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

doi:10.21203/rs.3.rs-58029/v2

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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

https://doi.org/10.21203/rs.3.rs-58029/v2

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published 07 Jan, 2021

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Background

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.

Methods

We performed a systematic literature search through October 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 RA indirectly. Risk ratios (RRs) with corresponding 95% confidence interval (CI) were synthesized.

Results

Thirteen studies were selected with a total of 24,887 patients. SGLT-2 inhibitors led to a risk reduction in MACE and renal events (RR [95 %CI]; 0.86 [0.74-0.99] and 0.68 [0.62-0.75], respectively). However, GLP-1 RAs did not reduce cardiovascular and renal risk (RR 0.91 [0.79-1.05] and 0.91 [0.81-1.02], respectively). Compared to GLP-1 RAs, SGLT-2 inhibitors did not demonstrate a significant difference in MACE (RR 0.9 [0.75-1.08]), while SGLT-2 inhibitors were associated with. a lower risk of renal events compared to GLP-1 RAs (RR 0.75 [0.64-0.87]). A sensitivity analysis revealed that GLP-1 analogues significantly decreased MACE than placebo (RR 0.81 [0.68-0.97]), while exendin-4 analogues did not (RR 1.03 [0.86-1.23]).

Conclusions

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, while exendin-4 analogues did not.

Cardiac & Cardiovascular Systems

SGLT2 inhibitors

GLP-1 receptor agonist

meta-analysis

Cardiovascular disease

renal outcomes

diabetes mellitus

chronic kidney disease

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); it accounts for about 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.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a new class of glucose-lowering agents. SGLT-2 inhibitors function through reducing renal tubular glucose reabsorption, producing a reduction in blood glucose without stimulating insulin release. Several large cohort studies and randomized controlled trials (RCTs) have demonstrated favorable cardiovascular and renal outcomes associated with SGLT-2 inhibitors. [6-10] Moreover, recent RCTs revealed that SGLT-2 inhibitors are associated with favorable cardiovascular outcomes in CKD patients. [11, 12]

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) decrease hemoglobin A1c by both stimulating glucose-dependent insulin secretion and reducing glucagon secretion. [13] GLP-1 RAs are known to reduce blood pressure (BP) [14] and body weight. [15] Large cohort studies and meta-analyses of RCTs demonstrated that GLP-1 RAs improve cardiovascular outcomes. [16-20] The American Diabetes Association (ADA) recommends SGLT-2 inhibitors or GLP-1 RAs in type 2 DM patients who have atherosclerotic cardiovascular disease or kidney disease. [21] However, it remains unclear if GLP-1 RAs are beneficial to type 2 DM patients with CKD as well.

Several studies have investigated which type is favorable for cardiovascular disease prevention; the results are inconclusive. [18, 22] Moreover, 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 of a high risk of morbidities. We herein investigated the benefits of SGLT-2 inhibitors and GLP-1 RAs in CKD patients by network meta-analysis.

Literature search

The search strategy was conducted in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) extension statement for network meta-analysis [23, 24]. We performed a systematic search of PubMed, Medline, EMBASE, and the Cochrane Library from inception to October 22,, 2020. The following keywords were applied: ("sodium-glucose cotransporter-2 inhibitors" [MeSH] OR "SGLT-2 inhibitor" OR SGLT-2 OR "empagliflozin" OR "dapagliflozin" OR "canagliflozin" OR "luseogliflozin" OR "ertugliflozin") OR (GLP-1 OR "glucagon-like peptide-1 receptor "[MeSH] OR "glucagon-like peptide-1 receptor agonist" OR "exenatide" OR "liraglutide" OR "lixisenatide" OR "semaglutide" OR "dulaglutide" OR "albiglutide") AND ("diabetes mellitus, type 2" [MeSH] OR "diabetes mellitus type 2" OR "type 2 diabetes mellitus" OR DM or diabetes) AND ("renal insufficiency, chronic" [MeSH] or CKD or "chronic kidney disease" or "kidney disease" or "kidney failure" or CKF or "chronic kidney failure" or "renal failure" or CRF or CRD or "chronic renal disease") AND ("myocardial infarction" [MeSH] OR MI OR "coronary artery disease" [MeSH] OR "cardiovascular disease" [MeSH] OR "cerebrovascular disorders" [MeSH] OR "stroke" [MeSH] OR CVA OR "cerebrovascular accident" OR MACE OR "major adverse cardiovascular event" OR "death" OR mortality [MeSH] OR "all-cause mortality" OR "cardiovascular mortality" OR "heart failure" OR "end stage renal disease" OR "renal failure" OR "kidney failure" OR ESRD OR "renal death" OR "albuminuria" OR "urine albumin" OR "proteinuria" OR "urine protein").

