Benefits of SGLT2 inhibitors combining with renin–angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis

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array:3 [ "entidad" => "Shanxi Medical University, Taiyuan, China" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Beneficios de los inhibidores de SGLT2 combinados con bloqueadores del sistema renina-angiotensina en los resultados cardiovasculares de los pacientes con enfermedad renal crónica: una revisión sistémica y un metaanálisis" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0035" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1860 "Ancho" => 2175 "Tamanyo" => 244414 ] ] "descripcion" => array:1 [ "en" => "Forest plot of meta-analyses comparing renal outcomes of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo." ] ] ] "textoCompleto" => "IntroductionChronic kidney disease (CKD) affects 8–16% of the global population and is associated with a high morbidity and mortality rates.<a class="elsevierStyleCrossRef" href="#bib0175">1</a> CKD has also been found to play a crucial role in the development of other diseases, and in all-cause and cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> The risk of such a death increases exponentially as kidney function deteriorates.<a class="elsevierStyleCrossRef" href="#bib0185">3</a> Therefore, it is important to prevent CKD progression.Renin–angiotensin-system (RAS) blockers have been shown to be cardioprotective because of their antihypertensive and proteinuric effects.<a class="elsevierStyleCrossRefs" href="#bib0190">4,5</a> Therefore, clinical practice guidelines recommend using RAS blockers for treating CKD or diabetic nephropathy.<a class="elsevierStyleCrossRef" href="#bib0180">2</a> However, the risk of disease progression in CKD patients remains high even after the use of RAS blockers, and clinicians look forward to new therapeutic approaches.Sodium-glucose cotransporter-2 (SGLT2) inhibitors are a new class of antidiabetic drugs, which inhibit the reabsorption of glucose in the proximal tubules of the kidney, thus exerting a hypoglycemic effect.<a class="elsevierStyleCrossRefs" href="#bib0200">6,7</a> Several large randomized controlled trials (RCTs), such as CREDENCE<a class="elsevierStyleCrossRef" href="#bib0210">8</a> and EMPA-REG,<a class="elsevierStyleCrossRef" href="#bib0215">9</a> have confirmed the cardiorenal protective effect of SGLT2 inhibitors, especially in diabetes patients with CKD. Furthermore, the 2020 KDIGO guidelines recommend using SGLT2 inhibitors in CKD patients who have diabetes.<a class="elsevierStyleCrossRef" href="#bib0220">10</a> An increasing number of studies have suggested that the renoprotective effect of SGLT2 inhibitors may be independent of their hypoglycemic effect.<a class="elsevierStyleCrossRef" href="#bib0225">11</a> The latest results of DAPA-CKD are exciting and provide evidence for the benefits of using SGLT2 inhibitors for the treatment of CKD.<a class="elsevierStyleCrossRef" href="#bib0230">12</a> Studies have demonstrated that both SGLT2 inhibitors and RAS blockers can reduce glomerular hyperfiltration,<a class="elsevierStyleCrossRef" href="#bib0235">13</a> and we found that RAS blockers are often used as background therapy in some RCTs reporting on SGLT2 inhibitors therapy for CKD. Thus, it is necessary to explore the significance of this combination for CKD treatment.MethodsThis study was pre-registered on PROSPERO (CRD42020218337) and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement (PRISMA)<a class="elsevierStyleCrossRef" href="#bib0240">14</a> and MOOSE.<a class="elsevierStyleCrossRef" href="#bib0245">15</a>Search strategyWe searched Embase, PubMed, Web of Science and Cochrane Library using a combination of subject terms and free words. The search terms included “renal insufficiency, chronic kidney insufficiency, sodium-glucose co-transporter 2 inhibitors, sodium glucose transporter 2 inhibitors, canagliflozin, empagliflozin, dapagliflozin, tofogliflozin, ipragliflozin, luseogliflozin”,and the search was conducted from the time the database was established to December 2020.Inclusion and exclusion criteriaInclusion criteria: (1) age≥18 years and a precise diagnosis of CKD with eGFR>30ml/min/1.73m2, with or without diabetes; (2) intervention group treated with SGLT2 inhibitors and the control group treated with placebo; with both groups being treated with RAS blockers as background therapy; (3) study outcome measures including the impact on renal and cardiovascular outcomes, 24-h urinary albumin excretion rate (24hUAE), and estimated glomerular filtration rate (eGFR); and (4) RCTs.Exclusion criteria: (1) study types such as reviews, conference abstracts, incomplete end indicators, and unpublished articles; (2) the intervention or control group not treated with RAS blockers as background therapy or the study subjects not receiving complete RAS blocker background therapy; and (3) previous severe heart or kidney disease in the subjects (eGFR<30ml/min/1.73m2, severe heart failure, angina, myocardial infarction or stroke occurring within 6 months before enrollment in the trial).Literature screening and data extractionThe retrieved literature was first deduplicated using the EndNote software and then manually deduplicated. After excluding duplicates, we browsed the titles and abstracts to exclude irrelevant literature; subsequently, we scanned full texts to determine the final inclusion according to the inclusion and exclusion criteria.We read the final included literature and extracted the following primary data: first author, year, study population, gender composition, mean age, GFR, sample size, and intervention and follow-up duration. The processes were independently performed by two researchers, and any disputes arising during the process were coordinated and resolved by a third researcher.Quality assessmentThe final included literature was evaluated for quality using the Cochrane Collaboration “risk of bias” assessment tool. The evaluation items included the following: (1) random sequences generation; (2) allocation concealment; (3) blinding of participants and personnel; (4) blinding of outcome assessment; (5) incomplete outcome data; (6) selective reporting; and (7) other bias. Each assessment item was classified as high risk, low risk, or unclear.Statistical analysisWe statistically analyzed the data using the metan command in Stata software 14.0, and calculated the study outcome measures using the inverse variance method. Continuous variables were expressed as weighted mean differences (WMDs) or standardized mean differences (SMDs) and 95% confidence interval (95% CI). Dichotomous variables were expressed as relative risk (RR) and 95% CI, and inter-study heterogeneity was expressed as I2 and p values. I2>50% or p<0.1 indicated evident heterogeneity between studies, and the random-effects model was used and further subgroup analysis was conducted to find the source of heterogeneity; I2<50% or p>0.1 indicated that the heterogeneity between studies is acceptable, and the fixed-effects model was used for analysis in this case. The combined effect measure was statistically significant at p<0.05.Trials sequential analysis (TSA)In a small sample trial, interim analyses cause false positive or false negative results, implying an increased risk of type I errors or type II errors. In particular, in a meta-analysis that included small samples of trials, the rate of random error is more significant. Therefore, to avoid an increase of random error, we performed the TSA by TSA software to estimate the minimum sample size required to obtain the outcomes of statistical significance for the intervention and control group (<a href="https://www.ctu.dk/tsa">https://www.ctu.dk/tsa</a>). We set the risk of type I error at an overall 5%, being the standard in most meta-analyses, to obtain the traditional boundary and the TSA threshold value. Then we calculated the required information size (RIS), meaning the minimum sample size needed to detect the intervention effect of a 25% relative risk reduction, at a power of 80%.ResultsLiterature searchA total of 962 articles were retrieved, and 833 articles remained after removing duplicates; 753 irrelevant articles were removed after the title and abstract browsing. After full-text reading of the remaining papers, 9 meeting abstracts, 2 incomplete outcome data, 42 papers without background treatment with RAS blockers, and 5 non-randomized controlled trials were excluded according to inclusion and exclusion criteria, resulting in the inclusion of 10 papers that met the criteria. The detailed literature screening process is shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig. 1</a>.