Cardiovascular and renal outcomes with SGLT-2 inhibitors versus GLP-1 receptor agonists in patients with type 2 diabetes mellitus and chronic kidney disease: a systematic review and network meta-analysis

Emerging evidence suggests that sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with decreased risk of cardiovascular and renal events in type 2 diabetes mellitus (DM) patients. However, no study to date has compared the effect of SGLT-2 inhibitors with that of GLP-1 RAs in type 2 DM patients with chronic kidney disease (CKD). We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. We performed a systematic literature search through November 2020. We selected randomized control trials that compared the risk of major adverse cardiovascular events (MACE) and a composite of renal outcomes. We performed a network meta-analysis to compare SGLT-2 inhibitors with GLP-1 RAs indirectly. Risk ratios (RRs) with corresponding 95% confidence intervals (CI) were synthesized. Thirteen studies were selected with a total of 32,949 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95% CI]; 0.85 [0.75–0.96] and 0.68 [0.59–0.78], respectively). However, GLP-1 RAs did not reduce the risk of cardiovascular or renal adverse events (RR 0.91 [0.80–1.04] and 0.86 [0.72–1.03], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.94 [0.78–1.12]), while SGLT-2 inhibitors were associated with a lower risk of renal events compared to GLP-1 RAs (RR 0.79 [0.63–0.99]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE when compared to placebo treatment (RR 0.81 [0.69–0.95]), while exendin-4 analogues did not (RR 1.03 [0.88–1.20]). In patients with type 2 DM and CKD, SGLT-2 inhibitors were associated with a decreased risk of cardiovascular and renal events, but GLP-1 RAs were not. SGLT-2 inhibitors significantly decreased the risk of renal events compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.


Background
Diabetes mellitus (DM) is a major public health problem with a high prevalence. The International Diabetes Federation estimated that 351.7 million people of working age (20-64 years) had DM in 2019, and this number is expected to increase to 417.3 million by 2030 [1]. Type 2 DM is the leading cause of chronic kidney disease (CKD), accounting for roughly 36% of adult CKD in the United States [2]. CKD with DM can progress to end-stage renal disease (ESRD) [3], which confers a poor overall prognosis. Moreover, type 2 DM and CKD increase the risk of cardiovascular disease [4,5]. Therefore, the prevention of CKD progression and cardiovascular events is essential for the management of patients with type 2 DM and CKD.
Several studies have investigated the impact of these novel agents on cardiovascular disease prevention; they show that SGLT-2 inhibitors and GLP-1 are comparable in their ability to decrease cardiovascular and renal events [18,22]. However, no study has compared the effect of SGLT-2 inhibitors on renal and cardiovascular diseases with that of GLP-1 RAs in CKD patients, who are at a high risk of morbidity. We herein investigate the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients by network meta-analysis.
We restricted the search to human studies. Reference lists included in meta-analysis studies were reviewed to minimize missing relevant studies. Two independent and blinded authors (TY and AB) reviewed the search results separately to select studies based on inclusion and exclusion criteria. When a consensus was not reached between the two authors, a third author (MW) was consulted to reach a decision. compared to GLP-1 RAs. Among GLP-1 RAs, GLP-1 analogues showed a positive impact on cardiovascular and renal outcomes, while exendin-4 analogues did not.

Study selection
Studies were selected if they met the following criteria: (1) they were published in peer-reviewed journals; (2) they included adult patients (≥ 18 years old) with type 2 DM; (3) they were RCTs that compared SGLT-2 inhibitors or GLP-1 RAs with a placebo; (4) they compared the risk of major adverse cardiovascular events (MACE) between treatment and placebo groups; (5) they compared the risk of renal outcomes; and (6) they showed an incidence of MACE and a composite of renal outcomes in patients with CKD (defined as estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m 2 ). There was no restriction on publication language. Studies were excluded if (1) they included non-human subjects and (2) there was insufficient data for estimating the risk ratio (RR) even after contacting the authors.

