Update on evidence-based clinical application of sodium-glucose cotransporter inhibitors: Insight to uncommon cardiovascular disease scenarios in diabetes

Table 1 Summary of clinical studies on sodium-glucose cotransporter inhibitors in ejection fraction preserved heart failure/heart failure with mildly reduced ejection fraction patients

Ref.	Type of article	Journal and published time	Drugs	Aim of study	Inclusive population	Intervention cycle	Number of cases	Main conclusion
Solomon et al[5]	RCT	N Engl J Med, 2022	Dapagliflozin (10 mg/d) or placebo	To evaluate whether SGLT2is are effective in patients with a higher LVEF	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin reduced the combined risk of worsening HF or cardiovascular death among patients with HFpEF/HFmrEF
Inzucchi et al[6]	RCT	Lancet Diabetes Endocrinol, 2022	Dapagliflozin (10 mg/d) or placebo	To assess the efficacy and safety of oral dapagliflozin in these patients by their baseline glycaemia categories	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin improved HF outcomes to a similar extent in normoglycaemia, prediabetes, and T2D
Peikert et al[7]	RCT	Circ Heart Fail, 2022	Dapagliflozin (10 mg/d) or placebo	To assess the efficacy and safety of oral dapagliflozin in these HFpEF patients with New York Heart Association functional class II-IV and LVEF > 40%	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin reduced the combined risk of cardiovascular death or worsening HF events across the spectrum of age
Myhre et al[8]	RCT	JACC Heart Fail, 2022	Dapagliflozin (10 mg/d) or placebo	To assess the treatment effect of dapagliflozin across baseline levels of NT-proBNP among patients with HFmrEF or HFpEF	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin is safe and improves outcomes irrespective of baseline NT-proBNP concentrations in HFmrEF or HFpEF
Butt et al[9]	RCT	J Am Coll Cardiol, 2022	Dapagliflozin (10 mg/d) or placebo	To examine the effects of dapagliflozin according to the presence or not of AF in the DELIVER trial	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin improved HF outcomes to a similar extent irrespective of type of AF at baseline
Butt et al[10]	RCT	Circulation, 2022	Dapagliflozin (10 mg/d) or placebo	To investigate the efficacy and tolerability of dapagliflozin according to frailty status in patients with HFpEF/HFmrEF randomized in DELIVER	Patients with HFpEF/HFmrEF	2.3 years	6263	The benefit of dapagliflozin was consistent across the range of frailty studied
Cunningham et al[11]	RCT	J Am Coll Cardiol, 2022	Dapagliflozin (10 mg/d) or placebo	To investigate clinical outcomes and response to dapagliflozin in patients with HFpEF/HFmrEF who were enrolled during or following hospitalization	Patients with HFpEF/HFmrEF	2.3 years	6263	Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without history of recent HF hospitalization
Nassif et al[12]	RCT	Nat Med, 2021	Dapagliflozin (10 mg/d) or placebo	To evaluate whether the SGLT2i dapagliflozin improves the primary endpoint of Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, a measure of HF-related health status, at 12 wk after treatment initiation	Patients with HFpEF	12 wk	324	Dapagliflozin significantly improved patient-reported symptoms, physical limitations, and exercise function in chronic HFpEF
Anker et al[14]	RCT	N Engl J Med, 2021	Empagliflozin (10 mg/d) or placebo	To investigate effects of empagliflozin in patients with HFpEF	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF, regardless of the presence of diabetes or not
