May 6, 2020 -- The FDA has approved a new use for the drug dapagliflozin (Farxiga) -- to reduce the risk of a hospital stay or death in people who have a type of heart failure.

People with heart failure are more likely to get complications and early death, even when they take other drugs for heart disease such as ACE inhibitors, beta-blockers, and angiotensin receptor blockers.

Farxiga's new approval is to treat heart failure with reduced ejection fraction, which means the left ventricle, or lower chamber, of the heart is too weak to pump blood out to the body very well.

“Heart failure is a serious health condition that contributes to one in eight deaths in the U.S. and impacts nearly 6.5 million Americans,” Norman Stockbridge, MD, PhD, director of the Division of Cardiology and Nephrology in the FDA’s Center for Drug Evaluation and Research, says in a news release.

The approval is good news for people with heart failure, says Wilson Tang, MD, a heart failure specialist and director of heart failure research at Cleveland Clinic's Heart & Vascular Institute. "This is an area where we have had few significant landmark studies and approvals over the past decade." 

Farxiga belongs to a class of diabetes drugs called sodium-glucose cotransporter-2 (SGLT2) inhibitors, which also includes canagliflozin (Invokana), empagliflozin (Jardiance), and ertugliflozin (Steglatro). All four drugs are already FDA-approved to treat type 2 diabetes. They lower blood sugar by stopping the kidneys from absorbing extra sugar in the urine back into the blood.

In October 2019, the FDA also approved Farxiga to reduce the risk of a hospital stay for heart failure in people with type 2 diabetes plus heart disease, or risks for heart disease.


Discovery of a Heart Failure Benefit

Researchers discovered the benefits of SGLT2 inhibitors for treating heart failure somewhat by accident, while studying the effects of these drugs in people with type 2 diabetes. In four large studies, people with type 2 diabetes who took an SGLT2 inhibitor were 25% to 35% less likely to be hospitalized for heart failure -- whether or not they had heart failure at the start of the study. Heart failure is an early and the most common heart-related complication in people with diabetes.

The new approval is based in part on a study called DAPA-HF, which was the first to look at the effects of an SGLT2 inhibitor specifically on heart failure. This study randomly assigned more than 4,700 people who had heart failure to take Farxiga or an inactive pill (placebo) along with their regular heart failure drugs.

After just over 18 months, when Farxiga was added to other heart failure medications, there was an 18% decrease in the risk of death from heart disease and a 17% lower risk of death from all causes. The drug also led to a 26% combined lower risk for a hospital stay due to heart failure, worsening heart failure, or heart-related death. The drug slowed heart failure from getting worse in people both with and without diabetes.

How Does It Treat Heart Failure?

"That's a great question. No one's 100 percent sure. There are lots of different theories," says Deepak Bhatt, MD, executive director of interventional cardiovascular programs at the Brigham and Women's Hospital Heart & Vascular Center. (Bhatt has received funding from AstraZeneca, Farxiga's maker, as well as from Sanofi-Aventis, for his research on SGLT2 inhibitors.)

"The simplest theory is that it's just a really good diuretic -- a medicine that removes fluid from the body," he says. "People with heart failure are often on a diuretic, also called a water pill, to get extra fluid out of their body." As the drug removes sugar from the urine, it also flushes out salt and fluid.

It's likely that other mechanisms are also involved. The drug might increase ketone bodies -- chemicals our bodies make when they break down fats to use for energy. Ketones might improve the heart's energy usage. Or Farxiga and other drugs like it might protect heart muscle cells from more damage.

Bhatt says it will take some time and further research to figure out exactly how Farxiga works to treat heart failure. "I think it could take years to sort it all out."

Side Effects

Genital yeast infections, dehydration, and urinary tract infections (UTIs) are the most common side effects, which happen as Farxiga puts extra sugar into the urine. "When urine has more glucose, there is a higher likelihood for patients to get a UTI," says Tang. Your doctor can check you for these infections if you take Farxiga, and treat you with an antifungal or antibiotic drug if you need it.

You may not be able to take Farxiga if you have severe kidney disease or you're on dialysis, because it could affect how your kidneys work.

Your doctor might do tests to check how well your kidneys are working while you're on this drug if you:

Farxiga can cause serious cases of necrotizing fasciitis of the genital area (Fournier’s gangrene) in people with diabetes and low blood sugar when combined with insulin.

SGLT2 Drugs for Heart Failure

The big challenge now is for cardiologists to figure out when to prescribe this together with several other drugs in their appropriate doses for their patients with heart failure, Tang says. "This always happens with new drug indications, particularly when the drug cost can be relatively high.”

A month's supply of Farxiga for diabetes costs $492. AstraZeneca expects the price to remain the same for heart failure treatment. The company says the amount people actually pay for the drug will depend on their health insurance coverage, their doctor, and any drug assistance programs or savings programs they use.

A remaining question is whether other SGLT2 drugs will also help people who have heart failure. Studies are underway to figure that out. These trials may also shed some light on exactly how this group of drugs works to treat heart failure, and whether they're as effective in people with the other type of heart failure.

Show Sources

AstraZeneca: “FARXIGA approved in the US for the treatment of heart failure in patients with heart failure with reduced ejection fraction,” "Farxiga granted FDA Priority Review for patients with heart failure with reduced ejection fraction," "What can I expect to pay for Farxiga?"

Deepak Bhatt, MD, executive director, interventional cardiovascular programs, Brigham and Women's Hospital Heart & Vascular Center.

Cardiovascular Diabetology: "Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion."

CDC: "Vaginal Candidiasis."

DiaTribe: "FDA Approves New Once-Daily Pill for Type 2 Diabetes: Steglatro."

FDA: "FDA Approves new treatment for a type of heart failure," "FDA Drug Safety Communication: FDA strengthens kidney warnings for diabetes medicines canagliflozin (Invokana, Invokamet) and dapagliflozin (Farxiga, Xigduo XR)," "Prescribing Information: Farxiga," "Sodium-glucose cotransporter-2 (SGLT2) inhibitors."

Mayo Clinic: "Heart failure with preserved ejection fraction (HFpEF): More than diastolic dysfunction."

Mount Sinai: "EMPEROR-HF: A phase III randomized, double-blind trial to evaluate efficacy and safety of once daily empagliflozin 10 mg compared to placebo, in patients with chronic heart failure with reduced ejection fraction (HFrEF)."

The New England Journal of Medicine: "Dapagliflozin in patients with heart failure and reduced ejection fraction."

News release, AstraZeneca.

Kimberly O'Grady, media relations, AstraZeneca.

Wilson Tang, MD, heart failure specialist; director, heart failure research, Cleveland Clinic Heart & Vascular Institute.

U.S. National Library of Medicine: "Dapagliflozin Evaluation to Improve the LIVEs of Patients with PReserved Ejection Fraction Heart Failure (DELIVER)."

UW Health: "Heart failure with reduced ejection fraction (Systolic heart failure)."


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