Sex in CKD trials: representation and treatment effects of cardiorenoprotective therapies

Vollständiger Abstract

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Abstract Background Women comprise a substantial proportion of the chronic kidney disease (CKD) population and differ from men in disease phenotype, progression, and treatment exposure. Underrepresentation of women and limited sex-specific reporting may therefore reduce the generalizability of evidence from contemporary CKD trials. Methods We conducted a meta-epidemiological study of randomized trials evaluating sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and non-steroidal mineralocorticoid receptor antagonists in adults with CKD. Female representation was quantified using the enrollment disparity difference (EDD), defined as the observed proportion of female trial participants minus the expected proportion derived from sex-specific Global Burden of Disease CKD prevalence estimates matched to trial population characteristics. Trial-level EDDs were pooled using random-effects meta-analysis. Meta-regression was used to examine trial-level correlates of EDD. Historical analyses extended the cohort to earlier cardiorenal pharmacotherapies to evaluate temporal trends, with pivotal CKD trials examined descriptively. Reporting of sex-specific cardiovascular and kidney outcomes was also assessed. Results Fifty-five randomized trials were included. Median female enrollment was 33.1%, and 52 trials (94.5%) enrolled fewer women than expected. The pooled EDD was -0.17 (95% CI, -0.20; -0.14), with negative estimates across all intervention classes. In meta-regression, phase II design and albuminuria requirement were associated with greater female underrepresentation, whereas diabetes requirement and female first authorship were associated with smaller enrollment disparity, including after adjustment for other key trial characteristics. Sex-specific outcomes were reported in 13 trials (23.6%). Extension to 117 trials provided no statistically supported evidence of improvement in female representation over time, including after adjustment for intervention class; all 38 pivotal CKD trials enrolled fewer women than expected. Conclusions Women remain underrepresented in cardiorenoprotective therapy trials, with limited sex-specific outcome reporting. Historical benchmarking indicates that successive advances in CKD pharmacotherapy have not been accompanied by demonstrable improvement in the sex representativeness of the evidence base.