<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Data extractionThe 10 articles included are RCTs published from 2015 to 2020. Both intervention and control groups were treated with RAS blockers as background, and different types and doses of SGLT2is were used in the intervention group, while the same dose of placebo was used in the control group. Other necessary characteristics of the included literature are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Quality assessmentOf the ten articles included, only three did not explicitly account for random sequence generation and the remaining papers were low risk. Three articles had high risk of selection bias and one was not mentioned. For the double-blind experimental design, only one paper did not use blinding, and the rest of the literature described the double-blind design. The outcome data from the six papers were all relatively complete and no significant gaps were found. Reporting bias was unclear for five articles and other bias was unclear for six articles. The detailed quality evaluation results are shown in <a class="elsevierStyleCrossRef" href="#sec0135">Fig. A1 in appendix</a>.Effects on cardiovascular death and heart failure-related hospitalization ratesThere are three studies on the effects of SGLT2 inhibitors in combination with RAS blockers on cardiovascular outcomes. However, no significant heterogeneity was observed between these studies, and the analysis was performed using a fixed-effects model. The results showed that the combination of SGLT2 inhibitors and RAS blockers significantly reduced the incidence of cardiovascular death (RR=0.78, 95% CI: 0.66 to 0.91, p=0.002, <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 2</a>) and the heart failure-related hospitalization rate (RR=0.7, 95% CI: 0.61 to 0.8, p=0.000, <a class="elsevierStyleCrossRef" href="#fig0030">Fig. 2</a>) in CKD patients. These results suggest a protective role of SGLT2 inhibitors on cardiovascular outcomes and a significant cardiovascular benefit of using SGLT2 inhibitors with RAS blockers.<elsevierMultimedia ident="fig0030"></elsevierMultimedia>Effects on renal outcomesA total of 5 articles have reported the effects of SGLT2is in combination with RAS blockers on renal outcomes. The incidence of progression to end-stage renal disease (ESRD) in the intervention group is less than that in the control group (RR=0.69, 95% CI 0.59–0.81, p=0.000, <a class="elsevierStyleCrossRef" href="#fig0035">Fig. 3</a>). Pollock et al.<a class="elsevierStyleCrossRef" href="#bib0255">17</a> and Perkovic et al.<a class="elsevierStyleCrossRef" href="#bib0210">8</a> reported the effect of SGLT2is on creatinine elevation in the study subjects and found that the rate of creatinine elevation was significantly reduced in the SGLT2is group (RR=0.61, 95% CI: 0.51–0.74, p=0.000, <a class="elsevierStyleCrossRef" href="#fig0035">Fig. 3</a>).<elsevierMultimedia ident="fig0035"></elsevierMultimedia>There were 2 studies mentioned the effects of two medicines combination on 24hUAE and other 3 about the change of eGFR. And the results shown that the 24hUAE was significantly decreased after the intervention (WMD=−0.17, 95%CI −0.18 to −0.17, p=0.000, <a class="elsevierStyleCrossRef" href="#fig0040">Fig. 4</a>). Although it also decreased the estimated eGFR (WMD=−5.4, 95% CI: −7.24 to −3.57, p=0.000, <a class="elsevierStyleCrossRef" href="#fig0040">Fig. 4</a>), this effect was reversible.<elsevierMultimedia ident="fig0040"></elsevierMultimedia>Renal-related adverse events and renal death have also been reported in four pieces of literature. The results showed that there were no differences between the two groups in incidence of renal-related adverse events and renal death (RR=0.83, 95%CI 0.68–1.01, P=0.061; RR=0.36, 95%CI 0.12–1.14, p=0.083, <a class="elsevierStyleCrossRef" href="#fig0035">Fig. 3</a>).Effects on adverse eventsThe effect of SGLT2 is on the incidence of adverse events was reported in six studies, and there was no significant heterogeneity among them. We found that the incidence of gential infection was increased (RR=3.65, 95% CI 2.68–4.97, p=0.000, <a class="elsevierStyleCrossRef" href="#sec0135">Fig. A2 in appendix</a>). There were no significant changes in the incidence of hypoglycemia, fractures, urinary tract infection, or volume depletion (p=0.431, 0.573, 0.849 and 0.215, respectively, <a class="elsevierStyleCrossRef" href="#sec0135">Fig. A2 in appendix</a>).Effects on other parametersOnly one study mentioned changes in N-terminal-pro hormone B-type natriuretic peptide (NT-pro BNP), and the results were not statistically significant. Furthermore, no change in the heart rate or diastolic blood pressure was observed during treatment compared with the placebo.Reliability of cardiovascular outcomes resultOur results indicated that the RIS of cardiovascular outcomes was 6874 samples. The traditional boundary was the horizontal line at Z=1.96, which is considered to be the cut-off for statistical significance in the traditional sense. And TSA threshold value was the boundary line obtained by correcting for type I error (5%). Currently, the cumulative Z-curve have crossed the traditional boundary and TSA threshold value (<a class="elsevierStyleCrossRef" href="#sec0135">Fig. A3, A4 in appendix</a>), which suggested that the result of the effects on cardiovascular outcomes was reliability. What's more, the cumulative Z-curve also have crossed the RIS, indicating that the sample size was sufficient to account for the accuracy of the results obtained.DiscussionThis meta-analysis included clinical studies reporting on the effects of SGLT2 inhibitors on CKD patients treated in combination with background therapy with RAS blockers. The results proved that this treatment regimen could reduce the incidence of cardiovascular death and heart failure-related hospitalizations in CKD patients with or without diabetes while reducing the 24hUAE and delaying progression to ESRD. Although eGFR decreased during treatment, it was reversible after treatment discontinuation. Furthermore, on combining the two medicines, except for the increase in genital infections, the incidence of other adverse effects such as renal adverse effects and urinary tract infections did not increase significantly. Therefore, we reasonably deduced that the combined use of these agents could help improve the cardiovascular and renal prognosis in CKD patients. Furthermore, these data may help improve CKD-related guidelines, and benefit these patients.Cardiovascular events are a significant cause of death in patients with CKD, especially in diabetes patients with CKD.<a class="elsevierStyleCrossRef" href="#bib0285">23</a> Although RAS blockers are recommended as first-line treatment for CKD,<a class="elsevierStyleCrossRef" href="#bib0190">4</a> they insufficiently reduce cardiovascular events. A meta-analysis showed that SGLT2 inhibitors significantly reduced the incidence of cardiovascular events in diabetes patients,<a class="elsevierStyleCrossRefs" href="#bib0290">24,25</a> further, SGLT2 inhibitors have been recommended for use in diabetic diabetes patients with kidney diseases by the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease.<a class="elsevierStyleCrossRef" href="#bib0215">9</a> However, studies have suggested that the cardiovascular and renal benefits of SGLT2 inhibitors may be independent of its hypoglycemic effect.<a class="elsevierStyleCrossRef" href="#bib0300">26</a> Therefore, the combined use of SGLT2 inhibitors, and RAS blockers may have unprecedented efficacy in CKD patients, but there is not enough evidence supporting it. Our meta-analysis used RAS blockers as background treatment, focusing on patients with CKD, including diabetic nephropathy, immunoglobulin A nephropathy (IgAN), and focal segmental glomerulosclerosis (FSGS). Results showed that SGLT2 inhibitors combined with RAS blockers could also reduce cardiovascular mortality and heart failure-related hospitalization rates in CKD patients. The present meta-analysis filled the gaps in evidence and provided a basis for the combination of two medicines for CKD.In terms of renal outcomes, we also observed that the combined use of SGLT2 inhibitors and RAS blockers delayed progression to ESRD, decreased the 24hUAE and improved renal function; furthermore, the study population was not limited to diabetes patients with CKD. Furthermore, both DAPA-CKD and DIAMOND trails included IgAN and FSGS patients diagnosed with CKD. Although no subgroup analysis was conducted for these patients, the results can prove to a certain extent that SGLT2 inhibitors combined with RAS blockers have a good effect on IgAN and FSGS. Similarly, Hiddo et al.,<a class="elsevierStyleCrossRef" href="#bib0230">12</a> and Cherney et al.,<a class="elsevierStyleCrossRef" href="#bib0250">16</a> have reported that SGLT2 inhibitors delayed renal disease progression and reduced the risk of renal complex outcomes in CKD with or without diabetes.Several studies can explain the protective effect of this combination on the kidneys. SGLT2 inhibitors increase the excretion of sodium and glucose in the proximal tubules. Further, they lead to the vasoconstriction of renal inflow arterioles via glomerular feedback, relieve glomerular hyperperfusion and hyperfiltration, and play a renal protection effect.<a class="elsevierStyleCrossRef" href="#bib0305">27</a> Further, the addition of RAS blockers has a better effect on delaying renal disease progression, which may be associated with the diastolic effect of RAS on the glomerular arterioles of the kidney and the further reduction of renal pressure in the glomerulus.<a class="elsevierStyleCrossRef" href="#bib0310">28</a>It is noteworthy that the mechanisms of SGLT2 inhibitors and RAS blockers respective effects on the heart and kidney are synergistic in many ways. For example, they regulate blood pressure through neurological and humoral pathways, thereby improving the cardiovascular function.<a class="elsevierStyleCrossRefs" href="#bib0315">29,30</a> Furthermore, they are synergistic in reducing inflammatory and oxidative stress in the renal tissue.