Literature search and included studies
A diagram of the study selection is shown in Figure 1. Initially, a total of 889 studies were obtained in the primary search from databases, and nineteen studies were identified through references. We removed 134 duplicate studies; 774 studies were screened. By screening titles and abstracts, 743 papers were excluded because they did not meet the inclusion criteria. By assessing full-text articles, eighteen studies were excluded due to missing data. Finally, thirteen studies published up to October 22, 2020, were selected for our meta-analysis according to the inclusion criteria. [11, 12, 28-38] Out of thirteen studies, six studies were RCTs that compared SGLT-2 inhibitors (Canagliflozin, [12, 29] Dapagliflozin, [11, 31] Empagliflozin,  and Ertugliflozin ) with placebo; seven studies compared GLP-1 RAs (Albiglutide,  Dulaglutide weekly,  Exenatide weekly,  Liraglutide,  Lixisenatide,  Semaglutide subcutaneously weekly,  and Semaglutide oral ) with placebo. The pooled population consisted of 12,044 patients in SGLT-2 inhibitors studies (6,696 in the group treated with SGLT-2 inhibitors and 5,348 in the control group) and 12,843 patients in GLP-1 RAs 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  and from 30 to 59 ml/min/1.73m2 in other studies, with one study that did not mention its lower limit [31, 37]. In DAPA-CKD Trial,  the subgroup data of eGFR between 25 and 45 were available. The median length of follow-up ranged from 28.8 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. For renal outcomes, all studies included ESRD; all studies included renal death; five studies included macroalbuminuria defined as urine albumin creatinine ratio more than 300 mg/g; [30, 32, 34, 36, 37] one study defined reduced kidney function as a decrease in eGFR ≥ 30%,  three as a decrease in eGFR ≥ 40%, [29, 31, 34] one as a decrease in eGFR ≥ 50%,  and five as a doubling creatinine. [12, 28, 30, 36, 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 and Table 2, respectively. All studies defined CKD as eGFR < 60 ml/min/1.73m2. The quality evaluation of the included studies is shown in Figure 2.
Network meta-analysis of treatment groups compared with placebo
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]; 0.86 [0.74-0.99]), but GLP-1 RAs were not (RR 0.91 [0.79-1.05]). Compared to GLP-1 RAs, SGLT-2 inhibitors did not show a significant difference in the risk of MACE-3 (RR 0.94 [0.77-1.16]) (Figure 4). However, there was moderate heterogeneity (I2= 52.9%, p= 0.024).
We also performed a network meta-analysis of the risk of renal events. SGLT-2 inhibitors significantly decreased renal events (RR 0.68 [0.62-0.75]). GLP-1 RAs did not reach to statistically significant difference (RR 0.91 [0.81-1.02]). SGLT-2 inhibitors were also associated with lower risk compared to GLP-1 RAs (RR 0.75 [0.64-0.87]) (Figure 5). There was no heterogeneity (I2= 0%, p= 0.96).
We performed a sensitivity analysis for studies that defined MACE-3 as the primary outcome. Compared to placebo, neither SGLT-2 inhibitors nor GLP-1 RAs was associated with a decreased risk of MACE-3 (RR 0.88 [074-1.05], and RR 0.91 [0.78-1.05], respectively). There was no significant difference between SLGT-2 inhibitors and GLP-1 RA (RR 0.97 [0.77-1.22]). There was moderate heterogeneity (I2= 55.4%, p= 0.022).
Next, we conducted another sensitivity analysis excluding ELIXA,  which included unstable angina to MACE. The results were consistent; GLP-1 RAs did not show significant difference compared to placebo (RR 0.88 [0.74-1.04]) with moderate heterogeneity (I2= 55.1%, p= 0.023). SGLT-2 inhibitors did not reduce MACE-3 significantly compared to GLP-1 RAs (RR 0.97 [0.77-1.22]).
