Table 1.
Large-scale clinical trials of SGLT2 inhibitors for the incidence of adverse cardiorenal outcomes.
| Clinical Trials | EMPA-REG OUTCOME8 | CANVAS Program9 | DECLAR-TIMI 5810 | VERTIS CV11 | DAPA-HF12 | EMPEROR-Reduced13 | SOLOIST-WHF14 | EMPEROR-Preserved16 | SCORED15 | CREDENCE17 | DAPA-CKD18 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Intervention | Empagliflozin 10 or 25 mg vs. placebo | Canagliflozin 300 or 100 mg vs. placebo | Dapagliflozin 10 mg vs. placebo | Ertugliflozin 5 or 15 mg vs. placebo | Dapagliflozin 10 mg vs. placebo | Empagliflozin 10 mg vs. placebo | Sotagliflozin 200–400mg vs. placebo | Empagliflozin 10 mg vs. placebo | Sotagliflozin 200–400mg vs. placebo | Canagliflozin 100 mg vs. placebo | Dapagliflozin 10 mg vs. placebo |
| Population (n) | 7020 | 10,142 | 17,160 | 8246 | 4744 | 3730 | 1222 | 5988 | 10,584 | 4401 | 4304 |
| Follow-up (year) | 3·1 | 3·6 | 4·2 | 3·5 | 2 | 0·7 | 0·75 | 2·18 | 1·33 | 2·6 | 2·4 |
| T2DM (%) | 100 | 100 | 100 | 100 | 42 | 49·8 | 100 | 49 | 100 | 100 | 67·5 |
| ASCVD* or HFrEF† or HFpEF‡ | > 99% with ASCVD* | 72·7% with ASCVD* | 40·6% with ASCVD* | 100% with ASCVD* | 100% with HFrEF† | 100% with HFrEF† | 100% with recent worsening HF | 100% with HFpEF‡ | 19·9% with HFrEF† | 50·4% with ASCVD* | 37·4% with ASCVD* |
| eGFR (mL per min per 1·73m2) | ≥30 | ≥30 | ≥60 | ≥30 | ≥30 | ≥20 | ≥30 | ≥20 | 25–60 | 30–89 | 25–75 |
| Primary outcome (HR, 95%CI) | MACE§: 0·86 (0·74–0·99) | MACE§: 0·86 (0·75–0·97) | MACE§: 0·93 (0·84–1·03) | MACE§: 0·97 (0·85–1·11) | Worsening HF or cardiovascular death: 0·74 (0·65–0·85) | Cardiovascular death or hospitalization for worsening HF: 0·75 (0·65–0·86) | The total number of cardiovascular deaths and hospitalizations and urgent visits for HF: 0·67 (0·52–0·85) | A composite of cardiovascular death or hospitalization for HF: 0·79 (0·69–0·90) | The total number of cardiovascular deaths and hospitalizations and urgent visits for HF: 0·74 (0·63–0·88) | ESRD, a doubling of the Scr level, or renal or cardiovascular death: 0·70 (0·59–0·82) | A sustained decline in the eGFR≥50%, ESRD, or renal or cardiovascular death: 0·61 (0·51– 0·72) |
| Cardiovascular death (HR, 95%CI) | 0·62 (0·49–0·77) | 0·87 (0·72–1·06) | 0·98 (0·82–1·17) | 0·92 (0·77–1·11) | 0·82 (0·69–0·98) | 0·92 (0·75–1·12) | 0·84 (0·58–1·22) | 0·91 (0·76–1·09) | 0·90 (0·73–1·12) | 0·78 (0·61–1·00) | 0·81 (0·58–1·12) |
| All-cause mortality (HR, 95%CI) | 0·68 (0·57–0·82) | 0·87 (0·74–1·01) | 0·93 (0·82–1·04) | 0·93 (0·80–1·08) | 0·83 (0·71–0·97) | 0·92 (0·77–1·10) | 0·82 (0·59–1·14) | 1·00 (0·87–1·15) | 0·99 (0·83–1·18) | 0·83 (0·68–1·02) | 0·69 (0·53–0·88) |
| Hospitalization for HF (HR, 95%CI) | 0·65 (0·50–0·85) | 0·67 (0·52–0·87) | 0·73 (0·61–0·88) | 0·70 (0·54–0·90) | 0·70 (0·59–0·83) | 0·69 (0·59–0·81) | / | 0·71 (0·60– 0·83) | 0·67 (0·55–0·82) | 0·61 (0·47–0·80) | / |
| Renal outcomes (HR, 95%CI) | / | Progression of albuminuria: 0·73 (0·67–0·79); Sustained 40% reduction in eGFR, RRT, or renal death: 0·60 (0·47–0·77) | ≥ 40% decrease in eGFR to < 60 mL per min per 1·73m2, ESRD, or renal death: 0·53 (0·43–0·66) | Death from renal causes, RRT, or doubling of the Scr level: 0·81 (0·63–1·04) | A sustained decline in the eGFR ≥ 50% or ESRD, or renal death: 0·71 (0·44–1·16) | Mean slope of change in eGFR per year: –0·55 vs –2·28 mL per min per 1·73m2 (P<0·01) | Mean change in eGFR: −0·16 (–1·30– 0·98) | Mean slope of change in eGFR per year: –1·25 vs –2·62 mL per min per 1·73m2 (P<0·01) | A sustained decline in the eGFR≥50%, from baseline or sustained eGFR<15 mL per min per 1·73m2 for ≥30 days, RRT | ESRD, a doubling of the Scr level, or renal death: 0·66 (0·53–0·81) | Decline in eGFR≥50%, ESRD, or renal death: 0·56 (0·45–0·68) |
ASCVD*: atherosclerotic cardiovascular disease, involving the coronary, cerebrovascular, or peripheral arterial systems; HFrEF†: heart failure with reduced ejection fraction (New York Heart Association class II–IV and an LVEF≤40%); HFpEF‡: heart failure with a preserved ejection fraction (New York Heart Association class II–IV and an LVEF>40%); MACE§: major adverse cardiovascular events, representing a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Abbreviations: EMPA-REG OUTCOME: the Empagliflozin Cardiovascular Outcome Event Trial in T2DM Patients; CANVAS Program: the Canagliflozin Cardiovascular Assessment Study Program; DECLARE-TIMI 58: the Dapagliflozin Effect on Cardiovascular Events-Thrombosis in Myocardial Infarction 58; VERTIS CV: the Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial; DAPA-HF: the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure Trial; EMPEROR-Reduced: the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Reduced Ejection Fraction; SOLOIST-WHF: the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure Trial; EMPEROR-PRESERVED: the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction; SCORED: the Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk Trial; CREDENCE: the Canagliflozin and Renal Events in Diabetes and Established Nephropathy Clinical Evaluation Trial; DAPA-CKD: the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease Trial; SGLT2: sodium-glucose co-transporter 2; T2DM: type 2 diabetes mellitus; HF: heart failure; eGFR: estimated glomerular filtration rate; HR: hazard ration; CI: confidence interval; RRT: renal-replacement therapy; ESRD: end-stage renal disease; CKD: chronic kidney disease; Scr: serum creatinine.