The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial

Abstract

Patients with heart failure and preserved ejection fraction (HFpEF) have a high burden of symptoms and functional limitations, and have a poor quality of life. By targeting cardiometabolic abmormalities, sodium glucose cotransporter 2 (SGLT2) inhibitors may improve these impairments. In this multicenter, randomized trial of patients with HFpEF (NCT03030235), we evaluated whether the SGLT2 inhibitor dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CS), a measure of heart failure-related health status, at 12 weeks after treatment initiation. Secondary endpoints included the 6-minute walk test (6MWT), KCCQ Overall Summary Score (KCCQ-OS), clinically meaningful changes in KCCQ-CS and -OS, and changes in weight, natriuretic peptides, glycated hemoglobin and systolic blood pressure. In total, 324 patients were randomized to dapagliflozin or placebo. Dapagliflozin improved KCCQ-CS (effect size, 5.8 points (95% confidence interval (CI) 2.3–9.2, P = 0.001), meeting the predefined primary endpoint, due to improvements in both KCCQ total symptom score (KCCQ-TS) (5.8 points (95% CI 2.0–9.6, P = 0.003)) and physical limitations scores (5.3 points (95% CI 0.7–10.0, P = 0.026)). Dapagliflozin also improved 6MWT (mean effect size of 20.1 m (95% CI 5.6–34.7, P = 0.007)), KCCQ-OS (4.5 points (95% CI 1.1–7.8, P = 0.009)), proportion of participants with 5-point or greater improvements in KCCQ-OS (odds ratio (OR) = 1.73 (95% CI 1.05–2.85, P = 0.03)) and reduced weight (mean effect size, 0.72 kg (95% CI 0.01–1.42, P = 0.046)). There were no significant differences in other secondary endpoints. Adverse events were similar between dapagliflozin and placebo (44 (27.2%) versus 38 (23.5%) patients, respectively). These results indicate that 12 weeks of dapagliflozin treatment significantly improved patient-reported symptoms, physical limitations and exercise function and was well tolerated in chronic HFpEF.

Empagliflozin, Health Status, and Quality of Life in Patients With Heart Failure and Preserved Ejection Fraction: The EMPEROR-Preserved Trial

“… 15 The EMPERIAL-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) did not show a significant effect of empagliflozin on KCCQ-TSS in a 12-week trial in ≈300 mildly symptomatic patients with HFpEF. 17 In contrast, the PRESERVED-HF trial (Dapagliflozin in Preserved Ejection Fraction Heart Failure) showed a significant improvement in the KCCQ-CSS with dapagliflozin in patients with HFpEF 16 ; the trial enrolled patients with obesity in the United States with >40% having New York Heart Association class III to IV symptoms.…”

Direct cardiac effects of SGLT2 inhibitors

“…This obviously deviates from chronic treatments in large clinical trials, and it is therefore not known to which degree the direct and acute cardiac effects described in this review persist in the chronic condition. However, recently studies have reported that SGLT2i also improve outcome in the acute phase of heart failure in patients [ 86 ] and EMPA-Response trial [ 87 ], suggesting that also clinically SGLT2i have acute beneficial effects.…”

The Role of Systemic Microvascular Dysfunction in Heart Failure with Preserved Ejection Fraction

“…The following supporting information can be downloaded at: , Table S1: Techniques and stimuli used in clinical research to assess microvascular function in HFpEF; Table S2: Studies on peripheral microvascular function in HFpEF; Table S3: Studies on coronary microvascular function in HFpEF; Table S4: Intervention studies in HFpEF targeting the nitric oxide—protein kinase G pathway. References [ 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 , 202 ] are cited in the supplementary materials…”