Growth Differentiation Factor-15 and the Effect of Dapagliflozin in Heart Failure: Insights From the DAPA-HF Trial

BACKGROUND: Growth differentiation factor (GDF)-15, a stress-induced cytokine implicated in systemic energy homeostasis, is associated with adverse outcomes in heart failure (HF). This study evaluated the associations between baseline GDF-15 and the clinical characteristics and outcomes in patients with HF with reduced ejection fraction in the DAPA-HF (Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure) trial. The effect of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on circulating GDF-15 levels and the effect of dapagliflozin on clinical outcomes in relation to baseline GDF-15 concentrations were also examined. METHODS AND RESULTS: DAPA-HF was a randomized trial of dapagliflozin in patients with HF and LVEF ≤ 40%. GDF-15 was measured at baseline and 12 months. The primary outcome was the composite of worsening HF or cardiovascular death. The median baseline GDF-15 level was 1888 (IQR: 1323-2755) pg/mL. Higher GDF-15 levels were associated with older age, lower body mass index, and greater HF symptom burden. There was a stepwise increase in adjusted risk for the primary outcome across quartiles of baseline GDF-15 (adjusted hazard ratio [Q4 vs Q1] 2.30, 95% CI 1.66-18; P trend < 0.001). Dapagliflozin did not significantly change GDF-15 concentrations over 12 months, compared to placebo (placebo-corrected relative change +4%; 95% CI, -2% to +10%). The relative effect of dapagliflozin on the primary outcome was consistent across GDF-15 quartiles (P interaction = 0.96), with a greater absolute benefit in those with higher GDF-15 (P trend < 0.01). CONCLUSIONS: In DAPA-HF, GDF-15 was independently prognostic of worsening HF or cardiovascular death. Absolute risk reduction with dapagliflozin was greater in patients with higher baseline GDF-15, but the benefit was not associated with an effect on GDF-15 itself.