Sodium glucose cotransporter 2 inhibitors: New horizon of the heart failure pharmacotherapy

Table 1 Landmark clinical trials of sodium-glucose cotransporter 2 inhibitors

Ref.	Population (n)	Age, yr (mean)	Intervention	Follow-up period (median)	Patients with a history of HF	Patients with a history of CVD	Main results
EMPA-REG[1]	T2DM (7028)	63.1	Empagliflozin	3.1 yr	10.1%	100%	CV death or HF (HR, 0.66; 95%CI, 0.55–0.79)
							HF (HR, 0.65; 95%CI, 0.50–0.85)
							CV death (HR, 0.62; 95%CI, 0.49–0.77)
CANVAS[3]	T2DM (9734)	63.3	Canagliflozin	2.4 yr	14.4%	65.6%	CV death or HF (HR, 0.78; 95%CI, 0.67–0.91)
							HF (HR, 0.67; 95%CI, 0.52–0.87)
							CV death (HR, 0.87 95%CI, 0.72–1.06)
DECLARE-TIMI 58[4]	T2DM (17160)	63.9	Dapagliflozin	4.2 yr	10.0%	40.6%	CV death or HF (HR, 0.83; 95%CI, 0.73–0.95)
							HF (HR, 0.73; 95%CI, 0.61–0.88)
							CV death (HR, 0.98; 95%CI, 0.82–1.17)
VERTIS-CV[5]	T2DM (8246)	64.4	Ertugliflozin	3.5 yr (mean)	23.7%	71.4%1	CV death or HF (HR, 0.88; 95%CI, 0.75–1.03)
							HF (HR, 0.70; 95%CI, 0.54–0.90)
							CV death (HR, 0.92; 95%CI, 0.77–1.11)

¹Numbers are % of patients with coronary artery disease. T2DM: Type 2 diabetes mellitus; CV: Cardiovascular; HF: Heart failure; CVD: Cardiovascular disease; HR: Hazard ratio; CI: Confidence interval.

Table 2 Summary of clinical trials of sotagliflozin

Ref.	Population (n)	Age, yr (median)	Follow-up period (median)	Patients with a history of HF	Patients with a history of CAD	Main results
SCORED[7]	T2DM and CKD (10584)	63	16 mo	31.0%	22.4%	CV death or HF (HR, 0.74; 95%CI, 0.63–0.88)
						CV death (HR, 0.90; 95%CI, 0.73–1.12)
SOLOIST-WHF[8]	T2DM and HF (1222)	70	9.2 mo	100%	58.3%	CV death or HF (HR, 0.67; 95%CI, 0.52–0.85)
						CV death (HR, 0.84; 95%CI, 0.58–1.22)

HF: Heart failure; CAD: Coronary artery disease (numbers indicate % of patients with coronary revascularization in the SCORED trial and % of those with ischemic heart disease in the SOLOIST-WHF trial); T2DM: Type 2 diabetes mellitus; CKD: Chronic kidney disease; CV: Cardiovascular; HF: Heart failure; HR: Hazard ratio; CI: Confidence interval.

Table 3 Summary of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the EMPEROR-Reduced trials

Ref.	Population (n)	Patients with T2DM	Intervention	Follow-up period (median)	Main results
DAPA-HF[22]	HFrEF with or without T2DM (4744)	42%	Empagliflozin	18 months	CV death or HF (HR, 0.71; 95%CI, 0.65–0.85)
					HF (HR, 0.70; 95%CI, 0.59–0.83)
					CV death (HR, 0.82; 95%CI, 0.69–0.98)
EMPEROR-Reduced[9]	HFrEF (3730)	49.8%	Empagliflozin	16 months	CV death or HF (HR, 0.75; 95%CI, 0.65–0.86)
					HF (HR, 0.69; 95%CI, 0.59–0.81)
					CV death (HR, 0.92; 95%CI, 0.75–1.12)

T2DM: Type 2 diabetes mellitus; CV: Cardiovascular disease; HF: Heart failure; HR: Hazard ratio; CI: Confidence interval.

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Table 4 Subgroup analyses for the primary outcomes in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure and the EMPEROR-Reduced trials

Subgroup	HR (95%CI) of dapagliflozin compared to placebo	HR (95%CI) of empagliflozin compared to placebo
Age
≤ 65 yr	0.78 (0.63–0.96)	0.71 (0.57–0.89)
> 65 yr	0.72 (0.60–0.85)	0.78 (0.66–0.93)
Sex
Male	0.73 (0.63–0.85)	0.80 (0.68–0.93)
Female	0.79 (0.59–1.06)	0.59 (0.44–0.80)
T2DM
Yes	0.75 (0.63–0.90)	0.72 (0.60–0.87)
No	0.73 (0.60–0.88)	0.78 (0.64–0.97)
eGFR < 60 mL/min/1.73 m2
Yes	0.72 (0.59–0.86)	0.83 (0.69–1.00)
No	0.76 (0.63–0.92)	0.67 (0.55–0.83)

T2DM: Type 2 diabetes mellitus; HR: Hazard ratio; CI: Confidence interval.

Table 5 Summary of ongoing heart failure outcome trials of sodium-glucose cotransporter 2 inhibitors

	PRESERVED-HF	DELIVER	DAPA ACT HF-TIMI 68	EMPEROR-Preserved	EMPULSE
NCT number	03030235	03619213	04363697	03057951	04157751
Population	HFpEF with or without T2DM	HFpEF with or without T2DM	Acute heart failure with reduced ejection fraction	HFpEF with or without T2DM	Acute Heart Failure
Sample size	320	4700	2400	5750	500
Intervention	Dapagliflozin/placebo	Dapagliflozin/placebo	Dapagliflozin/placebo	Empagliflozin/placebo	Empagliflozin/placebo
Primary endpoint	Change from baseline in NT-proBNP	Time-to-first occurrence of CV death, HF hospitalization, or urgent HF visit	CV death or worsening HF	Time-to-first event of HF hospitalization	Death, number of HF events
Status	Estimated completion; February 2021	Estimated completion; June 2021	Estimated completion; October 2022	Estimated completion; April 2021	Estimated completion; June 2021

HFpEF: Heart failure with preserved ejection fraction; T2DM: Type 2 diabetes mellitus; CV: Cardiovascular; HF: Heart failure; NT-proBNP: N-terminal pro-brain natriuretic peptide.