Outcomes
The primary efficacy outcome of this analysis was 3-point MACE (MACE-3), including cardiovascular death, myocardial infarction (MI), and stroke. The secondary outcome was a composite of renal outcomes, including ESRD, a decline in kidney function (such as worsening of eGFR or increasing creatinine), albuminuria, and renal or cardiovascular death. For studies reporting multiple renal outcomes, renal outcomes without albuminuria were prioritized for consistency.

Data extraction and quality assessment
All data from eligible studies were abstracted independently by two investigators (TY and AB). Any conflicts in data extraction or quality assessment were resolved by a third reviewer (MW). For each study, data regarding the incidence of MACE and a composite of renal outcomes in each group were abstracted. We used the Cochrane risk of bias assessment to explore sources of bias in the RCTs included in this analysis [25]. Applying this tool, we evaluated the risk of bias in random sequence generation, allocation concealment, the blinding of participants and researchers, the blinding of outcome assessments, selective reporting, incomplete outcome data, and other metrics.

Statistical analysis
We performed a network meta-analysis using the "netmeta" package (version 1.1-0) and R programming language (R Foundation for Statistical Computing, Vienna, Austria). The RRs and 95% confidence intervals (CIs) were estimated using Mantel-Haenszel methods. A random-effects model was used for the analysis. Heterogeneity was assessed by the probability value of the I 2 variable [26,27]. Heterogeneity was considered to be low, moderate, or high if I 2 was 25%, 50%, or 75%, respectively.

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/1.73 m 2 . The quality evaluation of the included studies is shown in Fig. 2. Subclasses of GLP-1 RAs (exendin-4 analogues or human GLP-1 RA analogues) in included studies are outlined in Additional file 1: Table S1.

Mace-3
The results of sensitivity analyses are summarized in Table 3

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 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 Additional file 1: 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.