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.

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 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/1.73m²). 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 death. When the included studies have multiple renal outcomes, we selected renal outcomes based on the priority order: primary outcome, a prespecified secondary outcome, and post-hoc outcomes.

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] According to this scale, we evaluated the risk of bias in random sequence generation, allocation concealment, blinding of participants and researchers, blinding of outcome assessment, selective reporting, incomplete outcome data, and other metrics.

Statistical analysis

We performed a network meta-analysis using “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 I² variable [26, 27]. Heterogeneity was considered to be low, moderate, or high if I² was 25%, 50%, or 75%, respectively.

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, [30] and Ertugliflozin [28]) with placebo; seven studies compared GLP-1 RAs (Albiglutide, [33] Dulaglutide weekly, [32] Exenatide weekly, [34] Liraglutide, [36] Lixisenatide, [38] Semaglutide subcutaneously weekly, [37] and Semaglutide oral [35]) 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/1.73m²in one study [32] 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, [11] 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%, [32] three as a decrease in eGFR ≥ 40%, [29, 31, 34] one as a decrease in eGFR ≥ 50%, [11] 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

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]; 0.86 [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).

Renal outcomes

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).

Sensitivity analyses

MACE-3

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, [38] 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]).

Renal outcomes

Since most studies set renal outcomes as secondary endpoints, we conducted a sensitivity analysis without studies that set renal events as primary outcomes. [12] 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.

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 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).

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 included 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 decrease the risk of renal outcomes. Sensitivity analyses showed a similar tendency. Interestingly, a sensitivity analysis among GLP-1 RAs class 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. [39] A recent RCT revealed that in patients with heart failure with reduced ejection fraction, empagliflozin was associated with a lower risk of cardiovascular death or hospitalization for heart failure. [40] The effect can be at least partially attributed to diuretic effects. Diuretic effects lead to BP reduction, which is an important factor that confers cardiovascular benefits and renoprotective effects. Second, SGLT-2 mitigates low-grade inflammation. SGLT-2 inhibitors prevent glucose entry into proximal tubular cells, which limits glucotoxicity, potentially leading to oxidative stress. [41] 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. [42, 43]

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. [44] Our study also revealed that SGLT-2 inhibitors have cardiovascular and renal benefits independent of CKD stages.

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. [45] Other possible mechanisms are the reduction of reactive oxygen species and inflammation [46, 47] and improvement of endothelial function. [48] However, our study did not reach a significant difference between GLP-1 RAs and placebo even though the RR was less than 1.0. A subgroup analysis of a prior meta-analysis by Kristensen et al. [17] also revealed that GLP-1 RAs were not associated with significantly reduced risk of MACE, although the RR was 0.88. Our sensitivity analysis among GLP-1 RAs drug class revealed a beneficial effect of GLP-1 analogues, while exendin-4 analogues were not. Zenliker et al. revealed a similar tendency. [18] There are several differences between these two classes. First, exendin-4 analogues are metabolized and eliminated by the kidneys. GLP-1 analogues, in contrast, are endogenously metabolized. [49] 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. [50] As far as we know, there are no studies that evaluated the difference in the cardiovascular benefits between these classes. We can hypothesize that there may be a class effect for cardiovascular and renal risk reduction. Further investigation can be warranted for the differences among GLP-1 RAs classes.

