Table 1.
Renoprotective effects of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus
| Parameters | Empagliflozin [64, 65] | Empagliflozin [62] | Canagliflozin [80] | Dapagliflozin [87] | Dapagliflozin [66, 86] |
|---|---|---|---|---|---|
| NCT (ClinicalTrials.gov identifier) number | NCT01131676 | NCT01164501 | NCT00968812 | NCT00663260 | NCT01730534 |
| Number of enrolled patients | 7020 | 741 | 1450 | 166 (post hoc) | 17,190 |
| Median observation time/follow-up period | 3.1 years | 52 weeks | 24 weeks | 104 weeks | 4.2 years |
| Baseline glycemic, renal, cardiac eligibility |
eGFR ≥ 30 mL/min/1.73 m2 Established CVD HbA1c = 7–9% |
HbA1c = 7–10% eGFR ≥ 90 mL/min/1.73 m2 |
Patients with HbA1c between ≥ 7% and ≤ 9.5% at Week 2 |
HbA1c = 7–11% eGFR = 30 to 59 mL/min/1.73 m2 Stage 3 CKD Increased albuminuria (≥ 3.4 mg/mmol) |
High risk for CV events |
| Intervention | Empa 10 or 25 mg |
Stage 2 CKD: Empa 10 or 25 mg OD Stage 3 CKD: Empa 25 mg OD Stage 4 CKD: Empa 25 mg OD |
Cana 100 or 300 mg once daily + metformin | Dapa 5 or 10 mg | Dapa 10 mg |
| Control | Glimepiride (up-titrated to 6 or 8 mg/day) | ||||
| Renal outcomes | |||||
| Worsening of nephropathya |
Empa: 525/4124 (12.7%) HR 0.61 (95% CI 0.53–0.70, p < 0.001) |
Not reported | Not reported | Not reported | Not reported |
| Time to first event of renal composite endpointb | Not reported | Not reported | Not reported | Not reported |
Dapa: 127/8582 (4-year event rate: 1.5%) HR 0.53 (95% CI 0.43–0.66, p < 0.0001) |
| Annual eGFR decline | Not reported | Not reported |
Glimepiride: 3.3 mL/min/1.73 m2 (95% CI 2.8–3.8) Cana 100 mg: 0.5 mL/min/ 1.73 m2 (95% CI − 0.0 to 1.0) Cana 300 mg: 0.9 mL/min/1.73 m2 (95% CI 0.4–1.4) |
Not reported | Not reported |
| eGFR decline | Not reported | Not reported |
Overall patientsd Compared with glimepiride Cana 100 mg: 6.7% (HR 0.66, 95% CI 0.42–1.04, p = 0.07) Cana 300 mg: 9.0% (HR 0.93, 95% CI 0.62–1.42, p = 0.75) Patients with urine ACR ≥ 30 mg/g Cana 100 mg: 0.37% (95% CI 0.15–0.90, p = 0.03) Cana 300 mg: 0.69% (95% CI 0.33–1.45, p = 0.33) |
Not reported |
Dapa: 120/8582 (4-year event rate 1.4%)e HR 0.54 (95% CI 0.43–0.67, p < 0.0001) |
| Urine ACR | Not reported |
Mean difference at 52 weeks vs. placebo Stage 2 CKD: Empa 10 mg: − 184.59 (95% CI − 393.57 to 24.38, p = 0.0831) Empa 25 mg: − 235.86, (5% CI − 442.85 to − 28.86) p = 0.0257) Stage 3 CKD − 183.78 (95% CI − 305.18 to − 62.38, p = 0.0031) |
ACR decrease compared with glimepiride Overall patients Cana 100 mg: 5.7% (95% CI 22.3–13.1, p = 0.16) Cana 300 mg: 11.2% (95% CI 3.6–18.3, p < 0.01) Patients with urine ACR ≥ 30 mg/g Cana 100 mg: 31.7% (95% CI 8.6–48.9, p = 0.01) Cana 300 mg: 49.3% (95% CI 31.9–62.2, p < 0.001) |
ACR reduction compared with placebo Dapa 10 mg: − 57.2% (95% CI − 77.1 to − 20.1) Dapa 5 mg: − 43.8% (95% CI − 71.0 to 9.0) |
Not reported |
| Reduction in urine ACR | Not reported | Not reported | Not reported |
Dapa 10 mg: 33.9% Dapa 5 mg: 39.6% |
Not reported |
| Progression to macroalbuminuria |
Empa: 459/4091 (11.2%) HR 0.62 (95% CI 0.54–0.72) |
Empa 25 mg: 2% | Not reported | Not reported | Not reported |
| Improvement from macroalbuminuria at baseline to microalbuminuria | The difference in adjusted geometric mean compared with placebo − 29% (95% CI − 44 to − 10, p = 0.0048) | Empa 25 mg: 32.6% | Not reported | Not reported | Not reported |
| Improvement from microalbuminuria at baseline to albuminuria | Difference adjusted geometric mean compared with placebo − 22% (95% CI − 32 to − 11, p = 0.0003) | Empa 25 mg: 27.5% | Not reported | Not reported | Not reported |
| Doubling of serum creatininec |
Empa: 70/4645 patients (1.5%) HR 0.56 (95% CI 0.39–0.79) |
Not reported | Not reported | Not reported | Not reported |
| Initiation of RRT |
Empa: 13/4687 (0.3%) HR 0.45 (95% CI 0.21–0.97) |
Not reported | Not reported | Not reported | Not reported |
| Death from renal disease | Empa: 3/4687 (0.1%) | Not reported | Not reported | Not reported |
Dapa: 6/8582 (4-year event rate: 0.1%) HR 0.60 (95% CI 0.22–1.65, p = 0.32) |
ACR Albumin:creatinine ratio, CI confidence interval, Cana canagliflozin, CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, Dapa dapagliflozin, eGFR estimated glomerular filtration rate, Empa empagliflozin, ESRD end-stage renal disease, HbA1c glycated hemoglobin, HR hazards ratio, OD once a day, T2DM type 2 diabetes mellitus, RRT renal replacement therapy
aProgression to macroalbuminuria, a doubling of the serum creatinine level, accompanied by an eGFR of ≤ 45 mL/min/1.73 m2, the initiation of RRT, or death from renal disease
bConfirmed sustained ≥ 40% decrease in eGFR to < 60 mL/min/1.73 m2 and/or ESRD and/or renal or CV death
cAccompanied by an eGFR of ≤ 45 mL/min/1.73 m2
d30% eGFR decline endpoint
eSustained eGFR decrease of 40% to eGFR < 60 mL/ min/1.73 m2