<a class="elsevierStyleCrossRefs" href="#bib0305">27,31–33</a> Previously, RAS blockers were thought to be the only drugs used to prevent renal failure in CKD patients.<a class="elsevierStyleCrossRef" href="#bib0335">33</a> Our study demonstrates that the combination of SGLT2 inhibitors and RAS blockers allows this effect to be superimposed and more effective. However, it should be noted that the baseline eGFRs of the subjects were>30ml/min/1.73m2, and the safety of SGLT2 inhibitors in CKD patients with eGFR<30ml/min/1.73m2 remains to be evaluated.Although SGLT2 inhibitors have cardiovascular and renal benefits when combined with RAS blockers, their safety profile needs to be considered. This meta-analysis showed that the incidence of genital infections increased after SGLT2 inhibitor intervention, and there was no significant difference in the incidence of hypoglycemia, fractures, and urinary tract infections between the two groups. Our results are generally consistent with previous studies.<a class="elsevierStyleCrossRefs" href="#bib0300">26,34</a> Therefore, based on the current results, the clinical use of SGLT2 inhibitors has a broad safety profile with few adverse effects.LimitationsFirst, two of the included studies used canagliflozin and four used dapagliflozin; this may cause some heterogeneity in the results because of the use of different medicines between studies. Second, fewer clinical indicators of renal function were included in this study, including only 24hUAE and eGFR. Third, we included CKD patients with eGFRs>30ml/min/1.73m2; accordingly, it is unclear whether the same results would be obtained in patients with eGFRs less than 30ml/min/1.73m2, and further clinical studies are needed to evalute this.ConclusionThese data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients.Authors’ contributionsTL, RL and XW contributed equally to this work. TL, RL and XW conceived and designed the study. RL and XW contributed to the literature search, data extraction, risk-of-bias assessment, and article writing. TL resolved the inconsistencies between reviewers. XW, RL and XG analyzed the data. TL and XZ were responsible for revision of this manuscript for important intellectual content. All authors read and approved the final manuscript.FundingThe meta-analysis research funding was supported by [International Cooperation of Shanxi Science and Technology] (Fund number: 201803D421063).Conflict of interestThere was no conflict of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:14 [ 0 => array:3 [ "identificador" => "xres1744714" "titulo" => "Abstract" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1537462" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres1744713" "titulo" => "Resumen" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1537461" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:6 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Search strategy" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion and exclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Literature screening and data extraction" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Quality assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical analysis" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Trials sequential analysis (TSA)" ] ] ] 6 => array:3 [ "identificador" => "sec0045" "titulo" => "Results" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Literature search" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Data extraction" ] 2 => array:3 [ "identificador" => "sec0060" "titulo" => "Quality assessment" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Effects on cardiovascular death and heart failure-related hospitalization rates" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Effects on renal outcomes" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Effects on adverse events" ] 3 => array:2 [ "identificador" => "sec0085" "titulo" => "Effects on other parameters" ] ] ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Reliability of cardiovascular outcomes result" ] ] ] 7 => array:2 [ "identificador" => "sec0095" "titulo" => "Discussion" ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Limitations" ] 9 => array:2 [ "identificador" => "sec0105" "titulo" => "Conclusion" ] 10 => array:2 [ "identificador" => "sec0110" "titulo" => "Authors’ contributions" ] 11 => array:2 [ "identificador" => "sec0115" "titulo" => "Funding" ] 12 => array:2 [ "identificador" => "sec0120" "titulo" => "Conflict of interest" ] 13 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2021-04-08" "fechaAceptado" => "2021-09-02" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1537462" "palabras" => array:5 [ 0 => "Sodium-glucose co-transporter 2 inhibitors" 1 => "RAS blockers" 2 => "Cardiovascular outcomes" 3 => "Chronic kidney disease" 4 => "Meta-analysis" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1537461" "palabras" => array:5 [ 0 => "Inhibidores del cotransportador de sodio-glucosa 2" 1 => "Bloqueadores del SRA" 2 => "Resultados cardiovasculares" 3 => "Enfermedad renal crónica" 4 => "Metaanálisis" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "Background and objectiveEfficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors in combination with renin–angiotensin-system (RAS) blockers for CKD remains controversial. We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease (CKD) patients. MethodsWe searched Embase, PubMed, Web of Science, and Cochrane Library databases with the following keywords.“Renal Insufficiency, Chronic” or “Diabetic Nephropathies” and “Sodium-glucose cotransporter 2 inhibitors”. We included randomized controlled trials (RCTs) based on angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. The outcome events included cardiac and renal outcomes and other adverse events. This study is registered with PROSPERO: CRD42020218337. ResultsTen RCTs including 16,983 CKD patients met the inclusion criteria. Compared with placebo plus RAS blockers, SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates (RR=0.78, 95% CI: 0.66–0.91, p=0.002; RR=0.7, 95% CI: 0.61–0.8, p=0.000). We also performed trials sequential analysis (TSA) and the results indicated that our results are reliable. Additionally, it significantly reduced the 24-h urinary albumin excretion rate (24hUAE) and the creatinine elevation rate (WMD=−0.19, 95% CI: −0.24 to −0.14; RR=0.61, 95% CI: 0.51–0.74, p=0.000), delayed progression to end-stage renal disease (ESRD) (RR=0.69, 95% CI: 0.59–0.81, p=0.000). Further, it had no significant effect on the incidence of renal-related adverse events or renal-related mortality. Although it decreased the estimated glomerular filtration rate (eGFR) (WMD=−5.4, 95% CI: −7.24 to −3.57), this effect was reversible. ConclusionsThese data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0005" "titulo" => "Background and objective" ] 1 => array:2 [ "identificador" => "abst0010" "titulo" => "Methods" ] 2 => array:2 [ "identificador" => "abst0015" "titulo" => "Results" ] 3 => array:2 [ "identificador" => "abst0020" "titulo" => "Conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "Antecedentes y objetivosLa eficacia de los inhibidores del cotransportador de sodio-glucosa 2 (SGLT2) en combinación con los bloqueadores del sistema renina-angiotensina (SRA) para la enfermedad renal crónica (ERC) sigue siendo controvertida. Se realizó este metaanálisis para explorar el efecto de los inhibidores del SGLT2 en combinación con los bloqueadores del SRA sobre los resultados cardiovasculares en los pacientes con ERC. MétodosSe realizaron búsquedas en las bases de datos Embase, PubMed, Web of Science y Cochrane Library con las siguientes palabras clave: «Renal Insufficiency, Chronic» o «Diabetic Nephropathies» y «Sodium-glucose cotransporter 2 inhibitors». Se incluyeron ensayos controlados aleatorios (ECA) basados en el tratamiento con inhibidores de la enzima convertidora de angiotensina (IECA) o bloqueadores de los receptores de la angiotensina II (BRA). Los eventos de resultado incluyeron resultados cardíacos y renales y otros eventos adversos. Este estudio está registrado en PROSPERO: CRD42020218337. ResultadosDiez ECA que incluían 16.983 pacientes con ERC cumplieron los criterios de inclusión. En comparación con el placebo más bloqueadores del SRA, los inhibidores de SGLT2 más bloqueadores del SRA redujeron significativamente la mortalidad cardiovascular y las tasas de hospitalización relacionadas con la insuficiencia cardíaca (RR=0,78; IC del 95%: 0,66 a 0,91; p=0,002; RR=0,7; IC del 95%: 0,61 a 0,8; p=0,000). También se realizó un análisis secuencial de ensayos (TSA) y los resultados indicaron que nuestros resultados son fiables. Además, redujo significativamente la tasa de excreción urinaria de albúmina en 24h (24h UAE) y la tasa de elevación de creatinina (DMP=−0,19; IC del 95%: −0,24 a −0,14; RR=0,61; IC del 95%: 0,51 a 0,74; p=0,000), retrasó la progresión a la enfermedad renal terminal (ESRD) (RR=0,69; IC del 95%: 0,59 a 0,81; p=0,000). Además, no tuvo un efecto significativo sobre la incidencia de eventos adversos relacionados con el riñón o la mortalidad relacionada con el riñón. Aunque disminuyó la tasa de filtración glomerular estimada (TFGe) (DMP=−5,4; IC del 95%: −7,24 a −3,57), este efecto fue reversible. ConclusionesEstos datos proporcionan un testimonio bien documentado de los beneficios del uso combinado de inhibidores de SGLT2 y bloqueadores del SRA para los resultados cardiovasculares y renales en pacientes con ERC." "secciones" => array:4 [ 0 => array:2 [ "identificador" => "abst0025" "titulo" => "Antecedentes y objetivos" ] 1 => array:2 [ "identificador" => "abst0030" "titulo" => "Métodos" ] 2 => array:2 [ "identificador" => "abst0035" "titulo" => "Resultados" ] 3 => array:2 [ "identificador" => "abst0040" "titulo" => "Conclusiones" ] ] ] ] "NotaPie" => array:1 [ 0 => array:3 [ "etiqueta" => "1" "nota" => "Ting Liu, Rui Li and Xiaoxia Wang contributed equally to this paper." "identificador" => "fn0005" ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><elsevierMultimedia ident="fig0020"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0135" ] ] ] ] "multimedia" => array:9 [ 0 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2737 "Ancho" => 2925 "Tamanyo" => 419315 ] ] "descripcion" => array:1 [ "en" => "Flow diagram of study screening." ] ] 1 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1549 "Ancho" => 2083 "Tamanyo" => 173990 ] ] "descripcion" => array:1 [ "en" => "Forest plot of meta-analyses comparing cardiovascular death and heart failure hospitalization rates of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo." ] ] 2 => array:7 [ "identificador" => "fig0035" "etiqueta" => "Fig. 