Table 8.

Characteristics of included studies and their reports for dapagliflozin

Author	Title	Journal	Methods	Findings
Solomon et al. (2022) (DELIVER Trial)	Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction	The New England Journal of Medicine	6263 patients with HF and LVEF >40% (HF with mildly reduced [HFmrEF] and preserved [HFpEF] ejection fractions) participated in the trial, and were randomized to dapagliflozin 10 mg or placebo, along with usual therapy. The primary outcome assessed was a composite of worsening HF, defined as unplanned HHF or urgent visit for HF or CV death.	Treatment of HF patients with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) with dapagliflozin yielded an 18% risk reduction in the composite of worsening HF or cardiovascular death, regardless of presence or absence of diabetes. Additionally, there was a similar incidence of adverse events in patients with LVEF ≥60% and those with LVEF <60%. This effect of dapagliflozin was consistent, suggesting that this SGLT2 inhibitor is beneficial in these groups of HF patients, in whom limited therapies are available.
Heerspink et al. (2020) (DAPA‐CKD Trial)	Dapagliflozin in Patients with Chronic Kidney Disease	The New England Journal of Medicine	The trial involved 4304 participants with eGFR 25 to 75 mL/min/1.73 m2 and a UACR of 200 to 5000, who were randomized to dapagliflozin 10 mg or placebo. Sustained decline in the eGFR of at least 50%, ESKD, or death from renal or CV causes, were evaluated as a composite of the primary outcome.	Primary outcome event occurred in 9.2% of patients in the dapagliflozin group and 14.5% in the placebo group. Dapagliflozin treatment resulted in a significant 39% risk reduction in the composite of a sustained 50% decline in the eGFR, ESKD, or death from renal or cardiovascular causes among patients with chronic kidney disease, irrespective of diabetes status.
McMurray et al. (2019) (DAPA‐HF Trial)	Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction	The New England Journal of Medicine	4744 patients with NYHA class II, III, or IV HF and a LVEF ≤40%, received either dapagliflozin 10 mg or placebo, in addition to recommended therapy. Worsening HF was the primary composite outcome that was evaluated, defined as hospitalization or an urgent visit followed by intravenous therapy for HF, or CV death.	With dapagliflozin treatment, the risk of the key composite outcome of worsening HF was reduced by 30%, a finding that was comparable in diabetic and non‐diabetic patients.
Wiviott et al. (2019) (DECLARE‐TIMI 58 Trial)	Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes	The New England Journal of Medicine	17 160 patients with T2DM who had ASCVD or were at risk for developing it were randomized to dapagliflozin or placebo. MACE, defined as CV death, myocardial infarction, or ischaemic stroke, was the primary safety outcome assessed.	There was no difference between dapagliflozin treatment and placebo in the rate of MACE in patients with T2DM with or at risk for ASCVD, but it did lead to reductions in the rate of CV death or HHF; this finding reveals a lower rate of hospitalization for HF.
Reports from DAPA‐HF, DECLARE‐TIMI 58, and DAPA‐CKD
Heerspink et al. (2022)	A pre‐specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA‐CKD) randomized controlled trial on the incidence of abrupt declines in kidney function	Kidney International	Participants from DAPA‐CKD trial were assessed for an abrupt decline in kidney function in terms of serum creatinine doubling between two subsequent visits and AKI‐related adverse events.	The risk of a sudden deterioration in kidney function was reduced with dapagliflozin treatment in patients with CKD and substantial albuminuria, whereby doubling of serum creatinine occurred in 22.9% of patients. Serious adverse events linked to AKI occurred in 2.5% of patients receiving dapagliflozin, with no discernible difference between the two groups.
Berg et al. (2021)	Time to Clinical Benefit of Dapagliflozin and Significance of Prior Heart Failure Hospitalization in Patients With Heart Failure With Reduced Ejection Fraction	JAMA Cardiology	In participants from DAPA‐HF trial, the timing of onset of clinical benefit with dapagliflozin as compared with placebo was examined, and the timing of the most recent HF hospitalization was considered to categorize patients.	Dapagliflozin therapy was linked to a fast decline in the risk of cardiovascular death or worsening HF (by 49%), with a sustained statistically significant benefit emerging very early, 28 days after randomization.
McMurrary et al. (2021)	Effects of Dapagliflozin in Patients With Kidney Disease, With and Without Heart Failure	JACC: Heart Failure	In DAPA‐CKD trial patients, who were randomized to dapagliflozin 10 mg and placebo, composite endpoint of ≥50% decline in eGFR, ESKD, and cardiovascular or renal death was assessed.	Regardless of a history of HF, dapagliflozin improved survival in CKD patients with or without T2DM by lowering the risk of renal failure, CV death, or HHF.
Zelniker et al. (2021)	Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes A Prespecified Secondary Analysis of a Randomized Clinical Trial	JAMA Cardiology	In participants from DECLARE‐TIMI 58 trial, the cardiovascular efficacy and safety of dapagliflozin were assessed using the baseline eGFR and UACR.	Dapagliflozin's effect on the relative risk for CV events was consistent regardless of kidney function or albuminuria status; patients with a lower eGFR and albuminuria experienced absolute major benefit regarding CV death or HHF composite.
