
==== Front
Eur Heart J
Eur Heart J
eurheartj
European Heart Journal
0195-668X
1522-9645
Oxford University Press UK

38976372
10.1093/eurheartj/ehae417
ehae417
Fast Track – Clinical Research
AcademicSubjects/MED00200
Eurheartj/12
Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis
Iatan Iulia Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada

Akioyamen Leo E Department of Medicine, University of Toronto, Toronto, Ontario, Canada

https://orcid.org/0000-0002-9491-8028
Ruel Isabelle Department of Medicine, Research Institute of the McGill University Health Centre, 1001, Decarie blvd. Office EM1.2212, Montreal, Quebec H4A 3J1, Canada

Guerin Amanda Department of Medicine, Research Institute of the McGill University Health Centre, 1001, Decarie blvd. Office EM1.2212, Montreal, Quebec H4A 3J1, Canada

Hales Lindsay McGill University Health Center Libraries, Montreal, Quebec, Canada

https://orcid.org/0000-0002-7735-5315
Coutinho Thais Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA

Brunham Liam R Department of Medicine, Centre for Heart Lung Innovation, Providence Health Care, University of British Columbia, Vancouver, British Columbia, Canada

https://orcid.org/0000-0003-2248-9663
Genest Jacques Department of Medicine, Research Institute of the McGill University Health Centre, 1001, Decarie blvd. Office EM1.2212, Montreal, Quebec H4A 3J1, Canada

Corresponding author. Email: jacques.genest@mcgill.ca
Iulia Iatan and Leo E Akioyamen contributed equally to this work and share first authorship.

14 9 2024
08 7 2024
08 7 2024
45 35 Focus Issue on Dyslipidaemias, Heart Failure and Cardiomyoptahies 32313250
03 2 2024
20 4 2024
18 6 2024
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.
2024
https://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background and Aims

Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297).

Methods

MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH.

Results

Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66–.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74–.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality.

Conclusions

Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

Structured Graphical Abstract

Structured Graphical Abstract Sex differences in the treatment of familial hypercholesterolaemia: a systematic review and meta-analysis. CI, confidence interval; CVD, cardiovascular disease; FH, familial hypercholesterolaemia; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; MACE, major adverse cardiovascular events; OR, odds ratio; PCSK9, proprotein convertase subtilisin/kexin type 9; RR, risk ratio.

Familial hypercholesterolaemia
Atherosclerotic cardiovascular disease
Lipid-lowering treatment
Sex differences
Females
Systematic review
Canadian Institutes of Health Research 10.13039/501100000024
==== Body
pmc See the editorial comment for this article ‘Familial hypercholesterolaemia: need for equitable treatment in women and men’, by R.D. Santos, https://doi.org/10.1093/eurheartj/ehae464.

Introduction

Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by lifelong elevated blood levels of LDL cholesterol (LDL-C). Its worldwide prevalence is 1/311 with an estimated 25–30 million people affected globally.1 Left untreated, it leads to premature atherosclerotic cardiovascular disease (ASCVD), particularly coronary artery disease (CAD), in addition to greater medical costs and a reduced health-related quality of life.2–4 Prompt recognition and treatment with statins and other lipid-lowering therapies (LLTs) is highly efficacious and can normalize life expectancy.

Despite this, FH remains under-recognized and under-treated worldwide. The reasons for under-treatment remain incompletely understood, and there is limited information on barriers to care in FH. As an autosomal semi-dominant trait, FH affects males and females equally. Yet, there is growing recognition that sex may play a role in the clinical presentation and management of this illness, contributing to barriers to care. Increasing reports from our groups and others suggest that female patients with FH may have an increased burden of LDL-C compared with males, are diagnosed later, treated less aggressively with guideline-mandated medical therapies, and are less likely to reach recommended LDL-C targets or thresholds.5–8 These treatment differences were observed in both adults and children from the Familial Hypercholesterolaemia Studies Collaboration (FHSC), the largest global registry of patients with FH worldwide.6,9 Furthermore, whether sex is an independent predictor of outcomes in FH remains debated. While some studies have demonstrated greater ASCVD in males,6 others have shown no difference or greater risk in females.10–12 The FHSC reported that in 42 167 patients from 56 countries (53.6% females) the prevalence of CAD (17.4%), increasing with untreated LDL-C levels, was two times lower in females than in males, and the overall ASCVD risk was lower in index and non-index females.6 Despite this, females with FH are at greater risk of CAD mortality than non-FH females. Additionally, the same FH diagnostic criteria are used for both males and females, without consideration of variability of LDL-C levels by sex throughout life, especially during pregnancy and in post-menopausal years.