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. ADA preferably recommended 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 alternative options. A large sample size could be strong enough to reveal a statistically significant difference.

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, baseline hemoglobin A1c, follow-up duration, and medications and doses varied among studies. Since we indirectly compared the events between two medications, the differences in the population can be a risk of heterogeneity. 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, which can lead to heterogeneity. Most GLP-1 RAs included macroalbuminuria to renal outcomes, while SGLT-2 inhibitors studies did not. A prior meta-analysis reported that the reduction rate of renal outcomes (including macroalbuminuria) in SGLT-2 inhibitors was higher than that in GLP-1 RAs and that the difference was even higher when macroalbuminuria is not considered. [18, 51] This tendency can be consistent in our population as well. Lastly, we defined CKD as eGFR < 60 ml/min/1.73m²; we did not included 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/1.73m². Ongoing RCTs, including EMPA-KIDNEY, SOUL, and FLOW, will provide better insight into cardiorenal effects of SGLT-2 inhibitors and GLP-1 RAs. [52-54] Further research, including head-to-head comparison, is warranted to explore the effects of SGLT-2 inhibitors and GLP-1 RAs in CKD patients. [55]

In patients with type 2 DM and CKD defined as eGFR <60 ml/min/1.73m², 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.

DM: Diabetes mellitus; CKD: chronic kidney disease; ESRD: end-stage renal disease; Sodium-glucose cotransporter-2: SGLT-2; RCT: randomized controlled trial; GLP-1 RA: Glucagon-like peptide-1 receptor agonist; ADA: American Diabetes Association; BP: blood pressure; PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses; MACE: major adverse cardiovascular events; eGFR: estimated glomerular filtration rate; RR: risk ratio; 3-point MACE: MACE-3; MI: myocardial infarction; CI: confidence interval;

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors declare that they have no competing interests.

Funding

The author (KT) received a fund from the Japan Society for the Promotion of Science, and Japan Agency for Medical Research and Development (AMED). The funding agency had no role in designing the study, conducting the analysis, interpreting the data or writing the manuscript.

Authors’ contributions

T.Y.: Designed the study, collected the data, contributed to the statistical analysis, and served as the primary author of the manuscript.

M.W.: Collected the data, contributed to the statistical analysis, and served as an author of the manuscript (equivalent contributor).

A.B.: Collected the data and contributed to the statistical analysis.

N.C.: Contributed to the statistical analysis and assisted with the writing of the manuscript.

H.M.: Contributed to the writing of the manuscript and provided critical feedback to shape the manuscript.

T.M.: Contributed to the writing of the manuscript and provided critical feedback to shape the manuscript.

H.U.: Contributed to the writing of the manuscript and provided critical feedback to shape the manuscript.

T.F.: Contributed to the writing of the manuscript and provided critical feedback to shape the manuscript.

Y.S.: Contributed to the data collection and data analysis.

T.Y.: Contributed to the data collection and assisted with the writing of the manuscript.

K.A.: Contributed to the statistical analysis and assisted with the writing of the manuscript.

S.U.: Contributed to the data collection and assisted with the writing of the manuscript.

T.S.: Contributed to the data collection and assisted with the writing of the manuscript.

E.A.: Contributed to the data collection and assisted with the writing of the manuscript.

H.W.: Contributed to the statistical analysis and assisted with the writing of the manuscript.

K.T.: Contributed to the statistical analysis and assisted with the writing of the manuscript.

Acknowledgments

Financial Support: This work was supported by grants from the Japan Society for the Promotion of Science, Salt Science Research Foundation (20C4), and Japan Agency for Medical Research and Development (AMED).

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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.

