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SGLT2 Inhibitors and Cardiovascular Outcomes in Heart failure: Discussion of EMPEROR-Reduced Trial
Assurance Nshom, PharmD candidate 2021
Davida Braxton, PharmD candidate 2021
Sullivan University College of Pharmacy and Health Sciences, Louisville, KY

An estimated 6.2 million Americans >20 years of age are living with heart failure (HF) and the prevalence is projected to grow by 46% by 2030.¹ There are several classes of medications which have proven mortality benefits in HF, including beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARB), and an angiotensin receptor-neprilysin inhibitor (ARNI). However, due to therapeutic challenges such asinability to titrate these drugs to target doses, adverse effects, and high residual morbidity or mortality in some cases, there is a need for an additional drug class that could provide benefits in HF.

Based on recent cardiovascular (CV) trials, SGLT2 inhibitors have emerged as a class of medications that could address this need. The American Diabetes Association (ADA) 2020 Standards of Care and American College of Cardiology 2020 Expert Consensus Decision Pathway encourages the use of SGLT2 inhibitors in patients with diabetes and HF.^2,3 Dapagliflozin is currently the only diabetes medication with an FDA-approved indication for heart failure with reduced ejection fraction (HFrEF) in people with and without diabetes. Recently, the EMPEROR-Reduced trial contributed more support for the use of SGLT2 inhibitors in all individuals with HFrEF.

EMPEROR-Reduced
The EMPEROR-Reduced trial was a double-blind, randomized, placebo-controlled trial that evaluated the ability of empagliflozin to provide cardiovascular benefit in 3,730 patients with HFrEF.⁴ The primary outcome was a composite of cardiovascular death or hospitalization for worsening heart failure. All patients in the trial were required to have chronic HF (New York Heart Association [NYHA] functional class II/III/IV) and a left ventricular ejection fraction ≤40%. After randomization, patients received either empagliflozin 10 mg by mouth once daily or placebo in addition to standard HF therapy. The median duration of follow-up was 16 months.

EMPEROR-Reduced Results
Baseline characteristics of the patient population included:

• Mean age: 67 years
• Type 2 diabetes: 50%
• Estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m²: 48%
• NYHA functional class II: 75%
• Left ventricular ejection fraction (EF) ≤30%: 73%
• History of hospitalization for heart failure within the past 12 months: 31%
• Medications:
  • ACE inhibitor/ARB: 70%
  • Angiotensin receptor-neprilysin inhibitor: 19%
  • Beta-blocker: 94%
  • Mineralocorticoid receptor antagonist: 71%

The primary composite outcome for empagliflozin versus placebo was 19.4 versus 24.7% (hazard ratio [HR], 0.75; 95% confidence interval [CI] 0.65-0.86; P<0.001) and the number needed to treat was 19. The number of HFhospitalizations was lower with empagliflozin versus placebo (HR, 0.70; 95% CI, 0.58-0.85; P<0.001). Additionally, the rate of decline in eGFR was slower with empagliflozin, a between-group difference in slope of 1.73 ml/min/1.73m² per year (95% CI, 1.10-2.37; P<0.001). Although uncomplicated genital tract infections occurred more with empagliflozin compared to placebo (1.7% vs. 0.6%), there were no other significant differences in adverse events between groups.

Compared to the DAPA-HF trial, EMPEROR-Reduced extended the benefits of SGLT2 inhibitors in patients with stable HFrEF. The trial enrolled participant's with markedly reduced ejection fraction (73.2% with EF ≤30%) and increased NT-proBNP levels. The mean left ventricular EF in the empagliflozin arm was 27.7% versus 31.2% in the dapagliflozin arm of the DAPA-HF trial. Additionally, empagliflozin positively influenced renal outcomes in patients with diabetes and/or heart failure.  

Discussion
The results of the EMPEROR-Reduced trial indicate that empagliflozin is superior to placebo in reducing the risk of cardiovascular death and hospitalizations for patients with HFrEF who are receiving standard heart failure therapy. This trial, in addition to the DAPA-HF trial, strengthens the evidence for use of SGLT2 inhibitors in patients with heart failure regardless of the presence or absence of diabetes. The ADA continues to recommend metformin as first-line therapy for all patients with type 2 diabetes. In contrast, the most recent European Society of Cardiology/ European Association for the Study of Diabetes guidelines now recommend starting with an SGLT2 inhibitor or glucagon-like peptide-1 receptor agonist before metformin in patients newly diagnosed with type 2 who are treatment naïve and either have established CV disease or are at very high CV disease risk. Ultimately, SGLT2 inhibitors will likely have a major role in future heart failure management guidelines.

References

1. Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke atatistics-2020 update: a report from the american heart association. Circulation. 2020;141(9):e139-e596.
2. 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.
3. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in aiabetes-2020. Diabetes Care. 2020;43(Suppl 1):S98-S110. doi:10.2337/dc20-S009
4. 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.