In order to better understand the scope and extent of this question, we aimed to characterize sex-related disparities in management and ASCVD in patients with FH. To address this, we conducted a systematic review and meta-analysis of studies examining the associations between sex and treatment, response, achieved LDL-C levels, and guideline-recommended targets in FH, both in clinical trials to detect whether response to fixed doses of LLT differs between sexes and in real-world observational data from registries and cohort studies. Associations between sex and cardiovascular disease (CVD) risk among patients with FH were subsequently investigated.

Methods

Protocol and registration

This systematic review study was registered in the PROSPERO prospective database for systematic reviews (CRD42022353297) and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA),13 Meta-analysis Of Observational Studies in Epidemiology (MOOSE),14 and Sex and Gender Equity in Research (SAGER)15 consensus statements.

Information sources and search strategy

Search strategies were developed and executed with the assistance of a medical librarian (L.H.) with expertise supporting systematic reviews. Database searches were completed for MEDLINE, Embase, The Cochrane library, PubMed, Scopus, and PsycInfo. Clinical trial registries including ClinicalTrials.gov, the International Clinical Trials Registry Platform, UK Clinical Trials Gateway, and the ProQuest Dissertations and Theses database were also searched. Grey literature was sourced from Google Scholar and Open Grey. Reference lists of relevant systematic reviews were also searched for additional citations. No language limits were applied. Searches were conducted from database inception to 21 July 2020; the Medline search was rerun prior to manuscript preparation in 26 April 2023. A complete description of the search strategy is provided in the Supplementary data online, Appendices. The authors acknowledge that while ‘female’ or ‘male’ refer to an individual's biological sex and ‘woman’ or ‘man’ refer to an individual's gender, historically these terms have been used interchangeable in the literature; all these terms were included in the search strategy. However, in the present study the terms ‘female’ or ‘male’ are used for consistency as it pertains to biological sex.

Study selection and eligibility criteria

Candidate titles, abstracts, and full-text articles were evaluated in duplicate by five independent reviewers (A.G., J.G., I.I., I.R., L.E.A.) using Rayyan systematic review software (www.rayyan.ai). Disagreements were resolved by discussion to consensus. Studies were considered eligible for inclusion if they: (i) were interventional and/or observational studies in adult participants (age ≥18 years) with heterozygous FH (diagnosed using genetic and/or common clinical criteria) and (ii) reported data separately for male and female participants on our outcomes of interest, as described below. Non-human studies, case reports, editorials, conference abstracts, and narrative reviews were excluded. Any clinical definition of FH used in studies was accepted.

Outcomes

Our primary outcome consisted of the number of females vs. males treated with any LLTs in the included studies. Treatment with specific drug classes where studies reported them [statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors] was also examined. The secondary outcomes consisted of: (i) absolute and relative reductions in LDL-C experienced by male and female patients with FH treated with LLTs and (ii) attainment of guideline-recommended LDL-C reduction targets in these patients (defined as ≥50% reductions in LDL-C from baseline, LDL-C < 2.5 mmol/L, LDL-C < 1.8 mmol/L). Sex-specific differences in fatal and non-fatal major adverse cardiovascular events (MACE) were examined afterwards.

Data extraction

Data were extracted from studies deemed to meet eligibility criteria by at least two independent reviewers (A.G., J.G., I.I., I.R., L.E.A.). These included details on general study characteristics (first author, design, recruitment period, duration of follow-up); information about the studied population (mean age, number and proportion of males and females, diagnostic and treatment characteristics); and information on the outcomes in the study. Characteristics of studies were summarized in tabular format and narratively synthesized. Unadjusted and adjusted measures of relative risk and 95% confidence intervals (CIs) were also extracted. Maximally adjusted risk measure that was available from studies and risk estimates corresponding to the longest duration of follow-up were used. Study authors were not contacted for additional data. Quality of eligible studies was assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for quantitative studies after assessing the following domains: selection bias, study design, confounders, blinding, data collection method, and withdrawals and dropouts.16 Generally, the global rating of a study was considered to be strong if none of the quality domains were rated as weak; moderate if one domain was rated as weak; and weak if two or more domains were rated as weak.

