FDA approves dapagliflozin for HFrEF regardless of diabetes status

Gregg C. Fonarow, MD, FACC, FAHA, FHFSA

This FDA approval of a new-labeled indication of dapagliflozin for HF patients with or without diabetes to lower the risk for CV death and hospitalization for HF represents a critical milestone. This provides clinicians and patients with HF a new treatment option that provides incremental benefits to sacubitril/valsartan (Entresto, Novartis), beta-blockers and aldosterone antagonists. This sets the stage for integrating SGLT2 inhibitors as part of the new gold standard of care for HFrEF.

This therapy provides meaningful improvements in health status, reductions in the risk hospitalization and rehospitalization, and clinically relevant reductions in CV death. Further, dapagliflozin reduces all-cause mortality in patients with HFrEF, demonstrating the overall benefits outweigh the summation of any potential risks.

This is the first approved labeling for use in patients without diabetes, establishing SGLT2 inhibitors and, specifically, dapagliflozin as an evidence-based, FDA-approved HF medication.

The label approval will all translate to greater access, formulary additions, coverage and awareness regarding the benefit of this class of therapy as a HF treatment.

All physicians that care for patients with HF should be prescribing this therapy to eligible HFrEF patients without contraindications. This includes cardiologists.

Many cardiologists were reluctant to prescribe these medications previously, viewing them as diabetes medications, and best left to the patients’ endocrinologist or primary care physician, leaving very few patients treated. The DAPA-HF trial and the new FDA-approved labeling require a reframing of this therapy as one of the essential components of evidence-based HF therapy.

We just published a paper in JAMA Cardiology (Bassi NS, et al. JAMA Cardiol. 2020;doi: 10.1001/jamacardio.2020.0898.) on optimal implementation of SGLT2 inhibitors in the U.S. In this study, we demonstrate that the addition of SGLT2 inhibitor therapy to the standard medical regimen for patients with HFrEF would be estimated to save 34,125 lives each year in the United States.

There is a critical need for implementation of randomized clinical trial evidence for SGLT2 inhibitors into routine clinical practice in a timely manner to achieve important population health benefits and to reduce the substantial mortality burden of HF.

Mikhail Kosiborod, MD, FACC, FAHA

Until now, SGLT2 inhibitors have been considered mainly as diabetes medications. We have previously learned from several large outcome trials that they can effectively reduce the risk of the two most common and deadly complications of type 2 diabetes, namely CVD (especially HF) and kidney disease. The FDA indications for various SGLT2 inhibitors, including those for reducing CV and kidney disease risk, have all been specifically in patients with type 2 diabetes until now.

This new indication for dapagliflozin truly opens a new ear for SGLT2 inhibitors. It is based on the results of the DAPA-HF trial, which proved two key hypotheses: Dapagliflozin can be used not just for prevention of HF, but it is an effective agent to treat HFrEF in patients that already have it, and, secondly, the CV benefit of dapagliflozin in patients with HF is identical in patients with and without type 2 diabetes. This, along with the FDA indication (first of its kind for the class) just formally marked a transition of dapagliflozin (and SGLT2 inhibitors) from being a diabetes medication to being a HF medication for all patients with this condition regardless of diabetes.

Based on what we just heard about the DAPA-CKD trial a few weeks ago, I suspect we will see something similar in chronic kidney disease soon.

This indication offers a new treatment option for patients with HFrEF, which is a malignant condition with high risk of death and disease progression. This new treatment option (dapagliflozin), when added to standard of care, addresses all of the key goals of management in HF. Specifically, it reduces the risk of death, reduces the risk of hospitalization and improves symptoms and physical limitations due to HF, all with a favorable safety profile. I hope that based on the results of the DAPA-HF trial and this new FDA indication, SGLT2 inhibitors will also be carefully considered in future HF guidelines.

Effective implementation of efficacious treatments into clinical practice has been a big challenge in general. However, these medications have been in clinical practice for a number of years now and have a well-established safety profile. SGLT2 inhibitors including dapagliflozin are once-daily pills that do not require titration and tend to be well tolerated in most patients. There are no significant drug-drug interactions with other HF or CV medications that we have seen. The benefit-risk balance is very favorable in most patients with HFrEF. Educating the cardiologists about the clinical trial data, the effectiveness and safety of SGLT2 inhibitors and on their appropriate use will be critical for clinical adoption.

Sometimes, one needs to question conventional wisdom. When SGLT2 inhibitors were first introduced into clinical practice, there were a lot of cautions expressed about their use, especially in high-risk patients, including those with HF, because these patients are already receiving a lot of other medications such as diuretics, those with chronic kidney disease, older patients, etc. Turns out that these are exactly the patient populations that benefit the most from these agents.

This is really a great success story for the class of agents that was markedly underappreciated in terms of its capabilities when it was first introduced. I suspect that the story has not been fully told yet.