DAPA-HF: Heart Failure Toolbox Poised to Add a New Family of Drugs

November 19, 2019

PHILADELPHIA — A generation of clinicians wanting new drug therapies for their patients with heart failure (HF) and reduced ejection fraction (HFrEF) suffered a long drought that only recently ended with the advent of sacubitril/valsartan (Entresto, Novartis).

Now they are speaking of abundance as the field seems ready to add an entirely new category of agents to the toolbox, the sodium-glucose cotransporter 2 (SGLT2) inhibitors, a drug family commonly described as antidiabetic, with waning precision.

In the DAPA-HF trial, treatment with the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca) on top of standard HFrEF meds, compared with standard meds only, led to significantly improved risk not only for its clinical composite primary endpoint, but for mortality and a slew of other meaningful secondary outcomes.

Researchers are sure that the benefits were not mediated by the well-recognized antiglycemic effects of the SGLT2 inhibitor.

DAPA-HF entered more than 4700 patients with HFrEF without regard to their diabetes status. As the world learned in August of this year, patients assigned to receive dapagliflozin on top of standard HFrEF meds showed at least a one fourth drop in risk of the clinical primary endpoint compared with those on standard meds alone over a median 18 months — also regardless of diabetes status.

The drug had also been shown, in the recent DEFINE-HF trial, to improve symptoms and quality of life in a similar HF population, again in patients with or without diabetes. SGLT2 inhibitor benefits for HF endpoints in patients who primarily have diabetes have already been established.

Now it is known that in DAPA-HF, the drug seemed to benefit its 45% of patients with, and 55% without, type-2 diabetes (T2D) to a nearly equal extent for its primary endpoint — cardiovascular (CV) death, HF hospitalization, or urgent HF visit requiring IV therapy — as well as those events individually plus all-cause mortality and other important endpoints.

The new analysis, which also demonstrated dapagliflozin's relative safety in patients with and without diabetes, was reported here at the American Heart Association (AHA) Scientific Sessions 2019.

Plumbing the DAPA-HF dataset for effect differences by subgroups, especially by diabetes status, "has been dreadfully boring, almost, because we're struggling to find anything that doesn't look good. It's quite remarkable," John J.V. McMurray, MBChB, MD, University of Glasgow, United Kingdom, told theheart.org | Medscape Cardiology.

Importantly, dapagliflozin's effect on the primary endpoint was virtually the same regardless of baseline glycosylated hemoglobin (A1c) levels.

"That is mind-boggling, because I think a lot of people thought this," that is, SGLT2 benefits in patients with HFrEF, "was all going to be about prediabetes, because a lot of patients with heart failure have prediabetes," said McMurray, who presented the findings here at the sessions.

"But it's even in people with completely normal hemoglobin A1c that you can see the benefits. It's absolutely consistent across the spectrum of hemoglobin A1c."

Table 1. Primary Endpoint* Hazard Ratio (HR), Dapagliflozin vs Placebo, by Baseline HbA1c Tertiles in DAPA-HF

Baseline HbA1c (%)

HR (95% CI)

Tertile 1, ≤5.6

0.74 (0.53 - 1.04)

Tertile 2, 5.7-5.9

0.71 (0.48 - 1.04)

Tertile 3, ≥6.0           

0.72 (0.52 - 1.00)

Nonsignificant P value for interaction.

*CV death or HF hospitalization or urgent HF visit requiring IV therapy


The current DAPA-HF findings "we feel are really quite strong evidence that dapagliflozin, which was recently introduced as a diabetes drug, clearly is a drug that is beneficial in heart failure, including patients with heart failure who do not have type-2 diabetes," McMurray said.

"We know that SGLT2 inhibitors are a good option for patients with type-2 diabetes and heart failure, and after today, we know definitively that these are good drugs for people with heart failure and reduced ejection fraction but without diabetes," Larry A. Allen, MD, MHS, University of Colorado School of Medicine, Aurora, told the theheart.org | Medscape Cardiology.

The drug class is approved widely for T2D, and therefore available to clinicians. "Many of us are now using dapagliflozin in diabetes with HF," observed Allen, who wasn't part of DAPA-HF. In the United States, there are no regulatory obstacles to that, and by extension there are no unusual hindrances on reimbursement for patients with diabetes.

But it's another story in HFrEF without diabetes. Off-label use is possible but would present challenges to reimbursement. "DAPA-HF suggests that there are probably strong reasons to consider it and for payers to think about paying for it," Allen said.

Who can say without tea leaves, everyone theheart.org | Medscape Cardiology contacted for this story implied, but the entirety of DAPA-HF results seems enough to convince regulators that the indication for dapagliflozin, at least, should not require the presence of T2D.

"I think actually it's pretty strong. You have a very large study, and it's quite impressive how consistent the results are regardless of hemoglobin A1c," Allen observed. "There is strong statistical significance in the nondiabetic group. The majority of patients in this study were nondiabetics. It was a prespecified approach, where they were stratified by diabetes vs nondiabetes."

