DAPA HF: Dapagliflozin Offers New HF Therapy, Even Sans Diabetes

Patrice Wendling

September 01, 2019

PARIS — The diabetes drug dapagliflozin (Farxiga, AstraZeneca) provides substantial benefits among patients with chronic heart failure with reduced ejection fraction (HFrEF) — even in those without diabetes, according to the DAPA HF trial.

The sodium-glucose cotransporter 2 (SGLT2) inhibitor reduced the relative risk for the primary outcome — a composite of time to first cardiovascular (CV) death or HF hospitalization or urgent HF visit requiring intravenous therapy — by 26% when added to standard therapy, compared with standard care alone (hazard ratio [HR], 0.74; 95% CI, 0.65 - 0.85; P = .00001). The number needed to treat was 21.

The treatment effect was consistent across all 14 prespecified subgroups, including, most importantly, patients with (HR, 0.75) and without (HR, 0.73) baseline diabetes.

In addition, dapagliflozin reduced the risk for all-cause death by 17% (HR, 0.83; 95% CI, 0.71 - 0.97) and patient-reported HF symptoms, without an increase in adverse events.

"We believe these results suggest that dapagliflozin offers a new approach to the treatment of patients with heart failure and reduced ejection fraction," principal investigator John McMurray, MD, University of Glasgow, Scotland, said in a hotline session here at the European College of Cardiology (ESC) Congress 2019.

Invited discussant Marco Metra, MD, University of Brescia, Italy, said, DAPA HF is a "landmark trial" and that the HRs for the primary and secondary endpoints are similar to, if not larger than, those in recent major successful trials, such as SHIFT, EMPHASIS-HF, and PARADIGM-HF. Importantly, quality of life in DAPA HF was also similar, if not better.

"It is a new era in heart failure medical treatment and medicine as well," Metra concluded.

SGLT2 inhibitors are known to prevent HF in patients with type 2 diabetes, but this is the first randomized outcomes trial to show they are valuable in patients with established HFrEF with or without type 2 diabetes. Patients with type 1 diabetes were excluded.

"It unmistakably demonstrates the role of the SGLT2 inhibitor class of agents for managing risk in patients with heart failure," James Januzzi, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology. "It will be easy to envision this drug will be added to the armamentarium of standard heart failure therapies."

The results are not entirely unexpected, given the strong HF signal with SGLT2 inhibitors in patients with diabetes in the EMPA-REG OUTCOME and CANVAS trials, he said. American College of Cardiology (ACC) and American Diabetes Association guidelines also say SGLT2 inhibitors should be considered, in general, in patients with diabetes and a hemoglobin A1c more than 7% regardless of the presence of HF.

"From the perspective of what this changes, it shifts the vision away from the hemoglobin A1c and broadens it to patients who don't even have the diagnosis of diabetes anymore," Januzzi said. "Is it time to begin prescribing an SGLT2 to patients with heart failure? No. We need to see the report published, we need regulatory approval, and I would prefer to see it in the guidelines of how it should fit in with other heart failure therapies."

The results reinforce current guidelines, but, "at the moment, I would absolutely not advocate using these drugs in patients with heart failure who don't have diabetes — because that subset of patients, that really new finding in this trial —  needs to be reviewed by regulators and the guideline writers need to look at it and see what is the appropriate recommendation," McMurray told theheart.org | Medscape Cardiology.   

Contemporary Care

DAPA HF enrolled 4744 patients with HFrEF (New York Heart Association class II to IV), a left ventricular ejection fraction of 40% or less, and a moderately elevated N-terminal pro-B-type natriuretic peptide concentration and randomly assigned them to once-daily dapagliflozin 10 mg or placebo. Patients were receiving excellent contemporary therapy, including a renin-angiotensin system inhibitor in 94%, a β-blocker in 96%, a mineralocorticoid receptor antagonist (MRA) in 71%, and the more recent addition, sacubitril/valsartan (Entresto, Novartis), in 11%, McMurray noted.

The two treatment groups were well balanced, with a mean left ventricular ejection fraction of 31%, chronic kidney disease in 41%, and diabetes in 45%.

Dapagliflozin lowered the risk for worsening HF events by 30% (10% vs 13.7%; HR, 0.70; 95% CI, 0.59 - 0.83), HF hospitalizations by 30% (9.7% vs 13.4%; HR, 0.70; 95% CI, 0.59 - 0.83), and CV death by 18% (9.6% vs 11.5%; HR, 0.82; 95% CI, 0.69 - 0.98).

