Sodium glucose cotransporter-2 inhibitors and heart disease: Current perspectives

Table 1 Major cardiovascular outcome trials of sodium glucose cotransporter 2 inhibitors

	EMPA-REG outcome		CANVAS	DECLARE-TIMI 58	VERTIS-CV	SCORED
Intervention	Empagliflozin 10 and 25 mg vs placebo		Canagliflozin 100 and 300 mg vs placebo	Dapagliflozin 10 mg vs placebo	Ertugliflozin 5 and 15 mg vs placebo	Sotagliflozin vs placebo
Population	n = 7020, T2DM with established CV disease		n = 10142 patients, T2DM with established CV disease or ≥ 2 CV risk factors	n = 17160 patients, T2DM with established CV disease or risk factors for atherosclerotic CV disease	n = 8246, T2DM with established CV disease	10584 patients with T2DM and established CV disease or risk factors for atherosclerotic CV disease
Established CV disease (%)	99		66	41	99	48.6
Follow up period (yr)	3.1		3.6	4.2	3.5	1.3
HbA1c (%) at baseline	7.0% to 10.0% (for those on a stable background therapy); 7.0%-9.0% (for medication-naive patients)		7.0% to 10.5%	6.5% to 12.0%	7.0% to 10.5%	> 7%
Estimated GFR	≥ 30		≥ 30	≥ 60	≥ 30	25-60
Primary outcome, HR (95%CI)	3P-MACE, 0.86 (0.74-0.99)		3P-MACE, 0.86 (0.75-0.97)	3P-MACE, 0.93 (0.84-1.03); CV death or hospitalization for HF, 0.83 (0.73-0.95)	3P-MACE, 0.97 (0.85-1.11)	Total no. of deaths from cardiovascular causes, hospitalizations for HF, and urgent visits for HF 0.74 (0.63-0.88)
Key secondary outcome (s), HR (95%CI)	4P-MACE, 0.89 (0.78-1.01)		All-cause mortality (as below); CV death (as below); progression of albuminuria, 0.73 (0.67-0.79); CV death or hospitalization for HF 0.78 (0.67-0.91)	≥ 40% decline in eGFR to < 60 mL/min/1.73 m2 or new onset end-stage renal disease or renal/CV mortality, 0.76 (0.67-0.87); all-cause mortality (as below)	CV death or hospitalization for HF, 0.88 (0.75-1.03); CV death (as below); renal death or dialysis/transplant or doubling of serum creatinine from baseline, 0.81 (0.63-1.04)	Total No. or hospitalizations for HF and urgent visits for HF HR: 0.67 (0.55-0.82); deaths from cardiovascular causes (as below)
Other secondary outcomes
CV death, HR (95%CI)		0.62 (0.49-0.77)	0.87 (0.72-1.06)	0.98 (0.82-1.17)	0.92 (0.77-1.11)	0.90 (0.73-1.12)
All-cause mortality, HR (95%CI)		0.68 (0.57-0.82)	0.87 (0.74-1.01)	0.93 (0.82-1.04)	0.93 (0.80-1.08)	0.99 (0.83-1.18)
Fatal or non-fatal myocardial Infarction, HR (95%CI)		0.87 (0.70-1.09)	0.89 (0.73-1.09)	0.89 (0.77 − 1.01)	1.04 (0.86-1.26)	0.68 (0.52-0.89)
Fatal or non-fatal stroke, HR (95%CI)		1.18 (0.89-1.56)	0.87 (0.69-1.09)	1.01 (0.84-1.21)	1.06 (0.82-1.37)	0.66 (0.48-0.91)
Hospitalization for HF, HR (95%CI)		0.65 (0.50-0.85)	0.67 (0.52-0.87)	0.73 (0.61-0.88)	0.70 (0.54-0.90)	0.67 (0.55-0.82)

EMPA-REG outcome: Empagliflozin and canagliflozin in the empagliflozin cardiovascular outcome; event trial in type 2 diabetes mellitus patients; CANVAS: Canagliflozin cardiovascular assessment study; DECLARE-TIMI 58: Dapagliflozin effect on cardiovascular events-thrombolysis in myocardial infarction 58; T2DM: Type 2 diabetes mellitus; CV: Cardiovascular; GFR: Glomerular filtration rate; HR: Hazard ratio; 3P-MACE: 3 point - major adverse CV event; HF: Heart failure; eGFR: Estimated glomerular filtration rate.

