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DEFINE-HF: Dapagliflozin improves HF-related health regardless of diabetes status
PHILADELPHIA — In patients with HF with reduced ejection fraction with or without diabetes, the SGLT2 inhibitor dapagliflozin was associated with clinically meaningful improvements in HF-related health status or N-terminal pro-B type natriuretic peptide at 12 weeks, according to results of the DEFINE-HF trial presented at the Heart Failure Society of America Scientific Meeting.
While dapagliflozin (Farxiga, AstraZeneca) met its co-primary endpoint of meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, it did not meet its other co-primary endpoint of improvement in mean NT-proBNP at an average of 6 and 12 weeks, Mikhail Kosiborod, MD, FACC, FAHA, cardiologist at Saint Luke’s Mid America Heart Institute and professor of medicine at the University of Missouri-Kansas City School of Medicine said during a presentation here.
In related news, AstraZeneca announced that the FDA has granted fast-track status for development of dapagliflozin to reduce CV death or HF worsening in patients with HF with reduced or preserved ejection fraction. The program accelerates the development and review of new medicines for which there is an unmet need, according to a company press release.
As Healio previously reported, in the DAPA-HF trial presented at the European Society of Cardiology Congress, dapagliflozin reduced risk for CV death or HF worsening when added to standard therapy in patients with HFrEF with or without diabetes.
For the new, investigator-initiated DEFINE-HF trial, researchers randomly assigned 263 patients with HF with ejection fraction of 40% or less, NYHA class II or III status, estimated glomerular filtration rate at least 30 mL/min/1.73m2 and elevated natriuretic peptide to receive dapagliflozin 10 mg daily or placebo for 12 weeks. Most patients were on optimal medical therapy.
“No prior trials have focused specifically on the early effects of SGLT2 inhibitors on health status and natriuretic peptides,” Kosiborod said. “The DEFINE-HF trial was specifically designed to address this knowledge gap.”
The first primary endpoint was mean NT-proBNP at an average of 6 weeks and 12 weeks. The second primary endpoint was percentage of patients with at least a 5-point increase in HF-specific health status on the KCCQ overall summary score or at least a 20% decrease in NT-proBNP at 12 weeks. The findings were simultaneously published in Circulation.
Mean NT-proBNP at an average of 6 weeks and 12 weeks was 1,133 pg/nL in the dapagliflozin group and 1,191 pg/nL in the placebo group (P = .43), according to the researchers.
However, 61.5% of patients in the dapagliflozin group met the second primary endpoint compared with 50.4% of the placebo group (adjusted OR = 1.8; 95% CI, 1.03-3.06; number needed to treat = 10), Kosiborod said during the presentation.
The results of the second primary endpoint did not differ between patients with and without diabetes (P for interaction = .304), nor by renin-angiotensin-aldosterone inhibitor used, sex, age, race, history of atrial fibrillation, NT-proBNP level (above vs. below median), LVEF, KCCQ overall summary score, loop diuretic dose, ischemic vs. nonischemic HF type and estimated glomerular filtration rate, according to the researchers.
Three domains of the KCCQ score — total symptoms, physical limitations and quality of life — showed greater improvement at 12 weeks in the dapagliflozin group than in the placebo group, while the fourth domain, social limitations score, did not, according to the researchers.
In a time-to-first-event analysis, there was no difference between the groups in adjudicated HF events (HR = 0.84; 95% CI, 0.35-1.97).
Adverse events were similar between the groups, Kosiborod said.
“Collectively, we find these results [of DEFINE-HF and DAPA-HF] support the use of dapagliflozin as a treatment option in patients with HFrEF, regardless of diabetes status,” Kosiborod said during his presentation. “We believe these results have important implications for clinical practice.” – by Erik Swain
References:
Kosiborod M, et al. Late-Breaking Clinical Trials. Presented at: Heart Failure Society of America Scientific Meeting; Sept. 13-16, 2019; Philadelphia.
Nassif ME, et al. Circulation. 2019;doi:10.1161/CIRCULATIONAHA.119.042929.
Disclosures: The trial was initiated by the investigators and funded by AstraZeneca. Kosiborod reports he received grant/research support from AstraZeneca and Boehringer Ingelheim, honoraria from AstraZeneca, Boehringer Ingelheim and Novo Nordisk, and consultant fees from Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eisai, GlaxoSmithKline, Glytec, Intarcia, Janssen, Merck, Novartis, Novo Nordisk and Sanofi Aventis. Please see the study for the other authors’ relevant financial disclosures.
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The DEFINE-HF study using dapagliflozin in patients with HFrEF showed a few interesting findings. First, in the short term, there were no significant differences in NT-pro BNP levels between patients randomized to dapagliflozin vs. placebo. Other studies with SGLT2 inhibitors have also previously shown that natriuretic peptide levels with SGLT2 inhibitors may not decrease, but these drugs may prevent a rise in levels. Second, the combined endpoint of NT-pro BNP and KCCQ score was positive, as was KCCQ by itself. The quality of life of these patients in DEFINE-HF did improve significantly, and these results complement the results of clinical outcomes benefits seen in DAPA-HF trial. Lastly, in a secondary analysis, the proportion of patients whose NT-pro BNP decreased by at least 20% was greater in the dapagliflozin group, even if the overall average was not.
Importance of NT-pro BNP levels after treatment with dapagliflozin has been reduced now that we know the actual clinical outcomes data from the DAPA-HF results. The fact that NT pro-BNP levels did not go down is actually not surprising because studies of canagliflozin (Invokana, Janssen) in other populations have also shown an SGLT2 inhibitor did not reduce NT-pro BNP levels. Unlike loop diuretics, theoretically while the congestion goes down and so does the overall volume, but there is also a reduction in GFR initially that may reduce NT-pro BNP clearance. Hence, levels may be concentrated and therefore not visibly reduced when assessed. This is a physiologically plausible explanation of why SGLT2 inhibitors may not decrease NT-pro BNP, but we need further studies in this respect.
The DAPA-HF results show significant morbidity and mortality benefit with dapagliflozin in patients with HFrEF, and the DEFINE-HF results show improved KCCQ score, complementing the DAPA-HF results that the patients not only live longer but with better health status. The KCCQ results were not only positive in a relatively short timeframe, but also at a very meaningful level. The degree of improvement was greater than has been seen in trials of some other drugs. From a clinical perspective, it means you can tell the patient that they will live longer and feel better.
Despite the encouraging results of DEFINE-HF and DAPA-HF, we should be contemplative about these results. DAPA-HF results will be reviewed by the regulatory agencies as well as guideline committees. There is a good chance that dapagliflozin is now a treatment for all patients with HFrEF, but we should wait to see what the regulatory agencies and the guidelines say before jumping to conclusion. Confidence in these data will be enhanced if the results are replicated by other ongoing trials with different SGLT2 inhibitors, as well as trials in patients with HFpEF.