Subgroup analysis
The results of subgroup analyses are summarized in Table 4

Discussion
Our study revealed that SGLT-2 inhibitors decrease the risk of cardiovascular and renal events in type 2 DM patients with CKD, which is compatible with RCTs of CKD patients [11,12]. On the other hand, GLP-1 RAs did not lead to significantly lower cardiovascular or renal endpoints, although they showed numerically better results. An indirect comparison of SGLT-2 inhibitors with GLP-1 RAs revealed that SGLT-2 inhibitors significantly decreased the risk of renal outcomes. Sensitivity analyses showed a similar tendency. Interestingly, a sensitivity analysis among GLP-1 RA subclasses revealed that GLP-1 analogues significantly reduced MACE-3 and renal events, while exendin-4 analogues did not. Several mechanisms have been proposed for the positive impact of SGLT-2 inhibitors. First, SGLT-2 inhibitors have mild natriuretic and diuretic effects [40]. Recent RCTs reveal that in patients with heart failure with reduced ejection fraction, SGLT-2 inhibitors were associated with a lower risk of cardiovascular death or hospitalization for heart failure [41,42]. This can be at least partially attributed to diuretic effects, which lead to BP reduction and thereby confer cardiovascular and renoprotective benefits. Second, SGLT-2 inhibitors mitigate low-grade inflammation. SGLT-2 inhibitors prevent glucose entry into proximal tubular cells, which limits glucotoxicity, potentially leading to less oxidative stress [43]. Third, SGLT-2 inhibitors block sodium reuptake in the proximal tubule; an increased delivery of sodium to the macula densa leads to afferent arteriolar constriction and a reduction in intraglomerular pressure [44,45].
Since SGLT-2 inhibitors antagonize glucose reabsorption in the renal tubule, we can anticipate that the effect of SGLT-2 inhibitors is dependent on eGFR. However, a pooled analysis of clinical trials revealed that SGLT-2 inhibitors decrease body weight, BP, and albuminuria regardless of eGFR, although glucose-lowering effects decreased as eGFR declined [11,46]. Our study also revealed beneficial effects of SGLT-2 inhibitors in both eGFR 30-44 ml/min/1.73 m 2 and 45-59 ml/ min/1.73 m 2 groups.
In addition to glycemic control, several mechanisms explain the beneficial effects of GLP-1 RAs. First, GLP-1 RAs lead to BP reduction, [14] which can be attributed to natriuresis [47]. Other possible mechanisms are the reduction of reactive oxygen species and inflammation [48,49] and improvement of endothelial function [50]. However, our study did not find a significant difference between GLP-1 RAs and placebo. A subgroup analysis of a prior meta-analysis by Kristensen et al. [17] also revealed that GLP-1 RAs were not associated with a significantly reduced risk of MACE, although the RR was 0.88. Our sensitivity analysis among GLP-1 RAs drug subclasses revealed a beneficial effect of GLP-1 analogues, while exendin-4 analogues were not. Zelniker et al. revealed a similar tendency [18]. There are several differences between these two subclasses. First, exendin-4 analogues are metabolized and eliminated by the kidneys. GLP-1 analogues, in contrast, are endogenously metabolized [51]. Second, exendin-4 analogues are resistant to inactivation by dipeptidyl peptidase-4. Conversely, GLP-1 analogues can be partially metabolized to the metabolite, which could have an additional cardioprotective effect [52]. As far as we know, there are no studies that evaluate the difference in the cardiovascular benefits between these subclasses. Further investigation is warranted to explore the differences among GLP-1 RAs subclasses.
The major strength of our analysis is that this is the first study that investigates the effect of SGLT-2 inhibitors and GLP-1 RAs on cardiovascular and renal events in type 2 DM patients with CKD [53]. The ADA preferably recommends SGLT-2 inhibitors over GLP-1 RAs in CKD patients; [21] our study supports their recommendations, with additional evidence that GLP-1 analogues can be an alternative option. Our large sample size was another strength of our analysis, allowing us to tease out statistically significant differences among interventions.
Our meta-analysis has several limitations. First, there is still a concern that CKD patients may not be fully randomized since the studies included are subgroup analyses of RCTs. Second, high heterogeneity was observed, and this heterogeneity persisted in most sensitivity and subgroup analyses. As shown in Table 2, the proportions of advanced CKD stages and macroalbuminuria are noticeably different. Population variety among studies may be a source of this heterogeneity. The results should be interpreted with caution. Third, the patients included in each trial may have achieved different levels of hemoglobin A1c, which may be subject to bias as well. Fourth, definitions of renal outcomes are not consistent across studies, though we prioritized renal outcomes without macroalbuminuria in an attempt to reduce inconsistency. Since most GLP-1 RAs studies included macroalbuminuria as a prespecified renal outcome, analyzing renal outcomes without macroalbuminuria may lead to bias. Lastly, we defined CKD as eGFR < 60 ml/min/1.73 m 2 and excluded patients with albuminuria. Therefore, we were not able to investigate the effects of SGLT-2 inhibitors and GLP-1 RAs for those who have albuminuria and eGFR > 60 ml/ min/1.73 m 2 . Ongoing RCTs, including EMPA-KIDNEY, SOUL, and FLOW, will provide better insight into the cardiorenal effects of SGLT-2 inhibitors and GLP-1 RAs [54][55][56]. Further research, including head-to-head comparison, is warranted to explore the effects of SGLT-2 inhibitors and GLP-1 RAs in CKD patients [57].

Conclusion
In patients with type 2 DM and CKD defined as eGFR < 60 ml/min/1.73 m 2 , SGLT-2 inhibitors were associated with decreased risk of cardiovascular and renal events. GLP-1 RAs did not lead to significantly lower cardiovascular or renal endpoints, although they showed numerically better results. SGLT-2 inhibitors significantly decrease the risk of renal events compared to GLP-1 RAs. Sensitivity analyses were consistent. Among GLP-1 RAs, GLP-1 analogues showed a positive impact, while exendin-4 analogues did not.