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1860 "Ancho" => 2175 "Tamanyo" => 244414 ] ] "descripcion" => array:1 [ "en" => "Forest plot of meta-analyses comparing renal outcomes of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo." ] ] 3 => array:7 [ "identificador" => "fig0040" "etiqueta" => "Fig. 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1614 "Ancho" => 2175 "Tamanyo" => 175853 ] ] "descripcion" => array:1 [ "en" => "Forest plot of meta-analyses comparing 24hUAE and eGFR of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo." ] ] 4 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Study \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Female \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Mean age (years) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Mean aseline eGFR (ml/min/1.73m2) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Sample size \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Interventions \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Follow-up \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention Concorl \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention Concorl \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Heerspink<a class="elsevierStyleCrossRef" href="#bib0230">12</a> 2020 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">With or without type 2 diabetes, GFR of 25–75ml/min/1.73m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1425 (33.1%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61.8±12.1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">43.2±12.343.0±12.4 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">21522152 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dapagliflozin (10mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.4 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cherney<a class="elsevierStyleCrossRef" href="#bib0250">16</a> 2020 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">CKD 24h urinary protein excretion 500–3500mg and eGFR >25mL/min per 1.73m2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">17 (32%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">51±13 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">57.8 (25.5)58.9 (20.7) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2627 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dapagliflozin (10mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Pollock<a class="elsevierStyleCrossRef" href="#bib0255">17</a> 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes and moderate to severe chronic kidney disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">86 (59%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64.7 (8.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50.2 (13.0)47.7 (13.5) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">145148 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dapagliflozin (10mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Perkovic<a class="elsevierStyleCrossRef" href="#bib0210">8</a> 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes with chronic kidney disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1494 (33.9) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">63.0±9.2 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56.3±18.256.0±18.3 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">22022199 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">canagliflozin (100mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2.62 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Triantafylidis<a class="elsevierStyleCrossRef" href="#bib0260">18</a> 2019 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Diabetic kidney disease albumin:creatinine ratio>300mg/g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">0 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">67 ±8 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">56±21 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1414 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">empagliflozin (10mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wanner<a class="elsevierStyleCrossRef" href="#bib0215">9</a> 2018 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes with nephropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2004 (28.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46852333 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">empagliflozin (10/25mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Petrykiv<a class="elsevierStyleCrossRef" href="#bib0265">19</a> 2017 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes and albumin:creatinine ratio>100mg/g \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">8 (24.2) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61±9 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">72 (21) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">33 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">dapagliflozin (10mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">6 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Wanner<a class="elsevierStyleCrossRef" href="#bib0270">20</a> 2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes with nephropathy \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2004 (28.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46852333 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">empagliflozin (10/25mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 years \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">David Cherney<a class="elsevierStyleCrossRef" href="#bib0275">21</a> 2016 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes with microalbuminuria and ma croalbuminuria \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">337 (39.6%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">516335 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">empagliflozin (10/25mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 weeks \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Zinman<a class="elsevierStyleCrossRef" href="#bib0280">22</a> 2015 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 2 diabetes with kidney disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">2004 (28.5%) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46872333 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">empagliflozin (10/25mg/d) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">3 years \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "Basic characteristic of included study." ] ] 5 => array:5 [ "identificador" => "fig0005" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc1.jpeg" "Alto" => 1672 "Ancho" => 2167 "Tamanyo" => 248903 ] ] ] 6 => array:5 [ "identificador" => "fig0010" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc2.jpeg" "Alto" => 2409 "Ancho" => 2333 "Tamanyo" => 449824 ] ] ] 7 => array:5 [ "identificador" => "fig0015" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc3.jpeg" "Alto" => 1766 "Ancho" => 2175 "Tamanyo" => 166871 ] ] ] 8 => array:5 [ "identificador" => "fig0020" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "mmc4.jpeg" "Alto" => 1783 "Ancho" => 2175 "Tamanyo" => 174795 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:34 [ 0 => array:3 [ "identificador" => "bib0175" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Chronic kidney disease: global dimension and perspectives" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "V. 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Benefits of SGLT2 inhibitors combining with renin–angiotensin-system blockers on cardiovascular outcomes in chronic kidney disease patients: A systemic review and meta-analysis

Beneficios de los inhibidores de SGLT2 combinados con bloqueadores del sistema renina-angiotensina en los resultados cardiovasculares de los pacientes con enfermedad renal crónica: una revisión sistémica y un metaanálisis

Ting Liua,1, Rui Lib,1, Xiaoxia Wangb,1, Xingxing Gaob, Xiaodong Zhanga,

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zxdspl@163.com

Corresponding author.

