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.