Literature search and included studies
A diagram of the study selection is shown in Figure 1. Initially, a total of 894 studies were obtained in the primary search from databases, and nineteen additional studies were identified through references. We removed 134 duplicate studies; 779 studies were screened. By screening titles and abstracts, 747 papers were excluded because they did not meet the inclusion criteria. By assessing full-text articles, nineteen additional studies were excluded due to missing data. Finally, thirteen studies published up to November 20, 2020, were selected for our meta-analysis according to the inclusion criteria. [12, 28-39] Out of thirteen studies, six studies were RCTs that compared SGLT-2 inhibitors (Canagliflozin, [12, 29] Dapagliflozin, [31] Empagliflozin, [30] Ertugliflozin [28], and Sotagliflozin [32]) with placebo; seven studies compared GLP-1 RAs (Albiglutide, [34] Dulaglutide weekly, [33] Exenatide weekly, [35] Liraglutide, [37] Lixisenatide, [39] Semaglutide subcutaneously weekly, [38] and Semaglutide oral [36]) with placebo. The pooled population consisted of 20,106 patients in SGLT-2 inhibitor studies (10,716 in the group treated with SGLT-2 inhibitors and 9,390 in the control group) and 12,843 patients in GLP-1 RA studies (6,364 in the group treated with GLP-1 RAs and 6,479 in the control group). Hemoglobin A1c ranged from 6.5% to 12%. eGFR ranged from 15 to 59 ml/min/1.73m2 in one study [33], 25 to 59 ml/min/1.73m2 in one study, [32] and from 30 to 59 ml/min/1.73m2 in other studies, with two studies that not mentioned their lower limit [31, 38]. The median length of follow-up ranged from 16.0 months to 50.4 months in SGLT-2 inhibitor studies and 19.2 months to 64.8 months in GLP-1 RA studies. All studies defined MACE-3 as a composite outcome comprised of cardiovascular death, myocardial infarction, and stroke, except ELIXA, [39] which also includes unstable angina. For renal outcomes, all studies included ESRD; five studies included renal death; [28-30, 33, 35] two studies included renal or cardiovascular death; [12, 31] one study defined reduced kidney function as a decrease in eGFR ≥ 30%, [33] three as a decrease in eGFR ≥ 40%, [29, 31, 35] one as a decrease in eGFR ≥ 50%, [11] and four as a doubling of creatinine. [12, 28, 30, 37]
Study characteristics and quality assessment
The definitions of terms, including a composite of renal outcomes and characteristics of the included studies, are listed in Table 1. Table 2 highlights the demographics of included studies. All studies defined CKD as eGFR < 60 ml/min/1.73m2. The quality evaluation of the included studies is shown in Figure 2. Subclasses of GLP-1 RAs (exendin-4 analogues or human GLP-1 RA analogues) in included studies are outlined in Table S1.
Table 1
Definitions of terms in included studies
SGLT2i, sodium-glucose cotransporter-2; GLP-1 RA, glucagon-like peptide-1 receptor agonist; RCT, randomized control study; eGFR, estimated glomerular filtration rate; Hgb A1c, hemoglobin A1c; ESRD, end-stage renal disease; MACE, major adverse cardiovascular events; RCT, randomized control trial; CV, cardiovascular.
