Assistant Professor McGill University University of British Columbia Beaconsfield, Quebec, Canada
Background: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide. Familial Hypercholesterolemia (FH) is a common genetic disorder that markedly increases the risk of premature ASCVD due to lifelong elevations in low-density lipoprotein-cholesterol (LDL-C). As an autosomal semi-dominant trait, FH affects males and females equally; however, increasing evidence highlights sex-based disparities in diagnosis and management. The objective of this study was to investigate sex-related differences in clinical presentation, lipid-lowering therapy (LLT) use, LDL-C response, and cardiovascular outcomes among FH individuals in Canada.
METHODS AND RESULTS: We conducted a longitudinal analysis of adults (≥18 years) with definite or probable heterozygous FH enrolled in the national, multicenter FH Canada Registry. Baseline and follow-up data were compared by sex. We assessed LLT use, LDL-C levels, attainment of Canadian Cardiovascular Society guideline-recommended targets, and incidence of cardiovascular events. Among 3737 adults with a clinical or genetic diagnosis of FH in Canada, 48.5% were females. They were diagnosed at a significantly later age than males (mean 43.9 vs 39.1 years, p< 0.001). At baseline, females had lower rates of prior coronary artery disease (21% vs. 42.6%) and were less likely to be on LLT (44% vs. 53.8%, p< 0.001) despite higher baseline LDL-C levels (6.9 vs 6.6 mmol/L p< 0.001). At the last clinic follow-up available (n=1602, mean 11.9 years), both sexes showed marked LDL-C reduction with treatment. However, females were less likely to be on any LLT (79.3% vs 87.8%, p< 0.001), high-intensity statins (53.2% vs. 72.9%, p< 0.001) and combination therapy (38.4% vs 53.4%). Females also experienced a lesser reduction in LDL-C (41.9% vs 51.0%) and were less likely to achieve ≥50% LDL-C reduction (43% vs. 58.9%, p< 0.001) or an LDL-C < 2.0 mmol/L (10% vs. 27.6%, p< 0.001). Similar significant patterns were observed for non-HDL and apolipoprotein B levels. Event-free survival was significantly lower in males (p=0.002), likely attributable to higher baseline ASCVD burden. When stratified by primary vs. secondary prevention, females in the secondary prevention group remained less likely to reach target LDL-C levels despite comparable treatment response.
Conclusion: In this largest Canadian cohort of FH patients, we identified persistent sex disparities in diagnosis, treatment intensity, and lipid target achievement. These findings underscore the need for targeted strategies to improve identification and management of FH in females, particularly in the context of secondary prevention. Addressing these gaps is essential to ensure equitable care and improve outcomes for all Canadians living with FH.
