By: Adrian Wong, PharmD Candidate c/o 2021

On May 5, 2020, the Food and Drug Administration (FDA) announced its approval for Farxiga® (dapagliflozin) oral tablets to have a new indication: to lower the risk of cardiovascular death and hospitalization for adults with New York Heart Association (NYHA) functional class II-IV heart failure (HF) with reduced ejection fraction (HFrEF).¹ Dapagliflozin is part of a drug class called sodium-glucose cotransporter 2 (SGLT2) inhibitors. Dapagliflozin works by selectively inhibiting SGLT2 in the proximal renal tubules, thus leading to increased glucose excretion and subsequent decreased serum glucose concentrations.² By this mechanism, dapagliflozin, first approved for its use in the US in 2014, first carried a labeled indication as an antidiabetic agent to be used as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus (T2D).³

The initial intrigue into SGLT-2 inhibitors and their cardiovascular effects stemmed from the thought that these selective inhibitors (in addition to their effects on glucose) reduce sodium reabsorption and increases sodium delivery to the distal tubule, thus causing a decrease cardiac preload/afterload and overall, downregulate sympathetic activity.² This thought has been supported by large studies involving patients with T2D, including one funded by AstraZeneca titled, the Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58 (DECLARE-TIMI 58) trial. This trial concluded that patients with T2D who have an established cardiovascular disease or risk factors, had a lower rate of hospitalization for heart failure while on dapagliflozin.⁴ The results of this trial subsequently led the FDA in 2019 to approve dapagliflozin for the reduction of hospitalizations for heart failure in adults with T2D.⁵

Most recently, a phase 3, randomized, placebo-controlled trial funded by AstraZeneca titled, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) took a look at the effects dapagliflozin had on patients diagnosed with NYHA Class II-IV HF with an ejection fraction of ≤40% regardless if they had a diagnosis of T2D or not. Patients who were included in this study received standard heart-failure device therapies (e.g. implantable cardioverter-defibrillator) as well as a standard drug therapy regimen as appropriate (e.g. angiotensin converting enzyme inhibitors, angiotensin-receptor blockers, and/or beta blockers) in addition to either 10 mg of dapagliflozin once daily or placebo. The results of this study showed that when compared to placebo, patients receiving dapagliflozin had better outcomes with regards to worsening heart failure;16.3% of the 2373 patients receiving dapagliflozin experienced a worsening of HF, as compared with 21.2% of the 2371 patients who received placebo (Hazard ratio, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001).⁶ Furthermore, there were no statistically significant differences between the dapagliflozin group and placebo with regards to adverse effects.⁶

Overall, researchers of the trial concluded that patients who received SGLT2 inhibitor therapy had a lower risk of worsening HF or resultant death than those who received placebo regardless of their diabetic status. Results from this study prompted the FDA to quickly announce its approval for dapagliflozin to be indicated for the hospitalization and cardiovascular death risk reduction of NYHA HF Class II-IV patients with reduced ejection fraction. With this new exciting and groundbreaking approval, dapagliflozin is now the first drug in its class to carry this indication.

Sources:

1. Richards M. FDA approves new treatment for a type of heart failure. fda.gov. https://www.fda.gov/news-events/press-announcements/fda-approves-new-treatment-type-heart-failure. Published 05/05/2020
2. Dapagliflozin. Lexi-Drugs. Hudson, OH: Lexicomp, 2015. http://online.lexi.com/. Updated September 19, 2020. Accessed September 13, 2020.
3. Stewart J. Farxiga FDA Approval History. drugs.com. https://www.drugs.com/history/farxiga.html. Published 01/08/2014. Last Updated 05/06/2020.
4. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. doi: 10.1056/NEJMoa1812389
5. Melillo G. FDA approves Dapagliflozin to treat Heart Failure, breaking new ground in SGLT2 Competition. ajmc.com. https://www.ajmc.com/view/fda-approves-dapagliflozin-to-treat-heart-failure-breaking-new-ground-in-sglt2-competition. Published 05/06/2020.
6. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381(21):1995-2008. doi: 10.1056/NEJMoa1911303

Published by Rho Chi Post