Third, we performed another analysis based on the frequency of GLP-1 RAs dosing. Both daily and weekly GLP-1 RAs showed a similar tendency on MACE compared to placebo (RR 0.86 [0.72-1.04] and 0.88 [0.73-1.06], respectively). GLP-1 RAs were comparable to SGLT-2 inhibitors (RR 0.99 [0.78-1.26] and 0.98 [0.76-1.25], respectively). Both analyses showed moderate heterogeneity (I2= 54.2% and 60.7%, respectively)
Lastly, we divided GLP-1 RAs into two classes: GLP-1 analogues and exendin-4 analogues. GLP-1 analogues revealed significantly lower risk than placebo (RR 0.81 [0.68-0.97]), although there was a low heterogeneity (I2= 39.1%, p= 0.12). Risk reduction between SGLT-2 inhibitors and GLP-1 analogues were comparable (RR 1.05 [0.84-1.32]). Exendin-4 analogues, on the other hand, were not associated with a decreased risk of MACE-3 compared with placebo (RR 1.03 [0.86-1.23]), with low heterogeneity (I2= 40.4%, p= 0.14). SGLT-2 inhibitors did not reach to statistically significant difference between exendin-4 analogues (RR 0.83 [0.67-1.04]).
Since most studies set renal outcomes as secondary endpoints, we conducted a sensitivity analysis without studies that set renal events as primary outcomes.  SGLT-2 inhibitors reduced renal outcomes compared to placebo and GLP-1 RAs (RR 0.67 [0.58-0.78] and RR 0.74 [0.61-0.89], respectively). GLP-1 RAs did not reach to statistical difference (RR 0.91 [0.81-1.02]). No heterogeneity was appreciated (I2= 0%, p= 0.85).
We divided studies into two groups based on the definition of worsening kidney function; worsening eGFR and an increase in creatinine. For studies that defined worsening kidney function based on eGFR, SGLT-2 inhibitors were associated with decreased renal outcomes (RR 0.69 [0.58-0.81]), while GLP-1 RAs were not (RR 0.93 [0.81-1.06]). SGLT-2 inhibitors were superior to GLP-1 RAs (RR 0.74 [0.60-0.92]). There was no heterogeneity (I2= 0%, p= 0.83). The results were similar in creatinine-based studies. SGLT-2 significantly reduced renal events compared to placebo and GLP-1 RAs (RR 0.68 [0.60-0.76], and 0.77 [0.61-0.99], respectively) without heterogeneity (I2= 0%, p= 0.63). GLP-1 RAs did not show significant difference compared to placebo (RR 0.87 [0.71-1.08]).
Another analysis based on GLP-1 RAs frequency showed similar results. Weekly GLP-1 RAs did not decrease renal events compared to placebo (RR 0.93 [0.81-1.06]). There was no heterogeneity (I2= 0%, p= 0.93). SGLT-2 inhibitors were superior to weekly GLP-1 RAs (RR 0.74 [0.62-0.87]). 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 0.89 [0.78-1.01]) without heterogeneity (I2= 0%, p= 0.96). Compared to GLP-1 analogues, SGLT-2 inhibitors were associated with lower risk (RR 0.76 [0.65-0.90]). There was only one study that investigated renal risks for exendin-4 analogues.
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 a moderate heterogeneity (I2= 57.1%, p= 0.06). SGLT-2 inhibitors also showed beneficial effect on renal outcomes compared with placebo (RR 0.77 [0.63-0.94]), while GLP-1 RAs did not (RR 1.20 [0.76-1.91]). There was no heterogeneity (I2= 0%, p= 0.96). Compared to GLP-1 RAs, SGLT-2 inhibitors did not reach to statistically significant difference (RR 0.64 [0.38-1.06]).
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 0.86 [0.71-1.03], respectively). There was a low heterogeneity (I2= 44.8%, p= 0.12). In terms of renal outcomes, SGLT-2 inhibitors reduced renal outcomes (RR 0.61 [0.45-0.84]), but GLP-1 RAs did not (RR 0.92 [0.66-1.28]). Comparison between SGLT-2 inhibitors and GLP-1 RAs was not statistically significant (RR 0.67 [0.40-1.10]). No heterogeneity was observed (I2= 21.9%, p= 0.26).