Do Patients with Heart Failure Feel Better on Dapagliflozin?

This is a summarized version of the full in-depth article on Relias Media.

By Michael H. Crawford, MD. Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco.

Background

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, originally developed for diabetes management, have shown significant benefits in heart failure (HF) patients. Several large clinical trials have demonstrated that SGLT2 inhibitors reduce hospitalizations for heart failure and cardiovascular mortality in both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Additionally, improvements in patient symptoms have been observed, as measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ). However, objective improvements in physical function, such as exercise capacity, have been inconsistent across studies.

The DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test (6-WT) in Patients with Heart Failure) were designed to further explore the effects of dapagliflozin on both symptoms and physical function in HF patients with either reduced or preserved left ventricular ejection fraction (LVEF).

Study Design

The DETERMINE trials were two international, multicenter, double-blind, randomized, Phase III trials:

• DETERMINE-r: Focused on patients with HFrEF (LVEF ≤ 40%).

• DETERMINE-p: Targeted patients with HFpEF (LVEF > 40%).

Key Inclusion Criteria:

• Patients in DETERMINE-r had elevated N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels (> 400 pg/mL) and were required to have a baseline 6-WT distance between 100 m and 425 m.

• In DETERMINE-p, patients had structural heart disease (left ventricular hypertrophy or left atrial enlargement) and NT-proBNP levels ≥ 250 pg/mL.

Both trials excluded patients with low systolic blood pressure (< 90 mmHg), impaired renal function (estimated glomerular filtration rate < 25 mL/min/1.73 m²), type 1 diabetes, or those unable to undergo exercise testing.

Study Interventions:

• Participants were randomized to receive either dapagliflozin (10 mg/day) or placebo, in addition to guideline-directed medical therapy (GDMT), over 16 weeks.

Outcomes and Measurements

The primary endpoints combined assessments from three domains:

1. Distance covered during the 6-WT.

1. Scores from the KCCQ total symptom score (TSS).

1. The KCCQ physical limitations scale (PLS).

Secondary endpoints included an evaluation of vigorous physical activity using a wearable activity monitor (WAM) in a subset of 100 patients. Safety endpoints tracked serious adverse events and discontinuation of study drugs.

Key Findings

• HFrEF Patients:
  • In patients with HFrEF, dapagliflozin improved self-reported symptoms (mean difference in TSS of 4.2 points compared to placebo; P = 0.02). However, improvements in the other primary outcomes were not statistically significant.
  • The mean difference in the PLS was 4.2 (P = 0.06), suggesting a borderline improvement in physical limitations, while there was no significant change in the 6-WT (mean difference of 3.2 m, P = 0.7).
  • Physical activity measured by the WAM did not significantly differ between the dapagliflozin and placebo groups, although less than half of the WAM participants wore the monitor for sufficient time to assess data.

• HFpEF Patients:
  • In HFpEF patients, none of the primary outcomes (TSS, PLS, or 6-WT) showed statistically significant differences between the dapagliflozin and placebo groups.
  • Similarly, the secondary endpoint of physical activity from WAM data showed no significant improvements in this group.

• Safety:
  • Serious adverse events were relatively uncommon and did not differ significantly between the dapagliflozin and placebo groups in either HFrEF (12% vs. 15%) or HFpEF (10% vs. 8%) patients.

Commentary on the Results

While the DETERMINE trials reinforced the positive impact of dapagliflozin on self-reported symptoms in patients with HFrEF, they did not demonstrate improvements in exercise capacity as measured by the 6-WT. This inconsistency in objective physical performance aligns with prior studies of SGLT2 inhibitors and other heart failure therapies, such as sacubitril/valsartan. Notably, the only treatments that have consistently improved 6-WT performance in heart failure patients are intravenous iron and cardiac resynchronization therapy.

The authors noted several limitations of the DETERMINE trials:

• The baseline activity level of participants was higher than in previous heart failure studies, making it more difficult to detect improvements in physical function.

• COVID-19 restrictions affected the ability to gather comprehensive WAM data, underpowering the analysis of this secondary outcome.

• In the HFpEF cohort, the high use of beta-blockers may have limited the participants' exercise heart rate and physical performance capacity.

Despite these limitations, the DETERMINE trials highlight the role of dapagliflozin as part of a comprehensive heart failure treatment regimen. SGLT2 inhibitors should be considered in addition to, rather than as alternatives to, GDMT in managing heart failure.

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