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Evaluating the overall renal outcomes of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD)

Diabetology & Metabolic Syndrome volume 17, Article number: 5 (2025) Cite this article

Abstract

Background

Our meta-analysis fills gaps by assessing sodium-glucose cotransporter-2 (SGLT2) inhibitors’ renal outcomes in chronic kidney disease (CKD) patients including long-term effects and the subgroup analyses of estimated glomerular filtration rate (eGFR) values and follow-up times.

Methods

The literature search of relevant randomized controlled trials (RCTs) was conducted in Medline, Embase, and the Cochrane Central from the inception to 8 June 2023 on patients with CKD treated with SGLT2 inhibitors. We selected medical subject heading (MeSH) terms and free text terms associated with gliflozin and RCT. We calculated odds ratio (OR) or harzard ratio with 95% confidence intervals (CIs) for composite outcomes and dichotomous data, and weighted mean differences (WMD) for changes in eGFR.

Results

16 RCTs enrolling 52,306 patients were in the final population, with 26,910 being treated with SGLT2 inhibitors and 25,396 serving as controls were identified. We found that there was no decline in the rate of change in eGFR after 13 weeks and SGLT2 inhibitors treatment significantly improved the rate of change in eGFR after 64 weeks (64–104 weeks: WMD, 1.024 mL/min/1.73m2/per year, 95% CI 0.643–1.406; 104 weeks: 0.978, 0.163–1.794).SGLT2 inhibitors reduced the risk of acute kidney injury (AKI) (OR 0.836; 95% CI 0.747–0.936; I2 = 0%), mainly derived from empagliflozin (P = 0.001) and increased the incidence of volume-related adverse events (AEs) by 23%.However, no statically differences were observed in death due to kidney disease (P = 0.182) or events of eGFR < 15 mL/min/1.73 m2 (P = 0.202).

Conclusions

The results of our meta-analysis showed that after 64 weeks of treatment, SGLT2 inhibitors showed a significant benefit on eGFR rate with no further decline after 13 weeks and the improvement was slighter in lower eGFR values. Additionally, SGLT2 inhibitors reduce AKI when using empagliflozin, while there is an increased risk of volume-related AEs exclusively in stage 2 CKD.

Trial registration CRD42023437061.

Key message

The latest guidelines for endocrinology advocated for the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in chronic kidney disease (CKD) patients due to the potential beneficial effects on the kidney. However, the initial decline(dip) in estimated glomerular filtration rate (eGFR) and little data evaluating disparate stages of CKD serve as deterring factors for clinicians when using SGLT2 inhibitors. Different from other meta-analyses, we found that no decline in the rate of change in eGFR after 13 weeks and when the follow up duration more than 64 weeks of treatment, the improvement was significant and the benefit was slighter in lower eGFR values. Further, SGLT2 inhibitors reduce the risk of progression of the renal composite outcomes, but no statistically significant results were observed in death due to kidney disease or sustained eGFR<15 mL/min/1.73 m2. Moreover, our safety subgroup analyses indicate that SGLT2 inhibitors reduce AKI when using empagliflozin, and there is an increased risk of volume-related AEs exclusively in stage 2 CKD.

Introduction

Chronic kidney disease (CKD) is a progressive condition that affects more than 10% of the general population worldwide, emerging as the third fastest growing cause of death worldwide [1, 2]. It is often an asymptomatic complication of type 2 diabetes (T2D) that requires annual screening to diagnose [3]. Until 2021, the sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) dapagliflozin was approved for CKD [1]. Over the last 4 years, trials such as DAPA-CKD [4], CREDENCE [5], and EMPA-KIDNEY [6] have demonstrated the renal protective effects of SGLT2 inhibitors in CKD patients, irrespective of diabetes status, thus international guidelines advocated for the use of SGLT2 inhibitors in CKD patients [7, 8]. Despite well-established kidney protective outcomes advocating high levels of evidence for their use in people with CKD, the utilization of SGLT-2 inhibitors has been unexpectedly low in many countries [9, 10]. Additionally, a retrospective cohort study found that treatment with SGLT2 inhibitors occurred among fewer than 4% of patients with CKD and albuminuria and patient-level factors may.

