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| REVIEW ARTICLE |
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| Year : 2023 | Volume
: 55
| Issue : 2 | Page : 119-127 |
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Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials
Debdipta Bose, Miteshkumar Maurya, Mahanjit Konwar
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India
| Date of Submission | 29-Apr-2021 |
| Date of Decision | 19-Apr-2023 |
| Date of Acceptance | 28-Apr-2023 |
| Date of Web Publication | 03-Jun-2023 |
Correspondence Address:
Mahanjit Konwar
Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Parel, Mumbai - 400 012, Maharashtra
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/ijp.ijp_342_21
Sodium-glucose co-transporter 2 inhibitors (SGLT2is) are recommended as the next step therapy for the management of diabetes mellitus. The large clinical trials of SGLT2is demonstrated benefits on various renal endpoints. We conducted this meta-analysis of large trials on cardiovascular and renal safety trials to explore the renoprotective effect of this group of drugs. PubMed, Cochrane CENTRAL, and EMBASE databases were searched with specific keywords till January 19, 2021. Randomized trials of SGLT2is that evaluated the cardiovascular or renal composite outcome as a primary outcome measure were eligible. Random-effects model was used to calculate the overall risk ratios. The search yielded 716 studies and 10 studies were included. The SGLT2is reduced the risk of composite renal outcome (risk ratio [RR] = 0.64, 95% confidence interval [CI] = 0.58–0.72), decline in estimated glomerular filtration rate (eGFR) (RR = 0.62, 95% CI = 0.50–0.77), doubling of serum creatinine (RR = 0.67, 95% CI = 0.56–0.81), dialysis or renal replacement therapy (RR = 0.71, 95% CI = 0.59–0.86), sustained eGFR of <15 ml per min per 1.73 m2 for at least 30 days or more (RR = 0.66, 95% CI = 0.55–0.81), end-stage renal disease (RR = 0.70, 95% CI = 0.56–0.87), and acute kidney injury (RR = 0.79, 95% CI = 0.71–0.89). This analysis establishes the renoprotective effect of SGLT2is. This benefit is noted in patients who had eGFR of more or <60 ml per min per 1.73 m2. This benefit was uniform across all the SGLT2 inhibitors except ertugliflozin and sotagliflozin.
Keywords: Acute kidney injury, composite renal outcome, meta-analysis, renoprotective
How to cite this article:
Bose D, Maurya M, Konwar M. Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials. Indian J Pharmacol 2023;55:119-27 |
How to cite this URL:
Bose D, Maurya M, Konwar M. Impact of sodium-glucose co-transporter 2 inhibitors on renal outcomes in patients of diabetes mellitus: A meta-analysis of landmark renal and cardiovascular outcome trials. Indian J Pharmacol [serial online] 2023 [cited 2023 Oct 4];55:119-27. Available from: https://www.ijp-online.com/text.asp?2023/55/2/119/378029 |
| » Introduction | |  |
The sodium-glucose cotransporter-2 inhibitors (SGLT2is) are recommended by the American Diabetes Association as a second-line drug to treat type 2 diabetes mellitus (T2DM).[1] They inhibit the reuptake of glucose and sodium in the proximal convoluted tubule of the kidney.[2] In addition, SGLT2is enhances sodium excretion, reduction of intravascular volume, and alteration of intrarenal hemodynamics.[3],[4] All these properties probably contribute to their pleiotropic effect on blood pressure (BP), body weight, and albuminuria.[5],[6] However, both empagliflozin and dapagliflozin are not recommended for patients with an estimated glomerular filtration rate (eGFR) of <45 mL per min per 1.73 m2. Both canagliflozin and ertugliflozin are also recommended to stop if eGFR is found to be of <30 mL per min per 1.73 m2 due to their renal-based mechanism.[7],[8],[9],[10] Furthermore, the glucose-reducing impact of SGLT2is is found to be progressively attenuated as the renal function declines, but the nonglycemic effects seem to be similar irrespective of the baseline renal function. Thus, it is important to understand the benefits of SGLT2is among patients with variable eGFR.
