Effect of SGLT2i on symptoms and functional capacity in patients with heart failure

13/02/2024

In the DETERMINE program, dapagliflozin improved KCCQ-Total Symptom Score in patients with HFrEF compared with placebo, but not in patients with HFpEF. Dapagliflozin had no effect on 6-minute walk distance.

This summary is based on the publication of McMurray JJV, Docherty KFM, de Boer R, et al. - Effect of Dapagliflozin Versus Placebo on Symptoms and 6-Minute Walk Distance in Patients With Heart Failure: The DETERMINE Randomized Clinical Trials. Circulation 2023 Dec 7. doi: 10.1161/CIRCULATIONAHA.123.065061

Introduction and methods

Background

SGLT2 inhibitors reduce the risk of worsening HF and CV mortality in patients with HF across the full spectrum of LVEF [1-4]. SGLT2 inhibitors improve self-reported symptoms in patients with HF as measured with the KCCQ-score, but it remains unclear how SGLT2 inhibitors affect objective measures of functional capacity due to inconsistent data [3-10].

Aim of the study

The aim of this study was to evaluate the effects of the SGLT2 inhibitor dapagliflozin on symptoms and functional capacity in patients with HFrEF and HFpEF.

Methods

The DETERMINE (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure) program consisted of two different randomized, double-blind, placebo-controlled, phase 3-trials, which were DETERMINE-Reduced (n=313) and DETERMINE-Preserved (n=504). These trials evaluated the effects of treatment with dapagliflozin 10 mg once daily vs. placebo on top of standard of care on symptoms and functional capacity in patients with HFrEF and HFpEF, respectively. Inclusion criteria for DETRMINE-Reduced were: LVEF ≤40% and NT-proBNP ≥400 pg/mL (or ≥300 pg/mL if hospitalized for HF within the previous 12 months or ≥800 pg/mL if AF was present). Inclusion criteria for DETERMINE-Preserved were: LVEF >40% and NT-proBNP ≥250 pg/mL (or 500 pg/mL if AF was present). To asses symptoms and functional capacity, the Total Symptom Score (TSS) and Physical Limitation Scale (PLS) of the KCCQ-score and 6-minute walk distance (6MWD) were performed.

Outcomes

The primary outcomes were changes in the KCCQ-TTS, KCCQ-PLS, and 6MWD from baseline to 16 weeks.

Main results

DETERMINE-Reduced

  • In patients with HFrEF, KCCQ-TTS from baseline to 16 weeks improved in the dapagliflozin group compared with the placebo group (Hodges-Lehmann [HL] estimate of median difference between groups of 4.2; 95%CI: 1.0 to 8.2; P=0.022).
  • There was no difference in KCCQ-PLS and 6MWD between groups in patients with HFrEF (HL estimate of median difference of 4.2; 95%CI: 0.03 to 8.33; P=0.058; and 3.2; 95%CI: -6.5 to 13.0; P=0.686, respectively).

DETERMINE-Preserved

  • There was no difference in KCCQ-TTS, KCCQ-PLS, and 6MWD from baseline to 16 weeks between treatment groups in patients with HFpEF (HL estimate of median difference in KCCQ-PLS: 3.16; 95%CI: 0.36 to 6.01; P=0.079; in KCCQ-PLS: 3.12; 95%CI: -0.9 to 5.35; P=0.232; and in 6MWD: 1.6 meters; 95%CI: -5.9 to 9.0; P=0.668).

DETERMINE-Pooled

  • In an exploratory post hoc analysis including all patients of the DETERMINE program, treatment with dapagliflozin compared with placebo improved KCCQ-TSS and KCCQ-PLS from baseline to 16 weeks (HL estimate of median difference of 3.7; 95%CI: 1.5 to 5.9; P=0.005; and 4.0; 95%CI: 0.3 to 4.9; P=0.036, respectively).
  • There was no difference in 6MWD from baseline to 16 weeks between treatment groups (HL estimate of median difference of 2.15 meters; 95%CI: -3.5 to 8.4; P=0.499).

Conclusion

Dapagliflozin improved KCCQ-TSS, but not KCCQ-PLS and 6MWD, in patients with HFrEF compared with placebo. In patients with HFpEF, treatment with dapagliflozin had no effect on KCCQ-TTS, KCCQ-PLS, and 6MWD compared with placebo.

References

1. Anker SD, Butler J, Filippatos G, et al. Baseline characteristics of patients with heart failure with preserved ejection fraction in the EMPEROR-Preserved trial. Eur J Heart Fail. 2020;22:2383–2392.

2. Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387:1089–1098.

3. Jhund PS, Kondo T, Butt JH, et al. Dapagliflozin across the range of ejection fraction in patients with heart failure: a patient-level, pooled meta-analysis of DAPA-HF and DELIVER. Nat Med. 2022;28:1956–1964.

4. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. Lancet. 2022;400:757–767.

5. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381:1995–2008.

6. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. 2020;383:1413–1424.

7. Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation. 2019;140:1463–1476.

8. Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J. 2021;42:700–710.

9. Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27:1954–1960.

10. Spertus JA, Birmingham MC, Nassif M, et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med. 2022;28:809–813.

Find this article online at Circulation

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