inform implementation strategies to improve CKD treatment in people with T2D and facilitate guideline-recommended CKD care [3]. Available evidence illustrated that there was a significant difference in the impact of SGLT2 inhibitors among different CKD stages. This disparity might be associated with urinary glucose excretion (UGE) induced by SGLT2i and UGE gradually diminishes as renal impairment progresses, indicated by a decline in the estimated glomerular filtration rate (eGFR) [11, 12]. Furthermore, regarding varying follow-up durations, studies have shown an initial dip of GFR[13, 14]. However, it remains unclear when the specific timing of the eGFR recovery occurs and when the eGFR enhancement provides a renoprotective effect.

Studies involving numerous prospective cohorts, clinical trials, and simulations have shown that GFR rates meet the criteria for surrogacy as endpoints in clinical trials for CKD progression, with stronger support than albuminuria [15]. Prior meta-analyses in CKD focus on eGFR rate or subgroup analysis by follow-ups and baseline kidney function was limited [16,17,18]. A 2023 meta-analysis encompassed 13 RCTs exhibited that SGLT2 inhibitors slowed the overall and long-term rate of eGFR dip; however, the analysis was constrained by categorization limitations, with follow-up periods of only 2–8 weeks or beyond 8 weeks, and excluded patients with CKD stage 2 [13]. Conversely, another meta-analysis did not show a statistical reno-protective effect in eGFR in the long-term treatment period over 188 weeks, thereby leaving the timing of eGFR benefits subject to debate [13, 14]. Additionally, several RCTs observed an initial decline(dip) in eGFR after the initiation of SGLT2 inhibitors, attributed to the amelioration of volume overload through osmotic diuresis and renal tubule-glomerular feedback. This eGFR dip may impede physician adoption or lead to medication discontinuation, particularly among patients with severe kidney function [7], even recent clinical and preclinical studies have shown promising data for the application of SGLT2 inhibitors to the dialysis population and indicated that SGLT2 inhibitors may confer cardiovascular benefits in the dialysis population, not only by maintaining the residual kidney function and ameliorating anemia but also directly by reducing intracellular sodium and calcium levels, attenuating inflammation, modulating autophagy, and relieving oxidative stress and endoplasmic reticulum stress within cardiomyocytes and endothelial cells [19]. Consequently, in 2023, the Food and Drug Administration (FDA) removed dialysis dependency from the list of contraindications in the drug labels of SGLT2 inhibitors [19]. Nonetheless, most meta-analyses targeting CKD have included few patients with an eGFR < 30 mL/min/1.73 m2 [14, 20], thereby introducing a certain degree of bias. Thus, this study aimed to pinpoint the key timepoints of eGFR improvement and identify which eGFR subgroups exhibit significant differences in renal benefits to address the gaps in previous meta-analyses, such as insufficiently detailed classification of follow-up time, an inadequate exploration of different CKD stages (particularly stage 4 CKD), and the inconsistent definitions of renal composite outcomes.This comprehensive analysis may enhance confidence in the initiation of SGLT2 inhibitors and optimize their utilization across varying stages of renal insufficiency.

Materials and methods

Study registration and literature search

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) according to the preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) [21] guidelines and Cochrane Collaoration (CRD42023437061).

The literature search of relevant RCTs was conducted in Medline, Embase, and the Cochrane Central from the inception to 8 June 2023 on patients with chronic kidney disease (CKD) treated with SGLT2 inhibitors. We selected medical subject heading (MeSH) terms and free text terms associated with gliflozin and RCT. The detailed study algorithm is presented in Table S1.

Study selection and criteria

The trials were eligible included: (I) They were double-blind and placebo-controlled (excluding crossover trials) and they studied SGLT2 inhibitors compared to a placebo; (II) Trials involved patients with an estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 and performed in adults (age 18 years); and (III) Studies reporting should include rate of change in eGFR or kidney composites. To identify relevant trials, we excluded references from meta-analyses, reviews, case reports, cohort studies, and observational studies.