Study
|
Study design
|
Setting
|
Drug dose (mg/day)
|
Median follow up (months)
|
eGFR (ml/min/1.73m2)
|
Range of Hgb A1c
|
Primary outcome
|
Definition of renal outcomes
|
SGLT2i vs placebo
|
|
|
|
|
|
|
|
CANVAS Program
|
RCT
|
Multinational
|
Canagliflozin 300/100
|
29.0
|
30-59
|
7.0-10.5
|
MACE
|
≥ 40% eGFR decline, ESRD, renal death
|
CREDENCE
|
RCT
|
Multinational
|
Canagliflozin 100
|
31.4
|
30-59
|
6.5-12.0
|
Renal outcomes
|
Doubing creatinine, ESRD, renal or CV death
|
DECLARE-TIMI 58
|
RCT
|
Multinational
|
Dapagliflozin 10
|
50.4
|
<60
|
6.5-12.0
|
MACE
|
≥ 40% eGFR decline, ESRD, renal or CVdeath
|
EMPA-REG OUTCOME
|
RCT
|
Multinational
|
Empagliflozin 10/25
|
37.2
|
30-59
|
7.0-9.0
|
MACE
|
Doubling creatinine, ESRD, renal death
|
SCORED
|
RCT
|
Multinational
|
Sotagliflozin 400
|
16.0
|
25-60
|
> 7.0
|
MACE
|
≥ 50% eGFR decline, ESRD
|
VERTIS-CV
|
RCT
|
Multinational
|
Ertugliflozin 5/15
|
36.0
|
30-59
|
7.0-10.5
|
MACE
|
Doubing creatinine, ESRD, renal death
|
|
|
|
|
|
|
|
|
|
GLP-1 RA vs placebo
|
|
|
|
|
|
|
|
ELIXA
|
RCT
|
Multinational
|
Lixisenatide 20 mcg
|
25.2
|
30-59
|
5.5-11.0
|
MACE (including unstable angina)
|
N/A
|
EXSCEL
|
RCT
|
Multinational
|
Exenatide 2 (weekly)
|
38.4
|
30-59
|
6.5-10
|
MACE
|
≥ 40% EGFR decline, ESRD, renal death
|
HARMONY Outcomes
|
RCT
|
Multinational
|
Albiglutide 30/50
|
19.2
|
30-59
|
> 7.0
|
MACE
|
N/A
|
LEADER
|
RCT
|
Multinational
|
Liraglutide 1.8
|
45.6
|
30-59
|
> 7.0
|
MACE
|
Doubling of serum creatinine, ESRD
|
PIONEER-6
|
RCT
|
Multinational
|
Semaglutide 14 (oral)
|
15.9
|
30-59
|
N/A
|
MACE
|
N/A
|
REWIND
|
RCT
|
Multinational
|
Dulaglutide 1.5 (weekly)
|
64.8
|
15-59
|
< 9.5
|
MACE
|
≥ 30% eGFR decline, ESRD, renal death
|
SUSTAIN-6
|
RCT
|
Multinational
|
Semaglutide 0.5/1 (weekly)
|
25.2
|
<60
|
> 7.0
|
MACE
|
N/A
|
Table 2
Baseline characteristics of included studies in patients with GFR < 60 ml/min/1.73m2.
SGLT2i, sodium-glucose cotransporter-2 inhibitors; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; GFR, glomerular filtration rate; BMI, body mass index; sBP, systolic blood pressure; dBP, diastolic blood pressure; Hgb A1c, hemoglobin A1c; UACR, urine albumin-to-creatinine ratio; N/A, not available. Normoalbuminuria, microlabuminuria and macroalbuminuria defined as <30, 30-299, and ≥300 mg/g creatinine, respectively.
Study
|
Number of patients (GFR<60)
|
Age
|
Male (%)
|
BMI
|
sBP (mmHg)
|
dBP (mm Hg)
|
HgbA1c (%)
|
GFR <30 (%)
|
GFR 30-45 (%)
|
GFR 45-60 (%)
|
Median GFR in CKD
|
UACR (mg/g)
|
Noormo-albuminuria (%)
|
Microalbuminuria (%)
|
Macroalbuminuria (%)
|
SGLT2i vs placebo
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
CANVAS Program
|
2039
|
67.6
|
58.2
|
32.3
|
138
|
75
|
8.2
|
0.0
|
27.2
|
72.8
|
49.1
|
24.4
|
55.4
|
N/A
|
N/A
|
CREDENCE
|
2592
|
63.8
|
66.5
|
31.3
|
140
|
78
|
8.2
|
0.0
|
45.3
|
48.1
|
45.1
|
1012
|
N/A
|
N/A
|
N/A
|
DECLARE-TIMI 58
|
1265
|
67.3
|
64.3
|
34.5
|
134
|
75
|
8.2
|
N/A
|
N/A
|
N/A
|
51.4
|
N/A
|
55.6
|
30.9
|
13.5
|
EMPA-REG OUTCOME
|
1819
|
67.1
|
72.8
|
30.6
|
138
|
76
|
8.1
|
0
|
31.3
|
68.7
|
N/A
|
N/A
|
47.7
|
33.9
|
18.4
|
SCORED
|
10584
|
69.0
|
55.1
|
31.8
|
138
|
78
|
8.3
|
7.7
|
43.9
|
48.3
|
44.5
|
74.5
|
35.1
|
33.9
|
31.0
|
VERTIS-CV
|
1807
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Weighted average (SGLT-2 inhibitors)
|
67.8
|
59.5
|
31.9
|
137.9
|
77.2
|
8.2
|
|
40.8
|
53.4
|
|
|
40.8
|
33.6
|
27.7
|
GLP-1 RA vs placebo
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
ELIXA
|
1399
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
59.7
|
25.5
|