The large human trials of SGLT2is demonstrated benefits in various renal endpoints; however, each renal outcome across these studies was inconsistent. In the EMPA-REG OUTCOME trial, empagliflozin decreased the risk of requiring renal replacement therapy (RRT) but did not alter the risk of developing microalbuminuria. Similarly, in CANVAS program, canagliflozin lowered the chance of developing microalbuminuria and a 40% reduction of eGFR, but for RRT, no differences were noted.[11],[12] However, each component of composite renal outcomes was not observed in DECLARE-TIMI 58 study.[13] In addition, two of the recent trials DAPA-CKD and CREDENCE provided a comprehensive understanding of the renoprotective effect of SGLT2is specifically among the patients with varying degrees of chronic kidney disease (CKD).[14],[15]
Several systematic reviews and meta-analyses have evaluated the impact of SGLT2 inhibition among patients who had compromised renal function. However, these studies predominantly focused on cardiovascular safety along with the composite renal outcomes, but most did not focus on the individual components of composite renal outcome such as end-stage renal disease (ESRD), acute kidney injury (AKI), and doubling of serum creatinine (SrCr) level.[16],[17],[18],[19],[20] We, therefore, envisaged a meta-analysis of large trials on cardiovascular and renal safety to evaluate the renoprotective impact of SGLT-2is among patients irrespective of diabetes mellitus status.
| » Materials and Methods | | |
Ethics
The approval from the institutional ethics committee was not sought since the data were already available in the public domain. The study protocol was registered with PROSPERO [CRD42021229859].
Sources of data
Two reviewers (MK and DB) carried out the literature search of PubMed/Medline, Cochrane CENTRAL, and EMBASE databases till January 19, 2021, independently. The full-search strategy is elaborated in the Supplementary File. The eligible studies were identified as per the selection criteria (see below). The final reporting was done by maintaining the PRISMA guideline [Supplementary Table 1].[21]
Study selection criteria
The trials included in the present meta-analysis were randomized controlled trials (RCTs) of SGLT-2is that evaluated the cardiovascular or renal composite outcome as the primary outcome measure in patients irrespective of their diabetes status. We have excluded nonrandomized interventional studies and studies that did not have a cardiovascular or renal outcome as the primary outcome, studies on healthy volunteers, and also the studies that did not have the renal endpoints (mentioned below) used in our meta-analysis.
Data extraction and assessment of eligibility
Two authors (MK and DB) extracted the data independently. Any discrepancy was resolved by discussing with the third author (MM). The following information was collected from the included studies and entered in a datasheet: trial name, year of publication, study design, sample size, use of specific SGLT-2 inhibitor, use of comparator, use of renal outcome measure(s), and baseline eGFR of patients.
Two authors (MK and MM) evaluated available studies, and after assessing the eligibility criteria, all the potential studies were included for quantitative analyses.
Outcome measures
The following primary and secondary outcome measures were used for meta-analysis: primary outcome measure: proportion of patients with composite renal outcome used (death due to other kidney-related diseases, RRT, or rise in creatinine estimate or decline in estimated GFR of ≥40%) and secondary outcome measures: (1) reduction in eGFR of ≥40%, (2) doubling of SrCr level, (3) dialysis or RRT, (4) renal death, (5) maintenance of eGFR of <15 ml per min per 1.73 m2 for at least 30 days, (6) progression to macroalbuminuria, (7) ESRD, and (8) AKI.
Evaluation of risk of bias
Two authors (MM and DB) reviewed all the included studies to identify the important risk of bias (RoB) by using the Cochrane tool to assess RoB. In each domain, the ROB was divided into low, unclear, or high.[22]
Analysis by statistical method
The author DB and MK conducted the analysis, using Cochrane Review Manager 5.3 statistical software.[23] The overall risk ratios (RRs) along with 95% confidence interval (CI) were measured via random-effects model. Statistical heterogeneity was evaluated through I2 statistics. To assess the potential sources of heterogeneity, we performed multiple subgroup analyses based on the use of specific SGLT-2is and eGFR rate. The publication bias could not be evaluated as included studies were <10. The probability value <0.05 was noted as statistically significant.
| » Results | | |
Search of databases
The extensive searching of databases revealed a total of 716 studies. We identified 656 studies after removing all the duplicates. A total of 592 RCTs were removed after assessing the abstract and titles based on the abovementioned eligibility. A total of 64 potentially relevant articles were reviewed based on the full texts. Subsequently, 54 articles were excluded and a total of 10 studies were included for the quantitative analysis. This whole process is depicted in the flowchart [Figure 1].
