Jun 03, 2026
Sex Representation and Sex-Specific Treatment Effects in Randomized Trials of Novel Cardio-Renoprotective Therapies for Chronic Kidney Disease: A Meta-Epidemiological Study
- Ioannis Bellos1
- 1National and Kapodistrian University of Athens, Greece
Protocol Citation: Ioannis Bellos 2026. Sex Representation and Sex-Specific Treatment Effects in Randomized Trials of Novel Cardio-Renoprotective Therapies for Chronic Kidney Disease: A Meta-Epidemiological Study. protocols.io https://dx.doi.org/10.17504/protocols.io.eq2lymzyqlx9/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: June 03, 2026
Last Modified: June 03, 2026
Protocol Integer ID: 318447
Keywords: proportion of female participant, renoprotective therapies for chronic kidney disease, kidney outcome, chronic kidney disease, female enrollment, specific treatment effects in randomized trial, specific ckd prevalence estimate, specific ckd prevalence estimates from the global burden, female underrepresentation, specific effects on major cardiovascular, female participant, controlled trial, specific treatment effects in contemporary, sex representation, renoprotective therapies for adult, specific treatment effect, major cardiovascular, eligible trial, sglt2 inhibitor, novel cardio
Abstract
This meta-epidemiological study aims to evaluate sex representation and sex-specific treatment effects in contemporary randomized controlled trials of novel cardio-renoprotective therapies for adults with chronic kidney disease. Eligible trials will assess SGLT2 inhibitors, GLP-1 receptor agonists, or non-steroidal mineralocorticoid receptor antagonists and must report the number or proportion of female participants. Female enrollment will be quantified using the Enrollment Disparity Difference, comparing observed trial participation with expected sex-specific CKD prevalence estimates from the Global Burden of Disease Study. Sex-specific effects on major cardiovascular and kidney outcomes will also be examined where reported. Random-effects meta-analysis and meta-regression will be used to estimate pooled disparities, heterogeneity, and trial characteristics associated with female underrepresentation or differential treatment effects.
Aim and background Chronic kidney disease (CKD) represents a major global public health challenge, affecting more than 10% of the worldwide population. Cardiovascular disease is the leading cause of morbidity and mortality among individuals with CKD, reflecting the complex interplay between traditional and CKD-specific cardiovascular risk factors. In recent years, there has been increasing clinical and research interest in pharmacological interventions that may slow CKD progression and reduce the burden of cardiovascular complications. Several novel cardio-renoprotective drug classes have emerged as promising therapeutic options. These include sodium–glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, originally developed as antidiabetic agents but subsequently repurposed for cardiorenal protection. In addition, newer therapies such as non-steroidal mineralocorticoid receptor antagonists (ns-MRAs) have been evaluated in large randomized clinical trials involving patients with CKD. Despite advances in therapeutic development, concerns remain regarding the adequate representation of women in clinical trials. Historically, female participants have been under-represented in biomedical research, with clinical evidence frequently derived predominantly from male populations and subsequently generalized to women. Such disparities may have important clinical implications, as biological differences in physiology, pharmacokinetics, and pharmacodynamics may influence drug efficacy and safety profiles between sexes. The aim of the present meta-epidemiological study is to systematically identify contemporary randomized clinical trials evaluating novel cardio-renoprotective therapies in patients with CKD, including SGLT2 inhibitors, GLP-1 receptor agonists and ns-MRAs, and to assess potential disparities in sex representation as well as sex-specific differences in reported treatment effects.
Eligibility criteria The population of interest will include adult patients with chronic kidney disease (CKD). Trials enrolling mixed populations in which CKD patients constitute a subgroup will be excluded unless CKD-specific results are reported separately. Eligible interventions will include the following classes of cardio-renoprotective therapies: SGLT2 inhibitors, GLP-1 receptor agonists and ns-MRAs. Trials evaluating these interventions against placebo or any active intervention will be considered eligible. The primary outcome of interest will be female representation in the included trials. In addition, sex-specific treatment effects will be evaluated for trials reporting major clinical outcomes, including composite cardiovascular outcomes and composite kidney outcomes. Only randomized controlled trials (RCTs) will be eligible for inclusion, regardless of trial phase or blinding status. Observational studies, post-hoc analyses, secondary analyses of previously published trials, case series, and non-randomized studies will be excluded. Trials must report the number or proportion of female participants or provide sufficient data to derive this information.
Search strategy A systematic literature search will be conducted in the following electronic databases: PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials. All databases will be searched from their inception to the date of the final search. The search strategy will combine controlled vocabulary terms and free-text keywords related to chronic kidney disease and the investigated drug classes. The literature search and study selection will be performed independently by two reviewers. Discrepancies will be resolved through discussion and consensus, with involvement of a third reviewer if necessary.
Data extraction Data extraction will be performed independently by two reviewers using a standardized data extraction form. The following study-level characteristics will be collected: year of publication trial name or trial registry identifier (e.g., NCT number) geographical region population characteristics intervention and comparator trial phase blinding status funding source presence of a run-in phase sex-stratified randomization requirement for background renin–angiotensin system inhibitor therapy requirement for prior cardiovascular disease albuminuria and eGFR inclusion criteria body mass index (BMI) inclusion criteria requirements related to pregnancy testing, contraception use, or exclusion of women of childbearing potential placebo or active treatment as comparator total sample size primary outcome reporting of major clinical outcomes (cardiovascular and kidney outcomes) The following authorship characteristics will also be extracted: sex of the first author specialty of the first author sex of the last author specialty of the last author total number of female authors Additionally, the following baseline participant characteristics will be recorded when available: proportion of White race prevalence of diabetes mellitus prevalence of cardiovascular disease median or mean age body mass index estimated glomerular filtration rate (eGFR) urinary albumin-to-creatinine ratio (UACR) duration of follow-up
Data analysis Female representation in the included randomized controlled trials will be assessed using the Enrollment Disparity Difference (EDD) approach. The EDD represents the difference between the observed proportion of women enrolled in a trial and the expected proportion of women in the underlying CKD population. For each trial, the observed proportion of female participants (Pobs) will be calculated as the number of women divided by the total sample size. The expected proportion of women (Pexp) will be derived from sex-specific prevalence estimates of CKD obtained from the Global Burden of Disease Study. Because sex distribution differs by CKD etiology, separate prevalence estimates will be used for diabetic kidney disease and non-diabetic CKD, according to the population studied in each trial. The EDD will be calculated as: EDD= Pobs - Pexp Negative values will indicate underrepresentation of women, whereas positive values will indicate overrepresentation. The standard error (SE) of the EDD will be estimated assuming binomial variance of the observed proportion: SE(EDD)= sqrt[Pobs (1-Pexp )/N], where N is the total number of participants. Trial-specific EDD estimates will be pooled using random-effects meta-analysis, and results will be reported as pooled EDD values with 95% confidence intervals. Between-study heterogeneity will be assessed using the I² statistic. Random-effects meta-regression will be performed to identify trial characteristics associated with disparities in female enrollment. Sex-specific treatment effects will be analyzed for hard outcomes, including the composite cardiovascular and composite kidney outcomes. For each trial, sex-specific effect estimates (e.g., hazard ratios) and standard errors will be extracted. To assess whether treatment effects differ systematically between women and men across trials, a random-effects meta-regression will be performed using sex as moderator. The regression will be weighted by the inverse variance of the trial-specific estimates. The p value for the sex covariate will serve as the formal test of effect modification, with p < 0.05 considered evidence of a significant sex–treatment interaction.