European Society of Cardiology

European Society of Cardiology

Perspective from Ileana L. Pina, MD
Perspective from Robert A. Harrington, MD
Perspective from Deepak L. Bhatt, MD, MPH
September 01, 2019
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DAPA-HF: Dapagliflozin offers new approach to treatment of HFrEF, even without diabetes

Perspective from Ileana L. Pina, MD
Perspective from Robert A. Harrington, MD
Perspective from Deepak L. Bhatt, MD, MPH
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John J.V. McMurray

PARIS — In patients with HF, with and without diabetes, treatment with the SGLT2 inhibitor dapagliflozin reduced risk for worsening HF and CV death when added to standard therapy, according to anticipated results of the DAPA-HF trial.

Data presented today at the European Society of Cardiology Congress suggest that the benefits of dapagliflozin (Farxiga, AstraZeneca) extend beyond its effects as a diabetes drug.

“The most important finding of all is the benefit in patients without diabetes. This is truly a treatment for heart failure, and not just a drug for diabetes,” John J.V. McMurray, MD, professor of cardiology at the Institute of Cardiovascular and Medical Sciences at University of Glasgow in Scotland, said.

DAPA-HF enrolled 4,744 adults in 20 countries who had HFrEF (left ventricular EF 40%). At baseline, 45% had type 2 diabetes and 55% did not. Those enrolled also had moderately elevated N-terminal pro-B-type natriuretic peptide and an estimated glomerular filtration rate of 30 mL/min/1.732 or higher. All patients underwent random assignment to receive once-daily dapagliflozin 10 mg or matching placebo, in addition to standard care. Dapagliflozin is currently approved by the FDA to treat patients with type 2 diabetes.

Treatment with the SGLT2 inhibitor dapagliflozin reduced risk for worsening HF and CV death when added to standard therapy in patients with HF with reduced ejection fraction, regardless of diabetes status, according to results of the DAPA-HF trial.
Source: Adobe Stock

McMurray said the goal was to enroll a typical HFrEF population.

“We thought of dapagliflozin as a HF drug, not a diabetes drug, and we wanted to test it in an all-comers population,” he said during a press conference.

Improvement with, without diabetes

During a median follow-up of 18.2 months, the primary outcome of CV death or worsening HF was reduced by 26% in the group assigned dapagliflozin compared with those assigned placebo (16.3% vs. 21.2%; HR = 0.74; 95% CI, 0.65-0.85; number needed to treat = 21). Worsening HF was defined as unplanned HF hospitalization or an urgent HF visit requiring IV therapy.

Dapagliflozin was also associated with significant improvement when the researchers analyzed components of the primary composite endpoint separately, including a 30% reduction in worsening HF (HR = 0.7; 95% CI, 0.59-0.83; P = .00003) and an 18% reduction in CV mortality (HR = 0.82; 95% CI, 0.69-0.98; P = .029).

All-cause death, which occurred in 11.6% of the dapagliflozin group vs. 13.9% of the placebo group, was reduced by 17% with dapagliflozin treatment (HR = 0.83; 95% CI, 0.71-0.97).

The researchers found a consistent benefit across 14 prespecified subgroups. The “critically important” subgroup, McMurray said, was comparison based on the presence or absence of diabetes. The primary composite outcome was reduced by 25% with dapagliflozin in the patients with diabetes at baseline (HR = 0.75; 95% CI, 0.63-0.9) and by 27% in those without diabetes (HR = 0.73; 95% CI, 0.6-0.88).

“We saw an identical treatment effect in patients without diabetes, compared to those with diabetes,” McMurray said at the press conference.

Another important subgroup was patients treated or not treated with the angiotensin receptor neprilysin inhibitor sacubitril/valsartan (Entreso, Novartis). At baseline, only 11% of patients enrolled in DAPA-HF were receiving sacubitril/valsartan. McMurray said this therapy was just being introduced into practice when DAPA-HF started enrollment. Again, the overall treatment effect was consistent based on background treatment. The primary outcome was reduced by 25% with dapagliflozin in the patients receiving sacubitril/valsartan at baseline (HR = 0.75; 95% CI, 0.5-1.13) and by 26% in those not receiving sacubitril/valsartan (HR = 0.74; 95% CI, 0.65-0.86), according to McMurray.

