Less Heart Failure Hospitalization on Dapagliflozin in Diabetes at Any LVEF, Declares DECLARE-TIMI 58

Marlene Busko

April 04, 2019

NEW ORLEANS — Patients with type 2 diabetes who received dapagliflozin (Farxiga/Forxiga, AstraZeneca) in the DECLARE-TIMI 58 trial showed a reduced risk for heart-failure (HF) hospitalization, regardless of their baseline left-ventricular ejection fraction (LVEF).

Also, patients with an LVEF below 45% treated with the sodium glucose cotransporter 2 (SGLT2) inhibitor, compared with placebo control subjects, had lower all-cause mortality and fewer cardiovascular (CV) deaths in the prespecified secondary analysis of the randomized trial.

DECLARE-TIMI 58 had compared dapagliflozin wth placebo in about 17,000 patients with diabetes, including 7000 with established CV disease and 10,000 without CV disease but with multiple CV risk factors, all on a background of standard medical therapy.

In the trial's primary analysis reported last year, those treated with dapagliflozin showed a significant 27% reduced risk for the secondary end point of HF hospitalization over a median follow-up of 4.2 years. The drug also seemed renoprotective in this group.

The current analysis tries to tease out the possible benefits of dapagliflozin by HF history and LVEF, and notably suggests that the drug reduced the risk for HF hospitalization in patients, many with HF and preserved ejection fraction (HFpEF), observed Eri T. Kato, MD, MPH, PhD, Kyoto Graduate School of Medicine, Japan.

"I want to emphasize that dapagliflozin reduced hospitalization for heart failure regardless of ejection fraction," she said. So, although there was no survival benefit in patients without HF and reduced ejection fraction (HFrEF), there is at least some important clinical benefit in all the patients.

"We all know there are only a few therapies that would 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."

Kata presented the DECLARE-TIMI 58 secondary analysis during a late-breaking clinical trial session and press briefing at the recent American College of Cardiology 68th Annual Scientific Session (ACC.19). She is also lead author on the study's simultaneous publication in Circulation.

Not the Final Word

Kato acknowledged that the analysis has limitations that make it far from conclusive, including the fact that the trial wasn't an HF trial per se and LVEF was not consistently measured.

"The objective of this study was not really heart failure, and I found that the number of patients with reduced ejection fraction was rather small, agreed Valentin Fuster, MD, PhD, Mount Sinai Hospital, New York City, the assigned discussant at the press briefing. So, he added, "I would call these preliminary data."

Also, the analysis categorized patients in unconventional ways. For example, it defined patients with HFrEF, 3.9% of the total trial population, as having an LVEF below 45% whether or not there was also a history of clinical HF.

Of the remaining patients — classified as non-HFrEF — 7.7% had a history of clinical HF and 88.4% had no clinical history of HF. However, in both of these groups, there was no documentation that LVEF was below 45%, which could mean that LVEF was at least 45% or that LVEF was not documented.

Studies like this one, "that is, thought-provoking or hypothesis-generating," help clinicians identify which patients would be most likely to benefit from a therapy, press briefing moderator and ACC.19 vice chair Pamela Morris, MD, Medical University of South Carolina, Charleston, commented to theheart.org | Medscape Cardiology.

The current DECLARE-TIMI 58 analysis, she said, "would suggest that our HFrEF patients are going to be those we should really think hard about prescribing an SGLT2 inhibitor to."

Agreeing, coauthor and press-briefing panelist Deepak L. Bhatt, MD, MPH, Brigham and Women's Hospital, Boston, said: "I think it provides some insight into how SGLT2 inhibitors — I think it is a class effect — can reduce heart failure hospitalization across the full spectrum of patients with diabetes."

And as "the icing on the cake," he said, "there appears to be a reduction in all-cause mortality, largely confined to patients who have heart failure with reduced ejection fraction."

The current study isn't "the definitive word" on whether SLGT2 inhibitors can prolong survival in patients with HFpEF, Bhatt said. "But if I had to bet, this provides a pretty strong signal to me that a lot of the benefit in terms of hard events and end points might be in those with worse ejection fractions."

But, "that doesn't diminish the importance in those with HFpEF or in those with no heart failure at all."

Class Effect?

Treatment with the SGLT2 inhibitors dapagliflozin, empagliflozin (Jardiance, Boehringer Ingelheim), or canagliflozin (Invokana, Vokanamet, Janssen), which lower glucose levels by inhibiting renal absorption, has been associated with decreased risk for CV death or HF hospitalization for heart failure.

Those were the findings in DECLARE-TIMI 58 and the EMPA-REG OUTCOME and CANVAS trials, respectively.

In the current analysis, there was a 36% reduction in HF hospitalization in the patients with HFrEF who received dapagliflozin compared with placebo (hazard ratio [HR], 0.64; 95% CI, 0.43 - 0.95) and a 24% reduction in the non-HFrEF group (HR, 0.76; 95% CI, 0.62 - 0.92).