14.8
|
EXSCEL
|
3177
|
66.5
|
57.1
|
32.8
|
N/A
|
N/A
|
8.1
|
0
|
28.0
|
72.0
|
49.2
|
N/A
|
71.4
|
19.6
|
9.0
|
HARMONY Outcomes
|
2222
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
LEADER
|
2158
|
67.3
|
61.3
|
32.7
|
136.4
|
75.1
|
8.6
|
10.4
|
29.0
|
60.6
|
45.6
|
49.5
|
47.6
|
29
|
23.4
|
PIONEER-6
|
856
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
REWIND
|
2199
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
SUSTAIN-6
|
832
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
N/A
|
Weighted average (GLP-1 RAs)
|
66.8
|
58.8
|
32.8
|
|
|
8.3
|
|
28.4
|
67.4
|
|
|
61.3
|
23.8
|
14.8
|
Network meta-analysis of treatment groups
MACE-3
Network plots were shown in Figure 3. SGLT-2 inhibitors were associated with a decreased risk of MACE-3 compared with placebo (RR [95% CI]; 0.85 [0.75-0.96]), but GLP-1 RAs were not (RR 0.91 [0.80-1.04]). Compared to GLP-1 RAs, SGLT-2 inhibitors did not show a significant difference in the risk of MACE-3 (RR 0.94 [0.78-1.12]) (Figure 4). However, there was significant heterogeneity (I2= 47.8%, p= 0.039).
Renal outcomes
We also performed a network meta-analysis of the risk of renal events and found that SGLT-2 inhibitors significantly decreased renal events (RR 0.68 [0.59-0.78]), while the impact on renal events of GLP-1 RAs was not statistically significant (RR 0.86 [0.72-1.03]). SGLT-2 inhibitors were also associated with lower risk compared to GLP-1 RAs (RR 0.79 [0.63-0.99]) (Figure 5). There was no heterogeneity (I2= 0%, p= 0.92).
Sensitivity analyses
MACE-3
The results of sensitivity analyses are summarized in Table 3. First, we performed a sensitivity analysis for studies that defined MACE-3 as the primary outcome. Compared to placebo, SGLT-2 inhibitors had a tendency to decrease a risk of MACE-3 (RR 0.87 [0.76-1.00]), while GLP-1 RAs did not (RR 0.91 [0.79-1.04]). There was no significant difference between SLGT-2 inhibitors and GLP-1 RA (RR 0.96 [0.79-1.17]). There was significant heterogeneity (I2= 50.4%, p= 0.033).
Table 3 The summary of sensitivity analyses.
SGLT2i, sodium-glucose cotransporter-2 inhibitors; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; CI, confidence intervals; MACE-3, 3-point major adverse cardiovascular event; vs., versus; N/A, not available.
MACE-3
|
Subjects
|
|
|
|
|
|
|
Sensitivity analysis
|
SGLT-2 inhibitors
|
GLP-1 RAs
|
Comparison
|
Risk ratio
|
95% CI
|
I2 (%)
|
p-value
|
MACE-3 as the primary outcome
|
17514
|
10644
|
SGLT-2 inhibitors vs. placebo
|
0.87
|
0.76-1.00
|
50.4
|
0.033
|
|
|
|
GLP-1 RAs vs. placebo
|
0.91
|
0.79-1.04
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.96
|
0.79-1.17
|
|
|
Without ELIXA
|
20106
|
14007
|
SGLT-2 inhibitors vs. placebo
|
0.85
|
0.75-0.97
|
49.5
|
0.037
|
|
|
|
GLP-1 RAs vs. placebo
|
0.88
|
0.76-1.03
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.97
|
0.79-1.18
|
|
|
Daily GLP-1 RAs
|
20106
|
6635
|
SGLT-2 inhibitors vs. placebo
|
0.84
|
0.75-0.96
|
47.7
|
0.053
|
|
|
|
GLP-1 RAs vs. placebo
|
0.86
|
0.73-1.02
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.99
|
0.80-1.21
|
|
|
Weekly GLP-1 RAs
|
20106
|
4009
|
SGLT-2 inhibitors vs. placebo
|
0.85
|
0.76-0.95
|
31.8
|
0.19
|
|
|
|
GLP-1 RAs vs. placebo
|
1.01
|
0.83-1.22
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.85
|
0.68-1.05
|
|
|
GLP-1 analogues
|
20106
|
6068
|
SGLT-2 inhibitors vs. placebo
|
0.85
|
0.76-0.95
|
30.6
|
0.17
|
|
|
|
GLP-1 RAs vs. placebo
|
0.81
|
0.69-0.95
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
1.05
|
0.86-1.27
|
|
|
Exendin-4 analogues
|
20106
|
4576
|