The safety profile of dapagliflozin was consistent with previous trials of the drug. Adverse events including volume depletion, major hypoglycemia, lower limb amputation, fracture and/or renal dysfunction were low overall and not significantly different between the two groups. The rate of serious adverse events, including death, was lower in the dapagliflozin group (38 vs. 42 events; P < .01). Moreover, adverse events leading to discontinuation were similar in both groups (4.7% with dapagliflozin vs. 4.9% with placebo; P = .79).

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In other results, patient symptoms were significantly improved with dapagliflozin treatment. From baseline to 8 months, more patients assigned dapagliflozin reported a clinically significant improvement in symptoms of HF based on the Kansas City Cardiomyopathy Questionnaire, compared with those assigned placebo (58% vs. 51%; OR = 1.15; 95% CI, 1.03-1.23).

“Overall, we found that dapagliflozin does what we would like any HF treatment to do: in other words, reduce worsening HF events, particularly hospital admissions; to reduce CV death; and to improve symptoms,” McMurray said here. “The absolute risk reduction [with dapagliflozin] is quite substantial and was consistent across subgroups.”

‘A new era in HF treatment’

DAPA-HF was a parallel-group, randomized, double-blind study performed in a broad spectrum of patients with HF. McMurray said it is important to note that the randomized therapies were administered in addition to standard care, including high use of ACE inhibitors, angiotensin receptor blockers, sacubitril/valsartan, beta-blockers and mineralocorticoid receptor antagonists.

“This is an important breakthrough for patients with a terrible disease. We think these [findings] show a completely new therapeutic approach to the management of patients with HF,” McMurray said. “This is the first beneficial heart failure treatment in 10 years not acting through neurohumoral mechanisms. [It was] beneficial when added to excellent existing therapy, including sacubitril/valsartan.”

Marco Metra, MD, FESC, FHFA, professor of cardiology at the University of Brescia, Italy, put the DAPA-HF findings into context during a discussion of the results at ESC Congress.

“If we compare the results on the primary and secondary outcomes in DAPA-HF with the results of successful trials of the last decade, we can see that all the hazard ratios are comparable, if not larger, than those in the major clinical trials in HF,” Metra said.

Questions remain regarding the mechanisms of action of dapagliflozin and also whether the effects can be translated to different HF phenotypes, such as HF with preserved EF, Metra said. However, these answers will come, as there are almost 20 ongoing trials underway with the SGLT2 inhibitors, including dapagliflozin and also empagliflozin (Jardiance, Boehringer Ingelheim), ertugliflozin (Steglatro, Merck) and sotagliflozin (Zynquista, Sanofi and Lexicon), he said.

“We are facing a new era in heart failure treatment,” Metra said.

SGLT2 inhibitors including dapagliflozin have been shown to reduce risk for developing HF in patients with type 2 diabetes. DAPA-HF was unique in that it is the first HF outcomes trial with an SGLT2 inhibitor investigating whether dapagliflozin was also useful in treating established HF, even in patients without diabetes.

Since dapagliflozin was first approved by the FDA in 2014 for the treatment of type 2 diabetes in adults, several studies have demonstrated the potential for SGLT2 inhibitors as a class in the prevention and treatment of HF. As previously reported, overall findings from the DECLARE-TIMI 58 CV outcome trial showed that dapagliflozin 10 mg reduced the composite endpoint of CV death and HF hospitalization over 4 years, mainly driven by a reduction in HF hospitalization, in a broad population of patients with type 2 diabetes. In a prespecified subanalysis presented in March at the American College of Cardiology Scientific Session, researchers reported that treatment with dapagliflozin reduced HF hospitalization in a broad range of LVEF and may provide even greater benefit with lower CV death and mortality in patients with HFrEF.

Dapagliflozin does not currently have an FDA indication to reduce the risk for HF or CV death. – by Katie Kalvaitis

Reference:

McMurray J, et al. Hot Line Session 1. Presented at: European Society of Cardiology Congress; Aug. 31-Sept. 4, 2019; Paris.

Disclosures: The DAPA-HF trial was funded by AstraZeneca. McMurray reports his institution was paid by AstraZeneca for his role as principal investigator in the DAPA-HF trial. Metra reports he receives honoraria from Amgen, Bayer, Fresenius, LivaNova, Novartis, Service and Vifor and he is a member of the executive committee for SOLOIST-HF.