Endocrine Abstracts

Cardiovascular disease (CVD) is the leading cause of death worldwide, affecting both men and women. This has led to the widespread prescription of statins, with over 145 million people taking them globally. However, recent clinical data has identified sex-specific variations in statin efficacy and statin-induced type 2 diabetes (T2D). Women have historically been underrepresented in basic research and clinical trials for statins, resulting in the mechanisms underlying sex disparities in statin responses being poorly understood. Macrophages and white adipose tissue play critical roles in the pathophysiology of both CVD and T2D. Using the well-established hypercholesterolemic Ldlr^-/- mouse model, this study investigated sex-specific in vivo responses to atorvastatin treatment over 6 months. Female mice exhibited significantly greater weight gain and larger gonadal fat depots relative to controls, whereas males showed slightly reduced weight gain without notable changes in gonadal fat deposition. Atorvastatin significantly increased insulin sensitivity, with this effect being more pronounced in female mice. RNA-seq analysis showed male bone marrow-derived macrophages exhibited more extensive transcriptomic changes compared to females (541 differentially expressed genes (DEGs) in males vs 69 in females), with statin treatment affecting genes related to motility, morphology, and viral defence responses. Conversely, atorvastatin treatment had a greater impact on gene expression in female gonadal white adipose tissue (15 DEGs in males vs 124 in females), influencing pathways associated with B cells, immunoglobulins and antiviral defence mechanisms. Protein validation of novel targets identified through RNA-seq is ongoing to further characterise the sex-specific responses to prolonged atorvastatin treatment. Overall, these findings demonstrate that sex significantly influences cellular and tissue-specific responses to statin treatment, highlighting the importance of integrating sex-specific considerations into the development and optimisation of CVD therapies for improved disease management across the whole population.