a Department of Nephrology, The First Hospital of Shanxi Medical University, Taiyuan, China

b Shanxi Medical University, Taiyuan, China

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Chronic kidney disease &#40;CKD&#41; affects 8&#8211;16&#37; of the global population and is associated with a high morbidity and mortality rates&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">1</span></a> CKD has also been found to play a crucial role in the development of other diseases&#44; and in all-cause and cardiovascular mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> The risk of such a death increases exponentially as kidney function deteriorates&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">3</span></a> Therefore&#44; it is important to prevent CKD progression&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Renin&#8211;angiotensin-system &#40;RAS&#41; blockers have been shown to be cardioprotective because of their antihypertensive and proteinuric effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">4&#44;5</span></a> Therefore&#44; clinical practice guidelines recommend using RAS blockers for treating CKD or diabetic nephropathy&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">2</span></a> However&#44; the risk of disease progression in CKD patients remains high even after the use of RAS blockers&#44; and clinicians look forward to new therapeutic approaches&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Sodium-glucose cotransporter-2 &#40;SGLT2&#41; inhibitors are a new class of antidiabetic drugs&#44; which inhibit the reabsorption of glucose in the proximal tubules of the kidney&#44; thus exerting a hypoglycemic effect&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">6&#44;7</span></a> Several large randomized controlled trials &#40;RCTs&#41;&#44; such as CREDENCE<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> and EMPA-REG&#44;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> have confirmed the cardiorenal protective effect of SGLT2 inhibitors&#44; especially in diabetes patients with CKD&#46; Furthermore&#44; the 2020 KDIGO guidelines recommend using SGLT2 inhibitors in CKD patients who have diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">10</span></a> An increasing number of studies have suggested that the renoprotective effect of SGLT2 inhibitors may be independent of their hypoglycemic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">11</span></a> The latest results of DAPA-CKD are exciting and provide evidence for the benefits of using SGLT2 inhibitors for the treatment of CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> Studies have demonstrated that both SGLT2 inhibitors and RAS blockers can reduce glomerular hyperfiltration&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">13</span></a> and we found that RAS blockers are often used as background therapy in some RCTs reporting on SGLT2 inhibitors therapy for CKD&#46; Thus&#44; it is necessary to explore the significance of this combination for CKD treatment&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Methods</span><p id="par0020" class="elsevierStylePara elsevierViewall">This study was pre-registered on PROSPERO &#40;CRD42020218337&#41; and conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis statement &#40;PRISMA&#41;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">14</span></a> and MOOSE&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">15</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Search strategy</span><p id="par0025" class="elsevierStylePara elsevierViewall">We searched Embase&#44; PubMed&#44; Web of Science and Cochrane Library using a combination of subject terms and free words&#46; The search terms included &#8220;renal insufficiency&#44; chronic kidney insufficiency&#44; sodium-glucose co-transporter 2 inhibitors&#44; sodium glucose transporter 2 inhibitors&#44; canagliflozin&#44; empagliflozin&#44; dapagliflozin&#44; tofogliflozin&#44; ipragliflozin&#44; luseogliflozin&#8221;&#44;and the search was conducted from the time the database was established to December 2020&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Inclusion and exclusion criteria</span><p id="par0030" class="elsevierStylePara elsevierViewall">Inclusion criteria&#58; &#40;1&#41; age<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>18 years and a precise diagnosis of CKD with eGFR<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; with or without diabetes&#59; &#40;2&#41; intervention group treated with SGLT2 inhibitors and the control group treated with placebo&#59; with both groups being treated with RAS blockers as background therapy&#59; &#40;3&#41; study outcome measures including the impact on renal and cardiovascular outcomes&#44; 24-h urinary albumin excretion rate &#40;24hUAE&#41;&#44; and estimated glomerular filtration rate &#40;eGFR&#41;&#59; and &#40;4&#41; RCTs&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">Exclusion criteria&#58; &#40;1&#41; study types such as reviews&#44; conference abstracts&#44; incomplete end indicators&#44; and unpublished articles&#59; &#40;2&#41; the intervention or control group not treated with RAS blockers as background therapy or the study subjects not receiving complete RAS blocker background therapy&#59; and &#40;3&#41; previous severe heart or kidney disease in the subjects &#40;eGFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; severe heart failure&#44; angina&#44; myocardial infarction or stroke occurring within 6 months before enrollment in the trial&#41;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Literature screening and data extraction</span><p id="par0040" class="elsevierStylePara elsevierViewall">The retrieved literature was first deduplicated using the EndNote software and then manually deduplicated&#46; After excluding duplicates&#44; we browsed the titles and abstracts to exclude irrelevant literature&#59; subsequently&#44; we scanned full texts to determine the final inclusion according to the inclusion and exclusion criteria&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">We read the final included literature and extracted the following primary data&#58; first author&#44; year&#44; study population&#44; gender composition&#44; mean age&#44; GFR&#44; sample size&#44; and intervention and follow-up duration&#46; The processes were independently performed by two researchers&#44; and any disputes arising during the process were coordinated and resolved by a third researcher&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Quality assessment</span><p id="par0050" class="elsevierStylePara elsevierViewall">The final included literature was evaluated for quality using the Cochrane Collaboration &#8220;risk of bias&#8221; assessment tool&#46; The evaluation items included the following&#58; &#40;1&#41; random sequences generation&#59; &#40;2&#41; allocation concealment&#59; &#40;3&#41; blinding of participants and personnel&#59; &#40;4&#41; blinding of outcome assessment&#59; &#40;5&#41; incomplete outcome data&#59; &#40;6&#41; selective reporting&#59; and &#40;7&#41; other bias&#46; Each assessment item was classified as high risk&#44; low risk&#44; or unclear&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Statistical analysis</span><p id="par0055" class="elsevierStylePara elsevierViewall">We statistically analyzed the data using the metan command in Stata software 14&#46;0&#44; and calculated the study outcome measures using the inverse variance method&#46; Continuous variables were expressed as weighted mean differences &#40;WMDs&#41; or standardized mean differences &#40;SMDs&#41; and 95&#37; confidence interval &#40;95&#37; CI&#41;&#46; Dichotomous variables were expressed as relative risk &#40;RR&#41; and 95&#37; CI&#44; and inter-study heterogeneity was expressed as <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> and <span class="elsevierStyleItalic">p</span> values&#46; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>50&#37; or <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;1 indicated evident heterogeneity between studies&#44; and the random-effects model was used and further subgroup analysis was conducted to find the source of heterogeneity&#59; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>50&#37; or <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>0&#46;1 indicated that the heterogeneity between studies is acceptable&#44; and the fixed-effects model was used for analysis in this case&#46; The combined effect measure was statistically significant at <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#46;05&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Trials sequential analysis &#40;TSA&#41;</span><p id="par0060" class="elsevierStylePara elsevierViewall">In a small sample trial&#44; interim analyses cause false positive or false negative results&#44; implying an increased risk of type I errors or type II errors&#46; In particular&#44; in a meta-analysis that included small samples of trials&#44; the rate of random error is more significant&#46; Therefore&#44; to avoid an increase of random error&#44; we performed the TSA by TSA software to estimate the minimum sample size required to obtain the outcomes of statistical significance for the intervention and control group &#40;<a href="https://www.ctu.dk/tsa">https&#58;&#47;&#47;www&#46;ctu&#46;dk&#47;tsa</a>&#41;&#46; We set the risk of type I error at an overall 5&#37;&#44; being the standard in most meta-analyses&#44; to obtain the traditional boundary and the TSA threshold value&#46; Then we calculated the required information size &#40;RIS&#41;&#44; meaning the minimum sample size needed to detect the intervention effect of a 25&#37; relative risk reduction&#44; at a power of 80&#37;&#46;</p></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Results</span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Literature search</span><p id="par0065" class="elsevierStylePara elsevierViewall">A total of 962 articles were retrieved&#44; and 833 articles remained after removing duplicates&#59; 753 irrelevant articles were removed after the title and abstract browsing&#46; After full-text reading of the remaining papers&#44; 9 meeting abstracts&#44; 2 incomplete outcome data&#44; 42 papers without background treatment with RAS blockers&#44; and 5 non-randomized controlled trials were excluded according to inclusion and exclusion criteria&#44; resulting in the inclusion of 10 papers that met the criteria&#46; The detailed literature screening process is shown in <a class="elsevierStyleCrossRef" href="#fig0025">Fig&#46; 1</a>&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Data extraction</span><p id="par0070" class="elsevierStylePara elsevierViewall">The 10 articles included are RCTs published from 2015 to 2020&#46; Both intervention and control groups were treated with RAS blockers as background&#44; and different types and doses of SGLT2is were used in the intervention group&#44; while the same dose