May 27, 2026
Cardiorenal Outcomes Associated with the Combined Use of Finerenone and SGLT2 Inhibitors: A Systematic Review and Meta-Analysis
- 1Department of Hygiene, Epidemiology and Medical Statistics, National and Kapodistrian University of Athens, Medical School, Athens, Greece
Protocol Citation: Ioannis Bellos 2026. Cardiorenal Outcomes Associated with the Combined Use of Finerenone and SGLT2 Inhibitors: A Systematic Review and Meta-Analysis. protocols.io https://dx.doi.org/10.17504/protocols.io.e6nvwwxxzvmk/v1
License: This is an open access protocol distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Protocol status: Working
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Created: May 26, 2026
Last Modified: May 27, 2026
Protocol Integer ID: 317938
Keywords: sglt2, finerenone, ckd, cardiorenal, meta-analysis, cardiorenal protective effects in patient, cardiorenal outcomes associated with the combined use, elevated cardiorenal risk, demonstrated cardiorenal protective effect, cardiorenal outcomes associated, chronic kidney disease, sglt2 inhibitor, cardiorenal risk, safety of combined finerenone, patients with ckd, major adverse cardiovascular, renal morbidity, combined finerenone, cardiorenal condition, related cardiorenal condition, kidney event, comparative efficacy, albuminuria reduction, additional clinical benefit, acute kidney injury, sglt2i, retrospective cohort study, primary efficacy outcome, diabetes, systematic review, secondary efficacy outcome
Abstract
Background: Chronic kidney disease (CKD) is associated with substantial cardiovascular and renal morbidity and mortality. Both sodium-glucose cotransporter-2 inhibitors (SGLT2i) and finerenone have demonstrated cardiorenal protective effects in patients with CKD and diabetes. Owing to their complementary mechanisms of action, combination therapy may provide additional clinical benefits; however, the available evidence remains limited and heterogeneous. This protocol describes a systematic review and meta-analysis aiming to evaluate the efficacy and safety of combined finerenone and SGLT2i therapy in patients with CKD or elevated cardiorenal risk.
Methods: This systematic review and meta-analysis will be conducted according to PRISMA guidelines. Medline (via PubMed), Scopus, Web of Science, CENTRAL, and ClinicalTrials.gov will be systematically searched from inception onward, without language restrictions. Randomized controlled trials and prospective or retrospective cohort studies comparing combined finerenone and SGLT2i therapy with either finerenone or SGLT2i monotherapy in adult patients with CKD, diabetes mellitus, or related cardiorenal conditions will be considered eligible. The primary efficacy outcome will be albuminuria reduction (≥30% and ≥50%). Secondary efficacy outcomes will include all-cause mortality and major adverse cardiovascular and kidney events, while safety outcomes will include acute kidney injury and hyperkalemia. Study selection, data extraction, risk of bias assessment, and GRADE evaluation will be independently performed by two reviewers. Random-effects meta-analyses will be conducted using restricted maximum likelihood estimation. Heterogeneity, publication bias, and potential sources of between-study variability will also be explored.
Discussion: This study will synthesize the currently available evidence regarding the comparative efficacy and safety of combined finerenone and SGLT2i therapy. The findings are expected to provide clinically relevant insights into the role of combination therapy in the management of patients with CKD and elevated cardiorenal risk.
Background and Objective Chronic kidney disease is a major global health burden and is strongly associated with increased cardiovascular morbidity and mortality, with cardiovascular disease representing the leading cause of death in this population. The risk of adverse cardiovascular outcomes increases progressively with declining kidney function and higher levels of albuminuria, reflecting shared pathophysiological mechanisms including inflammation, fibrosis, and neurohormonal activation. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated consistent reductions in cardiovascular events, heart failure hospitalization, and chronic kidney disease progression across both diabetic and non-diabetic populations. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has also been shown to improve renal and cardiovascular outcomes. Given their complementary mechanisms of action, combined therapy may provide additive benefits; however, evidence evaluating this strategy remains limited and heterogeneous. This systematic review and meta-analysis aims to evaluate the association between combined finerenone and SGLT2i therapy and major cardiovascular, kidney and safety outcomes in adults with chronic kidney disease or elevated cardiorenal risk.
Study design This systematic review and meta-analysis will be conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. As the analysis will utilize previously published aggregate data, ethical approval and informed consent are not required.