Features of analyzed trials
The features of the 10 studies are represented in [Supplementary Table 2].
All the RCTs were double-blind placebo-controlled. The mean age of the patients included in these RCTs was more than 60 years. The patients with T2DM and cardiovascular disease were included in 4 (40%) RCTs, 2 RCTs enrolled patients with heart failure (HF) without T2DM, 2 (20%) RCTs included patients who had T2DM and CKD, and one trial (10%) each included patients who had CKD and T2DM and also participants with HF only. Among the 10 RCTs, a total of 5 (50%) studies enrolled more than 5000 patients and the remaining 5 (50%) studies enrolled <5000 patients. A total of 6 (60%) trials had a study duration of more than 2 years and the remaining 4 (40%) trials had followed the patients for <2 years. Among the 10 RCTs, 3 RCTs used dapagliflozin, each of the 2 (20%) RCTs used canagliflozin, empagliflozin, and sotagliflozin, and 1 (10%) trial used ertugliflozin. The average baseline eGFR was <60 ml per min per 1.73 m2 among 3 (30%) of the RCTs. In the remaining 7 (70%) RCTs, eGFR was more than 60 ml per min per 1.73 m2. Among 10 studies, 71,553 patients were recruited.
Risk of bias evaluation
All 10 RCTs have a low RoB for all the seven domains of ROB assessment tool. The risk of various biases was low in ten studies [Supplementary Figure 1].
Synthesis of the results
Primary outcomes
Composite renal outcome
The pooled estimates of the nine studies showed that SGLT-2is decreased the chance of combined renal outcome among 70,000 patients as against placebo (RR = 0.64, 95% CI, 0.58–0.72, P < 0.0001, I2 = 29%) [Figure 2].
Secondary outcome measures
Decline in estimated glomerular filtration rate of ≤40%
The overall estimates of the four studies showed that SGLT-2 inhibitors reduced the risk of decline in eGFR in 34464 patients with or without T2DM as against placebo (RR = 0.62, 95% CI, 0.50–0.77, P < 0.0001, I2 = 59%) [Figure 3]. | Figure 3: Decline in eGFR of ≤40%. eGFR = Estimated glomerular filtration rate
Click here to view |
Doubling of serum creatinine
The overall estimates of the three studies showed that SGLT-2is reduced the chance of elevation of SrCr in 19,615 patients with or without T2DM than placebo (RR = 0.673, 95% CI, 0.56–0.812, P < 0.0001, I2 = 34%) [Figure 4].
Dialysis or renal replacement therapy
The overall assessment of five studies noted that SGLT-2is decreased the chance of dialysis or RRT in 28,705 patients with or without T2DM as against the placebo (RR = 0.71, 95% CI, 0.59–0.864, P = 0.0005, I2 = 0%) [Figure 5].
Renal death
The overall estimation of six RCTs revealed that SGLT-2is and placebo had a similar probability of renal death in 45,823 patients (RR = 0.531, 95% CI, 0.262–1.091, P = 0.084, I2 = 0%) [Figure 6].
Maintenance of estimated glomerular filtration rate <15 ml per min per 1.73 m2 for ≥30 days
The overall analysis of three RCTs denoted that SGLT-2is reduced the probability of maintained eGFR of <15 ml per min per 1.73 m2 for ≥30 days in 13,449 patients with or without T2DM than placebo (RR = 0.66, 95% CI, 0.553–0.812, P < 0.0001, I2 = 0%) [Figure 7]. | Figure 7: Sustained eGFR of <15 ml/min/1.73 m2 for ≥30 days. eGFR = Estimated glomerular filtration rate
Click here to view |
Progression to macroalbuminuria
The overall estimates of the two studies demonstrated that SGLT-2 inhibitors had a similar risk of progression to macroalbuminuria in 15139 patients irrespective of DM status than placebo (RR = 0.793, 95% CI, 0.623–1.001, P = 0.053, I2 = 91%] [Figure 8].