of placebo was used in the control group&#46; Other necessary characteristics of the included literature are shown in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Quality assessment</span><p id="par0075" class="elsevierStylePara elsevierViewall">Of the ten articles included&#44; only three did not explicitly account for random sequence generation and the remaining papers were low risk&#46; Three articles had high risk of selection bias and one was not mentioned&#46; For the double-blind experimental design&#44; only one paper did not use blinding&#44; and the rest of the literature described the double-blind design&#46; The outcome data from the six papers were all relatively complete and no significant gaps were found&#46; Reporting bias was unclear for five articles and other bias was unclear for six articles&#46; The detailed quality evaluation results are shown in <a class="elsevierStyleCrossRef" href="#sec0135">Fig&#46; A1 in appendix</a>&#46;</p><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Effects on cardiovascular death and heart failure-related hospitalization rates</span><p id="par0080" class="elsevierStylePara elsevierViewall">There are three studies on the effects of SGLT2 inhibitors in combination with RAS blockers on cardiovascular outcomes&#46; However&#44; no significant heterogeneity was observed between these studies&#44; and the analysis was performed using a fixed-effects model&#46; The results showed that the combination of SGLT2 inhibitors and RAS blockers significantly reduced the incidence of cardiovascular death &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;78&#44; 95&#37; CI&#58; 0&#46;66 to 0&#46;91&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#44; <a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 2</a>&#41; and the heart failure-related hospitalization rate &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;7&#44; 95&#37; CI&#58; 0&#46;61 to 0&#46;8&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#fig0030">Fig&#46; 2</a>&#41; in CKD patients&#46; These results suggest a protective role of SGLT2 inhibitors on cardiovascular outcomes and a significant cardiovascular benefit of using SGLT2 inhibitors with RAS blockers&#46;</p><elsevierMultimedia ident="fig0030"></elsevierMultimedia></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Effects on renal outcomes</span><p id="par0085" class="elsevierStylePara elsevierViewall">A total of 5 articles have reported the effects of SGLT2is in combination with RAS blockers on renal outcomes&#46; The incidence of progression to end-stage renal disease &#40;ESRD&#41; in the intervention group is less than that in the control group &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;69&#44; 95&#37; CI 0&#46;59&#8211;0&#46;81&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 3</a>&#41;&#46; Pollock et al&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> and Perkovic et al&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> reported the effect of SGLT2is on creatinine elevation in the study subjects and found that the rate of creatinine elevation was significantly reduced in the SGLT2is group &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; 95&#37; CI&#58; 0&#46;51&#8211;0&#46;74&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0035"></elsevierMultimedia><p id="par0090" class="elsevierStylePara elsevierViewall">There were 2 studies mentioned the effects of two medicines combination on 24hUAE and other 3 about the change of eGFR&#46; And the results shown that the 24hUAE was significantly decreased after the intervention &#40;WMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;17&#44; 95&#37;CI &#8722;0&#46;18 to &#8722;0&#46;17&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 4</a>&#41;&#46; Although it also decreased the estimated eGFR &#40;WMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;5&#46;4&#44; 95&#37; CI&#58; &#8722;7&#46;24 to &#8722;3&#46;57&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#fig0040">Fig&#46; 4</a>&#41;&#44; this effect was reversible&#46;</p><elsevierMultimedia ident="fig0040"></elsevierMultimedia><p id="par0095" class="elsevierStylePara elsevierViewall">Renal-related adverse events and renal death have also been reported in four pieces of literature&#46; The results showed that there were no differences between the two groups in incidence of renal-related adverse events and renal death &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;83&#44; 95&#37;CI 0&#46;68&#8211;1&#46;01&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;061&#59; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;36&#44; 95&#37;CI 0&#46;12&#8211;1&#46;14&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;083&#44; <a class="elsevierStyleCrossRef" href="#fig0035">Fig&#46; 3</a>&#41;&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Effects on adverse events</span><p id="par0100" class="elsevierStylePara elsevierViewall">The effect of SGLT2 is on the incidence of adverse events was reported in six studies&#44; and there was no significant heterogeneity among them&#46; We found that the incidence of gential infection was increased &#40;RR&#61;3&#46;65&#44; 95&#37; CI 2&#46;68&#8211;4&#46;97&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#44; <a class="elsevierStyleCrossRef" href="#sec0135">Fig&#46; A2 in appendix</a>&#41;&#46; There were no significant changes in the incidence of hypoglycemia&#44; fractures&#44; urinary tract infection&#44; or volume depletion &#40;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;431&#44; 0&#46;573&#44; 0&#46;849 and 0&#46;215&#44; respectively&#44; <a class="elsevierStyleCrossRef" href="#sec0135">Fig&#46; A2 in appendix</a>&#41;&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Effects on other parameters</span><p id="par0105" class="elsevierStylePara elsevierViewall">Only one study mentioned changes in N-terminal-pro hormone B-type natriuretic peptide &#40;NT-pro BNP&#41;&#44; and the results were not statistically significant&#46; Furthermore&#44; no change in the heart rate or diastolic blood pressure was observed during treatment compared with the placebo&#46;</p></span></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Reliability of cardiovascular outcomes result</span><p id="par0110" class="elsevierStylePara elsevierViewall">Our results indicated that the RIS of cardiovascular outcomes was 6874 samples&#46; The traditional boundary was the horizontal line at <span class="elsevierStyleItalic">Z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46;96&#44; which is considered to be the cut-off for statistical significance in the traditional sense&#46; And TSA threshold value was the boundary line obtained by correcting for type I error &#40;5&#37;&#41;&#46; Currently&#44; the cumulative <span class="elsevierStyleItalic">Z</span>-curve have crossed the traditional boundary and TSA threshold value &#40;<a class="elsevierStyleCrossRef" href="#sec0135">Fig&#46; A3&#44; A4 in appendix</a>&#41;&#44; which suggested that the result of the effects on cardiovascular outcomes was reliability&#46; What&#39;s more&#44; the cumulative <span class="elsevierStyleItalic">Z</span>-curve also have crossed the RIS&#44; indicating that the sample size was sufficient to account for the accuracy of the results obtained&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Discussion</span><p id="par0115" class="elsevierStylePara elsevierViewall">This meta-analysis included clinical studies reporting on the effects of SGLT2 inhibitors on CKD patients treated in combination with background therapy with RAS blockers&#46; The results proved that this treatment regimen could reduce the incidence of cardiovascular death and heart failure-related hospitalizations in CKD patients with or without diabetes while reducing the 24hUAE and delaying progression to ESRD&#46; Although eGFR decreased during treatment&#44; it was reversible after treatment discontinuation&#46; Furthermore&#44; on combining the two medicines&#44; except for the increase in genital infections&#44; the incidence of other adverse effects such as renal adverse effects and urinary tract infections did not increase significantly&#46; Therefore&#44; we reasonably deduced that the combined use of these agents could help improve the cardiovascular and renal prognosis in CKD patients&#46; Furthermore&#44; these data may help improve CKD-related guidelines&#44; and benefit these patients&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">Cardiovascular events are a significant cause of death in patients with CKD&#44; especially in diabetes patients with CKD&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">23</span></a> Although RAS blockers are recommended as first-line treatment for CKD&#44;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">4</span></a> they insufficiently reduce cardiovascular events&#46; A meta-analysis showed that SGLT2 inhibitors significantly reduced the incidence of cardiovascular events in diabetes patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">24&#44;25</span></a> further&#44; SGLT2 inhibitors have been recommended for use in diabetic diabetes patients with kidney diseases by the KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease&#46;<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> However&#44; studies have suggested that the cardiovascular and renal benefits of SGLT2 inhibitors may be independent of its hypoglycemic effect&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">26</span></a> Therefore&#44; the combined use of SGLT2 inhibitors&#44; and RAS blockers may have unprecedented efficacy in CKD patients&#44; but there is not enough evidence supporting it&#46; Our meta-analysis used RAS blockers as background treatment&#44; focusing on patients with CKD&#44; including diabetic nephropathy&#44; immunoglobulin A nephropathy &#40;IgAN&#41;&#44; and focal segmental glomerulosclerosis &#40;FSGS&#41;&#46; Results showed that SGLT2 inhibitors combined with RAS blockers could also reduce cardiovascular mortality and heart failure-related hospitalization rates in CKD patients&#46; The present meta-analysis filled the gaps in evidence and provided a basis for the combination of two medicines for CKD&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">In terms of renal outcomes&#44; we also observed that the combined use of SGLT2 inhibitors and RAS blockers delayed progression to ESRD&#44; decreased the 24hUAE and improved renal function&#59; furthermore&#44; the study population was not limited to diabetes patients with CKD&#46; Furthermore&#44; both DAPA-CKD and DIAMOND trails included IgAN and FSGS patients diagnosed with CKD&#46; Although no subgroup analysis was conducted for these patients&#44; the results can prove to a certain extent that SGLT2 inhibitors combined with RAS blockers have a good effect on IgAN and FSGS&#46; Similarly&#44; Hiddo et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> and Cherney et