Table 2.
Cardiovascular and kidney outcomes with SGLT2is in pivotal randomized clinical trials
| Trial Name | Key eligibility criteria | Sample size (N) | African Race N (%) |
Intervention | Median follow-up period (Years) | CV outcomes | Kidney endpoints | Outcomes |
|---|---|---|---|---|---|---|---|---|
| EMPA-REG OUTCOME (2015, 2016)64,65 (NCT01131676) |
HbA1c level: 7.0 to 9.0% Established CV disease eGFR: ≥30 ml/min per 1.73m2 |
7020 | Small sample size reported as limitation of the study | Empagliflozin (1:1:1) (either 10 mg or 25 mg or placebo once daily) |
3.1 | CV death, MI, stroke HR, 0.86; 95.02% CI, (0.74–0.99); P = 0.04 (for superiority) |
Worsening of nephropathy | Empagliflozin vs placebo 12.7% vs. 18.8%; HR, 0.61; 95% CI, (0.53–0.70); P < 0.001 |
| Hospitalization for HF HR, 0.65; 95% CI, (0.50–0.85); P = 0.002 |
Doubling of the serum creatinine level accompanied by eGFR of ≤45 ml/min per 1.73 m2 | 1.5% vs. 2.6%; HR, 0.56; 95% CI, (0.39–0.79); P < 0.001 |
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| Initiation of KRT | 0.3% vs. 0.6%; HR, 0.45; 95% CI, (0.21–0.97); P = 0.04 |
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| Progression to A3 albuminuria | 11.2% vs. 16.2%; HR, 0.62; 95% CI, (0.54–0.72); P < 0.001 |
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| Rate of incident albuminuria (in patients with normal albumin at baseline) | 51.5% vs. 51.2%; HR, 0.95; 95% CI, (0.87–1.04); P = 0.25 |
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| Death from kidney cause | Empagliflozin: 0.1% | |||||||
| CANVAS and CANVAS-R (2017)66 (CANVAS: NCT01032629; CANVAS-R: NCT01989754) | T2DM 30 years or older with a prior history of symptomatic ASCVD or 50 years or older with at least 2 CV risk factors eGFR ≥30 ml/min per 1.73 m2 |
10,142 (CANVAS: 4330, CANVAS-R: 5812) |
176 (3) | CANVAS (1:1:1) – canagliflozin (300 mg), canagliflozin (100 mg) or matching placebo CANVAS-R (1:1) – canagliflozin: 100 mg with an optional increase to 300 mg or matched placebo |
2.4 | CV death, MI, stroke Canagliflozin vs. placebo 26.9 vs. 31.5 participants per 1000 patient-years HR, 0.86; 95% CI, (0.75–0.97); P < 0.001 (for non-inferiority); P = 0.02 (for superiority) |
Progression of albuminuria (participants per 1000 patient-years) | 89.4 vs. 128.7 HR, 0.73; 95% CI, (0.67–0.79) |
| Hospitalization for HF 5.5 vs. 8.7; HR, 0.67; 95% CI, (0.52–0.87) |
Regression of albuminuria (participants per 1000 patient-years) | 293.4 vs. 187.5; HR, 1.70; 95% CI, (1.51–1.91) |
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| Progression to A3 albuminuria (participants per 1000 patient-years) | 89.4 vs 128.7; HR, 0.73; 95% CI (0.67–0.79) |
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| Composite outcome of sustained 40% reduction in eGFR, need for KRT, or death from kidney causes (participants per 1000 patient-years) | 5.5 vs. 9.0; HR, 0.60; 95% CI (0.47–0.77) |
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| CREDENCE (2019)67 (NCT02065791) |
T2DM patients with CKD eGFR: 30 to <90 ml/min per 1.73 m2 UACR >300 to 5000 mg/g HbA1c level: 6.5% to 12.0% |
4401 | 112 (5.1) | Canagliflozin 100 mg once daily vs. placebo | 2.62 | CV death, MI, stroke HR, 0.80; 95% CI, (0.67–0.95); P = 0.01 |
Relative risk of composite of KF, a doubling of the serum creatinine, or death from kidney or CV causes (participants per 1000 patient-years) | 43.2 vs. 61.2 HR, 0.70; 95% CI, (0.59–0.82); P = 0.00001 |
| Hospitalization for HF HR, 0.61; 95% CI, (0.47–0.80); P < 0.001 |
Kidney-specific composite of KF, a doubling of the serum creatinine level, or death from kidney causes | HR, 0.66; 95% CI, (0.53–0.81); P < 0.001 |
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| Relative risk of KF | HR, 0.68; 95% CI, (0.54–0.86); P = 0.002 |
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| EMPEROR-Reduced (2020)68 (NCT03057977) |
Chronic HFrEF | 3730 | 123 (6.6) | Empagliflozin 10 mg once daily vs. placebo | 1.3 | CV death or hospitalization for HF 19.4% vs. 24.7% (empagliflozin vs. placebo) HR, 0.75; 95% CI, (0.65–0.86); P < 0.001 |
Annual rate of decline in eGFR | Empagliflozin vs. placebo −0.55 vs. −2.28 ml/min/1.73 m2; P < 0.001 |
| DAPA-CKD (2020)69 (NCT03036150) |
Patients of CKD with or without T2DM eGFR: 25 to 75 ml/min per 1.73 m2 UACR: 200 to 5000 mg/g |