Eligibility Criteria The study population will include adult patients with chronic kidney disease, diabetes mellitus, or related cardiorenal risk conditions. The intervention of interest will be combination therapy with finerenone and SGLT2i, compared with either finerenone monotherapy or SGLT2i monotherapy. Studies including inactive or placebo-only comparator groups will not be considered eligible. Randomized controlled trials (RCTs), as well as prospective and retrospective cohort studies, will be eligible for inclusion. Case-control studies, cross-sectional studies, single-arm studies, case reports, case series, editorials, reviews, animal studies, and studies lacking extractable comparative outcome data will be excluded. The primary efficacy endpoint will be albuminuria reduction, evaluated according to thresholds of ≥30% and ≥50%. Secondary efficacy outcomes will include all-cause mortality and major adverse cardiovascular and kidney events, as defined by the individual studies. Safety outcomes will include acute kidney injury and hyperkalemia. Continuous measures of albuminuria will be summarized qualitatively because of anticipated heterogeneity in reporting methods and distribution characteristics.
Search Strategy Systematic literature search will be performed in Medline (via PubMed), Scopus, Web of Science, CENTRAL (Cochrane Central Register of Controlled Trials), and ClinicalTrials.gov from database inception until the date of the final search. Reference lists of all included studies and relevant reviews will also be manually screened to identify additional eligible studies. The search strategy will combine free-text terms with controlled vocabulary indexing terms, including Medical Subject Headings (MeSH), related to finerenone, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. No language restrictions will be applied.
Study Selection Study selection will be conducted in three sequential phases. Initially, titles and abstracts retrieved from the database search will be screened for potential eligibility. Subsequently, full-text articles of potentially relevant studies will be assessed in detail. Studies failing to meet the predefined eligibility criteria or not reporting the outcomes of interest will be excluded. All stages of study selection will be independently performed by two reviewers. Any disagreements will be resolved through discussion and consensus involving all investigators when necessary.
Data Extraction Data extraction will be independently performed by two reviewers using a predefined standardized form. The following information will be collected from each included study: year of publication, country or geographic region, study design, sample size, comparator group, proportion of male participants, median or mean age, body mass index (BMI), estimated glomerular filtration rate (eGFR), urinary albumin-to-creatinine ratio (UACR), and CKD and diabetes status. For outcome measures, absolute event counts and/or adjusted effect estimates with corresponding 95% confidence intervals (CIs) will be extracted whenever available. Discrepancies between reviewers will be resolved through consensus.
Quality Assessment The methodological quality of observational studies and post hoc analyses of RCTs will be evaluated using the ROBINS-I V2 (Risk Of Bias In Non-randomized Studies of Interventions, Version 2) tool. Risk of bias domains will include confounding, intervention classification, participant selection, missing data, outcome measurement, and selective reporting. The quality of randomized controlled trials will be assessed using the RoB 2 tool, which evaluates bias arising from the randomization process, deviations from intended interventions, incomplete outcome data, outcome assessment, and selective reporting. Risk of bias assessments will be conducted independently by two reviewers, with disagreements resolved through discussion and consensus.
Statistical Analysis Statistical analyses will be conducted using R software (R Foundation for Statistical Computing, Vienna, Austria), employing the “metafor” package. A two-sided p-value <0.05 will be considered statistically significant. Meta-analyses will be performed using random-effects models to account for expected methodological and clinical heterogeneity among studies. Between-study variance will be estimated using the restricted maximum likelihood (REML) method. Statistical heterogeneity will be quantified using the inconsistency statistic (I²), while 95% prediction intervals will also be calculated to estimate the range of effects expected in future studies. Prespecified meta-regression analyses will be undertaken to explore potential sources of heterogeneity according to study-level characteristics, including sample size, geographical setting, study design, population characteristics, and overall risk of bias. Potential publication bias will be evaluated through visual inspection of funnel plots using trim-and-fill methodology. Formal statistical tests for funnel plot asymmetry will not be planned unless a sufficient number of studies are available for a given outcome.
Certainty of Evidence The certainty of the evidence for each outcome will be assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The assessment will consider risk of bias, inconsistency, indirectness, imprecision, and publication bias. GRADE evaluations will be independently conducted by two reviewers, with disagreements resolved through consensus among all authors.