Table 3:
Kidney outcomes in participants with normoalbuminuria (UACR <30 mg/g) from EMPA-REG OUTCOME and EMPA-KIDNEY (data from [26] and [9]).
| EMPA-REG outcome, no CKD (eGFR ≥60 mL/min/1.73 m2, UACR <30 mg/g) | EMPA-KIDNEY (eGFR 20–45 mL/min/1.73 m2, UACR <30 mg/g) | |
|---|---|---|
| Follow-up 3.1 years | Follow-up 2.0 years | |
| Chronic eGFR slope (mL/min/1.73 m2/year and 95% CI) | ||
| Placebo | −0.95 (−1.34, −0.56) (n = 948) | −0.89 (−1.20, −0.58) (n = 663) |
| Empagliflozin | 0.22 (−0.02, 0.46) (n = 1946) | −0.11 (−0.44, 0.22) (n = 665) |
| Difference of empagliflozin versus placebo | 1.17 (0.71, 1.63) | 0.78 (0.32, 1.23) |
| Kidney events | Doubling of serum creatinine | Sustained decrease from baseline in the eGFR of ≥40% |
| Initiation of KRT | Initiation of KRT or sustained decrease in the eGFR to <10 mL/min/1.73 m2 | |
| Or death from kidney | Or death from renal causes | |
| Placebo | 20/1094 (1.8%) | 31/663 (4.7%) |
| Empagliflozin | 13/2205 (0.6%) | 30/665 (4.5%) |
| Empagliflozin versus placebo, HR (95% CI) | 0.31 (0.16, 0.63) | 0.97 (0.59–1.60) |
Note that despite differences between the datasets (prevalence of DM, baseline eGFR, follow-up time and other inclusion and exclusion criteria), placebo eGFR slope data are remarkably consistent in both trials and with the a priori expectation of persons with normoalbuminuria being populations at low risk for CKD progression. In both datasets there was also a remarkably similar response of chronic eGFR slopes to empagliflozin. However, there was a large difference in the impact of empagliflozin on the incidence of kidney events that, as expected, was low in both datasets. The differences noted in the HR for kidney events thus likely represent differences in the follow-up time (longer for EMPA-REG OUTCOME), number of participants (larger for EMPA-REG OUTCOME) and in the definition of the kidney events (stricter for EMPA-REG OUTCOME, as applied to the subgroup of participants in the present analysis), rather than different drug efficacy in participants with normoalbuminuria. As is the case for the results obtained when different definitions of kidney events are used in EMPEROR-Reduced and EMPEROR-Preserved (Table 2), the use of a stricter kidney endpoint may have contributed to observe differences between study arms in EMPA-REG OUTCOME. However, the definition of kidney event used in EMPA-KIDNEY may expect a larger contribution of the initial dip in eGFR towards reaching the threshold eGFR value that represents a kidney event (Supplementary data, Fig. S3), this being a source of confusion. A doubling of serum creatinine in a 60-year-old man with baseline eGFR of 60 mL/min/1.73 m2 represents a drop in eGFR of 34 mL/min/1.73 m2, while a 40% decrease in eGFR in a person with baseline eGFR of 20 mL/min/1.73 m2 represents a drop in eGFR of 8 mL/min/1.73 m2. In the same participants, reaching kidney failure would imply a loss of eGFR of 50 vs 10 mL/min/1.73 m2, and this drop would include the initial eGFR dip due to reduced hyperfiltration.