Table 1.
Summary of cardiovascular outcome trials with SGLT2 inhibitors.
| EMPA-REG Outcome | CANVAS Program | Declare-TIMI 58 | |
|---|---|---|---|
| Study drug | Empagliflozin | Canagliflozin | Dapagliflozin |
| Drug class | SGLT2 inhibitor | SGLT2 inhibitor | SGLT2 inhibitor |
| Comparator | Placebo | Placebo | Placebo |
| Selected inclusion criteria | Adults with T2D at high risk of CV disease; BMI ≤ 45 kg/m2; no glucose-lowering therapy in previous 12 weeks and HbA1c 7.0–9.0%, or stable glucose-lowering therapy and HbA1c 7.0–10.0% | T2D; HbA1c 7.0–10.5%; age ≥30 years with a history of CV events, or age ≥50 years with a high risk of CV events; eGFR ≥30 ml/min/1.73 m2 | T2D; HbA1c ≥6.5– |
| Selected exclusion criteria | ACS, stroke, or TIA in previous 2 months; planned cardiac surgery or angioplasty; liver disease; eGFR 2 | T1D; diabetic ketoacidosis; pancreas or beta-cell transplantation; diabetes secondary to pancreatitis or pancreatectomy; severe hypoglycaemic episode in previous 6 months | T1D; CrCl |
| Number of patients | 7,020 | 10,142 | 17,160 |
| Study aim | Assess CV safety outcomes with empagliflozin compared with placebo, on top of standard of care, in patients with T2D at high CV risk | To pool results from the CANVAS and CANVAS-R trials to assess CV safety outcomes with canagliflozin compared with placebo, on top of standard of care, in patients with poorly controlled T2D and a history of CV events, or high risk of CV events | Assess CV outcomes with dapagliflozin compared with placebo, on top of standard of care, in patients with T2D who either have or are at risk of atherosclerotic CV disease |
| Primary outcome | 3P-MACE (CV death, non-fatal MI or non-fatal stroke) | 3P-MACE (CV death, non-fatal MI or non-fatal stroke) | Primary safety outcome: non-inferiority for 3P-MACE (CV death, non-fatal MI or non-fatal ischemic stroke). Co-primary efficacy outcomes: 3P-MACE; CV death or hospitalization for heart failure |
| Other key outcomes | 4P-MACE (3P-MACE or hospitalization for unstable angina); CV death; hospitalization for heart failure; all-cause mortality; incident or worsening nephropathy | Individual components of composite endpoint; all-cause mortality; hospitalization for heart failure; progression of albuminuria | Composite kidney outcome (sustained ≥40% reduction in eGFR to 2, new ESKD, or kidney or CV death); all-cause mortality; hospitalization for heart failure |
| Number of events | 772 | 1,011 | – |
| Start date | 2010-07-01 | 2014-01-01 | 2013-04-01 |
| Median follow-up | 3.1 years | CANVAS: ~5.7 years; CANVAS–R: ~2.1 years; CANVAS Program: ~2.4 years | 4.2 years |
| Date of completion | 2015-04-01 | 2017-02-01 | 2018-09-01 |
| Key results | Primary outcome: HR 0.86 (95% CI 0.74, 0.99; p = 0.04 for superiority); 4P-MACE: HR 0.89 (95% CI 0.78, 1.01; p = 0.08 for superiority); CV death: HR 0.62 (95% CI 0.49, 0.77; p < 0.001) hospitalization for heart failure: HR 0.65 (95% CI 0.50, 0.85; p = 0.002); all-cause mortality: HR 0.68 (95% CI 0.57, 0.82; p < 0.001) incident or worsening nephropathy: HR 0.61 (95% CI 0.53, 0.70; p < 0.001) |
CANVAS Program ITT analysis Primary outcome: 3P-MACE: HR 0.86 (95% CI 0.75, 0.97; p = 0.02 for superiority); all-cause mortality: HR 0.87 (95% CI 0.74, 1.01); CV death: HR 0.87 (95% CI 0.72, 1.06); hospitalization for HF: HR 0.67 (95% CI 0.52, 0.87); progression of albuminuria: HR 0.73 (95% CI 0.67, 0.79) | Co-primary efficacy outcomes−3P-MACE: HR 0.93 (95% CI 0.84, 1.03; p = 0.17 for superiority); CV death or hospitalization for heart failure: HR 0.83 (95% CI 0.73, 0.95; p = 0.005 for superiority); exploratory outcomes—kidney composite outcome: HR 0.76 (95% CI 0.67, 0.87); all-cause mortality: HR 0.93 (95% CI 0.82, 1.04); hospitalization for heart failure: HR 0.73 (95% CI 0.61, 0.88); CV death: HR 0.98 (95% CI 0.82, 1.17) |
| References | Zinman et al. N Engl J Med 2015; 373:2117; Wanner et al. N Engl J Med 2016; 375:323; NCT01131676 | Neal et al. N Engl J Med 2017; 377:644; Neal et al. Diabetes Obes Metab 2017;19:926 | Wiviott et al. N Engl J Med 2019; 380:347; NCT01730534 |
| Sponsor | Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance | Janssen Research and Development, The George Institute for Global Health | AstraZeneca |