Six articles2,3,10,15–17 were finally included in our study, involving two trials for finerenone and four trials for SGLT2 inhibitors. Only the DAPA-CKA and EMPA-KIDNEY trials focused on patients with CKD with or without type 2 diabetes, and the other four trials focused on patients with CKD and type 2 diabetes. The baseline characteristics of the patients enrolled in the six trials included in this study are shown in Table 1. All the trials were judged to be at low risk of bias via Cochrane’s Collaboration tool for risk assessment (Table S1).
Indirect comparison of finerenone and SGLT2 inhibitors: the composite of renal outcomes
The composite of renal outcomes showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 1.14, 95% CI 0.92–1.88, Fig. 1, Table 2). In patients with type 2 diabetes and CKD, the composite of renal outcomes showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.97, 95% CI 0.50–1.69, Fig. 1). The composite of renal outcomes also showed no significant difference in the comparison between finerenone and dapagliflozin (OR 1.51, 95% CI 0.71–3.17, Fig. 2), finerenone and canagliflozin (OR 1.27, 95% CI 0.62–2.67, Fig. 2), finerenone and empagliflozin (OR 1.14, 95% CI 0.55–2.40, Fig. 2), finerenone and sotagliflozin (OR 1.17, 95% CI 0.54–2.69, Fig. 2). We ranked the risk of the composite of renal outcomes in patients with CKD. As a result, dapagliflozin was identified as having the lowest risk of the composite of renal outcomes (Fig. 3).
Table 1. Baseline characteristics of patients enrolled in the six trials
|
|
|
|
|
FIDELIO-DKD
|
FIGARA-DKD
|
CREDENCE
|
DAPA-CKD
|
SCORED
|
EMPA-KIDNEY
|
|
Finerenone
|
Placebo
|
Finerenone
|
Placebo
|
Canagliflozin
|
Placebo
|
Dapagliflozin
|
Placebo
|
Sotagliflozin
|
Placebo
|
Canagliflozin
|
Placebo
|
Numbers, no.
|
2833
|
2841
|
3686
|
3666
|
2202
|
2199
|
2152
|
2152
|
5292
|
5292
|
3304
|
3305
|
Follow-up
|
2.6 years
|
3.4 years
|
2.62 years
|
2.4 years
|
16 months
|
2.0 years
|
Mean age (years)
|
65.4
|
65.7
|
64.1
|
64.1
|
62.9
|
63.2
|
61.8
|
61.9
|
69.0
|
69.0
|
63.9
|
63.8
|
Female, no. (%)
|
880 (31.1)
|
811 (28.5)
|
1158 (31.4)
|
1089 (29.7)
|
762 (34.6)
|
732 (33.3)
|
709 (32.9)
|
716 (33.3)
|
2347 (44.3)
|
2407 (45.5)
|
1097 (33.2)
|
1095 (33.1)
|
Race, no. (%)
|
|
|
|
|
|
|
|
|
|
|
|
|
White
|
1777 (62.7)
|
1815 (63.9)
|
2672 (72.5)
|
2605 (71.1)
|
1487 (67.5)
|
144 (65.7)
|
1124 (52.2)
|
1166 (54.2)
|
4402 (83.2)
|
4347 (82.2)
|
1939 (58.7)
|
1920 (58.1)
|
Black
|
140 (4.9)
|
124 (4.4)
|
113 (3.1)
|
145 (4.0)
|
112 (5.1)
|
112 (5.2)
|
104 (4.8)
|
87 (4.0)
|
176 (3.3)
|
188 (3.6)
|
128 (3.9)
|
134 (4.1)
|
Asian
|
717 (25.3)
|
723 (25.4)
|
715 (19.4)
|
739 (20.2)
|
425 (19.3)
|
452 (20.6)
|
749 (34.8)
|
718 (33.4)
|
317 (6.0)
|
365 (6.9)
|
1194 (36.1)
|
1199 (36.3)
|
Other
|
199 (7.0)
|
179 (6.3)
|
177 (4.8)
|
170 (4.6)
|
178 (8.1)
|
191 (8.7)
|
175 (8.1)
|
181 (8.4)
|
397 (7.5)
|
392 (7.3)
|
43 (1.3)
|
52 (1.6)
|
T2DM, no. (%)
|
2833 (100)
|
2841 (100)
|
3686 (100)
|
3666 (100)
|
2202 (100)
|
2199 (100)
|
1455 (67.6)
|
1451 (67.4)
|
5292 (100)
|
5292 (100)
|
1525 (46.2)
|
1515 (45.8)
|
Estimated GFR, mL/min/1.73m2
|
44.4
|
44.3
|
67.6
|
68.0
|
56.3
|
56.0
|
43.2
|
43.0
|
44.4
|
44.7
|
37.4
|
37.3
|
Median UACR(mg/g)
|
833
|
867
|
302
|
315
|
923
|
931
|
965
|
934
|
74
|
75
|
331
|
327
|
Notes: GFR= glomerular filtration rate; T2DM= type 2 diabetes mellitus; UACR= urinary albumin-to-creatinine ratio; NA=not available;
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|
|
Table 2. OR and 95% CI for network meta-analysis of different outcomes for patients with CKD
|
Outcomes
|
Strategy
|
Finerenone
|
SGLT2 inhibitors
|
Placebo
|
A
|
Finerenone
|
1.00 (1.00, 1.00)
|
1.14 (0.92, 1.88)
|
0.84 (0.53, 1.37)
|
|
SGLT2 inhibitors
|
0.88 (0.50, 1.65)
|
1.00 (1.00, 1.00)
|
0.73 (0.53, 1.09)
|
|
Placebo
|
1.19 (0.73, 1.90)
|
1.36 (0.92, 1.88)
|
1.00 (1.00, 1.00)
|
B
|
Finerenone
|
1.00 (1.00, 1.00)
|
0.94 (0.58, 1.56)
|
0.83 (0.55, 1.24)
|
|
SGLT2 inhibitors
|
1.06 (0.64, 1.73)
|
1.00 (1.00, 1.00)
|
0.88 (0.65, 1.17)
|
|
Placebo
|
1.21 (0.81, 1.81)
|
1.14 (0.85, 1.53)
|
1.00 (1.00, 1.00)
|
C
|
Finerenone
|
1.00 (1.00, 1.00)
|
1.04 (0.78, 1.43)
|
0.88 (0.70, 1.13)
