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Low EF Heart Failure Benefits Most From SGLT2 Diabetes Drug

NEW ORLEANS — Heart failure benefits with dapagliflozin (Farxiga) for patients with type 2 diabetes are greatest with low ejection fraction (EF), although the effects also accrued for those with preserved EF, according to a prespecified subanalysis of the large DECLARE-TIMI 58 trial reported here.

The sodium glucose co-transporter 2 (SGLT2) inhibitor reduced composite heart failure hospitalization and cardiovascular death risk by a relative 38% in heart failure with an ejection fraction under 45% (HFrEF) compared with 12% in the rest of the study population (P=0.046 for interaction), said Eri Kato, MD, MPH, PhD, of Kyoto University Graduate School of Medicine, at the American College of Cardiology meeting. Findings were also published simultaneously online in Circulation.

Both components were significantly reduced with dapagliflozin in the HFrEF patients, while the other patients saw only a heart failure hospitalization benefit (HR 0.76, 95% CI 0.62-0.92).

All-cause mortality likewise dropped by a relative 41% in HFrEF with dapagliflozin (for a number needed to treat of 16 over 4 years) but was not significantly reduced for others (P=0.016 for interaction), Kato reported at the late-breaking clinical trial session.


“Although we did not see a mortality benefit in those without HFrEF, I think that there is a benefit to all patients,” Kato told attendees. “These patients include heart failure with preserved ejection fraction. And we all know there are few therapies that improve cardiac outcomes in HFpEF patients, so the fact that we saw a reduction in hospitalization for heart failure in HFpEF patients is important and huge.”

Session discussion panelist Donald Lloyd-Jones, MD, of Northwestern University in Chicago, questioned the small absolute effect in patients without HFrEF: “I back-of-the-envelope calculated numbers needed to treat of about 200 for the composite endpoint, 166 for the heart failure hospitalization endpoint, and 500 for the cardiovascular death endpoint.”

That may throw cost-effectiveness into question, he told MedPage Today in an interview. “These data open up for me the question, should we only focus these medications on the low ejection fraction patients, which are a small minority of the group, or is that small benefit enough that we should treat everybody” for cardiovascular event prevention, aside from glucose lowering effects.

“This is perhaps suggesting a more limited use of the medication than we previously thought,” he added, but “there are trials coming that I hope will give us more insight into this.”

Roughly 40% of the HFpEF population has diabetes, so it’s an important question, noted Kim Eagle, MD, of the University of Michigan in Ann Arbor.

“We’ve been looking for kind of the ‘holy grail’ of treating HFpEF, and at least in the diabetics we have a tool that appears to address that,” he said, referring to the heart failure hospitalization reduction. “And certainly the DECLARE results also say this class of drugs must strongly be considered in patients with reduced ejection fraction if they are diabetic.”

Clyde Yancy, MD, of Northwestern University in Chicago, noted the consensus recommendation support given to using SGLT2 inhibitors and other drugs proven to have a heart benefit in diabetes.

However, he cautioned, “if in heart failure we’ve been so careful to articulate an algorithm, a process of care, let’s not just short-circuit everything else about diabetes and go straight to a new drug. Think about the diet, think about other diabetes therapies, think about the monitoring system, incorporate the SGLT2 inhibitor in the correct place … so that the use will generate the kind of outcomes we wish.”


DECLARE was not a dedicated HF trial, so while baseline heart failure status was available for all 17,160 participants, only about 5,000 had data on EF.

Only 671 patients (3.9%) had HFrEF, while 1,316 patients (7.7%) had HF without a reduced EF (808 with documented preserved EF and 508 without a documented EF). The rest, without a history of HF or documented EF under 45%, were also pooled into the no-HFrEF group.

“These findings must be treated with caution given that they reflect subgroup analyses, and because there are many data on EF missing,” cautioned Subodh Verma, MD, PhD, of the University of Toronto, and John McMurray, MD, of the University of Glasgow, in an accompanying Circulation editorial. Also, they pointed out the observations were “based on small numbers (<100 cardiovascular deaths in each heart failure subgroup) and is thus purely hypothesis generating."

Less than half of the HFrEF patients were on a loop diuretic at baseline, noted Lloyd-Jones. “I wonder if the well-known diuretic effects of this drug were actually helping patients who should have been on a loop diuretic anyway? Are we just seeing the diuretic effect of this medication?”

Kato acknowledged that heart failure medication was left to the treating physician, so there may have been diuretic titration, which her group plans to look at in a separate analysis.

But taking the main trial findings together with those of the other SGLT2 inhibitors, “I think the mechanism is really multifactorial. I think it’s not just fluid loss,” Kato responded, pointing to the blood pressure and weight reductions seen as well.

Lloyd-Jones agreed, noting that diuretic effects would not fully explain the difference in mortality.

DECLARE-TIMI 58 was funded by AstraZeneca.

Kato reported personal fees from Daiichi Sankyo, grants and personal fees from Ono Pharmaceutical, personal fees from AstraZeneca, personal fees from Bristol-Myers Squibb, and personal fees from Tanabe-Mitsubishi Pharma, outside the submitted work. MGS reported grants from the John S. LaDue Memorial Fellowship from Harvard Medical School, and from the ZOLL Foundation.

Verma reported relationships with Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Valeant. He is a member of the scientific excellence committee of the EMPEROR-Preserved and EMPEROR-Reduced trials; a member of the scientific committee of the DETERMINE-A and DETERMINE-B trials; a member of the global expert panel of the SELECT study; and a national lead investigator of the Dapa-HF, DELIVER, DETERMINE-A, DETERMINE-B, EMPEROR-Preserved, EMPEROR-Reduced, SELECT, and SOLOIST studies.

McMurray reported relationships through his employer, the University of Glasgow, with AbbVie, AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, DalCor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Stealth, Theracos, and Sanofi-Aventis.


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