DAPA-HF Details: Dapagliflozin Slashes HF Outcomes, Even in Nondiabetics

PARIS, France (UPDATED)—Dapagliflozin, when given on top of standard therapy, markedly reduces the risk of worsening heart failure events and cardiovascular death and improves symptoms among heart failure patients with reduced ejection fraction (HFrEF), full results from the DAPA-HF trial show.

Importantly, the relative and absolute risk reductions in death and hospitalizations were consistent across subgroups, which included patients both with and without diabetes, presenter John McMurray, MD (University of Glasgow, Scotland), said here at the European Society of Cardiology Congress 2019, prompting hoots of surprise and scattered applause from the audience. McMurray’s concluding remarks were met with sustained applause and at least one man gave the results a standing ovation.

Marco Metra, MD (University of Brescia, Italy), discussing the results after McMurray’s presentation, pointed out that scale of the benefits—a 26% reduction in the composite endpoint, a 30% reduction on worsening heart failure events, and mortality reductions of 18% for both cardiovascular and all-cause deaths. These, he said, are all equal to or surpass the achievements other landmark trials in this space, dating back more than two decades.

“Also, with respect to quality of life, and this is very important when we treat patients every day, there was a marked improvement in quality of life, again comparable if not numerically larger than what we’ve seen in recent trials,” Metra said.

Commenting on the findings for TCTMD, Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), could scarcely contain his excitement. “I had high expectations going into this trial, but never expected this,” he said. “This is just a ‘wow’ finding that will change practice, hopefully quickly."

Also reacting to the full presentation, Subodh Verma, MD, PhD (St Michael’s Hospital/University of Toronto, Canada), Canadian lead investigator for DAPA-HF, called the results “transformative.”

“These . . . mark the beginning of a new day for heart failure—a grievous and recalcitrant problem which is on the rise,” he told TCTMD by email. “The height of the bar was formidable for DAPA-HF to jump over: demonstrating efficacy on top of excellent standard of care, including ARNI is remarkable. The story of SGLT2 inhibitors is truly one of serendipity, science, and research tenacity that has yielded hope for vulnerable patients with poor prognosis.”

The win for a sodium glucose co-transporter 2 (SGLT2) inhibitor in a heart failure population marks a major step for this class of drugs, coming more than a decade after the US Food and Drug Administration first mandated cardiovascular outcomes trials for up-and-coming diabetes medications. Over the last few years, trials of the SGLT2 inhibitors, developed for the treatment of type 2 diabetes, have also been shown to reduce heart failure hospitalizations in diabetic patients. But as McMurray said here, the magnitude of the benefit in diabetes patients seemed greater than what could be expected by the impact on hemoglobin A1c (HbA1c) levels.

Top-line results for the trial were released last month by the manufacturer AstraZeneca, as reported by TCTMD.

DAPA-HF Details

DAPA-HF enrolled 4,744 patients with heart failure and reduced ejection fraction in 20 countries. Just under half of these patients were found to have diagnosed or undiagnosed diabetes, which McMurray characterized as typical in a HFrEF population. Importantly, patients randomized to 10 mg daily dapagliflozin (Farxiga; AstraZeneca) or matching placebo were given these pills on top of standard care. Most patients were already being managed with an ACE inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor (ARNI), although this last was taken by just 11%, said McMurray. Nearly all patients were taking a beta-blocker, and 71% were taking a mineralocorticoid receptor antagonist.

The primary outcome, a composite of first episode of worsening heart failure (defined as hospitalization or an urgent care HF visit requiring IV therapy) or death from cardiovascular causes, occurred in 16.3% of patients in the dapagliflozin group and in 21.2% of the placebo group (HR 0.74; 95% CI 0.65-0.85). Analyzed separately, worsening heart failure and CV deaths were both significantly reduced in the dapagliflozin-treated patients. Rates of adverse events, however, were low and no different between groups.

To TCTMD, McMurray explained that the investigators were committed to enrolling a representative population of heart failure patients with reduced ejection fraction, in whom diabetes is rampant, rather than attempting to enroll a population free of diabetes. But risk of the primary endpoint in patients without diabetes (HR 0.7 3, 95% CI 0.60-0.88) were nearly identical to those in patients with diabetes (HR 0.75, 95% CI 0.63-0.85). McMurray’s slide zeroing in on this subgroup produced a fresh wave of clapping from the audience.

Moreover, in separate analyses investigators have looked at drug effects according to baseline HbA1c levels, although these results were not part of today’s presentation, McMurray acknowledged at a morning press conference. Offering a glimpse at that analysis, however, McMurray said: “There is no difference across the range of hemoglobin A1c; it is as effective in people with and without elevated HbA1c.”