At 8 months, there was a 2.8-point improvement in total symptom score on the Kansas City Cardiomyopathy Questionnaire favoring dapagliflozin over placebo (6.1 vs 3.3 points; P < .001).

Rates of adverse events were low and did not differ between two groups, including a nearly identical rate of events leading to treatment discontinuation (4.7% vs 4.9%) and fewer serious adverse events with dapagliflozin (38% vs 42%; P < .01).

A post hoc analysis of the primary endpoint showed no difference between the 250 patients also on sacubitril/valsartan (HR, 0.75; 95% CI, 0.50 - 1.13) and those not on the drug (HR, 0.74; 95% CI, 0.65 - 0.86), McMurray said.

The analysis, however, had wide confidence intervals, noted Januzzi, who said more information is needed about the combined use of dapagliflozin and the increasingly used sacubitril/valsartan.

"How clinicians begin, titrate these two drugs together is far more complicated than just throwing a couple medications in a patient," he said. "This is going to be a challenge. Nonetheless, I envision a world where patients will be taking sacubitril/valsartan, a β-blocker at maximal dose, spironolactone or eplerenone, and an SGLT2 inhibitor.

"Interestingly, the drug I think that will lose the most in this discussion is loop diuretics," Januzzi said. "We will be able to remove diuretics much more easily with that combination of very favorable agents, each of which has a mortality benefit."

But How Do They Work?

"Perhaps the most obvious question all of us are asking is, How do these drugs work? How do they reduce risk? They are not simply a diuretic drug," Januzzi said.

During his discussion of the results, Metra pointed to some "peculiar aspects" of the trial, including an early divergence of the Kaplan-Meier curves at 1 month for the primary endpoint and worsening HF-related events.

"The early occurrence of the effects on heart failure hospitalizations and symptoms may be related to the diuretic effects, and also we know that the diuretic effects of these SGLT2 inhibitors tend to disappear during long term," he said. But the lack of interaction between treatment and HF severity in the subgroup analysis suggests "there are other mechanisms of action that may be important."

During a media briefing, McMurray said the benefits of dapagliflozin were consistent regardless of hemoglobulin A1c levels but noted that the mechanism of action is unknown. SGLT2 inhibitors obviously protect the kidneys, which play a crucial role in the causation of congestion and HF symptoms, but the drugs may also alter myocardial metabolism to make the failing heart more metabolically efficient and therefore contract better. There also may be other mechanisms relevant to HF, like the sodium hydrogen exchanger, which may be relevant to risk for sudden cardiac death, he said.

"At the end of the day, like most drugs, for example, mineralocorticoid receptor antagonists or β-blockers, we don't really know why there is a benefit," McMurray said.

Notably, there are almost 20 ongoing SGLT2 inhibitor trials that should shed light on whether the benefits of dapagliflozin will translate to other agents or to different HF phenotypes. All three men highlighted the forthcoming EMPEROR-Preserved trial of empagliflozin in HF with preserved ejection fraction.

A Learning Curve Ahead

Many heart failure cardiologists are already using SGLT2, but the broader cardiology community is not familiar with this class of drugs, McMurray said. This will require some education, particularly easing cardiologists' concerns about the risk for hypoglycemia, which might happen in patients on insulin but otherwise not. The other concern with these drugs is that a proportion of patients get a genital fungal infection, which is easily treatable with a topical fungicide but not something cardiologists are used to talking about and, in particular, male patients are used to treating.

"I suppose it's the unfamiliar things that we will have to educate the cardiologist about," McMurray said. "But in terms of ease of use, this is much easier to use than the things we normally use like ACE inhibitors, β-blockers, MRAs that cause renal dysfunction, hypokalemia, hypotension, and, of course, this drug doesn't do any of those things."

One source for guidance is the recent ACC Expert Consensus Decision Pathway on the role of newer antidiabetic drugs in cardiovascular disease, including SGLT2 inhibitors and glucagon-like peptide-1 receptor agonists, said Januzzi, who served on its task force.

"In the end I think cardiologists will pick them up, but the learning curve will probably be relatively steep at first," he said.

AstraZeneca sponsored the study. McMurray reports payment from AstraZeneca to his institution for his work in the trial. Januzzi reports research with Boehringer Ingelheim, Novartis, and Janssen. Metra reports honoraria from Amgen, Bayer, Fresenius, LivaNova, NovartisServier, and ViFor and being a member of the executive committee for SOLOIST-HF.

European Society of Cardiology (ESC) Congress 2019. Presented September 1, 2019.

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