Ferreira João Pedro, Vasques-Nóvoa Francisco, Saraiva Francisca, Oliveira Ana C, Almeida Jorge, Batista Ana Beatriz, Barbosa Arsénio, Ferreira Ana Filipa, Costa Cátia, Diaz Silvia O, Santos-Ferreira Diogo, Friões Fernando, Goncalves Cândida, Guimarães João Tiago, Leite Marta, Marques Pedro, Mascarenhas Joana, Matos Maria Inês, Pereira Catarina, Rodrigues Pedro, Sharma Abhinav, Silva Gualter, Pereira-Sousa Inês, Sousa Carla, Zannad Faiez, Pimenta Joana, Fontes-Carvalho Ricardo, Leite-Moreira Adelino
RISE-Health, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; Université de Lorraine, INSERM, Centre d'Investigations Cliniques, CHRU de Nancy, Inserm and INI-CRCT (Cardiovascular and Renal Clinical Trialists) F-CRIN Network, Nancy, France; Serviço de Medicina Interna, Unidade Local de Saúde Gaia/Espinho, Vila Nova de Gaia, Portugal.
RISE-Health, Departamento de Cirurgia e Fisiologia, Faculdade de Medicina, Universidade do Porto, Porto, Portugal; Serviço de Medicina Interna, Unidade Local de Saúde São João, Porto, Portugal.
J Am Coll Cardiol. 2025 Aug 5;86(5):320-333. doi: 10.1016/j.jacc.2025.05.033.
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and mineralocorticoid receptor antagonists improved heart failure outcomes in heart failure with mildly reduced ejection fraction or heart failure with preserved ejection fraction; however, their combination was not tested in a randomized manner. Whether the SGLT2i/mineralocorticoid receptor antagonist combination offers benefits compared to SGLT2i alone requires dedicated trials.
This study aims to compare the efficacy and safety of dapagliflozin/spironolactone combination vs dapagliflozin alone in heart failure with mildly reduced ejection fraction and heart failure with preserved ejection fraction.
This was a prospective randomized open, blinded endpoint crossover trial. A sample size of 108 patients was powered to detect 0.15 Log N-terminal pro-B-type natriuretic peptide (NT-proBNP) difference between the dapagliflozin/spironolactone combination and dapagliflozin alone sequences study primary outcome. Each treatment sequence was given for 12 weeks.
One hundred eight patients were randomized. The median age was 76 years (Q1-Q3: 71-81 years), 57% were women, estimated glomerular filtration rate (eGFR) 72 mL/min/1.73 m (Q1-Q3: 49-89 mL/min/1.73 m), potassium 4.3 mmol/L (Q1-Q3: 4.0-4.6 mmol/L), and 45% had diabetes. The median NT-proBNP was 746 pg/mL (Q1-Q3: 401-1,493 pg/mL) and median LogNT-proBNP 6.6 Log-units (Q1-Q3: 6.0-7.3 Log-units). Compared to dapagliflozin, dapagliflozin/spironolactone combination reduced LogNT-proBNP levels: -0.11 (95% CI: -0.22 to -0.01) Log-units (P = 0.035) corresponding to an 11% relative reduction and increased the odds of reaching ≥20% NT-proBNP reduction (OR: 2.27; 95% CI: 1.16-4.44; P = 0.016). Compared to dapagliflozin, dapagliflozin/spironolactone combination reduced systolic blood pressure (-5.2 mm Hg; 95% CI: -8.4 to -2.0 mm Hg), reduced Logurinary-albumin-to-creatinine ratio (-0.32 Log; 95% CI: -0.54 to -0.11 Log) decreased eGFR (-6.4 mL/min/1.73 m; 95% CI: -8.3 to -4.4 mL/min/1.73 m), and increased serum potassium (+0.32 mmol/L; 95% CI: 0.23-0.41 mmol/L) and the frequency of serum potassium (>5.5 mmol/L: 5 [4.8%] vs 1 [0.9%]).
Dapagliflozin/spironolactone combination reduced NT-proBNP more than dapagliflozin. A greater eGFR decline and potassium increase was observed with dapagliflozin/spironolactone combination (SOGALDI-PEF [Dapagliflozin With or Without Spironolactone for HFpEF]; NCT05676684).
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）和盐皮质激素受体拮抗剂可改善射血分数轻度降低的心力衰竭或射血分数保留的心力衰竭患者的心力衰竭结局；然而，尚未对它们的联合应用进行随机试验。与单独使用SGLT2i相比，SGLT2i/盐皮质激素受体拮抗剂联合应用是否具有益处需要专门试验。
本研究旨在比较达格列净/螺内酯联合用药与单用达格列净在射血分数轻度降低的心力衰竭和射血分数保留的心力衰竭患者中的疗效和安全性。
这是一项前瞻性随机开放、盲终点交叉试验。纳入108例患者，以检测达格列净/螺内酯联合用药组与单用达格列净组之间N末端B型利钠肽原（NT-proBNP）水平相差0.15对数单位作为研究主要结局的检验效能。每个治疗疗程为12周。
108例患者被随机分组。中位年龄为76岁（四分位间距：71-81岁），57%为女性，估计肾小球滤过率（eGFR）为72 mL/min/1.73㎡（四分位间距：49-89 mL/min/1.73㎡），血钾为4.3 mmol/L（四分位间距：4.0-4.6 mmol/L），45%患有糖尿病。NT-proBNP中位数为746 pg/mL（四分位间距：401-1493 pg/mL），LogNT-proBNP中位数为6.6对数单位（四分位间距：6.0-7.3对数单位）。与达格列净相比，达格列净/螺内酯联合用药可降低LogNT-proBNP水平：降低-0.11（95%置信区间：-0.22至-0.01）对数单位（P=0.035），相当于相对降低11%，并增加NT-proBNP降低≥20%的几率（比值比：2.27；95%置信区间：1.16-4.44；P=0.016）。与达格列净相比，达格列净/螺内酯联合用药可降低收缩压（-5.2 mmHg；95%置信区间：-8.4至-2.0 mmHg），降低Log尿白蛋白与肌酐比值（-0.32对数；95%置信区间：-0.54至-0.11对数），降低eGFR（-6.4 mL/min/1.73㎡；95%置信区间：-8.3至-4.4 mL/min/1.73㎡），并增加血钾水平（+0.32 mmol/L；95%置信区间：0.23-0.41 mmol/L）以及血钾>5.5 mmol/L的发生率（5[4.8%]比1[0.9%]）。
达格列净/螺内酯联合用药比达格列净更能降低NT-proBNP。观察到达格列净/螺内酯联合用药组eGFR下降幅度更大，血钾升高更明显（SOGALDI-PEF[达格列净联合或不联合螺内酯用于射血分数保留的心力衰竭研究]；临床试验注册号：NCT05676684）。
