Effect of SGLT2i on NT-proBNP levels and health status in HFrEF
Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction - The DEFINE-HF Trial
Introduction and methods
Guidelines and regulators recognize that improving symptoms in HFrEF patients is a key goal in management and is associated with lower risk of HF hospitalization [1,2]. Moreover, measures of symptoms and physical function are endorsed as acceptable and important by the FDA’s draft guidance to industry on drug development in HF . Trials investigating the effect of SGLT2i in a HF population are currently ongoing or results have just been released, but primary outcomes do not include early effects on HF disease-specific health status, function and quality of life or levels of natriuretic peptides.
The DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) trial examined whether treatment with the SGLT-2 inhibitor dapagliflozin improves natriuretic peptides and health status in well-phenotyped and optimally treated HFrEF patients, both with and without T2DM. DEFINE-HF was a randomized, double-blind, placebo controlled, multi-center trial that enrolled 263 patients with HFrEF to receive dapagliflozin or placebo in addition to guideline directed standard of care therapy for 12 weeks. Dual primary end points were the average of 6- and 12-week NT-proBNP and a composite of the proportion of patients that achieved a meaningful improvement in health status (≥5-point increase in average of 6- and 12-week Kansas City Cardiomyopathy Questionnaire- overall summary score [KCCQ-OS]) or NT-proBNP (≥20% decrease in average of 6- and 12-week NT-proBNP). 62% of patients had T2DM.
- The co-primary endpoint of average 6 and 12 week NT-proBNP was not different between those treated with dapagliflozin and placebo (1133 pg/dL, 95%CI: 1036–1238 vs 1191 pg/dL, 95%CI: 1089–1304, OR 0.95, 95%CI: 0.84–1.08).
- The other co-primary endpoint of proportion of patients with a meaningful improvement of ≥5 points in KCCQ-OS or ≥20% decrease in NT-proBNP was greater in the dapagliflozin group than the placebo group (61.5% vs 50.4%, OR: 1.8, 95%CI: 1.03–3.06, nominal P=0.039).
- Results were consistent for groups with and without T2DM.
- ≥5 point improvement in KCCQ-OS at 6 weeks was 47% in the dapagliflozin group vs 36% in the placebo group (OR 1.8, 95% CI: 1.04–3.12, P=0.03), and at 12 weeks 43% vs 33% (OR 1.7, 95% CI:0.98–3.1, P=0.06).
- There was no difference in the proportion of patients with ≥20% decrease in NT-proBNP at 6 weeks between those who took dapagliflozin or placebo, but at 12 weeks a greater proportion of patients with dapagliflozine had a ≥20% decrease in NT-proBNP (44.0 vs 29.4%; OR: 1.9, 95% CI: 1.1–3.3, P=0.02).
- There was no difference in 6-minute walk distance between the dapagliflozin group and the placebo group.
In HFrEF patients treated with dapagliflozin for 12 weeks, mean NT-proBNP was not reduced compared to those treated with placebo. However, proportion of patients who experienced improvement in health status or NT-proBNP was increased in the dapagliflozin group compared to the placebo group. Results were similar for non-diabetes and diabetes patients.