Table 2 Major heart failure trials with sodium glucose cotransporter 2 inhibitors

Trial and medication name	Primary endpoint	Median follow-up	Outcomes
HFrEF
DAPA-HF (dapagliflozin)	Primary composite outcome: Worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for HF) + cardiovascular death	18 months	Reduction in the primary composite outcome by 24%
EMPEROR-reduced (empagliflozin)	Primary composite outcome: Hospitalisation for heart failure + cardiovascular death	16 months	Reduction in the primary composite outcome by 22%
HFpEF
EMPEROR-preserved (empagliflozin)	Primary composite outcome: Hospitalisation for heart failure + cardiovascular death	26 months	19% reduction in the primary composite outcome
DELIVER (dapagliflozin)	Primary composite outcome: Worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for HF) + cardiovascular death	28 months	18% reduction in the primary composite endpoint

HFrEF: Heart failure with reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; HR: Hazard ratio.

Table 3 Role of sodium glucose cotransporter 2 inhibitors in the management a prevention of diabetes - position of different guidelines

Organize groups	Position of different guidelines
ADA, 2023	Among people with T2DM who have established ASCVD (a SGLT2i with demonstrated cardiovascular disease benefit is recommended as part of the comprehensive cardiovascular risk reduction and/or glucose - lowering regimens. (LOE: A)
	In people with T2DM who have established ASCVD, multiple atherosclerotic cardiovascular disease risk factors, or DKD, a SGLT2i with demonstrated cardiovascular benefit is recommended to reduce the risk of major adverse cardiovascular events and/or heart failure hospitalization. (LOE: A)
	In people with T2DM and established ASCVD or multiple risk factors for atherosclerotic cardiovascular disease, combined therapy with a SGLT2i and a GLP1-RA may be considered for additive reduction in the risk of adverse cardiovascular and kidney events. (LOE: A)
	In people with T2DM and established heart failure with either preserved or reduced ejection fraction, a SGLT2i with proven benefit in this patient population is recommended to reduce risk of worsening heart failure and cardiovascular death. (LOE: A)
	In people with T2DM and established heart failure with either preserved or reduced ejection fraction, a SGLT2i with proven benefit in this patient population is recommended to improve symptoms, physical limitations, and quality of life. (LOE: A)
AACE, 2023	SGLT2i should be started irrespective of glycemic target or other T2DM therapies in patients with T2DM and ASCVD or at high risk for ASCVD (albuminuria/proteinuria, hypertension and left ventricular hypertrophy, LV systolic or diastolic dysfunction, ankle-branchial index < 0.9)
ACC/AHA, 2022	In patients with symptomatic chronic HFrEF, SGLT2i are recommended to reduce hospitalisation for heart failure and CV mortality, irrespective of the presence of type 2 diabetes. (COR: 1, LOE: A)
	In patients with HFmrEF, SGLT2i can be beneficial in decreasing HF hospitalisation and CV mortality (COR: 1, LOE: A)
	In patients with HFpEF, SGLT2i can be beneficial in decreasing HF hospitalisation and CV mortality (COR: 1, LOE: A)
ESC, 2022	SGLT2i are recommended in all patients with HFrEF and T2DM to reduce the risk of HF hospitalization and CV death. (COR: 1, LOE: A)
	SGLT2i are recommended in patients with T2DM and LVEF > 40% (HFmrEF and HFpEF) to reduce the risk of HF hospitalization or CV death. (COR: 1, LOE: A)
	SGLT2i are recommended in patients with T2DM with multiple ASCVD risk factors or established ASCVD to reduce the risk of HF hospitalization. (COR: 1, LOE: A)

ADA: American Diabetes Association; AACE: American College of Clinical Endocrinologists; ACC/AHA: American College of Cardiology/American Heart Association; ESC: European Society pf Cardiology; HFrEF: Heart Failure with reduced ejection fraction; HFmrEF: Heart Failure with mildly reduced ejection fraction; HFpEF: Heart failure with preserved ejection fraction; COR: Class of recommendation; LOE: Level of evidence; T2DM: Type 2 diabetes mellitus; ASCVD: Atherosclerotic cardiovascular disease; SGLT2i: Sodium glucose cotransporter 2 inhibitors; LV: Left ventricle.