Statistical analyses

Meta-analyses were conducted using inverse-variance models incorporating random effects estimated using the method of DerSimonian and Laird.17 For dichotomous outcomes, pooled estimates of effect size were calculated as odds ratios (OR) with 95% CIs. Weighted mean differences were calculated for continuous outcomes. Summary estimates were displayed graphically with forest plots. Heterogeneity was assessed using the I2 statistic; heterogeneity was interpreted using the following thresholds: 0%–40%: might not be important; 30%–60%: may represent moderate heterogeneity; 50%–90%: may represent substantial heterogeneity; and 75%–100%: considerable heterogeneity. Publication bias was assessed visually using funnel plots, and where analyses included >10 studies, formally using Egger’s weighted regression and significance set at P < .10.18 If publication bias was present, we used the trim-and-fill method to control for publication bias. This technique may not be entirely suitable when excess heterogeneity is present,19 and we therefore also reported heterogeneity using the I2 statistic (see Limitations). Sources of heterogeneity in our primary outcome were investigated through subgroup analyses and meta-regression. Subgroups were stratified by: year of publication (set at before and after 2016 to represent the introduction of ICD-10 codes for FH), FH diagnosis criteria (majority (>50%) with genetic testing, 100% with clinical criteria, combination of minority (<50%) with genetic testing and remaining with clinical criteria, and 100% using LDL-C cut-offs), study sample size (fewer or more than 1000 participants), and World Health Organization (WHO) geographical location (Americas, Europe, Western Pacific, and International). χ2 statistical test was used to detect differences between subgroups. Univariate meta-regression was performed to explore potential sources of heterogeneity using the following covariates: year of publication, age of participants, proportion of females in included studies, mean LDL-C reduction, and the proportion of individuals with CVD. One study included in the analyses sourced data from multiple national registries,6 creating the potential for overlap with multiple cohorts; accordingly, additional sensitivity analyses in which this study was excluded were conducted. Meta-regressions were conducted using a mixed-effects approach to account for between- and within-study heterogeneity, with restricted maximum likelihood estimation of between-study variance. For subgroup and meta-regression analyses, two-sided P-values <.05 were considered significant. Additional details of our analyses are described in the Supplementary data online, Appendix. Analyses were performed in Review Manager 5.4 and RStudio (version 2023.03.0 + 386).

Results

Database searches identified 5601 records which were reduced to 4432 following duplicates removal. From initial abstract screening, 3836 studies were excluded, and a total of 596 full-text articles were reviewed. Of these, 133 studies met criteria for sex differences in the treatment of FH and were included in the qualitative analyses (Figure 1). These studies comprised 16 interventional clinical trials testing a lipid-lowering agent (eight randomized and eight non-randomized clinical trials), 36 observational studies presenting data on sex differences in FH treatment, and 81 observational studies on sex differences in CVD outcomes. Observational studies were prospective, retrospective, or cross-sectional cohort studies. Characteristics of all studies are shown in Supplementary data online, Table S1, while a risk of bias per study is presented in Supplementary data online, Appendix S3. When evaluated by the EPHPP tool, most clinical trials were rated as being moderate, while observational studies ranged from moderate to strong, with the greatest threats to validity being because of study design or blinding.

Figure 1 Preferred Reporting Items for Systematic reviews and Meta-Analyses flow chart of studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia. *Seven studies were describing both data on sex differences in the treatment of familial hypercholesterolaemia and cardiovascular disease outcomes in patients with treated familial hypercholesterolaemia. FH, familial hypercholesterolaemia

There were 16 clinical trials of LLTs in which an analysis by sex was provided (1840 participants; 49.4% females). In 12 studies in which a mean percent LDL-C reduction value was available, there were no differences between males and females in response to fixed doses of LLTs (Figure 2), suggesting that patient sex was a not a determinant of therapeutic response. Absolute LDL-C reductions in males and females from the reviewed clinical trials are reported in Supplementary data online, Figure S1, while mean LDL-C reductions from LLT are shown in Supplementary data online, Figure S2.