End-stage renal disease
The pooled estimates of three studies demonstrated that SGLT-2is reduced the probability of ESRD in 26,208 patients with or without as compared to placebo (RR = 0.702, 95% CI, 0.564–0.873, P = 0.001, I2 = 0%) [Figure 9].
Acute kidney injury
The overall estimates of six trials demonstrated that SGLT-2is reduced the chance of AKI among 42318 patients irrespective of DM status compared to placebo (RR = 0.79, 95% CI, 0.71–0.89, P < 0.0001, I2 = 0%) [Figure 10].
Subgroup analyses
Utilization of specific sodium-glucose co-transporter 2 inhibitors
Composite renal outcome
| » Canagliflozin | | |
The overall estimates of two studies showed that the SGLT-2is decreased the probability of combined renal outcome among 14,543 patients irrespective of DM status as against placebo (RR = 0.71, 95% CI, 0.614–0.82, P < 0.00001, I2 = 0%) [Supplementary Figure 2].
| » Dapagliflozin | | |
The overall estimates of the three trials demonstrated that SGLT2is lowered the chance of combined renal outcome measure among 26199 patients than placebo (RR = 0.573, 95% CI, 0.50–0.66, P < 0.00001, I2 = 0%) [Supplementary Figure 2].
| » Ertugliflozin | | |
The estimates of one study showed that SGLT-2is and placebo had a similar chance of combined renal outcome measure in 8246 participants as against the placebo (RR = 0.81, 95% CI, 0.64–1.023, P = 0.083, I2 = NA) [Supplementary Figure 2].
| » Empagliflozin | | |
Pooled estimates of the two studies demonstrated that SGLT-2is lowered the chance of combined renal outcome in 10698 patients with or without T2DM compared to the placebo arm (RR = 0.55, 95% CI = 0.43–0.71, P < 0.00001, I2 = 0%) [Supplementary Figure 2].
Sotagliflozin
Overall analysis of one study showed that SGLT-2is and placebo had a similar risk of composite renal outcome in 10584 participants (RR = 0.71, 95% CI, 0.47–1.083, P = 0.112, I2 = NA) [Supplementary Figure 2].
Baseline estimated glomerular filtration rate level
Composite renal outcome
| » Estimated glomerular filtration rate level ≤60 ml per min per 1.73 m2 | | |
Pooled estimates of four trials noted that SGLT-2is lowered the probability of composite kidney outcome for 7565 participants irrespective of T2DM as against placebo (RR = 0.65, 95% CI, 0.52–0.81, P < 0.0001, I2 = 40%) [Supplementary Figure 3].
| » Estimated glomerular filtration rate level more than 60 ml/min/1.73 m2 | | |
The pooled estimates of four studies demonstrated that Sglt2is lowered the chance of combined kidney endpoint measure in 23041 patients with or without T2DM as compared to placebo (RR = 0.628, 95% CI, 0.514–0.765, P < 0.0001, I2 = 51%) [Supplementary Figure 3].
| » Discussion | | |
Main findings
The effectiveness of SGLT2is in delaying the progression of renal failure has been already established in individual clinical trials. However, after extensive literature, we noted that this is the first meta-analysis where both composite renal outcomes and its components were evaluated individually. The current analysis helps to establish the renoprotective effect of SGLT2is among participants irrespective of diabetes or CKD. We found that SGLT-2is are beneficial in reducing the composite renal outcome. SGLT2is also deliver a favorable outcome in hard endpoints such as ESRD and renal death along with improvement of the surrogate endpoints like doubling of serum creatine in the present analysis. The overall risk of renal death was less with SGLT2is but failed to demonstrate statistical significance which could be due to the smaller number of events 35/45823 (0.07%) experienced in the participants.
