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. 2024 Apr 1;9(4):313-322.
doi: 10.1001/jamacardio.2023.5597.

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

Janneke W C M Mulder  1 , Tycho R Tromp  2 , Mutaz Al-Khnifsawi  3 , Dirk J Blom  4 , Krysztof Chlebus  5   6 , Marina Cuchel  7 , Laura D'Erasmo  8 , Antonio Gallo  9 , G Kees Hovingh  2 , Ngoc Thanh Kim  10   11 , Jiang Long  12 , Frederick J Raal  13 , Willemijn A M Schonck  2 , Handrean Soran  14 , Thanh-Huong Truong  15   16 , Eric Boersma  17 , Jeanine E Roeters van Lennep  1 ; Homozygous Familial Hypercholesterolemia International Clinical Collaborators
Collaborators, Affiliations

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia

Janneke W C M Mulder et al. JAMA Cardiol. .

Abstract

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH.

Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH.

Design, setting, and participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023.

Main outcomes and measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality.

Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75).

Conclusions and relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Blom reported personal fees from Amryt, Amgen, Sanofi, and Novartis and grants from LIB Therapeutics outside the submitted work. Dr Chlebus reported grants from Ministry of Health Poland during the conduct of the study and personal fees from Sanofi, Amgen, and Novartis outside the submitted work. Dr Cuchel reported grants from the National Heart, Lung, and Blood Institute during the conduct of the study and grants from Regenxbio and Regeneron and personal fees from Ultragenyx outside the submitted work. Dr D’Erasmo reported grants from Amryt and personal fees from Amryt, Swedish Orphan Biovitrum, Bayer, Novartis, Amarin, Aurora Biopharma, and Daiichi Sankyo outside the submitted work. Dr Gallo reported personal fees from Amgen, Sanofi, Novartis, Viatris, Amarin, Ultragenyx, Amryt, and MSD and grants from Amgen and Sanofi outside the submitted work. Dr Raal reported consulting fees for professional input and/or delivered lectures from Novartis, Sanofi, Regeneron, Amgen, and LIB Therapeutics outside the submitted work. Dr Soran reported personal fees from Amryt, Amgen, Akcea, Swedish Orphan Biovitrum, Ultragynex, Kowa, and Amarin and grants from Amryt, Amarin, and Akcea outside the submitted work. Dr Roeters van Lennep reported grants from Novartis (paid to institution) outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Untreated and Treated Total Cholesterol and Low-Density Lipoprotein (LDL) Cholesterol Levels
Values are shown in median (IQR) in mg/dL (to convert to mmol/L, multiply by 0.0259).
Figure 2.
Figure 2.. Cumulative Incidence of First Event After Diagnosis of Homozygous Familial Hypercholesterolemia
AVR indicates aortic valve replacement; MACCE, major adverse cardiovascular and cerebrovascular events.
Figure 3.
Figure 3.. Subdistribution Hazard Ratios (SHRs) by Sex for Cardiovascular End Points After Diagnosis of Homozygous Familial Hypercholesterolemia (HoFH)
The cumulative incidence is shown for 16 years’ follow-up post-HoFH diagnosis (75th percentile). The SHRs are calculated for the full follow-up duration. Aortic stenosis includes all patients with a clinical diagnosis of aortic stenosis with and without aortic valve replacement. AVR indicates aortic valve replacement; CABG, coronary artery bypass grafting; PCI, percutaneous coronary intervention; MACCE, major adverse cardiovascular and cerebrovascular events. aContains AVR, cerebrovascular disease stenting, carotid endarterectomy, and peripheral artery disease stenting or bypass. bShown as normal hazard ratio based on a Cox regression model.
See this image and copyright information in PMC

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