AstraZeneca Reports Full Results from DECLARE-TIMI 58 Cardiovascular Outcomes Trial for FARXIGA (dapagliflozin)

November 12, 2018;  Reproduced from StreetInsider

AstraZeneca today announced positive full results from the DECLARE-TIMI 58 cardiovascular (CV) outcomes trial (CVOT) for FARXIGA (dapagliflozin). The data were presented as a late-breaking abstract (#19485) at the American Heart Association (AHA) Scientific Sessions 2018 in Chicago, IL, and simultaneously published in the New England Journal of Medicine (NEJM).

Results from DECLARE-TIMI 58, the largest SGLT-2 inhibitor (SGLT-2i) CVOT conducted to date, including more than 17,000 patients across 33 countries, showed that FARXIGA significantly reduced the risk of hospitalization for heart failure (hHF) or CV death composite vs. placebo by 17% (4.9% vs. 5.8%; HR 0.83 [95% CI 0.73-0.95], p=0.005), one of the two primary efficacy endpoints. The reduction in hHF or CV death was consistent across the entire patient population, which included those with CV risk factors and those with established CV disease.1 FARXIGA is not indicated to reduce the risk of CV events or hHF.

Additionally, there were fewer major adverse cardiovascular events (MACE) observed with FARXIGA for the other primary efficacy endpoint, however this did not reach statistical significance (8.8% for FARXIGA vs. 9.4% for placebo; HR 0.93 [95% CI 0.84-1.03], p=0.17).1

DECLARE-TIMI 58 also confirmed the well-established safety profile for FARXIGA, which met the primary safety endpoint of non-inferiority vs. placebo, demonstrating no increase in the composite of MACE, defined as CV death, heart attack (myocardial infarction), or stroke.

Further, on other relevant safety measures, the trial showed no imbalance with FARXIGA vs. placebo in amputations (1.4% vs. 1.3%), fractures (5.3% vs. 5.1%), bladder cancer (0.3% vs. 0.5%) or Fournier’s gangrene (1 case vs. 5 cases). The respective incidences of diabetic ketoacidosis (0.3% vs. 0.1%) and genital infections (0.9% vs. 0.1%) were rare.1

Elisabeth Björk, Vice President, Head of Cardiovascular, Renal and Metabolism, Global Medicines Development, said: “These positive results are clinically relevant to the 425 million people worldwide living with diabetes, of whom those with type 2 diabetes have a two-to-five times greater risk of heart failure along with an increased risk of a heart attack or stroke. Heart failure survival rates are only 50% after five years from diagnosis, which is why these new findings are so important in broadening our understanding of how to go beyond blood glucose, so we may better address this serious and often overlooked cardiovascular complication.”2-6

Although secondary endpoints were only nominally significant, the renal composite endpoint showed that FARXIGA reduced the rate of new or worsening nephropathy by 24% vs. placebo across the broad patient population studied (4.3% vs. 5.6%; HR 0.76 [95% CI 0.67-0.87]), and there were fewer all-cause mortality events with FARXIGA vs. placebo (6.2% vs. 6.6%; HR 0.93 [95% CI 0.82-1.04]).1 FARXIGA is not indicated to reduce the risk of HF, other CV outcomes, nephropathy or all-cause mortality.

References:

Zinman, Bernard, et al. “Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.” New England Journal of Medicine 373.22 (2015): 2117-2128.

Wanner, Christoph, et al. “Empagliflozin and progression of kidney disease in type 2 diabetes.” New England Journal of Medicine 375.4 (2016): 323-334.

Neal, Bruce, et al. “Canagliflozin and cardiovascular and renal events in type 2 diabetes.” New England Journal of Medicine 377.7 (2017): 644-657.

Wiviott SD et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine Nov 12, 2018 DOI: 10.1056/NEJMoa1812389

Commentary:

Dapagliflozin is the third SGLT2 inhibitor that has completed a cardiovascular outcome trial (CVOT), as required for all new drugs approved for treatment of type 2 diabetes (see FDA Guidance).  Previous CVOT studies include EMPA-REG Outcome trial  for empagliflozin and the CANVAS study for canagliflozin.  The results for dapagliflozin are not as compelling since it did not reduce MACE compared to placebo. Another interesting finding with SGLT2 inhibitors is their ability to slow the progression of renal disease in type 2 diabetes and perhaps even in non-diabetic chronic kidney disease. The renal outcome trial of canagliflozin (CREDENCE trial) was recently stopped earlier than planned due to meeting the pre-specified primary composite endpoint.  The empagliflozin renal outcome trial is also ongoing and is based on encouraging secondary reno-protection data from the EMPA-REG Outcome trial (see here). These encouraging results open new therapeutic options to slow the progression of CKD not only in patients with type 2 diabetes and cardiovascular disease but in patients with CKD due to other causes. The result of the CANVAS trial are awaited with great enthusiasm from the renal community.

Copyright © M. Loghman-Adham, MD

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