Various mechanisms were proposed for the renal protective action of SGLT2is which predominantly alters the glomerular hemodynamics. They reduce hyperfiltration by promoting afferent arteriolar constriction and efferent vessel dilation leading to decrease albuminuria, kidney perfusion pressure, and slower annual loss of kidney function.[29],[30] They reduce BP, lead to volume depletion due to glucosuria, and increased delivery of sodium to distal convoluted tubule of juxtaglomerular apparatus which overall result in afferent arteriolar vasoconstriction, leading to lowering of gradient across the glomeruli and reduction in pressure-mediated glomerular injury.[31],[32],[33],[34],[35] This is indicated by an initial reduction of eGFR.[36] Another plausible mechanism of SGLT2is is by a metabolic and inflammatory pathway that enhances oxygenation of kidney and direct effect on the glomerular endothelial function, reducing sodium–hydrogen exchanger 3 activity and affecting mitochondrial function, all of these linked to their clinical benefits.[37],[38],[39],[40]
Comparison with previous analyses
The meta-analyses from Lo et al. and Toyoma et al. also demonstrated the renoprotective effect of SGLT2is preventing the renal composite outcome; however, the number of studies evaluated in the present analyses was higher than the earlier studies.[16],[17] Zelniker et al. in their meta-analyses on SGLT2is also noted a significant reduction in composite renal outcome; however, the reduction was less pronounced than our analysis.[18] Furthermore, the above meta-analyses included data only from the cardiovascular outcome trials, unlike our analysis where we have included data from both cardiovascular and renal outcome trials. One recent review has analyzed the effect of SGLT2is in the reduction of albuminuria among 30% of patients which resulted in a sustained reduction of ESRD by 23%.[19] Another meta-analysis evaluating the impact of SGLT2i in 15 RCTs noted a reduction of albuminuria by 39%.[40] A maximum of 38% reduction was noted in the present meta-analyses too.
Subgroup analysis and its implications
Subgroup analysis of the present study showed that the renoprotective effect of SGLT2is was seen in patients with eGFR of either more than or equal to 60 ml per min per 1.73 m2 or <60 ml per min per 1.73 m2. Lo et al. and Zelniker et al. also noted that the renal benefit was uniform across the various patients' populations such as patients with or without cardiovascular risk factors and also patients with variable baseline eGFR.[17],[18] We also observed that the renal protective effect was variable among the different SGLT2 inhibitors. The impact on composite renal outcome was consistent across dapagliflozin, empagliflozin, and canagliflozin with reduction of 43%, 45% and 29% respectively. On the contrary, both ertugliflozin and sotagliflozin in their respective CVOT trial VERTIS-CV and SCORED did not demonstrate statistical significance for the composite renal outcome.[24],[27]
Implication of the result
ESRD often leads to significant lowering of quality of life. In the past 20 years, no new interventions were introduced for the treatment of ESRD and clinicians had to rely on RAAS inhibition to prevent the progression of nephropathy.[41] The SGLT2is were usually not advised in advanced CKD patients and were believed to have reduced glycemic efficacy in patients with poor renal function.[42] The recent clinical trials in regards to renal end points,with SGLT2is helped to generate the evidence that would help to abolish the uncertainty regarding the use of SGLT2is in such patients.[43] Further, the current analysis would help to establish the renoprotective effect of SGLT2i among patients with or without CKD. Regulatory agencies have already granted permission to use canagliflozin to ameliorate the probability of ESRD, elevation of SrCr, death due to CV causes, and HHF among the participants with diabetes mellitus and diabetic nephropathy with albuminuria. This evidence was generated from the CREDENCE trial.[44] In fact, major international societies have already updated their guidelines and recommended SGLT2is for T2DM patients with eGFR as low as 30 ml/min/1.73 m2 specifically when the patient presents with severe albuminuria.[45] The DAPA-CKD trial which was stopped due to its overwhelming efficacy further corroborate its use in CKD patients. Another large renal outcome trial EMPA-Kidney (NCT03594110) is underway for composite renal outcome in 6000 participants.[46] This trial includes participants with eGFR of 20 mL per min per 1·73 m2. The data from this trial will provide a better understanding of SGLT2is in advanced kidney disease. The clinical impact of these results both at individual and population levels is immense.