Figure 2 Mean LDL cholesterol percent reduction in clinical trials included in the systematic review. Asterisks denote studies where participants received progressive escalations of therapy to reach maximal doses. CI, confidence interval; PCSK9, proprotein convertase subtilisin/kexin type 9

In the subsequent meta-analysis of real-world evidence data, observational studies with unavailable proportions of treated patients by sex, although implying sex differences in the treatment of FH, were excluded. Characteristics of patients from the remaining 25 observational studies are reported in Table 1.6–8,10,11,20–40 The majority of studies were published after the year 2016 (introduction of ICD-10 codes for FH) (n = 21). Excluding one large multi-national cohort,6 a total of 13 countries were represented in the sex differences in the treatment of FH meta-analyses, including Norway (n = 3), France (n = 3), Spain (n = 3), USA (n = 3), Canada (n = 2), and UK (n = 2), among others. A substantial number of studies comprised reports from national registries (n = 10), where ascertainment of FH was predominantly through a combination of clinical and genetic criteria (Table 1). Quality of included studies, as assessed by the EPHPP tool, was predominantly moderate or strong. Sex differences in treatment with LLT in observational studies are shown in Figure 3. Meta-analysis of data from the 25 studies (129 441 participants; 53.4% females) found that females with FH were less likely to be on LLT compared with males [OR .74 (95% CI .66–.85)], despite substantial heterogeneity (I2 = 90%). Age and previous history of ASCVD were not significantly different between males and females (data not shown). Mean LDL-C reductions in mmol/L and in percent change were compared between males and females as depicted in Figure 4. On average, LDL-C reductions inferred from baseline lipid values after treatment were greater in males than in females [mean difference in absolute LDL-C reduction of .18 mmol/L (.32–.05) mmol/L, and mean difference in percent LDL-C reduction of 3.42% (5.19–1.66)% greater in males vs. females] (Figure 4). This did not translate, however, in a statistical significant difference in absolute LDL-C reductions between sexes [−3.37 mmol/L (−3.17, −3.58) in males vs. −3.21 mmol/L (−2.95, −3.47) in females; P = .33] (Figure 5).

Figure 3 Meta-analysis of sex differences in treatment with lipid-lowering therapies in observational studies. Squares represent study-level odds ratios; horizontal lines represent 95% confidence intervals; large square represents pooled odds ratio derived under the random-effects model. CI, confidence interval

Figure 4 Sex differences in LDL cholesterol reductions in males and females in observational studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia with lipid-lowering therapies. Panel (A) depicts sex differences in mean LDL cholesterol reduction (mmol/L) reported in observational studies. Panel (B) depicts sex differences in mean LDL cholesterol reduction (%) from baseline levels reported in observational studies. CI, confidence interval; SD, standard deviation

Figure 5 Absolute LDL cholesterol reductions (mmol/L) in males and females in observational studies included in the systematic review of sex differences in the treatment of familial hypercholesterolaemia. This figure depicts difference in means of LDL cholesterol from baseline to follow-up measurements reported in observational data. Squares represent mean differences; horizontal lines show 95% confidence intervals. Area of the square is proportional to the inverse variance of the estimate. Diamonds represent pooled estimates with 95% confidence intervals derived under the random-effects model. Solid vertical line indicates null effect. Test of subgroup differences refers to variations in the difference of means between male and female subgroups; P-values <.1 are considered significant. CI, confidence interval; SD, standard deviation

Table 1 Characteristics of the 25 real-world observational studies included in the meta-analysis of sex differences in the treatment of familial hypercholesterolaemia with lipid-lowering therapies