Data extraction

Two authors (MJC and TTL) independently performed data extraction and quality assessment. The collected data included the following information: (I) first author, publication year, sample size, and follow-up duration; (II) patient demographics and clinical features especially the stage of the CKD; (III) type of SGLT2 inhibitors and other antidiabetic agents or placebo (IV) any kidney outcome-related parameters and adverse events (AEs). The main kidney outcome was the rate of change in eGFR as an indication of the improvement of renal function and kidney composites. Kidney composites were defined as meeting at least one of the following criteria: a sustained eGFR decrease (≥40%), or end-stage kidney disease (ESKD) (ie, the start of maintenance dialysis or a kidney transplant, or a sustained low eGFR < 15 mL/min per 1.73 m2) or death due to kidney disease. Adverse events were assessed based on their severity and the interested AEs including any AE, serious AE and AE to death, serious hypoglycemia, diabetic ketoacidosis (DKA), renal and urinary disorders, urinary tract infection, genital mycotic infection, acute kidney injury (AKI), volume-related AEs. We acquired additional data through relevant secondary analyses that were not included in the original text or supplementary materials.

Quality and bias assessment

The methodological quality and assessment of bias in each trial were evaluated using the Cochrane Risk of Bias Tool, which contains 6 items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment masking, incomplete outcome data, and selective reporting. Each item was assigned a risk level of unclear (U), low (L), or high (H). For instance, in the generation of the random sequence part, one study did not provide detailed descriptions and was considered to have an unclear risk of bias (U). Any inconsistencies were resolved by the corresponding author (FHS).

Data analysis

We calculated odds ratio (OR) with 95% confidence intervals (CIs) for kidney composite outcomes and weighted mean differences (WMD) to analyze continuous variables for change in eGFR. We also calculated the odds ratio (OR) with 95% CI for dichotomous data. We used a random-effects model and assessed heterogeneity between studies using the I2 (>50% was considered significant heterogeneity). To confirm the robustness of the result, we applied a leave-1-out sensitivity analysis. Potential publication bias was evaluated by quantitative analysis of the visual funnel plot with Begg’s test and Egger’s test. STATA version 13.1 was used to analyze the data and a P-value of less than 0.05 was considered statistically significant.

Since the analysis of different eGFR subgroups is essential for understanding the heterogeneous responses to SGLT2 inhibitors among CKD patients for guiding personalized clinical treatment decisions, even if the statistical power may be limited, these subgroups are of great clinical significance. We oversaw various eGFR subgroups (eGFR < 30, 30–59, 60–90 mL/min/1.73 m2). For nine studies the main kidney outcomes were unavailable in different eGFR subgroups, and thus we use a re-analysis of eGFR data to derive kidney outcomes [22,23,24,25,26,27,28,29,30,31].

Results

Search results and study characteristics

Initially, 6205 records were identified, and subsequently, 16 RCTs were included in this meta-analysis [4,5,6, 32,33,34,35,36,37,38,39,40,41,42,43,44]. The flow chart for study selection is presented in Fig. 1, and the patient demographics and clinical characteristics of the studies are detailed in Table S2.

Fig. 1
figure 1

Flow diagram for the selection of eligible RCTs

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Patients with eGFR more than 90 mL/min/1.73 m2 were excluded from all analyses, resulting in 52,306 patients in the final population, with 26,910 treated with SGLT2 inhibitors and 25,396 serving as controls. The mean age of participants was 63.0 to 74.5 years, and the proportion of males ranged from 48.7% to 74.5%, with a mean follow-up duration ranging from 24 to 161 weeks. All of the studies were placebo-controlled trials, including five types of gliflozins, empagliflozin in five studies (35.6%, 17,540/52,306), dapagliflozin also in five studies (33.5%, 18,618/52,306), three studies use canagliflozin (12.8%, 6709/52,306), two use sotagliflozin (20.8%, 10,861/52,306), and only one use ertugliflozin (3.4%, 1775/52,306). The mean baseline eGFR was from 24 to 73.4 mL/min/1.73 m2 regardless of diabetes status, and 8 RCTs included stage 2 CKD (30.0%, 15,690/52,306), 15 RCTs included stage 3 CKD (65.3%, 32,157/49,236), 6 RCTs involved stage 4 CKD (9.2%, 4,509/49,236), with the exception of the DELIVER study, in which the study did not specify the CKD stage for participants with eGFR < 60 mL/min/1.73 m2.

