SGLT2i improves CV outcomes in patients with HFmrEF or HFpEF regardless of kidney function
Dapagliflozin and Kidney Outcomes in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the DELIVER Randomized Clinical Trial
Introduction and methods
CKD affects approximately 50% of patients with HFmrEF or HFpEF . The presence of CKD increases the risk of CV death and hospitalization . Recently, it was demonstrated that SGLT2i treatment with empagliflozin slowed the rate of kidney function decline in patients with HFmrEF and HFpEF . The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial previously reported that the SGLT2i dapagliflozin reduced the risk of CV death or worsening HF events among patients with HFmrEF or HFpEF .
Aim of the study
The current prespecified analysis of the DELIVER trail evaluated whether the effects of dapagliflozin vary according to baseline kidney function, and whether dapagliflozin reduces the rate of estimated glomerular filtration rate (eGFR) decline and kidney outcomes.
The DELIVER trail was an international, prospective, randomized, double-blind, placebo-controlled trial with 6263 patients with symptomatic HFmrEF/HFpEF (NYHA class II–IV HF symptoms, LVEF >40%, elevated NT-proBNP levels). Patients were randomly assigned to receive dapagliflozin at a dose of 10 mg once daily (3131 patients) or placebo (3132 patients). For the current analysis, data from 6262 patients with mean eGFR measurements were available.
The primary outcome was CV death or worsening of HF. Prespecified analyses included assessment whether baseline kidney function (eGFR of <45mL/min/1.73m², ≥45 to <60mL/min/1.73m², ≥60mL/min/1.73m² and eGFR as a continuous variable) modified the effect of dapagliflozin on the primary outcome. Prespecified exploratory outcomes were a change in eGFR and a post hoc composite kidney outcome (≥ 50% decline in eGFR from baseline; first eGFR <15 mL/min/1.73 m²; end-stage kidney disease; death from kidney causes). Safety outcomes were serious adverse events and adverse events that led to discontinuation of treatment.
- Dapagliflozin reduced the risk of CV death or worsening of HR regardless of baseline kidney function (HR: 0.84; 95% CI: 0.70-1.00 for eGFR ≥60 mL/min/1.73m²; HR: 0.68; 95% CI: 0.54-0.87 for eGFR 45-<60mL/min/1.73 m²; HR: 0.93; 95% CI: 0.76-1.14 for eGFR <45 mL/ min/1.73m²; P for interaction=0.16). Comparable results were obtained when eGFR was analyzed as a continuous variable (P for interaction=0.45).
- In the patients treated with dapagliflozin an initial acute decline in eGFR was detected after 1 month of treatment (−3.7; 95% CI: −4.0 to −3.3 mL/min/1.73 m²). The eGFR rate stayed consistent from month 1 to month 36 in patients treated with dapagliflozin (0; 95% CI: −0.2 to 0.3 mL/min/1.73 m² per year). In contrast, in patients treated with placebo there was a small decline in eGFR rate from baseline to month 1 (−0.4; 95% CI: −0.8 to 0 mL/min/1.73 m²). The eGFR continued to decline from month 1 through month 36 in patients treated with placebo (−1.4; 95% CI: −1.7 to −1.1 mL/min/1.73 m² per year).
- The mean decline in total slope of eGFR (from baseline to month 36) and in the chronic slope (from month 1 to month 36) was lower in patients treated with dapagliflozin compared to patients treated with placebo (difference 0.5; 95% CI: 0.1-0.9 mL/min/1.73 m² per year; P=0.01 for total slope and difference 1.4; 95% CI: 1.0-1.8 mL/min/1.73 m² per year; P=0.001 for chronic slope).
- The effects of dapagliflozin on the decline in the chronic slope of eGFR were more apparent in patients with diabetes compared to patients without diabetes (difference of 2 mL/min/1.73 m² per year in diabetic patients vs. 1 mL/min/1.73 m² per year in non-diabetic patients).
- The incidence rate of the post hoc kidney composite outcomes was low in both treatment groups over a median follow-up period of 2.3 (1.7-2.8) years and did not differ between groups (79 patients (2.5%) in the dapagliflozin group and 73 patients (2.3%) in the placebo group; HR: 1.08; 95% CI: 0.79-1.49).
- There was no treatment effect on the composite kidney end point according to baseline kidney function (HR: 1.06; 95% CI: 0.66-1.70 for eGFR ≥60 mL/min/1.73 m²; HR: 0.80; 95% CI: 0.41-1.57 for eGFR 45- <60 mL/min/1.73 m²; HR: 1.46; 95% CI: 0.83-2.56 for eGFR <45 mL/min/1.73 m²; P for interaction=0.34).
- The incidence of serious adverse events was mostly comparable between the dapagliflozin group and the placebo group across the different category groups of baseline eGFR. However, there were a few exceptions. In patients with baseline eGFR of ≥60 mL/min/1.73m2, the incidence of adverse events that led to discontinuation of treatment was lower in the dapagliflozin group compared to the placebo group (183 patients (11%) vs. 219 patients (14%); P=0.03). In patients with baseline eGFR of 45-<60mL/ min/1.73 m2, the incidence of serious adverse events (338 patients (41%) vs. 389 patients (47%), P=0.01) and adverse events that led to discontinuation of treatment (115 patients (14%) vs. 146 patients (18%); P=0.04) was lower in the dapagliflozin group compared to the placebo group.
This prespecified analysis of the DELIVER trial demonstrated that dapagliflozin reduced the risk of CV death or worsening of HF in patients with HFmrEF or HFpEF regardless of baseline kidney function. The incidence of the kidney composite outcome was low in the dapagliflozin group and in the placebo group, and dapagliflozin did not further reduce this incidence. Dapagliflozin slowed the long-term rate of decline in eGFR compared to placebo. SGLT2i treatment with dapagliflozin has beneficial effects on both cardiovascular outcomes as well as kidney function in patients with HFmrEF or HFpEF.
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