CV benefits of dapagliflozin evident regardless of baseline kidney function

The cardiovascular (CV) benefit of dapagliflozin in patients with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF) is evident regardless of baseline kidney function, according to an analysis of the DELIVER* trial presented at Kidney Week 2022.

“[D]apagliflozin reduced the risk of the composite of CV death or worsening HF regardless of baseline kidney function,” said the authors. “[A] greater absolute risk reduction [was observed] in those with lower estimated glomerular filtration rate (eGFR),” they added.

The 6,262 patients aged ≥40 years (mean age 72 years, 56 percent male, 71 percent White) enrolled in the international DELIVER trial had HF with left ventricular EF >40 percent, elevated NT-proBNP** levels, structural heart disease in the previous year, and eGFR ≥25 mL/min/1.73 m² (mean 61 mL/min/1.73 m²). They were randomized 1:1 to receive dapagliflozin (10 mg QD) or placebo. Forty-nine percent of patients had eGFR <60 mL/min/1.73 m².

Previously published results showed that dapagliflozin reduced the risk of CV death or worsening HF compared with placebo (hazard ratio [HR], 0.82, 95 percent confidence interval [CI], 0.73–0.92; p<0.001). [N Engl J Med 2022;387:1089-1098]

The present prespecified analysis showed that this benefit of dapagliflozin was consistent regardless of baseline eGFR (HR, 0.84, 95 percent CI, 0.70–1.00 [eGFR ≥60 mL/min/1.73 m²]; HR, 0.68, 95 percent CI, 0.54–0.87 [eGFR 45 to <60 mL/min/1.73 m²]; HR, 0.93, 95 percent CI, 0.76–1.14 [eGFR <45 mL/min/1.73 m²]; p_interaction=0.16). [Kidney Week 2022, abstract TH-PO992; JAMA Cardiol;doi:10.1001/jamacardio.2022.4210]

At a median 2.3 years, the rate of the post hoc kidney composite outcome of first ≥50-percent decline in eGFR from baseline, first eGFR <15 mL/min/1.73 m², end-stage kidney disease (ESKD), or death from kidney causes was low (1.1 events per 100 patient-years) and occurred at a comparable rate between those in the dapagliflozin and placebo groups (2.5 percent vs 2.3 percent; HR, 1.08, 95 percent CI, 0.79–1.49). This effect was also consistent regardless of baseline eGFR (HRs, 1.06, 0.80, and 1.46 for eGFR ≥60, 45 to <60, and <45 mL/min/1.73 m², respectively; p_interaction=0.34) and baseline diabetes status (HRs, 1.09 and 1.07 for patients with and without diabetes, respectively; p_interaction=0.93).

The overall rate of eGFR decline from baseline was significantly reduced with dapagliflozin compared with placebo (difference, 0.5, 95 percent CI, 0.1–0.9 mL/min/1.73 m²/year; p=0.01). A significant slowing of eGFR decline with dapagliflozin vs placebo was also noted at 1–36 months (difference, 1.4, 95 percent CI, 1.0–1.8 mL/min/1.73 m²/year; p<0.001).

The attenuation of effects with dapagliflozin over placebo between month 1 and trial end was more evident in those with vs without diabetes (difference 2 vs 1 mL/min/1.73 m²/year).

“Overall, serious adverse events (AEs) and AEs that led to discontinuation of dapagliflozin or placebo were more commonly reported among those in lower categories of baseline eGFR,” the authors said.

In patients with eGFR ≥60 mL/min/1.73 m², the risk of AEs leading to treatment interruption was lower among patients on dapagliflozin than placebo (p=0.03). In those with eGFR 45 to <60 mL/min/1.73 m², serious AEs and AEs leading to treatment interruption were less common in the dapagliflozin than placebo group (p=0.01 and 0.04, respectively).

“[All in all,] results of this prespecified analysis showed that baseline kidney function did not modify the benefit of dapagliflozin in patients with HFmrEF/HFpEF. Dapagliflozin did not significantly reduce the frequency of the kidney composite outcome, although the overall event rate was low,” the authors noted.

“Following the initial expected acute decline in eGFR, dapagliflozin slowed the longer-term decline in eGFR, compared with placebo, with more pronounced effects among patients with baseline diabetes vs those without,” they concluded.