Sodium glucose cotransporter 2 inhibitors in the management of heart failure: Veni, Vidi, and Vici

Table 1 Number needed to treat in major heart failure trials

Study	Drug tested	Primary endpoints	Results	NNT	Year	Number of patients	Follow-up
EMPEROR-Reduced trial	Empagliflozin vs placebo	CV death or HF hospitalization	19.4% vs 24.7% HR: 0.75 (95%CI: 0.65-0.86)	19	2020	3730	16 months
DAPA-HF trial	Dapagliflozin vs placebo	CV death or HF hospitalization	16.3% vs 21.2% HR: 0.74 (95%CI: 0.65-0.85)	21	2019	4744	18.2 months
SOLOIST-HF trial	Sotagliflozin vs placebo	CV death or HF hospitalization	70% vs 98% HR: 0.67 (95%CI: 0.52-0.85)	4	2021	1222	9 months
PARADIGM-HF trial	ARNI vs enalapril	CV death or HF hospitalization	21.8% vs 26.5% HR: 0.80 (95%CI: 0.73-0.87)	21	2014	8442	27 months
RALES trial	Spironolactone vs placebo	Death from all causes	35% vs 46% HR: 0.70 (95%CI: 0.60-0.82)	9	1999	1663	24 months
EMPHASIS-HF	Eplerenone vs placebo	CV death or HF hospitalization	18.3% vs 25.9% HR: 0.63 (95%CI: 0.54-0.74)	19	2011	2737	1.8 years
EPHESUS	Eplerenone vs placebo	Death any cause CV death or HF hospitalization	HR: 0.85 (95%CI: 0.75-0.96); HR: 0.87 (95%CI: 0.79-0.95)	50 to prevent 1 death; 33 to prevent 1 CV death or HF hospitalization	2003	6642	16 months
MERIT-HF trial	Metoprolol vs placebo	All-cause death	7.2% vs 11% HR: 0.66 (95%CI: 0.53-0.81)	27	1999	3991	2.4 years
CIBIS II-HF trial	Bisoprolol vs placebo	All-cause death HF hospitalization	11.8% vs 17.3%; 33% vs 39%	18; 17	1999	2647	1.3 years
COPERNICUS trial	Carvedilol vs placebo	All-cause death and HF hospitalization	36.8% vs 44.7%	13	2001	2289	10 months
CHARM trial	Candesartan vs placebo	CV death and HF hospitalization	22% vs 24% HR: 0.89 (95%CI: 0.77-1.03)			3023	36.6 months
VA-HEFT Trial	Valsartan vs placebo	Mortality plus morbidity	No difference 28.8% vs 32.1% HR: 0.87 (95%CI: 0.77-0.97)		2001	5010	23 months
SHIFT trial	Ivabradine vs placebo	CV death and HF hospitalization	24% vs 29% HR: 0.82 (95%CI: 0.75-0.90)	27	2010	6558	22.9 months
SOLVD trial	Enalapril vs placebo	Mortality HF hospitalization			1991	2569	22-55 months

CHARM: Candesartan in heart failure assessment of reduction in mortality and morbidity; CI: Confidence interval; CIBIS II: The cardiac insufficiency bisoprolol study II; COPERNICUS: Carvedilol prospective randomized cumulative survival; CV: Cardiovascular; HF: Heart failure; HR: Hazard ratio; DAPA: Dapagliflozin and prevention of adverse outcomes; EMPEROR: Empagliflozin outcome trial in patients with chronic heart failure and a reduced ejection fraction; EMPHASIS: Eplerenone in mild patients hospitalization and survival study; EPHESUS: Eplerenone post–acute myocardial infarction heart failure efficacy and survival study; MERIT: Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients; NNT: Number needed to treat; PARADIGM: Prospective comparison of angiotensin receptor–neprilysin inhibitor with angiotensin-converting–enzyme inhibitor to determine impact on global mortality and morbidity; RALES: Randomized Aldactone evaluation study; SHIFT: Systolic heart failure treatment with the if inhibitor ivabradine trial; SOLOIST: Effect of Sotagliflozin on cardiovascular events in patients with type 2 diabetes worsening post heart failure; SOLVD: Studies of left ventricular dysfunction; VA-HEFT: The vasodilator-heart failure trial.