|
|
SGLT2 inhibitors
|
0.96 (0.70, 1.28)
|
1.00 (1.00, 1.00)
|
0.85 (0.70, 1.01)
|
|
Placebo
|
1.13 (0.88, 1.43)
|
1.17 (0.99, 1.43)
|
1.00 (1.00, 1.00)
|
D
|
Finerenone
|
1.00 (1.00, 1.00)
|
0.99 (0.73, 1.35)
|
0.88 (0.69, 1.11)
|
|
SGLT2 inhibitors
|
1.01 (0.74, 1.36)
|
1.00 (1.00, 1.00)
|
0.89 (0.73, 1.07)
|
|
Placebo
|
1.14 (0.90, 1.46)
|
1.12 (0.93, 1.38)
|
1.00 (1.00, 1.00)
|
Notes: Results are OR in the row-defining treatment compared with OR in the column-defining treatment.
|
For efficacy, OR<1 favor row-defining treatment. NA=not available; CKD=chronic kidney disease
|
A: The composite of renal outcomes;
|
|
B: The composite of cardiovascular dearth or hospitalization for heart failure
|
C: All-cause mortality; D: Cardiovascular dearth;
|
|
Indirect comparison of finerenone and SGLT2 inhibitors: the composite of cardiovascular death or hospitalization for heart failure
The composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.94, 95% CI 0.58–1.56, Fig. 1, Table 2). In patients with type 2 diabetes and CKD, the composite of cardiovascular death or hospitalization for heart failure showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.86, 95% CI 0.48–1.62, Fig. 1). The composite of cardiovascular death or hospitalization for heart failure also showed no significant difference in the comparison between finerenone and dapagliflozin (OR 1.15, 95% CI 0.68–2.01, Fig. 2), finerenone and canagliflozin (OR 1.22, 95% CI 0.72–2.03, Fig. 2), finerenone and empagliflozin (OR 0.97, 95% CI 0.56–1.64, Fig. 2), finerenone and sotagliflozin (OR 1.13, 95% CI 0.66–1.84, Fig. 2). We ranked the risk of the composite of cardiovascular death or hospitalization for heart failure in patients with CKD. As a result, canagliflozin was identified as having the lowest risk of the composite of cardiovascular death or hospitalization for heart failure (Fig. 3).
Indirect comparison of finerenone and SGLT2 inhibitors: all-cause mortality
All-cause mortality showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 1.04, 95% CI 0.78–1.43, Fig. 1, Table 2). In patients with type 2 diabetes and CKD, all-cause mortality showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.97, 95% CI 0.74–1.28, Fig. 1). All-cause mortality also showed no significant difference in the comparison between finerenone and dapagliflozin (OR 1.30, 95% CI 0.77–2.26, Fig. 2), finerenone and canagliflozin (OR 1.08, 95% CI 0.64–1.85, Fig. 2), finerenone and empagliflozin (OR 1.02, 95% CI 0.60–1.74, Fig. 2), finerenone and sotagliflozin (OR 0.89, 95% CI 0.53–1.48, Fig. 2). We ranked the risk of all-cause mortality in patients with CKD. As a result, dapagliflozin was identified as having the lowest risk of all-cause mortality (Fig. 3).
Indirect comparison of finerenone and SGLT2 inhibitors: cardiovascular death
Cardiovascular death showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.99, 95% CI 0.73–1.35, Fig. 1, Table 2). In patients with type 2 diabetes and CKD, cardiovascular death showed no significant difference in the comparison between finerenone and SGLT2 inhibitors (OR 0.95, 95% CI 0.65–1.38, Fig. 1). Cardiovascular death also showed no significant difference in the comparison between finerenone and dapagliflozin (OR 1.07, 95% CI 0.66–1.76, Fig. 2), finerenone and canagliflozin (OR 1.13, 95% CI 0.73–1.77, Fig. 2), finerenone and empagliflozin (OR 1.04, 95% CI 0.62–1.75, Fig. 2), finerenone and sotagliflozin (OR 0.96, 95% CI 0.63–1.48, Fig. 2). We ranked the risk of cardiovascular death in patients with CKD. As a result, canagliflozin was identified as having the lowest risk of all-cause mortality (Fig. 3).
Qualitative assessment
We assessed the risk of bias in the included trials using the Cochrane Collaboration’s recommended tool14. A summary of the quality assessment of each trial is shown in the table S1. Heterogeneity test shows no evidence of heterogeneity for the composite of cardiovascular death or hospitalization for heart failure (I2 = 0%, P = 0.50) all-cause mortality (I2 = 19%, P = 0.29), and cardiovascular death (I2 = 0%, P = 0.95). Heterogeneity test shows evidence of heterogeneity for the composite of renal outcomes (I2 = 67%, P = 0.009).