Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure - DETERMINE-Reduced/Preserved

Jan 02, 2024
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Author/Summarized by Author:
Amit Saha, MD
Summary Reviewer:
Anthony A. Bavry, MD, MPH, FACC
Trial Sponsor:
AstraZeneca
Date Published:
12/07/2023
Original Posted Date:
01/02/2024
References

Contribution To Literature:

The DETERMINE trials showed that dapagliflozin was associated with some improvement in self-reported symptoms in patients with HFrEF but not HFpEF and did not affect 6-minute walk distance in either HF subtype.

Description:

The goal of these trials was to assess the effect of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on symptom burden and functional capacity in patients with heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively).

Study Design

  • International
  • Randomized
  • Placebo-controlled

DETERMINE-Reduced and DETERMINE-Preserved were two simultaneously conducted trials of patients with HFrEF and HFpEF, respectively. Patients with symptomatic HF were randomized in either trial to receive once-daily dapagliflozin 10 mg daily (DETERMINE-Reduced: n = 156, -Preserved: n = 253) or placebo (DETERMINE-Reduced: n = 157, -Preserved: n = 251). Randomization was stratified by type 2 diabetes status. Symptoms and functional capacity were assessed and compared at baseline and follow-up using 6-minute walk distance (6MWD) and the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Physical Limitations Scale (KCCQ-PLS).

  • Duration of follow-up: 16 weeks

General inclusion criteria:

  • New York Heart Association (NYHA) functional class II-IV HF symptoms for ≥8 weeks
  • Baseline 6MWD ≥100 and ≤425 m
  • Stable doses of guideline-recommended medical therapy for HF and relevant comorbidities ≥4 weeks

Exclusion criteria:

  • Inability to perform exercise testing
  • Structured exercise training ≤1 month prior
  • SGLT2 inhibitor therapy ≤4 weeks prior
  • HF hospitalization ≤4 weeks prior
  • Myocardial infarction, unstable angina, or stroke ≤12 weeks prior
  • Estimated glomerular filtration rate (eGFR) <25 mL/min/1.73 m2

DETERMINE-Reduced:

  • Total number of enrollees: 313
  • Mean patient age: 69 years
  • Percentage female: 26%
  • Left ventricular ejection fraction (LVEF): ≤40%

DETERMINE-Preserved:

  • Total number of enrollees: 504
  • Mean patient age: 73 years
  • Percentage female: 37%
  • LVEF: >40%

Other salient features/characteristics, for DETERMINE-Reduced vs. -Preserved:

  • Median LVEF: 30% vs. 52%
  • Median N-terminal pro–B-type natriuretic peptide (NT-proBNP): 1,292 vs. 776 pg/mL
  • Percentage with diabetes: 46% vs. 44%
  • Percentage with NYHA class II symptoms: 81% vs. 84%
  • Median baseline KCCQ-TSS: 79.2-80.2 vs. 77.1-78.1
  • Median baseline KCCQ-PLS: 70.8-75.0 vs. 70.8-75.0
  • Median baseline 6MWD: 328-344 vs. 320-323 m

Principal Findings:

Co-primary outcome 1, median difference in KCCQ-TSS, for dapagliflozin vs. placebo:

  • Reduced: +4.2 (95% confidence interval [CI] 1.0, 8.2), p = 0.022*
  • Preserved: +3.16 (95% CI 0.36, 6.01), p = 0.079

Co-primary outcome 2, median difference in KCCQ-PLS, for dapagliflozin vs. placebo:

  • Reduced: +4.2 (95% CI 0.03, 8.33), p = 0.058
  • Preserved: +3.12 (95% CI -0.09, 5.37), p = 0.232

Co-primary outcome 3, median difference in 6MWD, for dapagliflozin vs. placebo:

  • Reduced: +3.2 m (95% CI -6.5, 13.0), p = 0.686
  • Preserved: +1.6 m (95% CI -5.9, 9.0), p = 0.668

*Statistically significant using a weighted Bonferroni distribution of a two-sided α = 0.05 across the three co-primary outcomes: KCCQ-TSS α = 0.04990, KCCQ-PLS α = 0.00005, 6MWD α = 0.00005

Post hoc pooled analysis of the co-primary outcomes in all HF for dapagliflozin vs. placebo:

  • Median difference in KCCQ-TSS: +3.7 (95% CI 1.5, 5.9), p = 0.005
  • Median difference in KCCQ-PLS: +4.0 (95% CI 0.3, 4.9), p = 0.036
  • Median difference in 6MWD: +2.5 m (95% CI -3.5, 8.4), p = 0.499

Secondary and exploratory outcomes for dapagliflozin vs. placebo:

  • Median change in time spent sedentary: Reduced, -0.19 vs. -0.15 hours/day; Preserved, -0.06 vs. -0.07 hours/day
  • Median difference in NT-proBNP: Reduced, -186 pg/mL; Preserved, -88 pg/mL

Adverse event leading to discontinuation of study drug, dapagliflozin vs. placebo:

  • Reduced: 5.8% vs. 7.6%
  • Preserved: 3.6% vs. 2.4%

Interpretation:

In the current data, dapagliflozin was associated with modest but statistically significant improvement in KCCQ-TLS in HFrEF at 16 weeks. Secondary analyses of DAPA-HF, EMPEROR-Reduced, and EMPERIAL-Reduced trials have similarly suggested potential improvement in KCCQ-TSS with both empagliflozin and dapagliflozin as early as 12 weeks. In DETERMINE-Preserved, however, the median difference in KCCQ-TSS was not significant despite being numerically similar to changes observed in analyses of DELIVER, EMPEROR-Preserved, and PRESERVED-HF trials.

No difference was observed in KCCQ-PLS, which assesses limitations in activities of daily living, or 6MWD compared with placebo in either DETERMINE-Reduced or -Preserved. Change in objective functional assessment using 6MWD was similar compared with placebo in both HFrEF and HFpEF, as was previously observed in the EMPERIAL trials with empagliflozin. These results differ from the PRESERVED-HF trial data, though this HFpEF population had much lower baseline functional capacity (median baseline 6MWD 244 vs. 320 m) and therefore may have had greater room for improvement. The authors do suggest that the limited data for 6MWD with even long-proven HFrEF therapies may point to an intrinsic weakness in this metric for meaningfully assessing functional capacity in HF.

Pooled analysis of both trials suggested similar numeric improvement in both symptom scores across the EF spectrum, but these findings remain exploratory. The current data provide further support for some improvement in HFrEF symptoms associated with SGLT2 inhibitors, although the evidence remains mixed for HFpEF. Future meta-analyses incorporating DETERMINE and preceding trials may be able to provide further insight.

References:

McMurray JJ, Docherty KF, de Boer RA, 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:[Epub ahead of print].

Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Acute Heart Failure, Exercise

Keywords: Exercise, Heart Failure, Sodium-Glucose Transporter 2 Inhibitors


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