Table 2 Landmark trials of sodium glucose cotransporter-2 inhibitors in heart failure

Trial	Year	Number of patients	SGLT-2i used vs placebo	Endpoints		P value
				SGLT-2 arm	Placebo arm
EMPAREG outcomes	2015	7028	Empagliflozin 10 or 25 mg	CV death, non-fatal MI or stroke: 10.5%	CV death, non-fatal MI or stroke: 12.1%	< 0.001
				All-cause mortality: 3.8%	All-cause mortality 5.1%	< 0.01
				HHF: 2.7%	HHF: 4.1%	0.002
DECLARE TIMI 58	2018	17160	Dapagliflozin 10 mg	CV death, MI, stroke: 8.8%	CV death, MI, stroke: 9.4%	0.17
				CV death or HHF: 4.9%	CV death or HHF: 5.8%	0.005
CANVAS	2017	10142	Canagliflozin	Composite of CV death, non-fatal MI or stroke: 26.9%	Composite of CV death, non-fatal MI or stroke: 31.5%	< 0.0001
				CV death or HHF: 16.3%	CV death or HHF: 20.8%
DAPA-HF	2019	4744	Dapagliflozin 10 mg	CV death or WHF: 16.3%	CV death or WHF: 21.2%	0.001
EMPEROR-Reduced	2020	3730	Empagliflozin 10 mg	CV death or HHF: 19.4%	CV death or HHF: 24.7%	< 0.001
EMPEROR-Preserved	2021	5988	Empagliflozin 10 mg	CV death or HHF: 13.8%	CV death or HHF: 17.1%	< 0.001
DELIVER	2022	6263	Dapagliflozin 10 mg	CV death or WHF: 16.4%	CV death or WHF: 19.5%	< 0.001
SOLOIST WHF	2021	1222	Sotagliflozin	CV death, HHF, urgent visit for HF: 51%	CV death, HHF, urgent visit for HF: 76%	0.001
EMPA RESPONSE	2020	80	Empagliflozin 10 mg	Change in VAS dyspnea score, wt. change, change in NT-proBNP, hospital stay length: 10%	Change in VAS dyspnea score, wt. change, change in NT-pro-BNP, hospital stay length: 13%	0.014
EMPULSE	2022	530	Empagliflozin 10 mg	Net clinical benefit: 53.9%	Net clinical benefit: 39.7%	0.0054
				CV death: 4.2%	CV death: 8.3%
				HF events: 10.6%	HF events: 14.7%
				Change in KCCQ-TSS: 4.5	Change in KCCQ-TSS	0.035
				Wt. change: -1.5 Kg	Wt. change	0.014
EMMY	2022	476	Empagliflozin 10 mg	Change in NT-pro-BNP: 15% lower vs placebo		0.026
				LVEF: 1.5% vs placebo		0.029
				E/e’: 6.8% vs placebo		0.015
				LVESV: 7.5 mL vs placebo		0.0003
				LVEDV: 9.7 mL vs placebo		0.0015

CANVAS: Canagliflozin cardiovascular assessment study; CV: Cardiovascular; DAPA: Dapagliflozin and prevention of adverse outcomes; DECLARE TIMI 58: Dapagliflozin effect on cardiovascular events-thrombolysis in myocardial infarction 58; DELIVER: Dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure; E/e’: Mitral inflow E wave velocity/annular tissue’ wave velocity; EMMY: Empagliflozin in patients with acute myocardial infarction; EMPAREG: Empagliflozin cardiovascular outcome event trial in type 2 diabetes mellitus patients; EMPA-RESPONSE: Effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure; EMPEROR: Empagliflozin outcome trial in patients with chronic heart failure; EMPULSE: Effect on clinical benefit, safety and tolerability of once daily oral empagliflozin 10 mg compared to placebo, initiated in patients hospitalized for acute heart failure who have been stabilized; HF: Heart failure; HHF: Heart failure hospitalization; KCCQ-TSS: Kansa city cardiomyopathy questionnaire total symptom score; LVEDV: Left ventricular end diastolic volume; LVEF: Left ventricular ejection fraction; LVESV: Left ventricular end systolic volume; MI: Myocardial infarction: NT-pro-BNP: N-terminal pro-B-type natriuretic peptide; SGLT-2is: Sodium glucose cotransporter-2 inhibitors; SOLOIST-WHF: Effect of Sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure; VAS: Visual analogue scale; WHF: Worsening heart failure; Wt.: Weight.