (based on orthopnea) |
530 patients hospitalized for worsening heart failure | NT-proBNP ≈3200 pg/ml | Double-blind, randomized, placebo-controlled parallel-group trial | Empagliflozin 10 mg/day vs. placebo, for 90 days | SGLT2i improved KCCQ at 15 and 30 days and decreased NT-proBNP at 30 days. Decrease in clinical congestion score (based on symptoms) at 15 days. Weight loss and increase in hematocrit at 15 days attributed to diuresis and hemoconcentration. | |