This is fantastic news for patients with heart failure because now, within the past 5 years, we’ve had two new drugs that reduce mortality in this disease and they work in a complementary way. John McMurray

In a post hoc analysis, McMurray and colleagues also looked at patients taking and not taking sacubitril/valsartan, the most recent blockbuster drug in this space. Here, too, he said, “we saw an entirely consistent benefit of dapagliflozin among patients taking sacubitril/valsartan and those not taking sacubitril/valsartan. And that’s what we expected to find because SGLT2 inhibitors and ARNIs work in completely different ways, and what these data show is that this benefit is additive. So as far as I’m concerned, this is fantastic news for patients with heart failure because now, within the past 5 years, we’ve had two new drugs that reduce mortality in this disease and they work in a complementary way.” 

A New Era?

Commenting on the study results for TCTMD, Scott Solomon, MD (Brigham and Women’s Hospital, Boston, MA), a DAPA-HF co-investigator, called them “absolutely outstanding.”

“This will offer one more therapy in the armamentarium for patients with heart failure and reduced EF,” he said. “In fact, if you look at all the drugs that we've tested for diabetes, the SGLT2 inhibitors just came out to be dramatically better at both preventing heart failure in diabetic patients at risk, but now for the first time in actually treating patients with heart failure.”

Likewise, Steen Dalby Kristensen, MD, DMSc (Cardiovascular Research Centre, Aarhus University, Skejby, Denmark), who was not involved in the trial, called the DAPA-HF data “very convincing.”

“This is really intriguing and could well be the start of new developments in the field,” he told TCTMD. “There are other companies that are doing these kinds of trials, so I think that this might be the start of a new era for patients with heart failure.”

Both Solomon and Kristensen acknowledged that price will be a factor. While ARNIs have looked favorable in cost-efficacy analyses, uptake of these expensive agents has been sluggish, with medication cost often blamed as the most likely explanation. SGLT2 inhibitors are also among the most expensive diabetes drugs, raising the possibility that costs might be prohibitive to patients in whom both agents are recommended.

“I think this is an area where we have to do a better job, especially in the United States—how do we get the appropriate people the healthcare they need?” said Solomon, who like Kristensen said that this will be an important question for regulators and payers.

But Solomon predicted the drugs will likely prove themselves, despite their price tag. “We haven't seen a cost-efficacy analysis yet for dapagliflozin, and I actually don't know what the cost is,” he said. “But we have ourselves done cost-efficacy analyses for sacubitril/valsartan and found that there is evidence that it is highly cost-effective. My guess is we’re going to see the same thing with dapagliflozin.”

Mechanism and Next Steps

Asked how dapagliflozin is exerting these serendipitous effects in heart failure, McMurray offered several possible explanations.

“One is that of course these drugs protect the kidneys, the kidneys contain sodium and water, and that's obviously crucial to the causation of congestion and heart failure symptoms. The second is that these drugs may alter myocardial metabolism to make the failing heart more metabolically efficient and therefore contract better. Thirdly, these drugs may act on other mechanisms that are relevant to heart failure, for example the sodium-hydrogen exchanger, and that may be relevant to, for example, risk of sudden death, and there are many other speculative mechanisms,” he continued. “At the end of the day, like most drugs, for example, the mineralocorticoid receptor antagonists or beta-blockers, we don’t really know how they exert their benefits.”

And of course, he continued, “that’s why we did this trial, because it looked as though the benefit couldn’t just be explained by glucose-lowering.” 

This is just a ‘wow’ finding that will change practice, hopefully quickly. Darren McGuire

Of note, the DAPA-HF study sponsor, AstraZeneca, is also investigating dapagliflozin in the setting of heart failure with preserved ejection fraction. Manufacturers of other SGLT2 inhibitors, such as empagliflozin (Jardiance; Boehringer Ingelheim/Eli Lilly) and canagliflozin (Invokana; Janssen), also have heart failure trials in the works.

Adding that he was thrilled to have been asked to be the one to comment on such a trial, Metra pointed out that with the exception of ivabradine all of the other drug therapies in this space have targeted neurohormonal activity. “With DAPA-HF, we are facing for the first time a new drug with a completely new mechanism of action,” Metra said. “This is the first time—here, now—that we face a new result in patients with heart failure, independent of diabetes, and these results are highly significant. Therefore I’m very proud and honored to be able to announce what in my view is a new era in heart failure medical treatment.”