Risk of bias

The Cochrane Collaboration’s risk of bias tool was utilized to evaluate the quality of the included RCTs, as indicated in Table S3. All 16 trials had low risk in terms of “blinding of participants and personnel”, “incomplete outcome data” and “selective reporting” part. Six studies were judged as moderate risk and seven as unclear. Three studies did not state the allocation concealment method and were evaluated as unclear risk bias, while six trials did not present “who assessed the outcomes” and were evaluated as unclear risk bias with regard to “blinding of outcome assessment”.

SGLT2 inhibitors on renal-related efficiency outcomes

Overall, we found that SGLT2 inhibitors treatment significantly improved the rate of changes of eGFR compared with placebo (WMD, 0.778 mL/min/1.73m2/per year, 95% CI 0.139–1.417, I2 99.7%; P = 0.017) and reduced the risk of kidney disease progression by 34% (OR 0.66, 95% CI 0.580–0.739, I2 = 44.9%).

Effect of SGLT2 inhibitors on changes in eGFR and UACR

13 trials provided the evaluation of changes in eGFR except that three studies[34, 35, 41] didn’t include the rate of change in eGFR and we found that SGLT2 inhibitors treatment significantly improved the rate of change in eGFR compared with placeboin Fig. 2A. Consistent benefits were also observed across canagliflozin and ertugliflozin except for opposite changes in sotagliflozin groups (WMD, − 0.250 mL/min/1.73m2/per year, 95% CI − 1.558 to 1.058, I2 0%).

Fig. 2
figure 2

Main efficacy outcomes of SGLT2 inhibitors versus control. ESKD, death due to kidney disease, or sustained 40% decline in eGFR (Composite outcome A), ESKD, death due to kidney disease, or sustained decline eGFR of ≥50% from baseline (Composite outcome B), ESKD, death due to kidney disease, sustained decline in eGFR of ≥40% from baseline, or eGFR lower than 15 mL/min per 1.73 m2 (Composite outcome C), ESKD, sustained decline in eGFR of ≥40% from baseline, or eGFR lower than 15 mL/min per 1.73 m2 (Composite outcome D). eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; ESKD, end stage kidney disease, ESKD; SGLT2 inhibitors, Sodium-glucose cotransporter-2 inhibitors

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We also observed an intriguing phenomenon that the rate of eGFR was inconsistent at different follow-up time and the favorable effect of SGLT2 inhibitors was more significant after 64 weeks, but the initial GFR dip was noted at 1–13 weeks and no inferiority at 24–52 weeks (follow up duration 4 weeks: WMD, − 2.938 mL/min/1.73m2/per year, 95% CI − 3.421 to − 2.454, I2 99.9%; 6–13 weeks: − 1.233, − 1.790 to − 0.676, I2 94.4%; 24–52 weeks: − 1.410, − 2.970 to − 0.149, I2 60.1%; 64–104 weeks: 1.024, 0.643 to 1.406, I2 98.4%; > 104 weeks: 0.978, 0.163 to 1.794, I2 99.9%). Therefore, for patients with a high risk of cardiovascular disease, the potential long-term renal protection and cardiovascular benefits of SGLT2 inhibitors may render the treatment worthy of consideration notwithstanding the initial eGFR dip, thus providing a useful reference for clinicians[3, 7]. Moreover, for those patients who can tolerate 64 weeks of treatment, the use of SGLT2 inhibitors can be more actively recommended.

As for changes in UACR, only five RCTs [1, 2, 5, 7, 9] included the outcomes, resulting in an average difference of 21% reduction compared with controls (WMD − 21%, 95% CI − 40 to − 2; I2 68.2%).

