Table 2. An outline summary of the clinical trials (n = number of patients in RCT).

RCT=Randomized Controlled Trial, MACE=Major Adverse Cardiovascular Events, CVD=Cardiovascular Disease, RF=Risk Factors, MI= Myocardial Infarction, HF= Heart Failure, eGFR=Estimated Glomerular Filtration Rate, ESRD=End Stage Renal Disease, BMI=Body Mass Index, ACEi=Angiotensin Converting Enzyme Inhibitors, ARB=Angiotensin Receptor Blockers, T2DM=Type 2 Diabetes Mellitus, HbA1c=Glycosylated Hemoglobin Type A1C, HDL=High Density Lipoprotein, SBP=Systolic Blood Pressure, HFrEF=Heart Failure with Ejection Failure, NYHA=New York Heart Association, LVEF=Left ventricular ejection fraction, NT-proBNP=N-Terminal pro B-type Natriuretic Peptide, ICD=Implantable cardiac defibrillator.

COCHRANE APPRAISAL	Study Design	Inclusion criteria	Intervention	Primary Outcome	Secondary Outcome	Conclusions
Wanner et al. 2016 [14] EMPA-REG	Multicentre randomized double-blind placebo-controlled trial	Insufficient glycemic control and High risk of CV events N = 7020	Empagliflozin 10mg, Empagliflozin 25mg or Placebo	First occurrence of MACE (3-point) which included death from CV causes, non-fatal MI, or nonfatal stroke.	Expanded occurrence of MACE to include unstable angina as well as HF exacerbation, renal events and transient ischemic attack	Primary outcome - significant lower risk of MACE in the empagliflozin group than in the placebo group
Neal et al. 2017 [10] CANVAS	Randomized double-blind placebo-controlled	Male or female T2DM ≥ 30yrs with symptomatic CVD or 50yrs or older with two or more RF for CVD N = 9734	Canagliflozin 100mg, Canagliflozin 300mg or Placebo	Composite of death from CV causes, nonfatal MI or nonfatal stroke	Death from any cause, from CV cause, progression of albuminuria and composite of death from hospitalization for HF	Pt. with T2DM with Canagliflozin had lower risk of death from CV cases, nonfatal myocardial infarction, nonfatal stroke than placebo
Wiviott et al. 2018 [7] DECLARE TIMI-58	Randomized double-blind placebo-controlled	Male or female T2DM ≥ 40 yrs with T2DM and High risk for CV Events N = 17160	Dapagliflozin 10mg or Placebo	Composite endpoint of CV death, MI, Ischemic stroke or Hospitalization due to HF	Renal Composite endpoint - ≥40% decrease in eGFR to eGFR <60 ml/min/1.73m2 and/or ESRD and/or Renal or CV death	Pt. with T2DM with treatment with dapagliflozin did not result in higher or lower MACE rate than placebo but did result in lower rate of CV death or hospitalization for HF.
Perkovic et al. 2019 [15] CREDENCE	Randomized double-blind placebo-controlled	T2DM with HbA1c ≥6.5 and ≤12% with eGFR ≥30 and ≤90, Pt. need to be on maximum tolerated dose of ACEi or ARB 4 weeks prior to randomization, urine albumin to creatinine ratio >300mg/g and <5000mg/g N = 4401	Canagliflozin 100mg or Placebo once daily	Composite of doubling of serum creatinine, ESRD and renal or CV death	Composite Endpoint of CV death and Hospitalized HF	Pt. with T2DM and kidney disease, the risk of CV events was lower in the canagliflozin group than placebo
Phrommintikul et al. 2019 [16]	Prospective randomized double-blinded study	Adults ≥21 or non-childbearing potential female, inadequately controlled T2DM with at least half maximum dose of metformin. Stable documented coronary artery disease N = 49	Dapagliflozin 10mg or Vildagliptin 50-100mg	Individuals who have ST segment depression, average SBP, myocardial dysfunction, myocardial injury, oxidative stress, ventricular wall stretch and inflammation event.	N/A	Cardiovascular benefits observed only in SGLT-2i
Bonora et al. 2019 [17]	Randomized single blind placebo control	Male and Female aged 18-75yrs, T2DM on oral agents +/- insulin, with T2DM duration > 6 months with HbA1c 7-10% N = 33	Dapagliflozin 10mg or Placebo	Change from baseline in reverse cholesterol transport, measured as cholesterol efflux capacity of patient's plasma	Change from baseline in HDL cholesterol levels, Changes from baseline in the distribution in HDL subclasses, and adverse events	Observed no changes in cardiac function parameters estimated by impedance cardiography in T2DM.
Petrie et al. 2020 [18] DAPA-HF	Randomized quadruple blinded placebo-controlled	Male or Female aged ≥18yrs, diagnosis of symptomatic HFrEF (NYHA class II-IV) present for 2 months, LVEF ≤40%, elevated NT-proBNP eGFR ≥30mL/min/1.73m2 N = 4742	Dapagliflozin 5mg, 10mg or Placebo	Composite endpoint of CV death, hospitalization due to heart failure or due to HF	Recurrent hospitalizations due to HF and CV death, composite endpoint of ≥50% sustained decline in eGFR, ESRD or Renal Death, endpoint of all-cause mortality	Dapagliflozin when added to recommended therapy significantly reduced the risk of worsening HF or CV death independent of diabetes status
Fuchigami et al. 2020 [19]	Randomized parallel open blinded study	Male and female pt. who are ≥20yrs but ≤80yrs, T2DM, no antidiabetic medication or only using beguanide, HbA1c ≥7.1%, BMI ≥23kg/m2 N = 340	Dapagliflozin 5mg or Sitagliptin 50mg	Achieving HbA1c ≤ 7%, Body weight loss of 3% and avoidance of hypoglycaemia	Reduction in fasting blood glucose, body weight, BMI, lipid metabolism marker and other cardiovascular parameters	Compared to sitagliptin, dapagliflozin was more effective at improving cardiometabolic RF
Packer et al. 2020 [20] EMPEROR-REDUCED	Randomized double blinded placebo-controlled	Male or female ≥18yrs, pt. with chronic HF and elevated NT-proBNP, use of medical devices such as ICDs N = 3730	Empagliflozin 10mg or Placebo	Time to first event of CV death or hospitalization for HF	Total number of HF events, eGFR slope of change from baseline, all-cause mortality, all-cause hospitalization	Empagliflozin group had lower risk of CV or HF hospitalization than placebo group whether diabetic or not
Cannon et al. 2020 [21] VERTIS-CV	Randomized double-blind placebo-controlled	T2DM diagnosis, HbA1c 7-10.5%, on stable anti-hyperglycaemic agents, BMI ≥18, hx of atherosclerosis or cerebro/peripheral vascular disease N = 8238	Ertugliflozin 5mg, 15mg or Placebo	Time to first MACE, change from baseline in HbA1c% at week 18, change from Haemoglobin baseline at week 18	Time to occurrence of CV death or HF hospitalization, composite of renal death, renal dialysis/transplant, or doubling serum creatinine	Pt. with T2Dm and atherosclerotic CV disease, ertugliflozin was not significantly different for MACE when compared to placebo