An Improved Prognosis in Subjects With Homozygous Familial Hypercholesterolemia Associated With Advances in LDL-Lowering Therapy

See article vol. 33: 884-894

LDL cholesterol is a causal factor in the development of coronary artery disease (CAD), and LDL-lowering therapies have contributed to reducing the risk of CAD for several decades. Among the affected populations, patients with homozygous familial hypercholesterolemia (HoFH) experience the poorest outcomes because of their extremely elevated LDL cholesterol levels and the near absence of any LDL receptor activity, which is essential for the efficacy of most LDL-lowering therapies ^{1 , 2)} . Before the advent of statins, the prognosis of HoFH was extremely poor, with an average life expectancy of only 10–20 years ³⁾ . The introduction of statins and lipoprotein apheresis has extended the life expectancy of such patients by an additional 10–20 years ⁴⁾ . More recently, LDL receptor–independent therapies such as lomitapide and evinacumab have improved outcomes ( Table 1 ) ⁵⁾ . In this context, Shishikura et al. compared the clinical phenotypes of HoFH and heterozygous FH (HeFH) and concluded that patients with HoFH should be regarded as a substantially higher-risk group than those with HeFH ⁶⁾ . Such a comparison has become feasible only in the modern era, when multiple LDL-lowering therapies are available for HoFH. Historically, most patients with HoFH have not survived beyond their twenties or thirties, making such comparative analyses impossible ⁷⁾ . Thus, the current landscape reflects a remarkable improvement in both LDL cholesterol levels and the overall prognosis among patients with HoFH. Despite these advances, our previous work demonstrated that, as of 2019, patients with HoFH in Japan still faced the challenges of underdiagnosis and insufficient LDL-lowering therapy ⁸⁾ . The median age at diagnosis was 27 years, and approximately 70% of such patients had already developed CAD, with a median LDL cholesterol level of 150 mg/dL. In contrast, the present study reported a median LDL cholesterol level of 84 mg/dL, partly due to the introduction of newer LDL-lowering agents, and a lower prevalence of CAD (40%) compared with the 2019 cohort. Another notable finding was that some patients with HoFH exhibited supravalvular aortic stenosis, whereas none of the patients with HeFH had this complication. This condition is considered to be characteristic of HoFH and it is typically observed only in true or severe forms of the disease ^{9 , 10)} . These observations underscore the importance of an early diagnosis and aggressive LDL-lowering therapy. Genetic testing plays a crucial role in assessing disease severity. Protein-truncating variants in the LDL receptor (LDLR) gene are associated with more severe phenotypes, whereas missense variants in apolipoprotein B (APOB) or proprotein convertase subtilisin/kexin type 9 (PCSK9) generally result in milder forms. Therefore, genetic testing for FH, regardless of zygosity, can aid not only in the diagnosis, but also in risk stratification, thereby ultimately contributing to an improved prognosis.

Table 1. Life expectancy of HoFH.

Period	Major therapies	Life expectancy
~1980	none/dietary therapy	＜10~20 years
1980~2000	statin, lipoprotein apheresis	20~30 years
2000~2010	statin + ezetimibe + lipoprotein apheresis	30~40 years
2010~2020	lomitapide, PCSK9 inhibitor	＞40 years
2020~	evinacumab	＞50 years

Conflict of Interest

None.