Author (year)	Drug dose (mg/day)	Median follow up (months)	GFR (ml/min/1.73m²)	Range of A1c (%)	Renal outcome
SGLT2i vs placebo
CANVAS Program	Canagliflozin 300/100	29.0	30-59	7.0-10.5	≥ 40% eGFR decline, ESRD, renal death
CREDENCE	Canagliflozin 100	31.4	30-59	6.5-12.0	Doubing creatinine, ESRD, renal death
DAPA-CKD	Dapagliflozin 5,/10	28.8	25-45	N/A	≥ 50% eGFR decline, ESRD, renal or CV death
DECLARE-TIMI 58	Dapagliflozin 10	50.4	<60	6.5-12.0	≥ 40% eGFR decline, ESRD, renal death
EMPA-REG OUTCOME	Empagliflozin 10/25	37.2	30-59	7.0-9.0	Macroalbuminuria, doubling creatinine, ESRD, death
VERTIS-CV	Ertugliflozin 5/15	36.0	30-59	7.0-10.5	Doubing creatinine, ESRD, renal death
GLP-1 RA vs placebo
ELIXA	Lixisenatide 20 mcg	25.2	30-59	5.5-11.0	N/A
EXSCEL	Exenatide 2 (weekly)	38.4	30-59	6.5-10	Macroalbuminuria, ≥ 40% EGFR decline, ESRD, renal death
HARMONY Outcomes	Albiglutide 30/50	19.2	30-59	>7	N/A
LEADER	Liraglutide 1.8	45.6	30-59	>7	Macroalbuminuria, doubling creatinine, ESRD, renal death
PIONEER-6	Semaglutide 14 (oral)	15.9	30-59	N/A	N/A
REWIND	Dulaglutide 1.5 (weekly)	64.8	15-59	<9.5	Macroalbuminuria, ≥ 30% eGFR decline, ESRD, renal death
SUSTAIN-6	Semaglutide 0.5/1 (weekly)	25.2	<60	>7	Macroalbuminuria, doubling creatinine, ESRD, renal death

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; UACR, urine albumin-to-creatinine ratio; MACE, major adverse cardiovascular events. Normoalbuminuria, microlabuminuria and macroalbuminuria defined as <30, 30-299, and ≥300 mg/g creatinine, respectively.

Author (year)	Number of patients (GFR<60)	GFR <30 (%)	GFR 30-45 (%)	GFR 45-60 (%)	Median GFR in CKD	UACR (mg/g)	Normoalbuminuria (%)	Microalbuminuria (%)	Macroalbuminuria (%)	Weighted averages in MACE (%)	Weighted averages in renal outcomes (%)
SGLT2i vs placebo
CANVAS Program	2039	0	27.2	72.8	49	22	69.8	22.6	7.6	9.7	5.7
CREDENCE	2592	0.0	45.3	48.1	N/A	N/A	12.1	11.3	76.6	10.5	15.6
DAPA-CKD	2522	14.5	44.1	30.85	43.1	949.5	N/A	N/A	N/A	N/A	14.6
DECLARE-TIMI 58	1265	N/A	N/A	N/A	51.4	N/A	55.6	30.9	13.5	8.3	4.1
EMPA-REG OUTCOME	1819	0	31.3	68.7	N/A	N/A	47.7	33.9	18.4	9.7	15.7
VERTIS-V	1807	N/A	N/A	N/A	75.97	N/A		N/A	N/A	9.4	3.5
GLP-1 RA vs placebo
ELIXA	1399	0	29.9	70.1	N/A	N/A	59.7	25.5	14.8	10.6	N/A
EXSCEL	3177	0	28.0	72.0	49.2	N/A	71.4	19.6	9.0	13.5	10.5
HARMONY Outcomes	2222	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	9.3	N/A
LEADER	2158	10.4	29.0	60.6	45.6	49.5	48.0	N/A	N/A	11.9	13.6
PIONEER-6	856	N/A	N/A	N/A	N/A	N/A	N/A	N/A	N/A	2.7	N/A
REWIND	2199	4.8	N/A	N/A	N/A	16.3	50.0	N/A	N/A	N/A	16.7
SUSTAIN-6	832	11.4	N/A	N/A	N/A	N/A	N/A	N/A	N/A	4.5	N/A

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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

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