Effect of SGLT2 inhibitors on kidney disease progression

11 trials provided the evaluation of kidney disease progression and found that SGLT2 inhibitors reduced the risk by 34%, with a similar trend for individual gliflozins in Fig. 2B. Nevertheless, when analyses were stratified by different types of kidney composite or individual kidney outcome, only for composite outcome C (ESKD, death due to kidney disease, sustained decline in eGFR of ≥40% from baseline, or eGFR lower than 15 mL/min per 1.73 m2), SGLT2 inhibitors showed significant reducing risk compared with placebo (OR 0.661, 95% CI 0.489–0.893, I2 = 84.1%), and no statically differences were observed in death due to kidney disease (P = 0.182) or events of eGFR < 15 mL/min/1.73 m2 (P = 0.202). Five of the studies were unavailable for inclusion in the analysis for the absent of kidney disease progression outcomes.

SGLT2 inhibitors on safety outcomes

Overall, SGLT2 inhibitors didn’t increase the risk of any AEs and AE to death but decreased the risk of serious AEs by 14% (OR 0.856, 95% CI 0.818–0.896, I2 = 0%). Additionally, SGLT2 inhibitors reduced the risk of AKI (OR 0.836; 95% CI 0.747–0.936; I2 = 0%) and increased the incidence of volume-related AEs by 23% (OR 1.231; 95% CI 1.123–1.349; I2 = 0%).

Effect of SGLT2 inhibitors on the extent of AEs

Data on reported safety outcomes for AEs were available from 11 trials (Fig. 3A) and excluded 5 studies for no data on safety outcomes. For the extent of AEs, we mainly included any AEs, serious AEs, and AEs leading to death. For further analysis of serious AEs, we also included serious hypoglycemia and DKA. Overall, SGLT2 inhibitors didn’t increase the risk of any AEs (P = 0.077) and AE to death (P = 0.074). As for serious AEs, a decrease of 14% was observed, and consistent benefits were noted with the exception of dapagliflozin and ertugliflozin. Serious hypoglycemia and DKA may lead to severe consequences; therefore, we involved these items in the analysis of safety outcomes. As for serious hypoglycemia, no significant differences were observed even when results were ordered by eGFR or gliflozins. Notably, a higher risk for DKA was found compared with placebo (OR 2.535, 95% CI 1.121–5.731, I2 = 20.4%), primarily associated with canagliflozin and sotagliflozin (OR 95% CI, canagliflozin: 10.985, 1.417–85.157; sotagliflozin: 2.147, 1.137–4.054) (Fig. 3B).

Fig. 3
figure 3

Safety outcomes of AEs of SGLT2 inhibitors vs control

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Effect of SGLT2 inhibitors on kidney related disorders

Figure 4 summarizes the safety outcomes on the kidney related disorders. As for renal and urinary disorders, we found no statistically significant differences (P = 0.976) with the exception of a reduced tendency in canagliflozin (OR 1.266; 95% CI 0.653–0.894; I2 = 0%). As for the urinary tract, SGLT2 inhibitors were associated with a higher risk (OR 1.266; 95% CI 1.042–1.537; I2 = 77.5%) but were not influenced by baseline eGFR category and various gliflozins. The consistent result was also observed for genital mycotic (OR 2.142; 95% CI 1.376–3.334; I2 = 0%), primarily associated with sotagliflozin and ertugliflozin (OR 95% CI, sotagliflozin:2.799, 1.990–3.936; ertugliflozin:2.959, 1.447–6.053). Nevertheless, there was no interaction of effectiveness in patients with eGFR less than 30 mL/min/1.73 m2. Clear evidence of benefit was apparent for AKI, mainly derived from empagliflozin (P = 0.001), but no evidence of differences was found across the other four gliflozins and CKD subgroup. Conversely, SGLT2 inhibitors increase the incidence of volume-related AEs by 23%, particularly in patients with eGFR 60–89 mL/min/1.73 m2 (OR 1.426; 95% CI 1.151–1.767; I2 = 0%; P = 0.001) and in three studied drugs (OR 95% CI, canagliflozin: 1.288, 1.007–1.646; dapagliflozin: 1.292, 1.067–1.565; sotagliflozin: 1.310, 1.123–1.349), compared with placebo.