Filippatos et al[15]	RCT	Circulation, 2022	Empagliflozin (10 mg/d) or placebo	To evaluate whether the effects of empagliflozin are consistent in patients with and without diabetes	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin significantly reduced the risk of HF outcomes irrespective of diabetes status
Böhm et al[16]	RCT	J Am Coll Cardiol, 2022	Empagliflozin (10 mg/d) or placebo	To evaluate the interplay of age and empagliflozin effects in EMPEROR-Preserved	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin reduced primary outcomes and first and recurrent HF hospitalization and improved symptoms across a broad age spectrum
Butler et al[17]	RCT	Circulation, 2022	Empagliflozin (10 mg/d) or placebo	To evaluate the influence of sex on the effects of empagliflozin in patients with HFpEF enrolled in the EMPEROR-Preserved trial	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin produced similar benefits on outcomes and health status in women and men with HFpEF
Ferreira et al[18]	RCT	J Am Coll Cardiol, 2022	Empagliflozin (10 mg/d) or placebo	To examine the effect of empagliflozin in mineralocorticoid receptor antagonists users and nonusers in the EMPEROR-Preserved trial	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin reduced the primary outcome, which is not related to the use of mineralocorticoid receptor antagonists or not
Butler et al[19]	RCT	Circulation, 2022	Empagliflozin (10 mg/d) or placebo	To evaluate the efficacy of empagliflozin on health-related quality of life in patients with HFpEF and whether the clinical benefit observed with empagliflozin varies according to baseline health status	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin reduced the risk for major HF outcomes across the range of baseline Kansas City Cardiomyopathy Questionnaire Clinical Summary scores
Savarese et al[20]	RCT	J Card Fail, 2021	Empagliflozin (10 or 25 mg/d) or placebo	To determine the effects of empagliflozin in HF with predicted HFrEF vs HFpEF vs non-HF	Patients with T2D and established cardiovascular disease and an estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2	31.0 mo	7001	The benefits of empagliflozin on HF and mortality outcomes were consistent in non-HF, predicted HFpEF, and HFmrEF/HFrEF
Packer et al[21]	RCT	Circulation, 2021	Empagliflozin (10 mg/d) or placebo	To evaluate the efficacy of empagliflozin on inpatient and outpatient HF events	Patients with HFpEF/HFmrEF	26.2 mo	5988	Empagliflozin produced a reduction in the risk and severity of inpatient and outpatient worsening HF events
Spertus et al[23]	RCT	Nat Med, 2022	Canagliflozin (100 mg/d) or placebo	To confirm benefits of canagliflozin in a new type of trial that was patient centered and conducted in a completely remote fashion	Patients with HF	12 wk	476	Canagliflozin significantly improves symptom burden in HF, regardless of EF or diabetes status
Pandey et al[24]	Meta-analysis	ESC Heart Fail, 2022	Dapagliflozin (10 mg/d), empagliflozin (10 mg/d), sotagliflozin (200 mg/d, with a possible dose increase to 400 mg) or placebo	To evaluate the efficacy of SGLT2is in HF patients with HFpEF/HFmrEF	Patients with HFpEF/HFmrEF	9-26 mo	15684	SGLT2is reduce cardiovascular death and HF hospitalization among patients with HF, regardless of left ventricular ejection fraction status
Karakasis et al[25]	Meta-analysis (overview)	Heart Fail Rev, 2023	Dapagliflozin, empagliflozin, canagliflozin, sotagliflozin, ertugliflozin, lusoglifozin, or placebo	To evaluate the effect of SGLT2is in HFmrEF or HFpEF	Patients with HFpEF/HFmrEF	3-50.4 mo	42224	The use of SGLT2i in HFpEF is both efficient and safe

