Registry Reveals Sex Differences in HoFH Diagnosis, Treatment, and Cardiovascular Outcomes

Among individuals who know they have homozygous familial hypercholesterolemia (HoFH), age at diagnosis and at first atherosclerotic cardiovascular disease (ASCVD) event were similar between men and women, but men were twice as likely to have myocardial infarction (MI), according to new research published in JAMA Cardiology.

HoFH is a rare genetic disorder characterized by significantly elevated low-density lipoprotein cholesterol (LDL-C) levels and early ASCVD. Using data from the HoFH International Clinical Collaborators (HICC) registry encompassing 88 institutions across 38 countries, researchers analyzed age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality among patients with HoFH. The retrospective cohort study used data entered from February 2016 to December 2020 and involved comparing women and men with HoFH regarding these factors, including the prevalence, onset, and incidence of ASCVD events such as MI and aortic stenosis.

The study included data from 389 women and 362 men with known HoFH, with a median (IQR) age at diagnosis of 13 (6-26) years for women and 11 (5-27) years for men. Aside from similar age at diagnosis, women and men also exhibited similarities in untreated LDL-C levels and prevalence of cardiovascular risk factors, except for smoking, which was higher in men.

Hand on heart | Image credit: Bangkok Click Studio – stock.adobe.com

Although the prevalence of MI was doubled among men (16.3%) compared with women (8%), both sexes had similar ages at first MI, which was 38 for men and 39 for women. Additionally, treated LDL-C levels and lipid-lowering therapy, including statins and lipoprotein apheresis, were comparable between sexes. Despite low rates of LDL-C goal achievement in both women (4.0%) and men (3.1%), which is consistent with previous findings in patients with HoFH, there was comparable attainment between sexes. According to the authors, these findings emphasize the importance of initiating early treatment with combination lipid-lowering therapy for individuals with HoFH. They also highlight the critical need for access to newer lipid-lowering therapies such as lomitapide and evinacumab worldwide, aiming to further decrease LDL-C levels and enhance goal attainment rates among patients.

“A possible explanation for the lack of sex differences in patients with HoFH with regard to treatment is the severity of the condition and the intensiveness of required treatment, which is offered in specialized lipid clinics,” the authors noted.

Over a 16-year follow-up period, women with HoFH had a statistically significant lower cumulative incidence of MI compared with men (5.0% vs 13.7%; subdistribution HR [SHR], 0.37; 95% CI, 0.21-0.66), along with nonsignificantly lower rates of all-cause (3.0% vs 4.1%; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% vs 4.1%; SHR, 0.87; 95% CI, 0.44-1.75). The authors were not able to provide a conclusive explanation for this.

“Considering the premenopausal age of the women in this study, they may still have experienced some hormonal cardiovascular protection in relation to the development of MI,” they suggested. “For instance, estrogens have been linked to increased [low-density lipoprotein receptor activity] and plaque stability. At the other hand, we do not exclude the possibility that the diagnosis of MI is more often missed in women, similar to previous reports of general population studies that observed that women more often had silent or missed MIs.”

Previous cohort studies on HoFH lacked sufficient power to analyze sex-specific differences due to small sample sizes, according to the study authors. However, although the HICC registry enabled detailed sex-specific analyses and survival analyses that accounted for competing risks, its limitations include its coverage starting from 2010, which could potentially exclude undiagnosed or untreated cases of HoFH, as well as its incomplete representation of all world regions and racial or ethnic groups.

Additionally, female-specific risk factors such as age at first menstruation were not included in the dataset, and data on smoking and other nonlipid risk factors were often missing, impacting the analysis of ASCVD outcomes. Finally, missing data on follow-up time for ASCVD outcomes could affect the accuracy of age at onset and cumulative incidence estimates.

“Additional research is needed to better understand this phenomenon, with particular focus on female-specific ASCVD risk factors,” the authors said. “The findings indicate that both women and men with HoFH have a very high risk of premature ASCVD, suggesting that early diagnosis and treatment are important steps in attenuating excessive cardiovascular risk in both sexes.”

Reference

Mulder JWCM, Tromp TR, Al-Khnifsawi M, et al. Sex differences in diagnosis, treatment, and cardiovascular outcomes in homozygous familial hypercholesterolemia. JAMA Cardiol. Published online February 14, 2024. doi:10.1001/jamacardio.2023.5597