DAPA-HF Published: 'Stunning Consistent Benefit With Dapagliflozin'

Marlene Busko

September 19, 2019

BARCELONA — Results of the landmark DAPA-HF trial 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.

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

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.

McMurray first presented the results of DAPA-HF at the European College of Cardiology (ESC) Congress 2019, as previously reported by Medscape Medical News. Now the published manuscript is available to digest, he noted.

"The results are important and impressive," agrees James C. Fang, MD, University of Utah, Salt Lake City, in an accompanying editorial, "especially since they substantiate observations from previous trials of SGLT2 inhibitors."

However, both he and McMurray wonder what sort of uptake this new drug will have among clinicians who are treating patients with/without diabetes who have heart failure — given the low uptake of angiotensin receptor neprilysin inhibitors (ARNIs), despite positive trial results 5 years ago.

Benefits of Dapagliflozin in Addition to Background Therapy for Heart Failure

DAPA-HF showed that patients with heart failure randomized to dapagliflozin as opposed to placebo had a 26% lower rate of the primary composite outcome of worsening heart failure (hospitalization or emergency visit resulting in IV therapy for heart failure) or cardiovascular death (hazard ratio [HR], 0.74; P = .00001), with a number needed to treat of 21.

The benefits of dapagliflozin "were remarkably consistent among the [primary and secondary] outcomes and prespecified subgroups," which "bolsters confidence in the conclusions," Fang writes.  

Moreover, he agrees with Inzucchi, dapagliflozin was associated with few adverse effects and no dangerous but rare adverse events, as have been seen in some trials of SGLT2 inhibitors.

And hypoglycemia and volume depletion were uncommon.

According to Fang, it is also "worth highlighting" that the benefit was seen in addition to excellent background therapies for heart failure, and it was similar in heart failure patients with or without diabetes.

These impressive outcomes were also "similar to and reminiscent of" the benefits of sacubitril-valsartan seen in the PARADIGM-HF trial, he adds.

But Will Doctors Use Dapagliflozin for Heart Failure?

Despite these remarkable results, it remains to be seen whether, and how soon, clinicians will incorporate this new class of heart failure medication into their daily practice, the physicians said here.

Patients and healthcare providers may be concerned about unexpected side effects or drug interactions.  

And paradoxically, the patients most likely to benefit may be the least likely to receive these new drugs.

When DAPA-HF was being conducted, sacubitril-valsartan was just being introduced and was expensive. The highest uptake (40%) was in Canada, with low rates of 5% in Latin America, McMurray noted to Medscape Medical News.

"It behooves us as clinicians to learn more about using...newer agents effectively," Fang also notes, adding "we have a long way to go."

Even though the Paradigm-HF trial showing the benefits of combination sacubitril and valsartan for heart failure with reduced ejection fraction was reported in 2014, it was estimated that fewer than 15% of eligible patients were receiving that combination drug in 2017.

"Will we be waiting until 2022 before SGLT2 inhibitors are used in the 15% of eligible patients with heart failure with reduced ejection fraction?" Fang wonders.

And McMurray stressed it is not cost but cost-effectiveness that is important, noting that, years ago, statins were considered too expensive to prescribe.

Mechanism of Action in Heart Failure Not Clear Yet

But McMurray conceded that it's not entirely obvious how dapagliflozin is working to reduce heart failure. It "clearly isn't just about glucose," he explained.

Inzucchi agreed. He told delegates that the metabolic effects of the drug were inconsistent in the trial. Those who didn't have diabetes in DAPA-HF "experienced essentially no change in either HbA1c or weight," in contrast to those with diabetes. 

But dapagliflozin's hemodynamic effects appeared to be consistent in both subgroups (diabetes and no diabetes), as were the clinical heart failure outcomes.

McMurray added the renal safety of dapagliflozin in DAPA-HF was also "pretty impressive."

And given that heart failure symptoms — edema, breathlessness, sodium, and water retention — indicate that both the heart and kidneys are involved, it's possible dapagliflozin may affect the sodium-hydrogen exchanger, he said.

Nevertheless, McMurray acknowledged there is a "big knowledge gap" about the exact mechanism of action.  

Have We Lost This Drug Class to Cardiologists?

Inzucchi finished his talk by commenting on the existing diabetes guidelines.

"What this means clinically is the ADA/EASD recommendation that these drugs [SGLT2 inhibitors] are favored in [diabetes] patients with prevalent heart failure is correct, at least for heart failure with reduced ejection fraction," he told Medscape Medical News.

"I'm not recommending that [these drugs] are used in heart failure patients without diabetes until the regulators have had a look at the data...because it's certainly not indicated right now outside of patients with diabetes," he stressed, but nevertheless wondered whether "this drug class of SGLT2 inhibitors" is ultimately going to be lost to cardiologists.

Session chair Naveed Sattar, MD, PhD, University of Glasgow, UK, told Medscape Medical News that some diabetologists may "start to look for heart failure more carefully, to think about giving those drugs to patients who are at very high risk of heart failure."

But, "To my mind this trial has probably got greater impact for cardiologists," he noted.  

"I think cardiologists will start to now really believe in this class of drugs as something that they should consider for their patients with existing...heart failure," Sattar said.

DAPA-HF was originally slated to be presented at the American Heart Association (AHA) meeting in November, but because of the impressive findings, ESC agreed to add it to their program at the last minute, McMurray revealed.

At the AHA meeting, researchers will "describe in detail the benefit in nondiabetic patients," he noted.

The study was funded by AstraZeneca. McMurray has reported nonfinancial and other support from AstraZeneca during the conduct of the study. Inzucchi has reported receiving personal fees and nonfinancial support from AstraZeneca during the conduct of the study and personal fees from Astra Zeneca. Additional disclosures are available with the manuscript at NEJM.org. Fang was an investigator on DELIVER.

EASD 2019 Annual Meeting. Presented September 19, 2019.

N Engl J Med. Published online September 19, 2019. Abstract, Editorial

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