SGLT-2 inhibitors vs. placebo
|
0.85
|
0.77-0.94
|
28.7
|
0.21
|
|
|
|
GLP-1 RAs vs. placebo
|
1.03
|
0.88-1.20
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.83
|
0.69-0.99
|
|
|
Renal outcomes
|
|
|
|
|
|
|
|
Renal endpoints as secondary outcomes
|
18583
|
7534
|
SGLT-2 inhibitors vs. placebo
|
0.67
|
0.55-0.83
|
0
|
0.86
|
|
|
|
GLP-1 RAs vs. placebo
|
0.86
|
0.72-1.03
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.78
|
0.59-1.03
|
|
|
Macroalbuminuria
|
1505
|
7534
|
SGLT-2 inhibitors vs. placebo
|
N/A
|
N/A
|
0
|
0.73
|
|
|
|
GLP-1 RAs vs. placebo
|
0.91
|
0.81-1.02
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
N/A
|
N/A
|
|
|
Weekly GLP-1 RAs
|
20088
|
5376
|
SGLT-2 inhibitors vs. placebo
|
0.65
|
0.55-0.78
|
0
|
0.73
|
|
|
|
GLP-1 RAs vs. placebo
|
0.91
|
0.81-1.02
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.71
|
0.58-0.89
|
|
|
GLP-1 analogues
|
20088
|
4357
|
SGLT-2 inhibitors vs. placebo
|
0.68
|
0.59-0.78
|
0
|
0.94
|
|
|
|
GLP-1 RAs vs. placebo
|
0.82
|
0.66-1.01
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.83
|
0.65-1.07
|
|
|
Next, we conducted another sensitivity analysis excluding ELIXA, [39] as ELIXA includes unstable angina in its definition of adverse events in addition to MACE-3. The results were consistent: GLP-1 RAs did not show a significant difference when compared to placebo (RR 0.88 [0.76-1.03]) with significant heterogeneity (I2= 49.5%, p= 0.037). SGLT-2 inhibitors did not reduce MACE-3 significantly when compared to GLP-1 RAs (RR 0.97 [0.79-1.18]).
Third, we performed another analysis based on the frequency of GLP-1 RA dosing. Daily GLP-1 RAs tended to reduce the risk of MACE-3 when compared to placebo (RR 0.86 [0.73-1.02]), while weekly GLP-1 RAs did not (RR 1.01 [0.83-1.22]). GLP-1 RAs were comparable to SGLT-2 inhibitors (RR 0.99 [0.80-1.21] and 0.85 [0.68-1.05], respectively). Both analyses showed moderate heterogeneity (I2= 47.7% and 31.8%, respectively).
Lastly, we divided GLP-1 RAs into two subclasses, GLP-1 analogues and exendin-4 analogues, and found that GLP-1 analogues displayed significantly lower risk than placebo (RR 0.81 [0.69-0.95]), although there was moderate heterogeneity (I2= 30.6%, p= 0.17). The risk reduction between SGLT-2 inhibitors and GLP-1 analogues was similar (RR 1.05 [0.86-1.27]). Exendin-4 analogues, on the other hand, were not associated with a decreased risk of MACE-3 compared to placebo (RR 1.03 [0.88-1.20]), with moderate heterogeneity (I2= 28.7%, p= 0.21). SGLT-2 inhibitors were associated with significantly lower risk compared to exendin-4 analogues (RR 0.83 [0.69-0.99]).
Renal outcomes
Since most studies classify renal outcomes as secondary endpoints, we conducted a sensitivity analysis excluding the study classifying renal events as primary outcomes. [12] When compared to placebo, SGLT-2 inhibitors reduced the incidence of renal outcomes (RR 0.67 [0.55-0.83]). GLP-1 RAs did not show a statistical difference when compared to placebo (RR 0.86 [0.72-1.03]). SGLT-2 inhibitors tended to reduce the risk when compared to GLP-1 RAs (RR 0.78 [0.59-1.03]). No heterogeneity was appreciated (I2= 0%, p= 0.86).
Since GLP-1 RA studies included macroalbuminuria as a prespecified renal outcome, we performed a sensitivity analysis of studies that included macroalbuminuria as a renal outcome. The prespecified definitions of renal outcomes are shown in Table S2. GLP-1 RAs were not associated with significantly reduced risk compared to placebo (RR 0.91 [0.81-1.02]). Only one SGLT-2 study included macroalbuminuria in renal outcomes.
