ORF32-02 - Long-Term Risk of Cardiometabolic Comorbidities Associated with Glucocorticoid Exposure and Androgen Control in Classic Congenital Adrenal Hyperplasia: A Cox Proportional Hazards Analysis from the CAHtalog™ Registry

Introduction: Classic congenital adrenal hyperplasia (CAH) requires lifelong glucocorticoid (GC) therapy for cortisol replacement, but typically supraphysiologic doses are needed to control androgen excess. Such exposure, variably associated with androgen oversuppression or persistent excess, may contribute to long-term morbidity. CAHtalog™ is a US registry capturing the natural history of CAH longitudinally based on large-scale real-world data derived from medical records. Building on prior descriptive analyses, we applied longitudinal time-to-event models to evaluate associations between GC exposure, androgen control, and incident comorbidities.

Methods: Outcomes included hypertension, overweight/obesity (OW/OB), and metabolic syndrome (MetS), defined using diagnosis codes and clinical measurements. Analyses were limited to patients >2 years old per monitoring guidance. Cox proportional hazards models used age as the time scale, with left truncation at first record and censoring at first outcome. Time-varying covariates included GC dose (mg/m²/day hydrocortisone equivalents), androstenedione (A4) expressed as age-/sex-specific upper limit of normal (ULN), and OW/OB status as appropriate. Models were adjusted for sex; proportional hazards and inference were assessed. Sensitivity analyses incorporated relevant medications and alternative androgen control representations to assess robustness of findings.

Results: Among 126 patients (40.5% male) queried in October 2025, mean follow-up was 8.99 years (pediatric) and 12.94 years (adult); 72 became adults during the analysis period. In hypertension analyses (n=107), each 1 mg/m²/day increase in GC dose was associated with a 20% higher risk of incident hypertension (hazard ratio [HR] 1.20; P=0.001) and each 0.5 ULN increase in A4 with a 29% higher risk (HR 1.29; P=0.048), after multivariable adjustment. GC exposure showed consistent risk-increasing associations with OW/OB and MetS (HR 1.08 [P=0.048] and 1.08 [P=0.27], respectively). For MetS, results suggested confounding between GC exposure and androgen levels, with evidence of sex-dependent interactions. Limitations include non-standardized A4 timing relative to GC dosing, gaps in longitudinal monitoring, and limited sample size.

Conclusion: In longitudinal age-based analyses, higher GC exposure was consistently associated with increased cardiometabolic risk, supporting a cumulative long-term morbidity burden related to chronic supraphysiologic GC exposure. Poorer androgen control was independently associated with incident hypertension and remains clinically important given its biologic and sex-dependent effects on cardiometabolic risk. These findings highlight the potential benefit of treatment strategies targeting improved androgen control and enabling GC dose reduction to mitigate long-term morbidity in classic CAH.