Table 4: Overview of sodium-glucose cotransporter 2 inhibitor outcome trials in patients with type 2 diabetes and cardiovascular disease.

	EMPA-REG OUTCOME14 CANVAS-PROGRAM16	Integrated analysis of CANVAS57 and CANVAS-R58
Design and population	7,028 patients with T2D and established CV disease Optimal care plus empagliflozin (10 mg or 24 mg daily) or placebo Follow-up: median 3.1 years	10,142 patients with T2D and established CV disease CANVAS, n=4,330; CANVAS-R, n=5,812 Optimal care plus canagliflozin or placebo Median follow-up: CANVAS-PROGRAM, 126.1 weeks; CANVAS, 93.3 weeks; CANVAS-R, 78 weeks
Primary outcome	3-point MACE: Empagliflozin, 10.5% (490/4,687) Placebo, 12.1% (282/2,333) HR, 0.86 (95% CI: 0.74, 0.99)	3-point MACE: Canagliflozin, 26.9 with event/1,000 patient-years Placebo, 31 with event/1,000 patient-years HR, 0.86 (95% CI: 0.75, 0.97)
Key secondary outcomes	HF hospitalisation or CV death: Empagliflozin, 5.7% Placebo, 8.5% HR, 0.66 (95% CI: 0.55, 0.79) CV death: Empagliflozin, 5.9% Placebo, 12.4% HR, 0.62 (95% CI: 0.49, 0.77) Death from any cause: Empagliflozin, 5.9% Placebo, 12.4% HR, 0.68 (95% CI: 0.57, 0.82) Hospitalisation for HF: Empagliflozin, 4.1% Placebo, 2.7% HR, 0.65 (95% CI: 0.50, 0.85) Incident or worsening nephropathy: Empagliflozin, 12.7% Placebo, 18.8% HR, 0.61 (95% CI: 0.53, 0.70)	Estimates for the fatal secondary outcomes were not significant for canagliflozin versus placebo: Death from any cause: HR, 0.87 (95% CI: 0.74, 1.01) CV death: HR, 0.87 (95% CI: 0.72, 1.06) Hospitalisation for HF: Canagliflozin, 5.5 with event/1,000 patient-years Placebo, 8.4 with event/1,000 patient-years HR, 0.67 (95% CI: 0.52, 0.87) CV death or HF hospitalisation Progression of albuminuria: Canagliflozin, 89.4 with event/1,000 patient-years Placebo, 128.7 with event/1,000 patient-years HR, 0.73 (95% CI: 0.67, 0.79)
Safety Total population	Any adverse event: empagliflozin 4,230/4,687 (90.2%); placebo 2,139/2333 (91.7%) Any confirmed hypoglycaemic adverse event: empagliflozin 27.8%; placebo 27.9% Urinary tract infection (men/women): empagliflozin 10.5%/36.4%; placebo 9.4%/40.6% Genital infection (men/women): empagliflozin 5.0%/10.0%; placebo 1.5%/2.6% Bone Fracture: empagliflozin 3.8%; placebo 3.9%	Any confirmed hypoglycaemic adverse event/1,000 patient-years: canagliflozin, 60.1; placebo, 51.7% Genital infection/1,000 patient-years (men/women): canagliflozin, 36.8/81.7; placebo, 10.6/20.1 Urinary tract infection/1,000 patient-years: canagliflozin, 37.6; placebo, 38.7 Low-trauma fracture: Canagliflozin, 11.58 with event/per 1,000 patient-years Placebo, 9.17 with event/1,000 patient-years HR, 1.23 (95% CI: 0.99, 1.52) Atraumatic lower limb amputation (CANVAS): History of amputation: Canagliflozin, 96.3 with event/per 1,000 patient-years Placebo, 59.16 with event/1,000 patient-years HR, 2.15 (95% CI: 1.11, 4.19) No history of amputation: Canagliflozin, 4.68 with event/per 1,000 patient-years Placebo, 2.48 with event/1,000 patient-years HR, 1.88 (95% CI: 1.27, 2.78)
Special populations	Chronic kidney disease at baseline: Any adverse event: empagliflozin, 91.3%; placebo, 95.1% Serious adverse event: empagliflozin, 45.5%; placebo, 52.9% HF at baseline: Any adverse event: empagliflozin, 89.4%; placebo, 94.3% Serious adverse event: empagliflozin, 43.7%; placebo, 51.6%

3-point MACE = Major Adverse Cardiac Events (defined as a composite outcome of death from CV causes, nonfatal myocardial infarction or nonfatal stroke); CANVAS = canagliflozin cardiovascular assessment; CANVAS-PROGRAM = integrated analysis of CANVAS and CANVAS-R; CANVAS-R = CANVAS-renal; CI = confidence interval; CV = cardiovascular; EMPA-REG OUTCOME = empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes study; HF = heart failure; HR = hazard ratio; T2D = type 2 diabetes.