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Inconclusive results for dapagliflozin treatment in heart failure

Presented by
Prof. John McMurray, University of Glasgow, UK
HFA 2021
Two trials on the efficacy of dapagliflozin in heart failure patients with preserved (HFpEF) and reduced (HFrEF) left ventricular function showed only partially significant results. Symptom improvement, for example, was found in HFrEF but not in HFpEF.

“In patients with HFrEF, SGLT2 inhibitors have been shown to improve symptoms, to reduce HF hospitalisations, and even to improve survival, but we don’t know their effect on walking distance,” said Prof. John McMurray (University of Glasgow, UK) [1]. Prof. McMurray presented the results of the DETERMINE trials, which investigated the effect of dapagliflozin on symptoms and exercise capacity in HF patients.

DETERMINE-Reduced (D-R; NCT03877237) enrolled 313 patients with HFrEF and DETERMINE-Preserved (D-P; NCT03877237) 504 patients with HFpEF. All patients had to be on stable treatment, demonstrated an initial performance of ≥100 metres and ≤425 metres in 6-minute walking distance (6MWD) testing, and also had an estimated glomerular filtration rate of ≥25 mL/min/1.73m2. The participants differed in left ventricular ejection fraction (≤40% in D-R and >40% in D-P) and the trials used different inclusion cut-offs for N-terminal pro B-type natriuretic peptide (NT-proBNP; ≥400 pg/mL in D-R and ≥250 pg/mL in D-P). In both trials, patients were randomised 1:1 to receive a daily dose of 10 mg dapagliflozin or placebo over 16 weeks. The primary endpoint consisted of 3 components: reduction in patient-reported HF symptoms, reduction in patient-reported physical limitations, and improvement of walking distance.

In D-R, the baseline characteristics in the dapagliflozin and the placebo arm were balanced. The mean age was 68.4 and 67.3 years, 71.2% and 77.7% were men, and 83.3% and 79.6% were in NYHA class II, respectively. Baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)-total symptom scores (TSS) were 79.2 in the dapagliflozin versus 80.2 in the placebo arm with correspondent values of 70.8 versus 75.0 in the KCCQ-physical limitation score (PLS) and 327.5 versus 344.0 metres in 6MWD. The results showed an average significant mean difference of 4.23 points in TSS (P=0.022) between dapagliflozin and placebo. Also, more patients reported a moderate or large improvement of ≥15 points in TSS, translating into a significant odds ratio (OR) of 1.6 (95% CI 1.0–2.7). The results in PLS (OR 1.6; 95% CI 0.9–2.6) and 6MWD (OR 1.1; 95% CI 0.7–1.8) failed to demonstrate a significant disparity between the study groups.

In the D-P trial, the overall mean patient age was 72 years, 63.5% were men, over 40% suffered from type 2 diabetes, and over 80% were NYHA class II. Median scores for TSS were between 77.1 and 78.1 and for PLS between 70.8 and 75.0. Median 6MWD was 320 metres. Interestingly, the assessment of possible treatment effects revealed no significantly different results in TSS, PLS, and 6MWD in the dapagliflozin versus the placebo arm.

Of note, the evaluation of exploratory outcomes in both trials showed a clear reduction in NT-proBNP with nominal P-values of 0.013 in D-R and 0.024 in D-P in favour of dapagliflozin therapy.

“At the moment, the therapeutic role of SGLT inhibition in HEpEF remains uncertain, although we are going to hear the results of a large trial in the next few weeks,” Prof. McMurray added.

    1. McMurray JJV. Effect of dapagliflozin vs placebo on symptoms and six-minute walk distance in patients with heart failure. LBT 3, Heart Failure and World Congress on Acute Heart Failure 2021, 29 June–1 July.


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