No specific drugs were available as such for CKD developed as a complication of diabetes and constituted a large part of the global population.[47] Hence, in light of the present scenario, these drugs have a significant role to play to ameliorate these conditions and subsequent improvement in the lives of many people globally. However, clinicians must ensure that these drugs should be prescribed to the right patient at the right dose for adequate duration. Dekkers and Gansevoort in their report stated that the SGLT2is could be useful even in nondiabetic kidney disease, though we could not perform subgroup analysis based on the diabetic status, but future meta-analysis with the data from nondiabetic patients could provide insight regarding the utility of SGLT-2is in patients with nondiabetic kidney disease.[48]
The US FDA issued a warning regarding the kidney injury in 2016 for canagliflozin and dapagliflozin due to the additional natriuretic effect of SGLT2 inhibitors which is accentuated in patients who received diuretics and renin–angiotensin–aldosterone system antagonists, leading to sudden reduction of GFR.[49] However, recently published EMPA-REG trial and CANVAS trials proved that the risk of AKI was not different between empagliflozin and canagliflozin and control arm. Another cohort study from Nadkarni et al. found no association of SGLT2is in an increased risk of AKI. The study included 12,704 patients with T2DM.[50] Despite this real-world evidence, the clinicians should maintain caution while prescribing SGLT2 inhibitors, especially among the patients with low GFR.
The validity of this meta-analysis is strengthened by the inclusion of high-quality trials with a low level of heterogeneity. However, few limitations need to be considered. We do not have the access to the individual patient data of the trials; hence, we could only evaluate the endpoints that were published in the literature. Further, only those trials were included which had a substantially long-term follow-up as the outcomes analyzed in our study are unlikely to be evaluated in trials with lesser follow-up duration. In addition, the reporting of renal endpoints was not uniform and the pooled results should be interpreted carefully as the baseline severity may vary across the trials.
| » Conclusion | | |
Our meta-analysis establishes the renoprotective role of SGLT2is. This benefit was noted in patients with variable baseline eGFR and uniformly across all the SGLT2 inhibitors except ertugliflozin and sotagliflozin. Hence, SGLT2i as a class is unique in mitigating the diverse aspect of T2DM and its impact on poor renal function.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
| » Supplementary Files | | |
Search algorithm
PubMed (n = 534)
(((((((canagliflozin) OR (empagliflozin)) OR (dapagliflozin)) OR (sotagliflozin)) OR (ertugliflozin)) OR (“Sglt2 inhibitor”)) OR (“Sodium-Glucose Transporter 2 Inhibitors”)) AND ((((((“type 2 diabetes”) OR (T2DM)) OR (renal)) OR (“chronic kidney disease”)) OR (“chronic renal failure”)) OR (kidney))) AND ((“Randomized controlled trial”) OR (“RCT”)).
EMBASE (n = 135)
(“canagliflozin”/exp OR canagliflozin OR “empagliflozin”/exp OR empagliflozin OR “dapagliflozin”/exp OR dapagliflozin OR “sotagliflozin”/exp OR sotagliflozin OR “ertugliflozin”/exp OR ertugliflozin OR “sglt2 inhibitor”/exp OR “sglt2 inhibitor” OR (sglt2 AND (“inhibitor”/exp OR inhibitor)) OR “sodium-glucose transporter 2 inhibitors”/exp OR “sodium-glucose transporter 2 inhibitors” OR (“sodium glucose” AND (“transporter”/exp OR transporter) AND 2 AND (“inhibitors”/exp OR inhibitors))) AND (type AND 2 AND diabetes OR t2dm) AND (chronic AND kidney AND disease OR chronic) AND renal AND failure AND (randomized AND controlled AND trial OR rct).
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
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