October 21, 2019 – The U.S. Food and Drug Administration (FDA) has granted market clearance for AstraZeneca's dapagliflozin (Farxiga) to reduce the risk of hospitalization for heart failure (HF) in adults with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or multiple cardiovascular (CV) risk factors.

The approval is based on results from the landmark DECLARE-TIMI 58 CV outcomes trial (CVOT).[1] It is the largest sodium-glucose co-transporter 2 (SGLT2) inhibitor CVOT conducted to date to evaluate T2D patients with multiple CV risk factors or established CV disease. The

“DECLARE-TIMI 58 is a landmark trial, offering compelling evidence that dapagliflozin can reduce the risk of heart failure in patients living with type 2 diabetes with multiple risk factors for or established cardiovascular disease," explained Stephen Wiviott, M.D., associate professor of cardiovascular medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, and a senior investigator with the TIMI Study Group and co-principal investigator of the trial. "These data could help change the way we approach diabetes management – going beyond a singular focus on glucose control to help address the risk of heart failure in a diverse population of patients.”

The drug is the first SGLT2 inhibitor approved in the United States to reduce the risk of hospitalization for heart failure in type 2 diabetes patients with established cardiovascular disease or multiple cardiovascular risk factors, said Ruud Dobber, executive vice president, AstraZeneca, BioPharmaceuticals Business Unit. He explained this is promising news for the 30 million people living with type 2 diabetes in the U.S., as heart failure is one of the earliest cardiovascular complications for them, before heart attack or stroke.

In August, the FDA granted Fast Track designation for dapagliflozin to reduce the risk of cardiovascular death, or the worsening of heart failure in adults with heart failure with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). This was based on the Phase III trials, DAPA-HF and DELIVER.[2-5] and Fast Track designation to delay the progression of renal failure and prevent CV and renal death in patients with chronic kidney disease (CKD) based on the Phase III DAPA-CKD trial. The drug is not indicated to reduce the risk of heart failure, CV death or kidney disease.

Dapagliflozin was also found to reduce death and hospitalization in patients who have HFrEF with and without diabetes. The late-breaking results of the DAPA-HF trial were presented in a Hot Line Session at European Society of Cardiology (ESC) in August 2019. “The most important finding of all is the benefit in patients without diabetes. This is truly a treatment for heart failure and not just a drug for diabetes,” said Principal Investigator John McMurray M.D., MB ChB, FRCP, FESC, FACC, FAHA, FRSE, of the University of Glasgow, U.K.

The FDA approval follows the update to the marketing authorization in the European Union in August 2019. Farxiga is also under regulatory review in China with a decision anticipated in the first half of 2020.

About DECLARE-TIMI 58 Study

DECLARE (Dapagliflozin Effect on Cardiovascular Events)-TIMI 58 is the largest CV outcomes trial conducted for a selective inhibitor of SGLT2 to date in a broad patient population. It is an AstraZeneca-sponsored, Phase III, randomized, double-blind, placebo-controlled, multicenter trial designed to evaluate the effect of dapagliflozin compared with placebo on CV outcomes in adults with T2D at risk of CV events, including patients with multiple CV risk factors or established CV disease and also assessed key renal secondary endpoints. The trial included more than 17,000 patients across 882 sites in 33 countries and was independently run in collaboration with academic investigators from the TIMI study group (Boston) and the Hadassah Hebrew University Medical Center (Jerusalem, Israel).

DECLARE-TIMI 58 showed that dapagliflozin significantly reduced the risk of the primary composite endpoint of hHF or CV death versus placebo by 17% (4.9% vs. 5.8%; HR 0.83 [95% CI 0.73-0.95], p=0.005). This finding was driven by a significant 27% reduction in the risk of hHF (2.5% vs. 3.3%; HR 0.73 [95% CI 0.61, 0.88]). The treatment benefit was consistent across patient subgroups. The Phase III DECLARE-TIMI 58 trial confirmed the well-established safety profile of dapagliflozin.

The full results of the DECLARE-TIMI 58 trial were published in The New England Journal of Medicine in January 2019.[2]

Related Dagliflozin Content:

Dagliflozin Reduces Death, Hospitalization in Heart Failure Patients

FDA Grants Fast Track Designation for Farxiga in Heart Failure

Diabetes Drug Effective Against Heart Failure in Wide Spectrum of Patients

Farxiga Significantly Reduces Cardiovascular Death and Worsening of Heart Failure

Farxiga Reduces Heart Failure Hospitalization, Cardiovascular Death for Type 2 Diabetes — AHA and ACC 2019 Late-breaker

References:

1. Furtado R.H.M., Bonaca M.P., Raz I., et al. Dapagliflozin and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Prior Myocardial Infarction: A Sub-analysis From DECLARE TIMI-58 Trial. Circulation, March 18, 2019. https://doi.org/10.1161/CIRCULATIONAHA.119.039996

2. Stephen D. Wiviott, Itamar Raz, Marc P. Bonaca, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. January 24, 2019. N Engl J Med 2019; 380:347-357. DOI: 10.1056/NEJMoa1812389.

3. McMurray JJV, DeMets DL, Inzucchi SE, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21:665–675. doi: 10.1002/ejhf.1432.

4. McMurray JJV, DeMets DL, Inzucchi SE, et al. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail. 2019. doi:10.1002/ejhf.1548.

5. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure. (DELIVER). NIH U.S. National Library of Medicine, ClinicalTrials.gov. Accessed Oct 21, 2019. https://clinicaltrials.gov/ct2/show/NCT03619213.