al&#46;&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> have reported that SGLT2 inhibitors delayed renal disease progression and reduced the risk of renal complex outcomes in CKD with or without diabetes&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Several studies can explain the protective effect of this combination on the kidneys&#46; SGLT2 inhibitors increase the excretion of sodium and glucose in the proximal tubules&#46; Further&#44; they lead to the vasoconstriction of renal inflow arterioles via glomerular feedback&#44; relieve glomerular hyperperfusion and hyperfiltration&#44; and play a renal protection effect&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">27</span></a> Further&#44; the addition of RAS blockers has a better effect on delaying renal disease progression&#44; which may be associated with the diastolic effect of RAS on the glomerular arterioles of the kidney and the further reduction of renal pressure in the glomerulus&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">28</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">It is noteworthy that the mechanisms of SGLT2 inhibitors and RAS blockers respective effects on the heart and kidney are synergistic in many ways&#46; For example&#44; they regulate blood pressure through neurological and humoral pathways&#44; thereby improving the cardiovascular function&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">29&#44;30</span></a> Furthermore&#44; they are synergistic in reducing inflammatory and oxidative stress in the renal tissue&#46;<a class="elsevierStyleCrossRefs" href="#bib0305"><span class="elsevierStyleSup">27&#44;31&#8211;33</span></a> Previously&#44; RAS blockers were thought to be the only drugs used to prevent renal failure in CKD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">33</span></a> Our study demonstrates that the combination of SGLT2 inhibitors and RAS blockers allows this effect to be superimposed and more effective&#46; However&#44; it should be noted that the baseline eGFRs of the subjects were<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; and the safety of SGLT2 inhibitors in CKD patients with eGFR<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span> remains to be evaluated&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">Although SGLT2 inhibitors have cardiovascular and renal benefits when combined with RAS blockers&#44; their safety profile needs to be considered&#46; This meta-analysis showed that the incidence of genital infections increased after SGLT2 inhibitor intervention&#44; and there was no significant difference in the incidence of hypoglycemia&#44; fractures&#44; and urinary tract infections between the two groups&#46; Our results are generally consistent with previous studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">26&#44;34</span></a> Therefore&#44; based on the current results&#44; the clinical use of SGLT2 inhibitors has a broad safety profile with few adverse effects&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Limitations</span><p id="par0145" class="elsevierStylePara elsevierViewall">First&#44; two of the included studies used canagliflozin and four used dapagliflozin&#59; this may cause some heterogeneity in the results because of the use of different medicines between studies&#46; Second&#44; fewer clinical indicators of renal function were included in this study&#44; including only 24hUAE and eGFR&#46; Third&#44; we included CKD patients with eGFRs<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#59; accordingly&#44; it is unclear whether the same results would be obtained in patients with eGFRs less than 30<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#44; and further clinical studies are needed to evalute this&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conclusion</span><p id="par0150" class="elsevierStylePara elsevierViewall">These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Authors&#8217; contributions</span><p id="par0155" class="elsevierStylePara elsevierViewall">TL&#44; RL and XW contributed equally to this work&#46; TL&#44; RL and XW conceived and designed the study&#46; RL and XW contributed to the literature search&#44; data extraction&#44; risk-of-bias assessment&#44; and article writing&#46; TL resolved the inconsistencies between reviewers&#46; XW&#44; RL and XG analyzed the data&#46; TL and XZ were responsible for revision of this manuscript for important intellectual content&#46; All authors read and approved the final manuscript&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Funding</span><p id="par0160" class="elsevierStylePara elsevierViewall">The meta-analysis research funding was supported by &#91;<span class="elsevierStyleGrantSponsor" id="gs1">International Cooperation of Shanxi Science and Technology</span>&#93; &#40;Fund number&#58; <span class="elsevierStyleGrantNumber" refid="gs1">201803D421063</span>&#41;&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Conflict of interest</span><p id="par0165" class="elsevierStylePara elsevierViewall">There was no conflict of interest&#46;</p></span></span>"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Background and objective</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Efficacy of sodium-glucose cotransporter 2 &#40;SGLT2&#41; inhibitors in combination with renin&#8211;angiotensin-system &#40;RAS&#41; blockers for CKD remains controversial&#46; We conducted this meta-analysis to explore the effect of SGLT2 inhibitors combining with RAS blockers on cardiovascular outcomes in chronic kidney disease &#40;CKD&#41; patients&#46;</p></span> <span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Methods</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">We searched Embase&#44; PubMed&#44; Web of Science&#44; and Cochrane Library databases with the following keywords&#46;</p><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">&#8220;Renal Insufficiency&#44; Chronic&#8221; or &#8220;Diabetic Nephropathies&#8221; and &#8220;Sodium-glucose cotransporter 2 inhibitors&#8221;&#46; We included randomized controlled trials &#40;RCTs&#41; based on angiotensin-converting enzyme inhibitor &#40;ACEI&#41; or angiotensin II receptor blocker &#40;ARB&#41; therapy&#46; The outcome events included cardiac and renal outcomes and other adverse events&#46; This study is registered with PROSPERO&#58; CRD42020218337&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Results</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Ten RCTs including 16&#44;983 CKD patients met the inclusion criteria&#46; Compared with placebo plus RAS blockers&#44; SGLT2 inhibitors plus RAS blockers significantly reduced cardiovascular mortality and heart failure-related hospitalization rates &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;78&#44; 95&#37; CI&#58; 0&#46;66&#8211;0&#46;91&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;002&#59; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;7&#44; 95&#37; CI&#58; 0&#46;61&#8211;0&#46;8&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#41;&#46; We also performed trials sequential analysis &#40;TSA&#41; and the results indicated that our results are reliable&#46; Additionally&#44; it significantly reduced the 24-h urinary albumin excretion rate &#40;24hUAE&#41; and the creatinine elevation rate &#40;WMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#46;19&#44; 95&#37; CI&#58; &#8722;0&#46;24 to &#8722;0&#46;14&#59; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;61&#44; 95&#37; CI&#58; 0&#46;51&#8211;0&#46;74&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#41;&#44; delayed progression to end-stage renal disease &#40;ESRD&#41; &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;69&#44; 95&#37; CI&#58; 0&#46;59&#8211;0&#46;81&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;000&#41;&#46; Further&#44; it had no significant effect on the incidence of renal-related adverse events or renal-related mortality&#46; Although it decreased the estimated glomerular filtration rate &#40;eGFR&#41; &#40;WMD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;5&#46;4&#44; 95&#37; CI&#58; &#8722;7&#46;24 to &#8722;3&#46;57&#41;&#44; this effect was reversible&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Conclusions</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">These data provide a well-document testimonial of the benefits of the combined use of SGLT2 inhibitors and RAS blockers for cardiovascular and renal outcomes in CKD patients&#46;</p></span>"
        "secciones" => array:4 [
          0 => array:2 [
            "identificador" => "abst0005"
            "titulo" => "Background and objective"
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          1 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Methods"
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          2 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Results"
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            "identificador" => "abst0020"
            "titulo" => "Conclusions"
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      "es" => array:3 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Antecedentes y objetivos</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">La eficacia de los inhibidores del cotransportador de sodio-glucosa 2 &#40;SGLT2&#41; en combinaci&#243;n con los bloqueadores del sistema renina-angiotensina &#40;SRA&#41; para la enfermedad renal cr&#243;nica &#40;ERC&#41; sigue siendo controvertida&#46; Se realiz&#243; este metaan&#225;lisis para explorar el efecto de los inhibidores del SGLT2 en combinaci&#243;n con los bloqueadores del SRA sobre los resultados cardiovasculares en los pacientes con ERC&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">M&#233;todos</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Se realizaron b&#250;squedas en las bases de datos Embase&#44; PubMed&#44; Web of Science y Cochrane Library con las siguientes palabras clave&#58; &#171;Renal Insufficiency&#44; Chronic&#187; o &#171;Diabetic Nephropathies&#187; y &#171;Sodium-glucose cotransporter 2 inhibitors&#187;&#46; Se incluyeron ensayos controlados aleatorios &#40;ECA&#41; basados en el tratamiento con inhibidores de la enzima convertidora de angiotensina &#40;IECA&#41; o bloqueadores de los receptores de la angiotensina II &#40;BRA&#41;&#46; Los eventos de resultado incluyeron resultados card&#237;acos y renales y otros eventos adversos&#46; Este estudio est&#225; registrado en PROSPERO&#58; CRD42020218337&#46;</p></span> <span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Resultados</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Diez ECA que inclu&#237;an 16&#46;983 pacientes con ERC cumplieron los criterios de inclusi&#243;n&#46; En comparaci&#243;n con el placebo m&#225;s bloqueadores del SRA&#44; los inhibidores de SGLT2 m&#225;s bloqueadores del SRA redujeron significativamente la mortalidad cardiovascular y las tasas de hospitalizaci&#243;n relacionadas con la insuficiencia card&#237;aca &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;78&#59; IC del 95&#37;&#58; 0&#44;66 a 0&#44;91&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;002&#59; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;7&#59; IC del 95&#37;&#58; 0&#44;61 a 0&#44;8&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;000&#41;&#46; Tambi&#233;n se realiz&#243; un an&#225;lisis secuencial de ensayos &#40;TSA&#41; y los resultados indicaron que nuestros resultados son fiables&#46; Adem&#225;s&#44; redujo significativamente la tasa de excreci&#243;n urinaria de alb&#250;mina en 24<span class="elsevierStyleHsp" style=""></span>h &#40;24<span class="elsevierStyleHsp" style=""></span>h UAE&#41; y la tasa de elevaci&#243;n de creatinina &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;0&#44;19&#59; IC del 95&#37;&#58; &#8722;0&#44;24 a &#8722;0&#44;14&#59; RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;61&#59; IC del 95&#37;&#58; 0&#44;51 a 0&#44;74&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;000&#41;&#44; retras&#243; la progresi&#243;n a la enfermedad renal terminal &#40;ESRD&#41; &#40;RR<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;69&#59; IC del 95&#37;&#58; 0&#44;59 a 0&#44;81&#59; p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;000&#41;&#46; Adem&#225;s&#44; no tuvo un efecto significativo sobre la incidencia de eventos adversos relacionados con el ri&#241;&#243;n o la mortalidad relacionada con el ri&#241;&#243;n&#46; Aunque disminuy&#243; la tasa de filtraci&#243;n glomerular estimada &#40;TFGe&#41; &#40;DMP<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;5&#44;4&#59; IC del 95&#37;&#58; &#8722;7&#44;24 a &#8722;3&#44;57&#41;&#44; este efecto fue reversible&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conclusiones</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Estos datos proporcionan un testimonio bien documentado de los beneficios del uso combinado de inhibidores de SGLT2 y bloqueadores del SRA para los resultados cardiovasculares y renales en pacientes con ERC&#46;</p></span>"
        "secciones" => array:4 [
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            "identificador" => "abst0025"
            "titulo" => "Antecedentes y objetivos"
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          1 => array:2 [
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            "titulo" => "M&#233;todos"
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          2 => array:2 [
            "identificador" => "abst0035"
            "titulo" => "Resultados"
          ]
          3 => array:2 [
            "identificador" => "abst0040"
            "titulo" => "Conclusiones"
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      0 => array:3 [
        "etiqueta" => "1"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Ting Liu&#44; Rui Li and Xiaoxia Wang contributed equally to this paper&#46;</p>"
        "identificador" => "fn0005"
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            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0135"
          ]
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      ]
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          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Flow diagram of study screening&#46;</p>"
        ]
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        "identificador" => "fig0030"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Forest plot of meta-analyses comparing cardiovascular death and heart failure hospitalization rates of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo&#46;</p>"
        ]
      ]
      2 => array:7 [
        "identificador" => "fig0035"
        "etiqueta" => "Fig&#46; 3"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr3.jpeg"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Forest plot of meta-analyses comparing renal outcomes of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo&#46;</p>"
        ]
      ]
      3 => array:7 [
        "identificador" => "fig0040"
        "etiqueta" => "Fig&#46; 4"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Forest plot of meta-analyses comparing 24hUAE and eGFR of combination therapy with SGLT2 inhibitors and RAS blockers versus placebo&#46;</p>"
        ]
      ]
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        "tipo" => "MULTIMEDIATABLA"
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                  \t\t\t\t" scope="col">Study&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Female&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Mean age &#40;years&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Mean aseline eGFR &#40;ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col">Sample size&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col">Interventions&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col">Follow-up&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention Concorl&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention Concorl&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Heerspink<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">12</span></a> 2020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">With or without type 2 diabetes&#44; GFR of 25&#8211;75<span class="elsevierStyleHsp" style=""></span>ml&#47;min&#47;1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">1425 &#40;33&#46;1&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">61&#46;8<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">43&#46;2<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;343&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>12&#46;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">21522152&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dapagliflozin &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">2&#46;4 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cherney<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">16</span></a> 2020&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CKD 24<span class="elsevierStyleHsp" style=""></span>h urinary protein excretion 500&#8211;3500<span class="elsevierStyleHsp" style=""></span>mg and eGFR &#62;25<span class="elsevierStyleHsp" style=""></span>mL&#47;min per 1&#46;73<span class="elsevierStyleHsp" style=""></span>m<span class="elsevierStyleSup">2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">17 &#40;32&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">51<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#46;8 &#40;25&#46;5&#41;58&#46;9 &#40;20&#46;7&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2627&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dapagliflozin &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pollock<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">17</span></a> 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes and moderate to severe chronic kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">86 &#40;59&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">64&#46;7 &#40;8&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#46;2 &#40;13&#46;0&#41;47&#46;7 &#40;13&#46;5&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">145148&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dapagliflozin &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Perkovic<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">8</span></a> 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes with chronic kidney disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1494 &#40;33&#46;9&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&#46;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56&#46;3<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;256&#46;0<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>18&#46;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">22022199&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">canagliflozin &#40;100<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#46;62 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Triantafylidis<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">18</span></a> 2019&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetic kidney disease albumin&#58;creatinine ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>300<span class="elsevierStyleHsp" style=""></span>mg&#47;g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">67 <span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">56<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>21&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1414&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">empagliflozin &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wanner<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">9</span></a> 2018&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes with nephropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2004 &#40;28&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46852333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">empagliflozin &#40;10&#47;25<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Petrykiv<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">19</span></a> 2017&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes and albumin&#58;creatinine ratio<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>100<span class="elsevierStyleHsp" style=""></span>mg&#47;g&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8 &#40;24&#46;2&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">61<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">72 &#40;21&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">33&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">dapagliflozin &#40;10<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wanner<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">20</span></a> 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes with nephropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2004 &#40;28&#46;5&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">46852333&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">empagliflozin &#40;10&#47;25<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3 years&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">David Cherney<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">21</span></a> 2016&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 2 diabetes with microalbuminuria and ma croalbuminuria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">337 &#40;39&#46;6&#37;&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">516335&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">empagliflozin &#40;10&#47;25<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">24 weeks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t">46872333&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">empagliflozin &#40;10&#47;25<span class="elsevierStyleHsp" style=""></span>mg&#47;d&#41;&nbsp;\t\t\t\t\t\t\n
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