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DAPA-HF: Dapagliflozin’s HFrEF efficacy confirmed in nondiabetics

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A dapagliflozin labeling change comes next

A labeling change for dapagliflozin that says the drug is approved for use in patients with heart failure with reduced ejection fraction (HFrEF) and without diabetes is critical so that payers will get on board with this new and important treatment. The evidence for efficacy and safety in patients without diabetes was so strong in the DAPA-HF trial that I don’t think a second trial will be needed for the Food and Drug Administration to add this indication to dapagliflozin’s label.

For patients with type 2 diabetes as well as HFrEF, it’s already full steam ahead to use dapagliflozin or another drug from the class of sodium glucose co-transporter 2 (SGLT2) inhibitors, empagliflozin and canagliflozin. However, so far these drugs are not being widely prescribed by clinicians to patients with HFrEF but without diabetes. We need to build up the familiarity of clinicians with the SGLT2 inhibitor drugs so that primary care physicians will feel comfortable starting HFrEF patients on them. It’s relatively easy to start patients on the drugs in this class because of their good safety and no signal of problems when using them with other HFrEF medications.

The growing list of key drugs to use on patients with HFrEF means that we need to become smarter on how we start patients on these agents. Currently it’s done without evidence for which order of introduction works best. We also need to confirm that all five types of drugs that now appear indicated for HFrEF patients are all truly additive: an angiotensin receptor blocker coupled with the angiotensin receptor neprilysin inhibitor sacubitril, a beta-blocker, a mineralocorticoid receptor antagonist, and now an SGLT2 inhibitor. I propose that researchers run studies that systematically stop one of these drugs to see whether the overall benefit to HFrEF patients remains unchanged, thereby identifying an agent that could be dropped from what is a growing list of drug classes, with possibly more classes to follow depending on results from studies now underway.

Dr. Christopher M. O'Connor, president, Inova Heart and Vascular Institute, Falls Church, Va.

Dr. Christopher M. O'Connor

Christopher M. O’Connor, MD, is a heart failure physician and president of the Inova Heart and Vascular Institute in Falls Church, Va. He has been a consultant to Arena, Bayer, Bristol-Meyers Squibb, Merck, and Windtree Therapeutics. He made these comments in an interview.



– The primary outcome results from the practice-changing DAPA-HF trial gave clinicians strong evidence that the diabetes drug dapagliflozin was equally effective at reducing cardiovascular death and acute exacerbations in patients with heart failure with reduced ejection fraction, whether or not they also had type 2 diabetes. More detailed findings from the 2,605 enrolled patients in DAPA-HF who lacked diabetes (55% of the total study population) have now sealed the deal.

Mitchel L. Zoler/MDedge News

Dr. John McMurray

“The relative and absolute reductions in cardiovascular death and hospitalizations or urgent visits for heart failure were substantial, clinically important, and consistent in patients with or without type 2 diabetes,” John McMurray, MD, declared at the American Heart Association scientific sessions as he summarized new trial results that confirmed the initial finding he reported previously.

While the initial report of the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) by the study’s lead investigator, Dr. McMurray, was limited to the finding that the relative risk reduction for the study’s primary endpoint was a highly statistically significant 25% in heart failure patients with diabetes and an equally strongly significant 27% relative cut among patients without diabetes (N Engl J Med. 2019 Sep 19;doi: 10.1056/NEJMoa1911303), the new data showed that same consistency across the range of outcomes studied in the trial as well as across the range of glycosylated hemoglobin levels that patients had at study entry.

In an analysis that divided the entire study population of 4,744 patients with heart failure with reduced ejection fraction (HFrEF) into tertiles based on their entry blood level of hemoglobin A1c, patients with a normal level at or below 5.6% had a 26% relative reduction in the study’s primary endpoint, essentially the same response as the 29% relative cut in adverse events in the tertile of patients with a glycosylated hemoglobin level of 5.7%-5.9% and the relative 28% relative reduction in events in patients diagnosed with type 2 diabetes and having a hemoglobin A1c of 6.0% or greater, reported Dr. McMurray, professor of cardiology at the University of Glasgow. The results also showed a very benign safety profile in the patients without diabetes, similar to patients with diabetes and to placebo, and with no episodes of major hypoglycemia or diabetic ketoacidosis.

“It’s quite impressive that the result was consistent regardless of the level of hemoglobin A1c,” commented Larry A. Allen, MD, professor of medicine at the University of Colorado in Aurora and designated discussant for the report. Even though the patients without diabetes constituted just over half of the full DAPA-HF enrollment, the comparison of the effect of dapagliflozin in patients with or without diabetes was prespecified in a trial that enrolled a relatively large number of patients into each of the two subgroups by diabetes status. “I think there a good chance dapagliflozin will get an indication” for treating HFrEF patients without diabetes, Dr. Allen suggested in a video interview.

If the DAPA-HF results persuade the U.S. Food and Drug Administration to grant a supplemental indication to dapagliflozin for use in cutting cardiovascular deaths and acute heart failure exacerbations in patients without diabetes, it would pave the way for health insurers to pay for the drug. Right now, even though Dr. Allen and other heart failure physicians have been impressed by the DAPA-HF findings and are eager to add the drug to the list of agents that HFrEF patients routinely receive, he’s been stymied so far by patients’ out-of pocket cost for using dapagliflozin off-label, roughly $500 a month.

“The DAPA-HF results suggest there is strong reason to consider dapagliflozin for patients without diabetes, and for payers to pay for it. I’m not prescribing dapagliflozin to HFrEF patients without diabetes right now; not because of the data, but because of noncoverage. Payers have not yet caught up with the data,” he said, and they likely will continue to not pay for the drug when used by patients without diabetes until a new labeled indication appears for those patients.

The immediate availability of dapagliflozin (Farxiga) and the two other approved members of the sodium-glucose co-transporter 2 inhibitor class of drugs, empagliflozin (Jardiance) and canagliflozin (Invokana), to treat patients with HFrEF, and the prospect of soon having dapagliflozin and possibly the other drugs in this class to treat patients with HFrEF but without diabetes also raises issues of drug sequencing in these patients and the overall number of drugs that HFrEF patients must now take to be on optimized medical therapy, Dr. Allen noted.

The already-existing lineup of medications for HFrEF patients includes starting on an ACE inhibitor or angiotensin receptor blocker and adding a beta-blocker, a mineralocorticoid receptor antagonist, then swapping out the initial renin-angiotensin system inhibitor for sacubitril/valsartan, and then, on top of all this, adding dapagliflozin or another drug in the same class. It raises questions of what is objectively the best way to introduce all these drugs into patients, and how to do it without subjecting patients to “financial toxicity,” Dr. Allen said during his discussion of the trial’s results.

DAPA-HF was sponsored by AstraZeneca, which markets dapagliflozin (Farxiga). The University of Glasgow received payment from AstraZeneca to compensate for the time Dr. McMurray spent running the study. Dr. Allen has been a consultant to ACI Clinical, Boston Scientific, and Janssen.

[email protected]

SOURCE: McMurray JJV. AHA 19, Late-Breaking Science 1.

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