Fig. 4
figure 4

Safety outcomes of the kidney related disorders of SGLT2 inhibitors vs control. CKD, chronic kidney disease; AE, adverse even; UTI, urinary tract infection; GMI, genital mycotic infection; AKI, acute kidney injury

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Sensitivity analyses and publication bias

The sensitivity analysis outcomes did not demonstrate any impact on our main results of each study, confirming the robustness of our findings (Table S4 and S5). Furthermore, no potential publication bias was observed using qualitative funnel plots and Begg’s and Egger’s tests, except for safety outcome on genital mycotic events using Begg’s Test (P = 0.02) (Figures S1 and S2).

Discussion

Main findings and previous studies

In our results, SGLT2 inhibitors have an overall improvement in the rate of eGFR and reduce the risk of progression of kidney disease, which are consistent with previous meta-analyses [13, 14, 18].

Additionally, regarding safety profile,consistent with previous findings, SGLT2 inhibitors reduce the risk of AKI, increase the risk of DKA, urinary tract infections, and genital mycotic infections, but do not increase the risk of hypoglycemia [12, 17, 45,46,47,48].

A previous study indicated that SGLT2 inhibitors did not increase the risk of AKI in CKD patients (P = 0.07) [13], while another meta-analysis showed that SGLT2 inhibitors reduce the risk of AKI (RR 0.81, 95% CI 0.67–0.98, P = 0.031) [45] compared with placebo. This disparity in results may be ascribed to the fact that the 2018 meta-analyses not only lacked large-scale RCTs such as the DAPA-CKD study and the SCORED study but also included patients with a baseline without prevalent kidney disease [4, 41]. Our meta-analysis including 16 RCTs with a total sample size of 52,306 subjects on CKD patients fills gaps by assessing SGLT2 inhibitors’ renal impacts, including long-term effects, stratified analyses, composite or specific endpoints, or drug safety. It addresses the scarcity of subgroup analyses of eGFR values and follow-up times, pinpointing the key time points of eGFR improvement and identifying which eGFR subgroups exhibit significant differences in renal benefits. Notably, the present study has some new findings: Firstly, SGLT2 inhibitors have renoprotective effects on improvement in the rate of change in eGFR when the follow up duration more than 64 weeks, showing no further decline after 13 weeks in CKD. Secondly, the improvement in the eGFR rate diminished with lower baseline eGFR values. Thirdly, no statistically significant results were observed in death due to kidney disease or a sustained eGFR < 15 mL/min/1.73 m2. Fourthly, SGLT2 inhibitors were found to reduce AKI (P = 0.02), with empagliflozin predominantly driving this effect.

Efficacy of SGLT2 inhibitors on renal related outcomes

It was reported that the GFR rate fulfills the criteria for surrogacy endpoints for the early stages of CKD progression, with stronger support for change in albuminuria [15]. Thus, we further refined the analysis into 5 categories of time points and different extents of renal dysfunction. Our results echo previous study that SGLT2 inhibitors induced an initial eGFR dip when during the early treatment period and gradually narrowed over time [12, 14]. However, the statistical reno-protective effect in eGFR rate in the long-term treatment period was still controversial (follow-up duration over 188 weeks: WMD, 3.10 mL/min/1.73m2, 95% CI − 1.88 to 4.32, I2 72.5%, P = 0.056; long-term: 0.13, 0.10 to 0.16, I2 91.0%; P < 0.001) [13, 14]. In our study, it is noteworthy that after 64 weeks of treatment, the improvement in the rate of change in eGFR was borderline significant. The differences in these findings relative to previous studies might be ascribed to the larger number of patients with an eGFR < 30 mL/min/1.73 m2 and a more detailed categorization of follow-up durations.Another novel and intriguing finding is that the magnitude of its eGFR benefit was attenuated by the lower baseline eGFR values, even SGLT2 inhibitors appear beneficial at low levels of kidney function. The reason may lead to its diminished urinary glucose excretion effect due to impaired renal filtration and excretion, resulting in reduced renal benefit [49]. Further subgroup analysis of the follow-up period noticed that when the treatment period was at 24 to 52 weeks, eGFR still declined but no statically significant effect was observed, which was inconsistent with previous results [14]. The main explanations may be that the previous meta-analysis didn’t involve the current large RCTs after 2019 and the absent date in eGFR from 60 to 90 mL/min/1.73 m2.

