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BARCELONA — Results of the landmark DAPA-HF trial 

https://clinicaltrials.gov/ct2/show/NCT03036124

showing that the glucose-lowering drug dapagliflozin (Farxiga, AstraZeneca) provides "quite stunning, pretty consistent benefit" in patients with heart failure, both with and without type 2 diabetes, were published online September 19 in the New England Journal of Medicine.

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https://www.nejm.org/doi/full/10.1056/NEJMoa1911303

ABSTRACT

Abstract

BACKGROUND

In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

METHODS

In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.

RESULTS

Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.

CONCLUSIONS

Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. 

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These comments come from the principal investigator John McMurray, MD, University of Glasgow, UK, who reported the findings here at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.

The trial enrolled almost 5000 patients with moderate heart failure and reduced ejection fraction (HFrEF) — with or without type 2 diabetes — and randomized them to once-daily dapagliflozin 10 mg or placebo on top of contemporary therapy for heart failure. 

Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, is already used to successfully treat type 2 diabetes and prevent development of heart failure in these patients, but DAPA-HF was a dedicated heart failure trial that now shows the drug can be used to treat pre-existing heart failure, even in patients without diabetes.

But the positive outcomes are also very important for diabetes patients, McMurray told endocrinologists here, because heart failure is the "most terrible complication of diabetes" and is more common than myocardial infarction, he said, "with a worse prognosis than breast cancer or colon cancer."

"If you had a drug that could reduce cancer by 30% or 40%, wouldn't you use it?" he asked rhetorically.

Endocrinologist Silvio Inzucchi, MD, Yale University, New Haven, Connecticut, also a study investigator, agreed.

He told delegates here that once heart failure develops "outcomes are poor in diabetes."

And regarding DAPA-HF, he told Medscape Medical News: "The signal that we saw in the large cardiovascular outcome trials for a benefit in heart failure with SGLT2 inhibitors pans out when you study this drug class in a heart failure-specific population."

The DAPA-HF findings also align with those of DEFINE-HF, a smaller, shorter trial of dapagliflozin in a similar patient population in the United States, which was also reported here 

https://www.medscape.com/viewarticle/918542

and reported at the recent Heart Failure Society of America (HFSA) 23rd Annual Scientific Meeting in Philadelphia.

https://ahajournals.org/doi/10.1161/CIRCULATIONAHA.119.042929

In DEFINE-HF, patients felt better as early as 12 weeks into treatment with dapagliflozin, said Inzucchi, and in DAPA-HF, significantly more patients felt better on the drug at 8 months compared with those on placebo, at least so far in the 18-months of follow-up available.

And importantly, dapagliflozin appeared to be "extremely safe" in this, "the sickest group of patients to date," in a large CV outcomes trial for an SGLT-2 inhibitor, he stressed.

If true, it would possibly show up as reduction in NT-proBNP, an indirect biomarker for fluid status — which didn't happen in DEFINE-HF, said Teerlink, of San Francisco VA Medical Center and University of California, San Francisco.

"I think it's very clear, looking at various data points now, that these [agents] are not just simple diuretics. They certainly have a lot more effects other than diuresis, and in fact I'm not sure how much of the effect that we see is diuresis at all," Kosiborod replied.

Also evident in DEFINE-HF is that dapagliflozin does not entirely share mechanisms with the RAS inhibitors in heart failure, he said in an interview.

That's because its patients benefited from addition of dapagliflozin regardless of which RAS inhibitor they were also taking, or whether they were taking a RAS inhibitor at all, he said. "The mechanisms appear to be nonoverlapping."

As to which mechanism, "We're still kind of scratching our heads," Eric J. Velazquez, MD, Yale School of Medicine, New Haven, Connecticut, told theheart.org | Medscape Cardiology.

"This data suggests that the impact, on at least patient-perceived quality of life, is independent of a major effect across the population in NT-proBNP," he noted.

"That actually is probably, at the end of the day, the most important contribution of DEFINE-HF, which is to highlight that this effect that we're seeing in the clinical outcome trials is not just because of better decongestion," Velazquez said. "It's something else."

When to "Jump" in HFrEF

Despite the appeal of SGLT-2 inhibitors, at least dapagliflozin, as a new class of heart failure medication, no one is currently recommending that they be used quite that way.

In patients with diabetes and "progressive heart failure symptoms," Velazquez said, "my suspicion is that people are going to jump very quickly to adding dapagliflozin in their population as an additional therapy."

"Frankly, if they have diabetes and heart failure, using one of these medications is a no-brainer," Kosiborod agreed when interviewed. Their trials show the drugs can lead to significant reductions in morbidity, mortality, and symptom burden, he said.

"These drugs we know also protect the kidneys in patients with diabetes. And they of course improve glycemic status. So you're killing not just one or two, but three birds with one stone in many of these patients."

But in those with heart failure without diabetes, he said, "there is not an indication yet. My prediction would be that it's likely going to be incorporated in guidelines, hopefully in the relatively near future. And I certainly hope there will be an indication in the reasonably near future, but that will be up to the regulators."

Indeed, AstraZeneca announced yesterday that the US Food and Drug Administration (FDA) has given dapagliflozin "fast track" status for a proposed indication to reduce cardiovascular death or worsening of heart failure in adults with either reduced- or preserved-ejection-fraction heart failure.