Additional analysis based on GLP-1 RA frequency showed similar results. Weekly GLP-1 RAs did not decrease renal events compared to placebo (RR 0.91 [0.81-1.02]). There was no heterogeneity (I2= 0%, p= 0.73). SGLT-2 inhibitors were superior to weekly GLP-1 RAs (RR 0.71 [0.58-0.89]). Only one study investigated daily GLP-1 RAs.
We performed another analysis for GLP-1 analogues. GLP-1 analogues had a trend towards a reduction in renal events compared to placebo (RR 0.82 [0.66-1.01]) without heterogeneity (I2= 0%, p= 0.94). Compared to GLP-1 analogues, SGLT-2 inhibitors were associated with lower risk (RR 0.68 [0.59-0.78]). There was only one study that investigated renal risks for exendin-4 analogues.
Subgroup analysis
We conducted a subgroup analysis based on eGFR: 30-44 ml/min/1.73m2 and 45-59 ml/min/1.73m2. In a subgroup of eGFR: 30-44 ml/min/1.73m2 patients, SGLT-2 inhibitors reduced MACE-3 significantly (RR 0.73 [0.54-0.97]), but GLP-1 RAs did not (RR 1.02 [0.78-1.33]). There was high heterogeneity (I2= 57.1%, p= 0.063). SGLT-2 inhibitors also showed beneficial effects on renal outcomes compared with placebo (RR 0.75 [0.62-0.91]), while GLP-1 RAs did not (RR 0.78 [0.46-1.32]). There was no heterogeneity (I2= 0%, p= 0.69). Compared to GLP-1 RAs, SGLT-2 inhibitors did not achieve a statistically significant difference (RR 0.96 [0.55-1.29]).
For patients with eGFR 45-59 ml/min/1.73m2, both SGLT-2 inhibitors and GLP-1 RAs had a similar tendency to reduce MACE-3 compared to placebo (RR 0.82 [0.66-1.01] and 0.85 [0.71-1.03], respectively). There was moderate heterogeneity (I2= 44.8%, p= 0.12). In terms of renal outcomes, SGLT-2 inhibitors reduced renal outcomes (RR 0.61 [0.48-0.77), but GLP-1 RAs did not (RR 1.18 [0.76-1.84]). A comparison between SGLT-2 inhibitors and GLP-1 RAs was not statistically significant (RR 0.52 [0.31-0.85]). No heterogeneity was observed (I2= 0%, p= 0.52).
Table 4
The summary of subgroup analyses.
SGLT2i, sodium-glucose cotransporter-2 inhibitors; GLP-1 RAs, glucagon-like peptide-1 receptor agonists; eGFR, estimated glomerular filtration rate; CI, confidence intervals; MACE-3, 3-point major adverse cardiovascular event; vs., versus; N/A, not available.
MACE-3
|
Subjects
|
|
|
|
|
|
|
Subgroup analysis
|
SGLT-2 inhibitors
|
GLP-1 RAs
|
Comparison
|
Risk ratio
|
95% CI
|
I2 (%)
|
p value
|
eGFR 30-44
|
2479
|
1934
|
SGLT-2 inhibitors vs. placebo
|
0.73
|
0.54-0.97
|
57.1
|
0.063
|
|
|
|
GLP-1 RAs vs. placebo
|
1.02
|
0.78-1.33
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.72
|
0.48-1.06
|
|
|
eGFR 45-59
|
3974
|
4576
|
SGLT-2 inhibitors vs. placebo
|
0.82
|
0.66-1.01
|
44.8
|
0.12
|
|
|
|
GLP-1 RAs vs. placebo
|
0.85
|
0.71-1.03
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.96
|
0.72-1.27
|
|
|
Renal outcomes
|
|
|
|
|
|
|
eGFR 30-44
|
2420
|
889
|
SGLT-2 inhibitors vs. placebo
|
0.75
|
0.62-0.91
|
0
|
0.69
|
|
|
|
GLP-1 RAs vs. placebo
|
0.78
|
0.46-1.32
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.96
|
0.55-1.29
|
|
|
eGFR 45-59
|
3976
|
2288
|
SGLT-2 inhibitors vs. placebo
|
0.61
|
0.48-0.77
|
0
|
0.52
|
|
|
|
GLP-1 RAs vs. placebo
|
1.18
|
0.76-1.84
|
|
|
|
|
|
SGLT-2 inhibitors vs. GLP-1 RAs
|
0.52
|
0.31-0.85
|
|
|