Exciting days ahead for dapagliflozin with expanding role in heart failure |
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Exciting days ahead for dapagliflozin with expanding role in heart failure
Dr Sanjay Kalra, DM (AIIMS); President-elect, SAFES, Bharti Hospital, Karnal, India; and Dr Sandeep Chaudhary, NMC Hospital, Dubai, UAE,  09 May 2022
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Adding to the evidence for dapagliflozin, the ground breaking DELIVER trial, released on Thursday, has further broadened the scope of its clinical application. Dapagliflozin was found to safely and effectively reduce the primary composite endpoint of cardiovascular death or hospitalization or emergency visit for HF in patients with mildly reduced or preserved ejection fraction (HFpEF) according to a press note.1

 

The international, multicenter, placebo-controlled Dapagliflozin Evaluation to improve the LIVEs of patients with pReserved ejection fraction heart failure (DELIVER) trial was conducted in  HFpEF patients with symptomatic HF and left ventricular ejection fraction (LVEF) greater than 40% with or without type 2 diabetes where in patients were randomized to dapagliflozin 10 mg once daily or placebo.

These results are an encore to the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) published in the New England Journal of Medicine in October 2021, where empagliflozin 10 mg reduced the risk of CV-related mortality and/or hospitalizations in HF patients (NYHA class II - IV) with preserved ejection fraction (>40%).

Though the outcomes in the DELIVER and the EMPEROR-Preserved trials were comparable and both demonstrated beneficial effects of the SGLT2 inhibitor under study in the respective trials, there is some difference in the composition of the trial population between the two, which perhaps tilts the scales in favor of dapagliflozin.

The EMPEROR-Preserved trial, which examined ≈5750 patients, excluded high risk patients such as those with heart diseases like ACS, stroke, or TIA within 90 days, acute decompensated HF, symptomatic hypotension and other comorbid conditions like acute or chronic liver or kidney disease (eGFR < 20 mL/min/1.73 m2), chronic and significant lung disease. N-terminal pro–B-type natriuretic peptide (NT-proBNP) was ≥300 pg/ml without atrial fibrillation (AF) and >900 pg/ml with AF. It included HF patients if they had been hospitalized within 12 months.

The DELIVERY trial is the largest trial to date of HFpEF patients conducted at 353 sites across 20 countries, with more than 6000 participants. It also included patients with mildly reduced ejection fraction. They were potentially at high risk because a significant proportion of them had comorbid conditions like type 2 diabetes, obesity (BMI ≥30 kg/m2). More than half had atrial flutter or atrial fibrillation. The median NT-proBNP levels  were also higher (1011 pg/ml). Besides outpatients, the trial also enrolled patients who were actively hospitalized or had been recently hospitalized (within 3 months of their recruitment). And, interestingly, it has included patients with improved LVEF (known LVEF <40% previously), a group which has generally been left out from HF trials and therefore has not been studied much until now.

Dapagliflozin is an oral sodium-glucose co-transporter-2 (SGLT2) inhibitor. It has been a widely studied drug as demonstrated by the expanding indications of clinical use.

It was the first of the gliflozins to be FDA-approved for the management of type 2 diabetes mellitus (T2DM) as an adjunct to diet and exercise in 2014. Subsequently, in 2019, it was approved to reduce the risk of hospitalization for HF in adult patients with type 2 diabetes and established CV disease or multiple CV risk factors in 2019. It was approved for use in patients with heart failure with reduced ejection fraction in 2020 based on the results of the DAPA-HF trial. And last year, it became the first SGLT2 inhibitor to be approved for use in CKD patients regardless of their diabetic status following the successful DAPA-CKD trial.

In India, dapagliflozin is approved as monotherapy for type 2 diabetes and recently it has also been approved for heart failure patients with reduced ejection fraction. It is particularly useful for diabetics who often have coexisting heart disease and/or chronic kidney disease.

Dapagliflozin is not yet approved for use in HF patients with preserved ejection fraction, but the DELIVER trial does make a strong case for its role in this patient population, which remains vulnerable to adverse CV outcomes for want of specific therapy, which also reduces mortality. Along with the DAPA-HF trial, “The results of DELIVER extend the benefit of dapagliflozin to the full spectrum of patients with heart failure”, said Dr Scott Solomon, Professor of Medicine at Harvard Medical School and Brigham and Women’s Hospital and Principal Investigator of the trial. But at this point of time, we do not have enough details to know the impact of dapagliflozin on the secondary end points of the trial. The complete results are awaited.

References

  1. https://www.astrazeneca-us.com/content/az-us/media/press-releases/2022/farxiga-met-primary-endpoint-in-deliver-phase-III-trial.html
  2. Solomon SD, et al. Baseline characteristics of patients with HF with mildly reduced and preserved ejection fraction: DELIVER Trial. JACC Heart Fail. 2022 Mar;10(3):184-197.
  3. Anker SD, et al; EMPEROR-Preserved Trial Investigators. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021 Oct 14;385(16):1451-1461.
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