Background
The first three cardiovascular safety trials of sodium-glucose contransporter-2 inhibitors (SGLT2is) mandated by the Food and Drug Administration all revealed an unexpected approximate 30% reduction in heart failure (HF) hospitalizations among patients with type 2 diabetes with and at risk for cardiovascular disease. A trend for a positive effect of SGLT2i agents on renal disease progression was also noted in those pivotal trials.^1-3 The surprising strength and consistency of the reduction in HF hospitalizations prompted subsequent studies to confirm those initial findings among diabetic patients with HF, and later studies to elucidate whether SGLT2i agents would also be beneficial for patients with HF without diabetes.

Two subsequent trials in patients with diabetes confirmed their benefit in reducing the risk of HF hospitalizations.^4,5 DAPA-HF was the first to also enroll patients without diabetes and showed reduced HF hospitalizations with dapagliflozin in this patient sub-group.⁵ In addition to the reduction in HF hospitalizations, the beneficial effect of SGLT2i agents on renal disease progression has been shown in both CREDENCE (canagliflozin)⁴ and DAPA-CKD (dapagliflozin).⁶ The multiple trials of SGLT2i agents are summarized in Table 1.

EMPEROR-Reduced
The EMPEROR-Reduced trial adds to the growing data about the benefits of SGLT2i agents and aimed to study the cardiac and renal benefits of empagliflozin in patients with a higher risk HF profile compared to DAPA-HF, across the spectrum of glycemia (normoglycemia, prediabetes, and diabetes).⁷ The trial enrolled patients with an average ejection fraction (EF) of 27% and over 70% of patients had an EF ≤30%; patients with EF >30% were only included if they had a HF hospitalization in the prior 12 months and met specific natriuretic peptide benchmarks.

At enrollment, 50% of the patients had type 2 diabetes, 34% had prediabetes, and 16% had an HbA1c <5.7%, and the estimated glomerular filtration rate (eGFR) was <60 ml/min in 48% of patients. In contrast, in the DAPA-HF trial the mean EF was 31% and 40% of patients had an EF ≤30%; in both studies a minority of patients were using cardiac resynchronization therapy. After an average of 16 months on treatment, empagliflozin reduced both the primary HF endpoint (cardiovascular death or HF hospitalization) and secondary renal endpoint (annual change in eGFR).⁸

Anker et al. further determined that these benefits were irrespective of the patients' baseline diabetes status and hemoglobin A1c level.⁹ Their analysis of the placebo arm confirmed that patients with diabetes were at higher risk of complications when compared to the patients with prediabetes and without diabetes, but in the treatment arm, patients across the spectrum of glycemic control shared the benefits of empagliflozin. A higher rate of genital mycotic infections was observed in the empagliflozin arm, but the rates of hypoglycemia, diabetic ketoacidosis and lower extremity amputations were not significantly different between the study arms.

Conclusion
The safety and efficacy of empagliflozin in the high-risk patient population of EMPEROR-Reduced trial reinforces its place in HFrEF treatment. The accumulated evidence of the beneficial effects of two agents from the SGLT2i class among HFrEF patients with and without diabetes has expanded their use from the treatment of diabetes into the realm of cardiology. The significant reduction in renal disease progression shown in CREDENCE, DAPA-CKD, and now EMPEROR-Reduced also points to an expanded role for three SGLT2is in nephrology practice as adjunctive agents to slow the progression of renal disease.

Table 1: SGLT2i Trials^10-12

	Empa-Reg Outcome	CANVAS Programs	DECLARE TIMI-58	DAPA HF	CREDENCE	DAPA CKD	Emperor- Reduced
Findings Published	2015	2017	2019	2019	2019	2020	2020
Agent	Empagliflozin	Canagliflozin	Dapagliflozin	Dapagliflozin	Canagliflozin	Dapagliflozin	Empagliflozin
Patients	7,020	10,142	17,160	4,744	4.401	4,304	3,730
Mean Follow-up	3.1 years	2.4 years	4.2 years	1.3 years	2.6 years	2.4 years	1.3 years
CAD	100%	65.6%	40.6%		50%	37%
HF	10.1%	14.4%	10%	100%	15%	11%	100%
EF < 30%	NR	NR	NR	40% (Mean EF 31%)	NR	NR	70% (Mean EF 27%)
Cardiac Resync Therapy	NR	NR	NR	8% Treatment 7% Placebo	NR	NR	11.8% Treatment 11.9% Placebo
eGFR <60ml/min	25.9%	20.1%	7.4%	41% (Mean eGFR 66)	59% (Mean 56)	89% (Mean eGFR 43)	48% (Mean eGFR 62)
Type 2 DM	100%	100%	100%	42%	100%	67%	50% DM 34% Prediabetes 16% No diabetes
Outcomes
MACE	0.86 (0.74–0.99)	0.86 (0.75–0.97)	0.93 (0.84–1.03)	NR	0.80 (0.67–0.95)	NR	NR
CV Death	0.62 (0.49–0.77)	0.87 (0.72-1.06)	0.92 (0.61 – 1.23)	0.82 (0.69 – 0.98)	0.78 (0.61-1.00)	0.81 (0.58-1.12)	0.92 (0.75 – 1.12)
First HF Hospitalization	0.65 (0.50–0.85)	0.67 (0.52–0.87)	0.73 (0.61–0.88)	0.70 (0.59–0.83)	0.61 (0.47–0.80)	NR	0.69 (0.59 – 0.81)
CV Death or HF Hosp	0.66 (0.55-0.79)	0.78 (0.67-0.91)	0.83 (0.73 – 0.95)	0.74 (0.65 – 0.85)	0.69 (0.57-0.83)	0.71 (0.55-0.92)	0.75 (0.65-0.86)
CKD Progression	Composite renal* 0.54 (0.40–0.75)	Composite renal* 0.60 (0.47–0.77)	Composite renal* 0.53 (0.43–0.66)	Composite renal* 0.71 (0.44–1.16)	Death or renal progression * 0.70 (0.59–0.82)	Death or renal progression * 0.61 (0.51-0.72)	Composite renal * 0.50 (0.32-0.77)

References

1. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117– 28.
2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-57.
4. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
5. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
6. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al.  Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-46.
7. Packer M, Butler J, Filippatos GS, et al. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 2019;21:1270-78.
8. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
9. Anker SD, Butler J, Filippatos G, et al. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status - results from the EMPEROR-Reduced Trial. Circulation 2021;143:337-49.
10. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31-39.
11. 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;76:1117-45.
12. Neuen BL, Young T, Heerspink HJL, et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019;7:845-54.

Clinical Topics: Arrhythmias and Clinical EP, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Implantable Devices, Acute Heart Failure

Keywords: Dyslipidemias, Hemoglobin A, Sodium, Diabetes Mellitus, Type 2, Prediabetic State, Heart Failure, Cardiovascular Diseases, Cardiac Resynchronization Therapy, Glomerular Filtration Rate, Diabetic Ketoacidosis, Nephrology, Glucose, Stroke Volume, United States Food and Drug Administration, Natriuretic Peptides, Hypoglycemia, Hospitalization, Disease Progression, Lower Extremity, Renal Insufficiency, Chronic, Amputation

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