AF: Atrial fibrillation; EF: Ejection fraction; EMPEROR-Preserved: Empagliflozin in Heart Failure with a Preserved Ejection Fraction; DELIVER: Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure.

Table 2 Summary of clinical studies on sodium-glucose cotransporter inhibitors in acute heart failure patients

Ref.	Type of article	Journal and published time	Drugs	Aim of study	Inclusive population	Intervention cycle	Number of cases	Main conclusion
Voors et al[26]	RCT	Nat Med, 2022	Empagliflozin (10 mg/d) or placebo	To evaluate whether empagliflozin can improve clinical outcomes when initiated in patients who are hospitalized for AHF	Patients with AHF or decompensated chronic HF	90 d	530	Empagliflozin results in significant clinical benefit in patients hospitalized for AHF
Biegus et al[27]	RCT	Eur Heart J, 2023	Empagliflozin (10 mg/d) or placebo	To evaluate effects of the SGLT2i empagliflozin on decongestion-related endpoints in the EMPULSE trial	Patients with AHF or decompensated chronic HF	90 d	530	Empagliflozin in patients hospitalized for AHF resulted in an early, effective, and sustained decongestion
Kosiborod et al[28]	RCT	Circulation, 2022	Empagliflozin (10 mg/d) or placebo	To investigate the effects of the SGLT2i empagliflozin on symptoms, physical limitations, and quality of life, using the KCCQ in the EMPULSE trial	Patients with AHF or decompensated chronic HF	90 d	530	Empagliflozin improved symptoms, physical limitations, and quality of life in patients hospitalized for AHF
Damman et al[29]	RCT	Eur J Heart Fail, 2020	Empagliflozin (10 mg/d) or placebo	To evaluate safety and clinical efficacy of SGLT2is in patients with acute decompensated HF	AHF patients with and without diabetes	30 d	80	Empagliflozin increased urinary output and reduced a combined endpoint of worsening HF, rehospitalization for HF, or death at 60 d
Charaya et al[30]	RCT	Open Heart, 2022	Dapagliflozin (10 mg/d in addition to standard therapy)	To evaluate safety and clinical efficacy of the SGLT2i dapagliflozin in patients with acute decompensated HF	Patients with AHF	30 d	102	Dapagliflozin did not improve the in-hospital and 30-d prognosis after discharge
Carvalho et al[31]	Meta- Analysis	Clin Res Cardiol, 2023	Dapagliflozin (10 mg/d), empagliflozin (10/25 mg/d), sotagliflozin (200-400 mg/d), or placebo	To compare cardiovascular outcomes, renal function, and diuresis in patients receiving standard diuretic therapy for AHF with or without the addition of SGLT2i	Patients with AHF	30 d to 2.3 years	2824	SGLT2i combined conventional diuretic therapy can reduce all-cause death, readmissions for HF, and the composite results

AHF: Acute heart failure; EMPULSE: Empagliflozin in Patients Hospitalized with Acute Heart Failure Who Have Been Stabilized; HF: Heart failure; KCCQ: Kansas City Cardiomyopathy Questionnaire; NT-proBNP: N-terminal pro B-type natriuretic peptide; SGLT2i: Sodium-glucose co-transporter-2 inhibitors; AHF: Acute heart failure.

Table 3 Summary of clinical studies on sodium-glucose co-transporter inhibitors in atrial fibrillation/atrial flutter and other arrhythmias patients

Ref.	Type of article	Journal and published time	Drugs	Aim of study	Inclusive population	Intervention cycle	Number of cases	Main conclusion
Li et al[33]	Meta- Analysis	Front Endocrinol (Lausanne), 2021	Dapagliflozin (10 mg/d), canagliflozin (100/300 mg/d), empagliflozin (10/25 mg/d), ertugliflozin (5/15 mg/d), sotagliflozin (200/400 mg/d), or placebo	To investigate whether SGLT2i use is associated with lower risks of AF/AFL	Patients with randomized placebo-controlled trials registered in comparing SGLT2is with matching placebo including recorded AF/AFL outcomes	60 d to 5.2 years	66685	SGLT2i use is associated with a 19.33% lower rate of SAEs of AF/AFL compared with the placebo
Hsiao et al[34]	Multicenter Study	J Clin Endocrinol Metab, 2022	Dapagliflozin (10 mg/d), empagliflozin (10 mg/d), canagliflozin (100 mg/d), or liraglutide or dulaglutide	To determine the comparative risk of new-onset AF with SGLT2is vs GLP-1RAs in Asian patients with T2D in a real-world setting	New-onset AF in patients with T2D	3.0 years	16566	SGLT2is were associated with lower risk of new-onset AF compared with GLP-1RAs among patients with T2D in a real-world practice
Zhuo et al[35]	Cohort study	JAMA Netw Open, 2022	Dapagliflozin (10 mg/d), empagliflozin (10 mg/d), canagliflozin (100 mg/d), or DPP-4i/GLP-1RA	To examine incident AF with initiation of an SGLT2i compared with initiation of a DPP-4i or a GLP-1RA among older adults (age ≥ 66 years) with T2D in routine clinical practice	Older adults with T2D who had no history of AF	April 1, 2013 to December 31, 2018	165984	SGLT2is reduced risk of incident AF compared with a DPP-4i or GLP-1RA
Pandey et al[36]	Meta-analysis	J Am Heart Assoc, 2021	Empagliflozin (10/20 mg/d), dapagliflozin (2.5/5/10 mg/d), canagliflozin (100/300 mg/d), ertugliflozin (5/15 mg/d), sotagliflozin (200/400 mg/d), or placebo	To determine whether SGLTis reduce AF and whether a history of AF modifies the effect of SGLTis on the composite of HF hospitalization or cardiovascular death	Patients regardless of prior AF history or other comorbidities	24-304 wk	75279	SGLTis may reduce AF events and likely reduce HF hospitalization/cardiovascular death to a similar extent in patients with and without AF
Zheng et al[37]	Meta- analysis	Pacing Clin Electrophysiol, 2024	Canagliflozin (100/300 mg/d), dapagliflozin (10 mg/d), empagliflozin (10/25 mg/d), or placebo	To investigate the effect of SGLT2is on the incidence of cardiovascular disease events in patients with AF	Patients with AF	2.3 to 3.3 years	38529	SGLT2is were associated with a lower incidence of cardiovascular disease events, especially HF hospitalization, in patients with AF
Fernandes et al[38]	Meta-analysis	Heart Rhythm, 2021	Dapagliflozin (2.5/5/10 mg/d), canagliflozin (100/300 mg/d), empagliflozin (10/25 mg/d), ertugliflozin (5/15 mg/d), or placebo	To evaluate the association of SGLT2is with arrhythmias in patients with T2D or HF	Patients with T2D or HF	24 wk to 5.7 years	63166	SGLT2is are associated with significantly reduced risks of incident atrial arrhythmias and sudden cardiac death in patients with T2D