As for kidney composite outcomes, the results were consistent with the primary analyses with a significant reducing risk regardless of baseline renal function levels or types of SGLT2 inhibitors [6, 18]. However, we observed variability in the definitions of kidney disease progression across different RCTs. For instance, in the EMPA-KIDNEY [6], the progression of kidney disease was defined as ESKD, a sustained decrease in eGFR to <10 ml/min/1.73 m2, or death from renal causes or a decrease in eGFR of ≥40% instead of ≥50% in DAPA-CKD study. Therefore, we reclassified kidney disease progression into four subgroups and conducted analyses on individual kidney outcomes. Notably, SGLT2 inhibitors only showed a significantly reduced risk compared with placebo only for composite outcome C, and when analyzing individual kidney outcomes, no statistically significant results were observed for death due to kidney disease or a sustained eGFR < 15 mL/min/1.73 m2.

Safety of SGLT2 inhibitors on the extent of AEs

Our results demonstrate that compared to the control group, treatment with SGLT2 inhibitors led to a decrease in the a serious AEs and highlight that canagliflozin and sotagliflozin users have a higher risk of DKA compared to users of the other two classes of SGLT2 inhibitors, in agreement with previous study [50, 51]. This may be primarily due to their lower SGLT-2/SGLT-1 selectivity compared with empagliflozin and dapagliflozin, which may have a higher risk of diarrhea or volume depletion, predisposing factors for DKA [50].

Safety of SGLT2 inhibitors on kidney related disorders

Regarding AKI, the SGLT2 inhibitors treatment group showed a significant reduction in risk compared with controls, consistent with previous studies [45,46,47,48]. Interestingly, further subgroup analyses revealed that the attenuated occurrence of AKI was mainly derived from empagliflozin. These differences may be partly explained by the patients’ characteristics of baseline diabetes (empagliflozin vs dapagliflozin: 55.8% vs 77.5%) and the other three SGLT2 inhibitors all assigned diabetes. Additionally, the limited reported trials in CKD patients for the other four SGLT2 inhibitors may impact the results (less than 2 trials), highlighting the need for larger subgroup studies. To date, the precise mechanism by which SGLT2 inhibitors prevent AKI remains unclear. The possible mechanisms include a reduction in intraglomerular pressure by enhancing afferent arteriolar vasoconstriction, decreasing tubular oxygen consumption, mitigating renal inflammation, and restoring the metabolism of cellular energy [46, 48]. More research is needed to confirm this finding and its underlying mechanism.

We also confirmed that SGLT2 inhibitors increase the risk of volume-related AEs with renal insufficiency compared with controls, consistent with the previous meta-analyses [12, 17]. However, our subgroup analysis revealed an increased risk exclusively in stage 2 CKD (OR 1.426, 95% CI 1.151–1.767, P = 0.001). This may be attributed to the diminished, but not entirely failed, renal capacity to regulate volume and sodium in the early stages of CKD. The diuretic effects of SGLT2 inhibitors were related to a higher risk of hypovolemia. Additionally, patients with stage 2 CKD may not fully recognize the severity of their condition and might not adhere strictly to treatment and monitoring guidelines. Therefore, SGLT2 inhibitors must be used with caution, especially in patients with extracellular volume depletion such as those using antihypertensive medications to manage hypertension or edema in CKD patients.

