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.
1. Canagliflozin (Invokana) [prescribing information]. Janssen Pharmaceuticals, Inc.; 2021.
2. Dapagliflozin (Farxiga) [prescribing information]. AstraZeneca Pharmaceuticals LP; 2021.
3. Empagliflozin (Jardiance) [prescribing information]. Boehringer Ingelheim Pharmaceuticals, Inc.; 2022.
4. Yancy CW, Jessup M, Bozkurt B, et al. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2017;136(6):e137-e161. doi:10.1161/CIR.0000000000000509
5. Das SR, Everett BM, Birtcher KK, et al. 2020 Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2020;76(9):1117–1145. doi:10.1016/j.jacc.2020.05.037
6. Writing Committee, Maddox TM, Januzzi JL Jr, et al. 2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues About Heart Failure With Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol. 2021;77(6):772–810. doi:10.1016/j.jacc.2020.11.022
7. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in Circulation. 2022 May 3;145(18):e1033]. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063
8. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117–2128. doi:10.1056/NEJMoa1504720
9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644–657. doi:10.1056/NEJMoa1611925
10. Sarraju A, Li J, Cannon CP, et al. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: Results from the CREDENCE trial. Am Heart J. 2021;233:141–148. doi:10.1016/j.ahj.2020.12.008
11. 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
12. McMurray JJV, DeMets DL, Inzucchi SE, et al. A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF). Eur J Heart Fail. 2019;21(5):665–675. doi:10.1002/ejhf.1432
13. Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation. 2019;140(18):1463–1476. doi:10.1161/CIRCULATIONAHA.119.042929
14. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413–1424. doi:10.1056/NEJMoa2022190
15. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;385(16):1451–1461. doi:10.1056/NEJMoa2107038
16. Packer M, Butler J, Zannad F, et al. Effect of Empagliflozin on Worsening Heart Failure Events in Patients With Heart Failure and Preserved Ejection Fraction: EMPEROR-Preserved Trial. Circulation. 2021;144(16):1284–1294. doi:10.1161/CIRCULATIONAHA.121.056824
17. Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27(11):1954–1960. doi:10.1038/s41591–021–01536-x