AF: Atrial fibrillation; AFL: Atrial flutter; CREDENCE: Canagliflozin and renal events in diabetes with established nephropathy clinical evaluation; DELIVER: Dapagliflozin evaluation to improve the lives of patients with preserved ejection fraction heart failure; DPP-4i: Dipeptidyl peptidase-4 inhibitor; GLP-1RA: Glucagonlike peptide-1 receptor agonist; HF: Heart failure; SAEs: Serious adverse events; SGLT1/2i: Sodium-glucose co-transporter-1/2 inhibitors; SGLT2i: Sodium-glucose co-transporter-2 inhibitors.

Table 4 Summary of clinical studies on sodium-glucose co-transporter inhibitors in primary prevention of atherosclerotic cardiovascular disease/cardiovascular disease patients

Ref.	Type of article	Journal and published time	Drugs	Aim of study	Inclusive population	Intervention cycle	Number of cases	Main conclusion
Katakami et al[39]	RCT	Cardiovasc Diabetol, 2020	Tofogliflozin (20 mg/d in addition to an alternative antidiabetic agent), or placebo	To investigate the preventive effects of tofogliflozin on atherosclerosis in T2D patients without apparent cardiovascular disease by monitoring carotid intima-media thickness	Patients with T2D and no history of apparent cardiovascular disease	104 wk	340	Tofogliflozin is a safe and effective treatment option for managing primary cardiovascular disease risk factors in this population
Kosiborod et al[40]	RCT	J Am Coll Cardiol, 2018	Dapagliflozin (2.5/5/10 mg/d), canagliflozin (100/300 mg/d), empagliflozin (10/25 mg/d), ipragliflozin (50 mg/d), tofogliflozin (20 mg/d), luseogliflozin (2.5 mg/d), or oGLD	To examine a broad range of cardiovascular outcomes in patients initiated on SGLT2is vs oGLD across 6 countries in the Asia Pacific, the Middle East, and North American regions	Patients initiated on SGLT2is vs oGLD	Start date ranged from December 2013 in Australia to April 2015 in Israel, last date of data collection from June 2016 in Australia to November 2017 in Singapore1	235064	SGLT2is were associated with a lower risk of cardiovascular events across a broad range of outcomes and patient characteristics
Zelniker et al[41]	Meta-analysis	Lancet, 2019	Empagliflozin (10/25 mg/d), canagliflozin (100/300 mg/d), dapagliflozin (10 mg/d), or placebo	To evaluate the magnitude of effect of SGLT2is on specific cardiovascular and renal outcomes and whether heterogeneity is based on key baseline characteristics	Patients with T2D	2.4-4.2 years	34322	SGLT2is have moderate benefits on atherosclerotic MACEs that seem confined to patients with established atherosclerotic cardiovascular disease
Rahman et al[42]	Meta-analysis	J Am Heart Assoc, 2023	Dapagliflozin (10 mg/d), canagliflozin (100 mg/d), sotagliflozin (400 mg/d), or placebo	To explore the benefit in patients without established ASCVD	Patients with prior ASCVD and T2D	69-218 wk	23987	SGLT2is significantly reduced atherosclerotic MACEs in both CKD and T2D without established ASCVD
Giugliano et al[43]	Meta-analysis	Diabetes Obes Metab, 2021	Dapagliflozin (2.5/5/10 mg/d), canagliflozin (100/300 mg/d), empagliflozin (10/25 mg/d), ertugliflozin (5/15 mg/d), sotagliflozin (200/400 mg/d), or placebo	To present a meta-analysis of cardiorenal outcomes of SGLT2is available in Europe or the United States in patients with T2D	Patients with T2D	1.5-4.2 years	65587	SGLT2is have moderate benefits on MACEs and major benefits on the progression of diabetic kidney disease