Clinical implications

Evidence of the time-dependent and CKD stage-dependent overall kidney outcomes, particularly the precise time of eGFR improvement was associated with the clinical utilization of SGLT2 inhibitors. The kidney function should be closely monitored within 13 weeks after starting SGLT-2 inhibitor treatment. If the initial eGFR dip within 13-week period is less than 30% from the baseline, it is not a contraindication for medication discontinuation. On the other hand, if the patient's eGFR stabilizes and shows no further decline after 13 weeks, the patient can continue long-term use of the drug with a significant improvement after 64 weeks of treatment. Subsequently, physicians can appropriately reduce the frequency of eGFR monitoring, but regular assessment of renal function and other relevant indicators is still necessary. Furthermore, the insight can empower clinicians to customize personalized treatment strategies with increased confidence for patients with severe kidney function.

Strengths and limitations

To our knowledge, this study represents a large meta-analysis of a population of CKD patients to investigate the impact of SGLT2 inhibitors on overall kidney outcomes. Furthermore, our subgroup analyses of eGFR values and follow-up times have pinpointed the key time points of eGFR improvement and identified which eGFR subgroups exhibit significant differences in renal benefits. However, some limitations should be noted. Firstly, some original studies were primarily focused on cardiovascular outcomes rather than renal endpoints, leading to insufficient power for our data analyses on kidney outcomes. Further inclusion of larger cohort studies in the meta-analysis might be needed. With the expansion of SGLT2 inhibitors’ usage duration and the indications in CKD following the National Medical Products Administration's (NMPA) approval of dapagliflozin in 2022 and empagliflozin in 2023, there will be more kidney-focused studies. Consequently, we will conduct an update study to incorporate these emerging data [4, 6]. Secondly, different units were utilized for eGFR, causing some inaccuracies in data computation. We have endeavored to perform conversions between different units and the methods are referenced, aiming to minimize the impact as much as possible [13]. Future studies with more standardized measures are warranted. Thirdly, different characteristics of participants, SGLT2 inhibitor type or dosage, and follow-up durations might introduce bias and clinical heterogeneity, thus we used a random effect model and conducted subgroup analyses as well as sensitivity analyses.

Conclusions

Our study revealed that SGLT2 inhibitors have renoprotective effects on improvement in the rate of change in eGFR when the follow up duration more than 64 weeks, showing no further decline after 13 weeks in CKD patients and the improvement was slighter in lower eGFR values. Additionally, empagliflozin was found to safely reduce the risk of AKI. In stage 2 CKD patients, SGLT2 inhibitors were associated with an increased risk of volume-related adverse events. The data from our study provide robust evidence for clinical use in CKD patients especially, particularly noting the initial decline in eGFR during the early stages of treatment.

Availability of data and materials

No datasets were generated or analysed during the current study.

Abbreviations

SGLT2:

Sodium-glucose cotransporter-2

RCT:

Randomized controlled trial

CKD:

Chronic kidney disease

eGFR:

Estimated glomerular filtration rate

UACR:

Urine albumin creatine ratio

AE:

Adverse event

MeSH:

Medical subject heading

OR:

Odds ratio

Cls:

Confidence intervals

WMD:

Weighted mean differences

AKI:

Acute kidney injury

ESKD:

End-stage kidney disease

DKA:

Diabetic ketoacidosis

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Acknowledgements

We thank all the authors for their contributions.

Funding

This study was supported by Shanghai Hospital Development Center Foundation (SHDC2022CRS052), the Fundamental Research Funds for the Central Universities (WKCX2022), and the Science and Technology Development Plan Guidance Project of Suzhou Pharmaceutical Association (SKYXD2022006).

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  1. Min-Jia Cao and Ting-Ting Liang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China

    Min-Jia Cao & Fang-Hong Shi

  2. Department of Pharmacy, Changshu Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu, People’s Republic of China

    Ting-Ting Liang

  3. Department of Nursing, Ren Ji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Li Xu

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MJC and TTL are the guarantors of the entire manuscript. FHS contributed to the study conception and design, critical revision of the manuscript for important intellectual content, and final approval of the version to be published. LX contributed to the data acquisition, analysis, and interpretation. All authors reviewed the manuscript.

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Correspondence to Fang-Hong Shi.

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Cao, MJ., Liang, TT., Xu, L. et al. Evaluating the overall renal outcomes of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD). Diabetol Metab Syndr 17, 5 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-024-01547-x

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Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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