"So I think most people, including those in the FDA, would view this very favorably."

Regulators will likely find the evidence strong, agreed Christopher O'Connor, MD, president of Inova Heart and Vascular Institute, Falls Church, Virginia, also not involved in DAPA-HF.

The quirky aspect of the SGLT2-inhibitor case in heart failure, he told theheart.org | Medscape Cardiology, is that the drug is already approved for T2D, "so people classify it as an antidiabetic drug."

But the DAPA-HF entry criteria did not require T2B for randomization, arguing for an indication in HFrEF regardless of diabetes status.

"If you do a study and you take all comers, and it shows a benefit in all comers, then there's no reason to exclude nondiabetics," O'Connor said.

"We give sacubitril/valsartan to diabetics and nondiabetics. We give beta-blockers to diabetics and nondiabetics. Because their trials took all comers."

Still, "we need to get it through the regulatory hoops," O'Connor said. "What I don't want to see is a slow uptake, once it gets the indication in nondiabetics. We have to think of this as a drug that you would prescribe like an ACE inhibitor, or a beta-blocker, or a mineralocorticoid receptor antagonist, or sacubitril/valsartan."

As previously reported, DAPA-HF enrolled 4744 patients with HFrEF (an NYHA class 2-4 functional class and a left ventricular ejection fraction of 40% or less) plus moderately elevated natriuretic peptides.

It randomly assigned them to once-daily dapagliflozin 10 mg or placebo on top of guideline-directed standard HFrEF medications; their use in the trial was remarkably high for most drug categories, McMurray and Allen observed.

The overall primary endpoint hazard ratio (HR) was 0.74 (95% CI, 0.65 - 0.85; P = .00001) favoring the SGLT2 inhibitor.

The trial's population had been prospectively stratified by diabetes status. Effects on the primary endpoint were nearly identical in patients with and without T2D (people with type-1 diabetes had been excluded), and essentially the same as the overall benefit.

The results were consistent across nearly all major secondary endpoints.

Table 2. Clinical Endpoint Hazard Ratios (HR), Dapagliflozin vs Placebo by Baseline Diabetes Status* in DAPA-HF


Diabetes, n = 2139

No Diabetes, n = 2605

CV Death/HF hospitalization/Urgent HF visit

(0.63 -0.90)

(0.60 -0.88)

CV Death

(0.63 -1.01)

(0.66 -1.10)

Worsening HF Event

(0.61 -0.95)

(0.48 -0.80)

CV death or first HF hospitalization

(0.63 -0.90)

(0.60 -0.89)

CV death or first and repeat HF hospitalizations

(0.63 -0.94)

(0.59 -0.91)

Death from any cause

(0.63 -0.97)

(0.70 -1.12)

*P= .80 for diabetes status interactions


"Patients without diabetes were less likely to have any of the adverse events of interest that we prespecified in the trial, compared to patients with diabetes," McMurray said. In particular, patients on the drug without T2D did not show a risk of hypoglycemia or diabetic ketoacidosis, which had been a concern.

Also, he said, there was no significant interaction by diabetes status for an endpoint reflecting worsening renal function. It was a composite of sustained reduction in estimated glomerular filtration rate (eGFR) of at least 50%, end-stage renal disease, or death from renal causes.

"In fact, very few patients discontinued therapy for adverse events overall," McMurray said.

"We know today that if you have heart failure from reduced ejection fraction, irrespective of diabetes status, we should consider the use of SGLT2 inhibitors. And the real question is, when do we add these? I would suggest potentially very early on in the sequencing," Allen said. "We do see that these drugs tend to be additive when used together."

The drug class new to heart failure worsens an already daunting challenge for some patients: a plethora of pills every day, especially in patients with multiple comorbidities that also require treatment.

The field needs to figure out "how we handle polypharmacy for patients, about the value of these drugs for society, but also the financial toxicity that multiple agents can cause for patients who have high out-of-pocket costs," Allen said.

"Without insurance, SGLT2 inhibitor therapy runs about $450 to $500 per month per patient, he observed. "If insurers are not covering much of the cost, the actual cost to an individual patient is pretty prohibitive at least for the vast majority."

Also, Allen noted, "We need to align incentives, so that clinicians are not paid for visits but paid to really optimize the use of these guideline-directed medical therapies and help patients avoid the financial toxicity of high-value drugs."

AstraZeneca sponsored DAPA-HF. McMurray has reported receiving payments from AstraZeneca to his institution for his work in the trial. Allen declared no conflicts relevant to SGL2T inhibitors but discloses consulting relationships with ACI Clinical, Janssen, and Boston Scientific. O'Connor has disclosed no relevant financial relationships.

American Heart Association (AHA) Scientific Sessions 2019: LBS.01 - Late Breaking Science I. Presented November 16, 2019.

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