Docherty et al. (2021)	Extrapolating Long‐term Event‐Free and Overall Survival With Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction An Exploratory Analysis of a Phase 3 Randomized Clinical Trial	JAMA Cardiology	In participants from DAPA‐HF trial, the long‐term treatment effects of dapagliflozin in HFrEF patients over the duration of a patient's lifetime were estimated, with primary composite outcome being time to first HHF, urgent HF visit followed by intravenous therapy, or CV death.	With dapagliflozin, the estimated event‐free and overall survival times were longer (8.3 years) compared with placebo (6.2 years), suggesting that dapagliflozin provides clinically meaningful gains in extrapolated event‐free and overall survival in HFrEF patients.
Butt et al. (2021)	Efficacy and Safety of Dapagliflozin in Men and Women With Heart Failure With Reduced Ejection Fraction A Prespecified Analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial	JAMA Cardiology	In DAPA‐HF trial participants, the efficacy and safety of dapagliflozin was investigated in men versus women with HFrEF, with the composite of an episode of worsening HF (HF hospitalization or urgent HF visit requiring intravenous therapy) or CV death.	Dapagliflozin was safe, well‐tolerated, reduced the risk of worsening HF, CV death, and all‐cause mortality, and was effective in improving symptoms, physical function, and health‐related quality of life comparably in men and women with HFrEF. Therefore, the effect of dapagliflozin was consistent in both men and women.
Solomon et al. (2020)	Effect of Dapagliflozin in Patients With HFrEF Treated With Sacubitril/Valsartan The DAPA‐HF Trial	JACC: Heart Failure	Patients from DAPA‐HF trial were analysed according to whether they were taking sacubitril/valsartan at randomization. Dapagliflozin's efficacy on the primary composite outcome, defined as CV death or episode of worsening HF, its components, and all‐cause mortality, was evaluated.	In patients receiving sacubitril/valsartan and those not on it, dapagliflozin was equally safe and effective (25% risk reduction) in the DAPA‐HF trial, indicating that combining the two medications could further decrease morbidity and mortality in HFrEF patients.
Docherty et al. (2020)	Effect of Dapagliflozin on Outpatient Worsening of Patients With Heart Failure and Reduced Ejection Fraction A Prespecified Analysis of DAPA‐HF	Circulation	In participants from DAPA‐HF trial, the frequency and significance of episodes of outpatient HF worsening, requiring the augmentation of oral therapy, and the effects of dapagliflozin on these additional events were assessed.	With dapagliflozin, there was a 27% risk reduction in participants who experienced the expanded outcome in DAPA‐HF compared with placebo. Outpatient episodes of HF worsening were common, were of prognostic importance, and were reduced by dapagliflozin.
Zelniker et al. (2020)	Relationship between baseline cardiac biomarkers and cardiovascular death or hospitalization for heart failure with and without sodium–glucose co‐transporter 2 inhibitor therapy in DECLARE‐TIMI 58	European Journal of Heart Failure	In DECLARE‐TIMI 58 trial participants, baseline NT‐proBNP and hsTnT levels were measured.	In HFrEF patients, dapagliflozin reduced the relative risk of CV death/HHF by 17%, irrespective of NT‐proBNP and hsTnT levels, with greater absolute risk reductions seen in those with higher baseline biomarker levels.
Kato et al. (2019)	Effect of Dapagliflozin on Heart Failure and Mortality in Type 2 Diabetes Mellitus	Circulation	In participants from DECLARE‐TIMI 58 trial, baseline HF status stratified by LVED, and composite of CV death, HHF, and all‐cause mortality were assessed.	Dapagliflozin reduced HHF in individuals with and without HFrEF and decreased CV death and all‐cause mortality in those with HFrEF by 38% in this study, the first SGLT2 inhibitor cardiovascular outcome trial to analyse patients with T2DM stratified by EF.
Mosenzon et al. (2019)	Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE–TIMI 58 randomized trial	The Lancet Diabetes & Endocrinology	Patients from DECLARE‐TIMI‐58 trial, with creatinine clearance of at least 60 mL/min were randomly assigned to 10 mg dapagliflozin or placebo. A sustained 40% decline in eGFR to <60 mL/min per 1.73 m2, ESKD, and or death from renal or cardiovascular causes were assessed.	Dapagliflozin significantly improved the cardiorenal outcome, revealing 46% reduction in a sustained decline in eGFR and a lower risk of ESKD or renal death.
Cahn et al. (2019)	Efficacy and Safety of Dapagliflozin in the Elderly: Analysis From the DECLARE– TIMI 58 Study	Diabetes Care	Participants from DECLARE‐TIMI 58 trial within age subgroups were assessed for the treatment effect with dapagliflozin and age‐based treatment interaction.	Dapagliflozin reduced the composite of CV death or HHF consistently by 12% in age‐group <65, by 23% in those ≥65 to <75 years of age, and by 6% in age group ≥75 years. There was no heterogeneity in the relative risk reduction for the secondary pre‐specified cardiorenal outcome (18% to 28%) in the different age groups, revealing a consistent efficacy and safety of dapagliflozin despite age.

AKI, acute kidney injury; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CV, cardiovascular; EF, ejection fraction; eGFR, estimated glomerular filtration rate; ESKD, end‐stage kidney disease; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HHF, hospitalization for heart failure; hsTnT, high‐sensitivity troponin T; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular events; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; SGLT2, sodium‐glucose cotransporter 2; T2DM, type 2 diabetes mellitus; UACR, urinary albumin‐to‐creatinine ratio.