¹Patients were followed from index date (initiation of either sodium-glucose co-transporter-2 inhibitors or other glucose-lowering drugs) until end of the index treatment (on-treatment analysis only), migration/leaving the practice/database, last date of data collection, outcome date, or censoring date.

CKD: Chronic kidney disease; MACEs: Major adverse cardiovascular events; oGLD: Other glucose-lowering drugs; SGLT2i: Sodium-glucose co-transporter-2 inhibitors; T2D: Type 2 diabetes.

Table 5 Summary of clinical studies on sodium-glucose co-transporter inhibitors in acute myocardial infarction patients

Ref.	Type of article	Journal and published time	Drugs	Aim of study	Inclusive population	Intervention cycle	Number of cases	Main conclusion
von Lewinski et al[44]	RCT	Eur Heart J, 2022	Empagliflozin (10 mg/d) or placebo	To investigate the effects of this drug class in patients with AMI	Patients with AMI accompanied by a large creatine kinase elevation (> 800 IU/L)	26 wk	476	Empagliflozin was associated with a significantly greater NT-proBNP reduction over 26 wk, accompanied by a significant improvement in echocardiographic functional and structural parameters
Hashikata et al[45]	RCT	Heart Vessels, 2020	Empagliflozin (10 mg/d)	To evaluate the effects of empagliflozin on neointimal response after drug-eluting stent implantation	T2D with coronary artery disease planned for drug-eluting stent placement	12 mo	28	Data possibly support a beneficial effect of empagliflozin in T2D required for coronary revascularization therapy
			or insulin, dipeptidyl peptidase-4 inhibitor, alpha-glucosidase inhibitor
Mozawa et al[46]	RCT	ESC Heart Fail, 2021	Empagliflozin (10 mg/d) or placebo	To evaluate the reno-protective effects of SGLT2i in patients with AMI	Patients with AMI and T2D	24 wk	96	Early administration of SGLT2i in these patients is considered desirable for renal protection
Adel et al[47]	RCT	Saudi Med J, 2022	Empagliflozin (10 mg/d) or placebo	To study the effects of low dose empagliflozin in improving outcomes in diabetic patients with acute coronary syndrome after percutaneous coronary intervention	Diabetic patients with acute coronary syndrome after percutaneous coronary intervention	6 mo	93	Low dose empagliflozin to standard care of acute coronary syndrome diabetic patients after percutaneous coronary intervention was associated with no significant reduction in negative cardiovascular outcomes during 6 mo
Butler et al[48]	RCT	N Engl J Med, 2024	Empagliflozin (10 mg/d) or placebo	To evaluate the safety and efficacy of empagliflozin in patients with AMI	Patients with AMI and T2D	17.9 mo	6522	Empagliflozin did not lead to a significantly lower risk of a first hospitalization for HF or death from any cause than placebo
Hernandez et al[49]	RCT	Circulation, 2024	Empagliflozin (10 mg/d) or placebo	To evaluate the effects of empagliflozin on first and recurrent heart failure events in patients after myocardial infarction	Patients with AMI and T2D	17.9 mo	6522	Empagliflozin reduced the risk of heart failure in patients after acute myocardial infarction with left ventricular dysfunction or congestion

AMI: Acute myocardial infarction; NT-proBNP: N-terminal pro B-type natriuretic peptide; SGLT2i: Sodium-glucose co-transporter-2 inhibitors; T2D: Type 2 diabetes.