4304 | 104 (4.8) | Dapagliflozin 10 mg vs. placebo once daily | 2.4 | CV death or hospitalization for HF HR, 0.71; 95% CI, (0.55–0.92); P = 0.009 |
Occurrence of the composite of a sustained decline in the eGFR of at least 50%, KF, or death from kidney or CV related causes | Dapagliflozin vs. placebo 9.2% vs. 14.5%; HR, 0.61; 95% CI, (0.51–0.72); P < 0.001 |
| Risk of composite of a sustained decline in the eGFR of at least 50%, KF, or death from kidney-related causes | HR, 0.56; 95% CI, (0.45–0.68); P < 0.001 |
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| DECLARE-TIMI 58 (2019, 2021)70,71 (NCT01730534) |
Patients with T2DM Established ASCVD or multiple risk factors for ASCVD HbA1c level: (6.5% to 12.0%) Creatinine clearance of ≥60 ml/min |
17,160 | Not mentioned | Dapagliflozin 10 mg once daily vs. matched placebo (1:1) | 4.2 | CV death or hospitalization for HF (among patients with multiple risk factors) HR, 0.84, 95% CI, (0.67–1.04) |
Cardiorenal composite outcome | HR, 0.76: 95% CI, (0.67 to 0.87); P < 0.0001 |
| Kidney-specific outcome | HR, 0.53; 95% CI, (0.43–0.66); P < 0.0001 |
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| KF or death from kidney causes | HR, 0.41; 95% CI, (0.20–0.82); P = 0.012 |
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| Sustained decline in eGFR by at least 40% to less than 60 ml/min per 1.73 m2 | HR, 0.54; 95% CI, (0.43–0.67); P < 0.0001 |
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| eGFR | Dapagliflozin group had higher eGFR compared to placebo P < 0.001 |
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| UACR | Dapagliflozin group had lower UACR compared to placebo P < 0.001 |
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| VERTIS CV (2020, 2021)72,73 (NCT01986881) |
T2DM Established ASCVD eGFR ≥30 ml/min per 1.73 m2 |
8246 | 166 (3) | Ertugliflozin 5 mg vs. ertugliflozin 15 mg vs. matched placebo once daily (1:1:1) | 3 | Composite of death from CV causes, MI, or stroke HR, 0.97; 95.6% CI, (0.85–1.11); P < 0.001 (for non-inferiority) |
Composite kidney outcome event of death from kidney causes, KRT, or doubling of the serum creatinine level from baseline | HR, 0.81; 95.8% CI, (0.63–1.04) |
| Death from CV causes or hospitalization for HF 8.1% vs. 9.1% (ertugliflozin vs. placebo) HR, 0.88; 95.8% CI, (0.75–1.03); P = 0.11 (for superiority) |
Composite kidney outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or kidney death (events per 1000 person-years) | Ertugliflozin vs. placebo 6.0% vs. 9.0%; HR, 0.66; 95% CI, (0.50–0.88) |
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| Death from CV causes HR, 0.92; 95.8% CI, (0.77–0.11) |
Change in eGFR (relative to baseline) | 2.6 ml/min per 1.73 m2 | ||||||
| change in UACR (relative to baseline) | −16.2% | |||||||
| SCORED (2021)74 (NCT03315143) |
Patients with T2DM and CKD, with or without albuminuria HbA1c level: ≥7%; eGFR: 25 to 60 ml/min per 1.73 m2 Risk for CV disease |
10,584 | 176 (3.3) | Sotagliflozin 200 mg to 400 mg once daily vs. matched placebo (1:1) |
1.3 | CV death, hospitalizations for HF, and urgent visits for HF 5.6 vs. 7.5 (no. of events/100 patient-years) HR, 0.74; 95% CI, (0.63–0.88); P < 0.001 |
First occurrence of sustained decline in eGFR ≥50% from baseline for at least 30 days, long-term dialysis, KRT, or sustained eGFR <15 ml/min per 1.73 m2 for ≥ 30 days | Sotagliflozin vs. placebo 0.5% vs. 0.7%; HR, 0.71; 95% CI, (0.46–1.08) |
| EMPA-KIDNEY (2023)75 (NCT03594110) |
Patients with CKD eGFR: ≥20 to <45 ml/min per 1.73 m2 or ≥45 to <90 ml/min per 1.73 m2 UACR: ≥200 mg/g |
6609 | 128 (4) | Empagliflozin 10 mg daily vs. matched placebo once daily (1:1) | 2 | CV death, hospitalization for HF 4.0% vs. 4.6% (Empagliflozin vs. placebo) |
Progression of kidney disease (KF, sustained decrease in eGFR to <10 ml/min per 1.73 m2, stained decrease in eGFR of ≥40% from baseline, or kidney death) or death from CV events | Empagliflozin group vs placebo 13.1% vs. 16.9%; HR, 0.72; 95% CI, (0.64–0.82); P < 0.001 |
ASCVD, atherosclerotic cardiovascular disease; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HbA1c, glycosylated hemoglobin; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; KF, kidney failure; KRT, kidney replacement therapy; MI, myocardial infarction; SGLT2i, sodium-glucose cotransporter-2 inhibitor; T2DM, type 2 diabetes mellitus; UACR, urine albumin-to-creatinine ratio.