In the group with HFrEF as defined in the analysis, those receiving dapagliflozin had an HR of 0.55 (95% CI, 0.34 - 0.90) for CV death and an HR of 0.59 (95% CI, 0.40 - 0.88) for death from any cause.

That means, the report states, that only 16 patients with type 2 diabetes and HFrEF would need to be treated for 4 years to prevent one death from any cause, and only 19 such patients to prevent one CV death.

However, non-HFrEF patients who received dapagliflozin or placebo showed a similar risk for CV death (HR, 1.08; 95% CI, 0.89 - 1.31) and for death from any cause (HR, 0.97; 95% CI, 0.86 - 1.10).

Dapagliflozin, which has diuretic properties, was not associated with an increase in risk for serious adverse events, symptoms from volume depletion, or acute renal failure in either of the HF groups.

Other Questions

"At baseline, less than half of the people were on a looped diuretic, and these are patients who have HFrEF," said Donald M. Lloyd-Jones, MD, Northwestern University, Chicago, alluding to what seemed to be diuretic undertreatment in that group.

"So is this drug just more furosemide, or some furosemide, for patients who maybe should have been on it anyway?" asked Lloyd-Jones from the panel after Kato's formal presentation of the analysis.

Other research suggests that dapagliflozin has a multifaceted mechanism of action, not just a diuretic effect, Kato replied.

"In patients with diabetes who have had a prior myocardial infarction, the use of an SGLT2 inhibitor should be strongly considered as part of routine secondary prevention. In these individuals, SGLT2 inhibitors will reduce ischemic, heart failure, and renal events, benefits which appear to be mediated largely via glucose-independent mechanisms," an accompanying editorial states.

"Whether patients with a recent acute coronary syndrome can also be treated safely and effectively with a SGLT2 inhibitor has not been studied, and a definitive recommendation cannot be given," write authors Subodh Verma, MD, PhD, University of Toronto, and John J.V. McMurray, MB, MD, University of Glasgow, United Kingdom.

"As for patients with heart failure, especially heart failure with preserved EF, we suggest waiting for the results of the dedicated studies with SGLT2 inhibitors which are ongoing in people with heart failure (and chronic kidney disease)."

Among those trials, Kato observed, are the Dapa-HF and EMPEROR-Reduced trials in patients with HFrEF, and the DELIVER, PRESERVED-HF, and EMPEROR-Preserved trials in patients with HFpEF.

"The ongoing trials," Verma and McMurray suggest, "will also answer the two remaining questions about the potential use of these drugs in patients with heart failure  —can they be used in patients without diabetes and can they be used in patients hospitalized with acute decompensation?"

DECLARE-TIMI 58 was funded by AstraZeneca. Kato reports receiving personal fees from Daiichi Sankyo, AstraZeneca, Bristol-Myers Squibb, and Tanabe-Mitsubishi Pharma; and grants and personal fees from Ono Pharmaceutical. Disclosures of the other authors are listed with the article. Morris discloses receiving consultant fees or honoraria from Amgen, Esperion, and Sanofi Regeneron. Fuster and Lloyd-Jones had no disclosures. Verma discloses receiving research grants and/or speaking honoraria from Amgen, AstraZeneca, Bayer Healthcare, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Servier, and Valeant; and that 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 reports that his employer, the University of Glasgow, paid for his participation in clinical trial committees by AbbVie, AstraZeneca, Amgen, Bayer, Bristol-Myers Squibb, Dalcor, GlaxoSmithKline, Merck, Novartis, Resverlogix, Stealth and Theracos and that these sponsors funded some costs to attend meetings; and the university paid for attendance by Novartis and Sanofi-Aventis advisory boards. Bhatt discloses serving on advisory boards of Cardax, Medscape Cardiology, PhaseBio, and Regado Biosciences; the board of directors of TobeSoft; the DSMB of the St. Jude Medical PORTICO trial funded by St. Jude Medical; the ExCEED trial funded by Edwards Lifesciences; and the ENVISAGE trial funded by Daiichi Sankyo; receiving honoraria for committee work on trials funded by Boehringer Ingelheim and Bayer and for serving on a WebMD steering committee; receiving research funding from Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Eisai, Ethicon, Forest Laboratories, Idorsia, Ironwood, Ischemix, Eli Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company; serving as site coinvestigator for Biotronik, Boston Scientific, St. Jude Medical, and Svelte; and having uncompensated research collaborations with FlowCo, Fractyl, Merck, Novo Nordisk, PLx Pharma, and Takeda

American College of Cardiology (ACC) 68th Annual Scientific Session: Abstract 409-14. Presented March 18, 2019.

Circulation. Published online March 18, 2019. Full text, Editorial

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