Nearly 10 years ago when the first sodium glucose co-transporter-2 (SGLT2) inhibitor, canagliflozin (Invokana®), received approval by the FDA, there was hope that this groundbreaking new drug class would be the cure-all for type 2 diabetes. After the approval of canagliflozin, other manufacturers followed suit, wanting to buy their own piece of the SGLT2 inhibitor market; we then saw the approval of dapagliflozin (Farxiga®) from AstraZeneca and empagliflozin (Jardiance®) from Boehringer Ingelheim in 2014. While the efficacy of SGLT2 inhibitors in the treatment of type 2 diabetes is legitimate, the real hype around this drug class is for another complicated and costly disease state — heart failure.
The major leap of SGLT2 inhibitors into the cardiovascular world started with the EMPA-Reg trial in 2015. In this landmark trial, empagliflozin was the first SGLT2 inhibitor to exhibit a reduction in major adverse cardiovascular events (MACE) such as death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Additionally, empagliflozin exhibited a reduction in cardiovascular death or hospitalization for heart failure; however, this was only an exploratory endpoint, which typically lacks the statistical power to detect any differences. As such, these results did not significantly change our clinical perception of SLGT2 inhibitors with respect to heart failure. In fact, SGLT2 inhibitors are not even mentioned in the 2017 American College of Cardiology/American Heart Association/Heart Failure Society of America guideline update for the management of heart failure.
As other manufacturers sought to explore the effects of their own SGLT2 inhibitor on atherosclerotic cardiovascular disease (ASCVD) outcomes, landmark trials for canagliflozin (CANVAS and CREDENCE) and the largest SGLT2 inhibitor trial to date, the DECLARE-TIMI trial (dapagliflozin), all exhibited a reduction in MACE in patients with type 2 diabetes. While there appeared to be a class effect on ASCVD, there was another intriguing trend observed in the aforementioned trials — SGLT2 inhibitors reduce hospitalization for heart failure. With these notable findings, a 2020 expert consensus report from the American College of Cardiology recommends SGLT2 inhibitors with proven cardiovascular benefit to reduce the risk of ASCVD in patients with type 2 diabetes. This document, however, was not focused on the emerging role of SGLT2 inhibitors for heart failure care.
Despite these exciting findings, SGLT2 inhibitors had only been evaluated in patients primarily with type 2 diabetes; their effects on heart failure outcomes had yet to be explored specifically in a heart failure population. This would soon change with the DAPA-HF trial, the first landmark trial to evaluate the effects of an SGLT2 inhibitor on patients with heart failure and a reduced ejection fraction (HFrEF). In DAPA-HF, dapagliflozin significantly reduced the risk of worsening heart failure and death from cardiovascular causes compared to placebo, regardless of the presence or absence of type 2 diabetes.
Shortly after, the DEFINE-HF study found dapagliflozin to produce clinically meaningful improvement in heart failure-related status or natriuretic peptide concentrations in HFrEF patients. Soon enough, dapagliflozin would receive a much-anticipated new indication — to reduce the risk of cardiovascular death and hospitalization for heart failure in adults with HFrEF. Around the same time, empagliflozin would exhibit its benefits in HFrEF patients in the EMPEROR-Reduced trial by significantly reducing cardiovascular death or heart failure hospitalization, again in the presence or absence of type 2 diabetes. Empagliflozin would go on to receive the same new indication as dapagliflozin.
In 2021, the American College of Cardiology released an update to the 2017 expert consensus. With this update, we saw the noteworthy addition of SGLT2 inhibitors, dapagliflozin and empagliflozin, to guideline-directed medical therapy (GDMT) for HFrEF. While we had found a revolutionary new drug class that can be used to treat diabetes and HFrEF, there was another, parallel disease state in the cardiovascular world that was severely lacking effective treatment recommendations — heart failure with preserved ejection fraction (HFpEF).
Over the years, many studies have failed to find any benefit with medications used in HFpEF patients; hence, the lack of GDMT options for HFpEF. Drugs such as Entresto® would make some noise but would still fail to achieve any clinical benefit in randomized controlled trials. This would soon change with the EMPEROR-Preserved trial, which found empagliflozin to significantly reduce the combined risk of cardiovascular death or hospitalization for heart failure in patients with an ejection fraction > 40%.
The results of the EMPEROR-Preserved trial led to empagliflozin receiving an expanded indication for HFpEF, a disease state for which few therapies have proved effective. Additionally, the updated 2022 heart failure guidelines also went on to recommend SGLT2 inhibitors to treat HFpEF and heart failure with mildly reduced ejection fraction (HFmrEF), a newly defined group of heart failure patients with an ejection fraction of 41 to 49 percent.
In another recent trial, PRESERVED-HF, dapagliflozin significantly improved patient-reported symptoms, physical limitations and exercise function in a HFpEF population; however, this was not enough to receive the expanded indication as empagliflozin did. This was most likely due to the lack of clinical outcomes evaluated such as hospitalization for heart failure and cardiovascular death.
Despite the lack of an expanded indication, results of the highly anticipated DELIVER trial (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) were recently published. Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with HFpEF and HFmrEF. With the completion of DELIVER, we now have a better understanding of dapagliflozin’s effects on clinical outcomes in HFpEF and HFmrEF patients; and it is expected to see an expanded indication for dapagliflozin in the near future.
So why are SGLT2 inhibitors, a class of medications initially used for the treatment of diabetes, suddenly moving to the top of the GDMT arsenal for heart failure? The answer to that question is multifaceted and not completely clear. However, one thing is certain — SGLT2 inhibitors may provide a new solution to heart failure, one of the most fatal and costly healthcare issues in the 21st century.
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