DEFINE-HF: Dapagliflozin Improves Function and QoL, but Not Biomarkers, in HFrEF

PHILADELPHIA, PA—Dapagliflozin added to optimal medical therapy results in meaningful improvements in symptoms and health-related quality of life in heart failure patients with reduced ejection fraction (HFrEF), results of the DEFINE-HF trial show. However, the sodium glucose co-transporter-2 (SGLT2) inhibitor did not reduce levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) compared with placebo.

The DEFINE-HF trial, presented here today at the Heart Failure Society of America annual meeting and simultaneously published in Circulation, follows closely on the heels of DAPA-HF, which was presented 2 weeks ago at the European Society of Cardiology Congress 2019. In that trial, dapagliflozin resulted in a 26% reduction in worsening heart failure or death from cardiovascular causes, a 30% reduction in worsening heart failure events, and an 18% reduction in death from both cardiovascular and all-cause deaths in patients with HFrEF. Both trials suggest that dapagliflozin benefits HFrEF patients with and without diabetes.

“Collectively, we believe these results support the use of dapagliflozin as a new treatment option in patients with HFrEF regardless of their diabetes status, and we believe this will result in important implications for guidelines and clinical practice,” said Mikhail Kosiborod, MD (Saint Luke’s Mid America Heart Institute, Kansas City, MO), presenting the DEFINE-HF results here.

“The findings from DEFINE-HF are wholly in line with the larger HF outcomes trial of dapagliflozin, DAPA-HF,” co-author Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), added in an email to TCTMD. “It will be very interesting to see the NT-proBNP results from DAPA-HF to see if there were differences over a longer period of time and if any associations between achieved NT-proBNP levels and hard clinical outcomes were observed.”

Clinically Meaningful Improvements

The multicenter DEFINE-HF trial randomized 263 patients with left ventricular ejection fraction ≤ 40%, NYHA class II to III, estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73m² , and elevated natriuretic peptides to receive either 10 mg of dapagliflozin or placebo on top of optimal medical therapy for 12 weeks. The median level of NT-proBNP was 1,136 pg/mL.

While there was no significant difference in average adjusted NT-proBNP at 6 and 12 weeks, more patients in the dapagliflozin group than in the placebo group met the second dual-primary outcome of clinically meaningful improvement in quality of life as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS) score or reduction in NT-proBNP level (61.5% vs 50.4%; P = 0.039). The study authors say this was attributable to both higher proportions of patients with ≥ 5-point improvement in KCCQ-OS (42.9% vs 32.5%; adjusted OR 1.73; 95% CI 0.98-3.05) and ≥ 20% reduction in NT-proBNP (44.0% vs 29.4%; adjusted OR 1.9; 95% CI 1.1-3.3) by 12 weeks. The results were consistent in patients with and without diabetes, and across other prespecified subgroups including gender, baseline LVEF, and A-fib.

This is an interesting biomarker study that moves us further in the direction of confirming that there is a symptom benefit to these agents in addition to the mortality benefit that we saw in DAPA-HF. John R. Teerlink

Further analyses showed that compared with placebo, mean KCCQ-OS was 3.7 points higher with dapagliflozin (P = 0.037) and mean clinical summary (KCCQ-CS) score was 4.6 points higher (P = 0.007) at 12 weeks. Additionally, three of four domains of the KCCQ showed significant improvement compared with placebo, and those benefits were amplified over time. Specifically, total symptom score increased by 4.8 points, QoL score by 5.4, and physical limitation score by 4.5.

“All of these differences, I would argue, are clinically meaningful and also statistically significant,” Kosiborod said.

Responder Analysis Bears Out Some Differences

The fourth domain, social limitations, was the only one that did not seem to be improved with dapagliflozin. An additional prespecified responder analysis found that dapagliflozin patients were less likely than placebo patients to have deterioration or no change in health status, and that they were more likely to have small-moderate, moderate-large, and very large improvements in KCCQ-OS and KCCQ-CS.

At 6 weeks, there was no difference between the dapagliflozin and placebo groups in terms of 20% reduction in NT-proBNP (34.4% vs 33.3%; P = 0.74), but there was a difference at 12 weeks, with more patients in the dapagliflozin group showing the reduction (44.0% vs 29.4%; P = 0.02). The results were similar for 20% decline in BNP, with a greater proportion of patients treated with dapagliflozin showing the reduction at 12 weeks (50.0% vs 33.9%; P = 0.01). Again, the responder analysis found that fewer patients treated with dapagliflozin versus placebo had moderate-large increase or no change in NT-proBNP and that they were more likely to have a moderate-large reduction in both.

Results of 6-minute walk tests were not statistically significantly different between the treatment and placebo groups, nor were there any significant between-group differences in weight, hemoglobin A1c, or systolic blood pressure.

Overall, there were 25 patients with adjudicated HF events. In a time-to-first-event analysis, there was no significant difference in adjudicated HF events with dapagliflozin compared with placebo, including hospitalization for HF or urgent HF visits. Adverse events occurred in 85 patients in the dapagliflozin group and 82 in the placebo group. There were no meaningful differences in safety, with one death in each treatment group, four MIs and one stroke in the placebo group, and none of these events in the dapagliflozin group. There was also one incidence of kidney injury in each group. Additionally, there were 19 volume depletion events (9.2% dapagliflozin and 5.3% placebo), and no episodes of diabetic ketoacidosis or amputations.

“The challenge for this study is that it was not adequately powered because of a high variance in NT-proBNPs,” co-moderator John R. Teerlink, MD (University of California, San Francisco), told TCTMD following the presentation. “That made it hard to see a difference. The fact that they were able to show a difference in the responder analysis was a way to get around the high heterogeneity.”

Teerlink added that while the DAPA-HF trial in and of itself “stands alone and doesn’t need support from [DEFINE-HF] or anyone else, this is an interesting biomarker study that moves us further in the direction of confirming that there is a symptom benefit to these agents in addition to the mortality benefit that we saw in DAPA-HF.”

AstraZeneca, the manufacturer of dapagliflozin, announced earlier today that its SGLT2 inhibitor has been granted Fast Track designation by the US Food and Drug Administration on the basis of the positive results from both DAPA-HF and the DELIVER trial, assuring an expedited review of a new indication: specifically, to reduce the risk of cardiovascular death or the worsening of heart failure in adults with reduced ejection fraction or preserved ejection fraction.