Two Primary Endpoints

DEFINE-HF randomly assigned 263 patients with optimally managed HFrEF to also receive dapagliflozin 10 mg daily or placebo for 12 weeks. They were required to be in NYHA class 2-3 functional class with elevated natriuretic peptides and good renal function and without a heart failure hospitalization or coronary revascularization in the past month. Patients with type 1 diabetes were excluded.

Nearly all were on beta-blockers and RAS inhibitors, including ACE inhibitors or angiotensin receptor blockers (ARBs) in 59% and sacubitril/valsartan (Entresto, Novartis) in 33%; 60% were on aldosterone inhibitors. About 35% were on biventricular pacing for heart failure.

The two groups didn't differ significantly in the average of adjusted 6-week and 12-week NT-proBNP levels, the first of two primary endpoints. The odds ratio (OR) for the effect of dapagliflozin on the endpoint was 0.95 (95% confidence interval [CI], 0.84 - 1.08; P = .43).

For the second primary endpoint, a composite of elevation in heart failure–specific health status by at least 5 points in the Kansas City Cardiomyopathy Questionnaire (KCCQ) summary score or at least a 20% decrease in NT-proBNP levels, the OR effect for dapagliflozin was 1.8 (95% CI, 1.03 - 3.06).

Both the KCCQ-score and NT-proBNP portions of the endpoint contributed to the "nominally significant" P value of .039, Kosiborod reported.

The results were consistent in all prespecified subgroup analyses, including by diabetes status.

Table 1. Odds Ratio (OR) for Outcomes, Dapagliflozin vs Placebo, by Relevant Subgroups in DEFINE-HF

Subgroup Parameters

OR (95% CI)

Interaction P value

History of Diabetes

.30

 Yes

1.4 (0.7 - 2.9)

 

 No

2.6 (0.9 - 7.4)

 

RAS Inhibitor Used 

.84

 ACE inhibitor or ARB

2.0 (0.9 - 4.5)

 

 Sacubitril/Valsartan

1.9 (0.6 - 5.8)

 

 Neither

1.5 (0.3 - 7.6)

 

*For the second primary endpoint reflecting clinically meaningful improvement in heart failure disease-specific health status or NT-proBNP levels.

The treatment groups didn't differ significantly in weight change nor in 6-minute walk distance at either 6 or 12 weeks.

Serious adverse events in the study were few, Kosiborod said, and they were similarly infrequent in the two groups. "Drug adverse events" occurred in 2.3% in both groups. The most common were "volume depletion events" in 9.2% on dapagliflozin and 5.3% on placebo.

The benefits of dapagliflozin "very clearly" represent a SGLT-2 class effect in the arena of heart failure prevention for people with diabetes. "We saw it consistently in all the trials, with different agents and different patient populations," Kosiborod said.

"I think it's more likely than not to be a class effect in heart failure treatment as well. Of course what we have the data for right now is dapagliflozin. It will be important to see data with other agents."

Heart Failure Society of America 23rd Annual Scientific Meeting: Late Breaking Clinical Trials. Presented September 16, 2019.

Circulation. Published September 16, 2019. Abstract

AstraZeneca. Published September 16, 2019. Press Release

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2019/fda-grants-fast-track-designation-for-farxiga-in-heart-failure.html

From www.medscape.com

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Läs mer i abstract:
John J.V. McMurray med flera. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine, publicerad online 19 september 2019. DOI: 10.1056/NEJMoa1911303

https://www.nejm.org/doi/full/10.1056/NEJMoa1911303?query=featured_home

Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction

Abstract

BACKGROUND

In patients with type 2 diabetes, inhibitors of sodium–glucose cotransporter 2 (SGLT2) reduce the risk of a first hospitalization for heart failure, possibly through glucose-independent mechanisms. More data are needed regarding the effects of SGLT2 inhibitors in patients with established heart failure and a reduced ejection fraction, regardless of the presence or absence of type 2 diabetes.

METHODS

In this phase 3, placebo-controlled trial, we randomly assigned 4744 patients with New York Heart Association class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either dapagliflozin (at a dose of 10 mg once daily) or placebo, in addition to recommended therapy. The primary outcome was a composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.

RESULTS

Over a median of 18.2 months, the primary outcome occurred in 386 of 2373 patients (16.3%) in the dapagliflozin group and in 502 of 2371 patients (21.2%) in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). A first worsening heart failure event occurred in 237 patients (10.0%) in the dapagliflozin group and in 326 patients (13.7%) in the placebo group (hazard ratio, 0.70; 95% CI, 0.59 to 0.83). Death from cardiovascular causes occurred in 227 patients (9.6%) in the dapagliflozin group and in 273 patients (11.5%) in the placebo group (hazard ratio, 0.82; 95% CI, 0.69 to 0.98); 276 patients (11.6%) and 329 patients (13.9%), respectively, died from any cause (hazard ratio, 0.83; 95% CI, 0.71 to 0.97). Findings in patients with diabetes were similar to those in patients without diabetes. The frequency of adverse events related to volume depletion, renal dysfunction, and hypoglycemia did not differ between treatment groups.

CONCLUSIONS

Among patients with heart failure and a reduced ejection fraction, the risk of worsening heart failure or death from cardiovascular causes was lower among those who received dapagliflozin than among those who received placebo, regardless of the presence or absence of diabetes. 

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