First author	Year	Country	Study design	Participants	Diagnosis criteria	Recruitment period	Males
n	Females
n	On LLT	LLT	Baseline
LDL-C	Treated
LDL-C	LDL-C % change	
Agarwala20	2023	USA	Retrospective cohort	HeFH	DLCN
SB
MEDPED
AHA
Genetic	NR	280	502	Statins
M: 84.0%
F: 78.0%	Statins
Ezetimibe
PCSK9i	NR	M: 3.00 ± 1.29
F: 3.23 ± 1.24	NR	
Amrock21	2017	USA	Cross-sectional analysis of registry data	HeFH
HoFH	SB
DLCN
MEDPED	2014–16	1246	1921	Statins
M: 74.6%
F: 66.7%	Statins
Ezetimibe
Bile acid seq
Niacin
PCSK9i	M: 6.27 ± 1.58
F: 6.31 ± 1.48	M: 3.53 ± 1.69
F: 3.96 ± 1.86	M: −43.7%
F: −37.2%	
Arnesen22	2020	Norway	Retrospective cohort	HeFH	DLCN
Genetic	2006	At last visit: 147	At last visit: 127	M: 96.6%
F: 89.8%	Statins
Ezetimibe
Resins
PCSK9i	NR	M: 2.8 (2.6–3.0)
F: 3.3 (3.0–3.5)	NR	
Beliard23	2014	France	Cross-sectional	HeFH	SB
DLCN
Genetic	1988–2011	826	843	M: 89.4%
F: 79.1%	Statins
Ezetimibe
Bile acid seq
Fibrate	NR	NR	NR	
Benn10	2012	Denmark	Cross-sectional	HeFH	DLCN Genetic	1977–2011	204	298	M: 50.0%
F: 47.0%	Statins
Ezetimibe
Bile acid seq
other	NR	NR	NR	
Gallo24	2017	France	Prospective	HeFH	Genetic	2015	56	56	M: 94.6%
F: 69.6%	Statins
Ezetimibe	NR	NR	NR	
Jackson26	2021	USA	Retrospective cohort	FH	USA ICD code for FH	2016–19	25 367	28 431	Statins
M: 65.8%
F: 59.6%	Statins
Ezetimibe
PCSK9i,
Fenofibrate
Other	NR	NR	NR	
Jiménez27	2023	Spain	Retrospective cohort—registry	HeFH	DLCN
Genetic	NR	1583	1778	Statins: 84.1%	Statins
PCSK9i	NR	NR	NR	
Korneva28	2019	Russia	Retrospective cohort—registry	HeFH	DLCN	NR	75	116	Statins
Overall: 65.0%
M: 58.7%
F: 69.0%	Statins	NR	NR	NR	
Krogh29	2016	Norway	Retrospective cohort—registry	FH	DLCN
Genetic	1989–2010	47
LLT data: 43	32
LLT data: 31	Statins: M: 93.0%
F: 87.1%	Statins
Ezetimibe
Bile acid seq
Niacin
Other	M: 9.8 ± 2.7
F: 9.4 ± 2.0	M: 4.7 ± 2.8
F: 5.3 ± 2.0	M: −52.0%
F: −43.6%	
Li30	2017	China	Retrospective cohort	FH	DLCN
Genetic	2011–16	162	119	CAD +
M: 88.8%
F: 78.6%
CAD-
M: 64.3%
F: 57.1%	Statins	NR	NR	NR	
Matta31	2021	Argentina	Prospective study	FH	DLCN	2015–20	30	85	Statins
M: 26.7%
F: 38.8%	Statins	NR	NR	NR	
Mattina32	2019	France	Prospective study	FH	Genetic	2015–16	70	84	M: 92.9%
F: 69.0%	Statins
Ezetimibe	NR	NR	NR	
Mundal11	2014	Norway	Registry	HeFH
HoFH	Genetic	1992–2010	59
LLT data: 38	54
LLT data: 30	88.2%	Statins ± other LLT	NR	M: 4.4 ± 1.4
F: 5.0 ± 1.6	NR	
Neil33	2004	UK	Cross-sectional study—registry	HeFH	SB	1980–96	211
CAD+:104
CAD−:107	199
CAD+: 55
CAD−:144	CAD +
M: 99.0%
F: 94.5%
CAD−
M: 92.5%
F: 74.3%	Statins	NR	NR	NR	
Pang34	2021	Australia	Registry	FH	DLCN
Genetic	2015–19	771	757	LLT
M: 84.3%
F: 77.3%	Statins
Ezetimibe
PCSK9i	M: 7.2 ± 2.6
F: 7.5 ± 2.4	M: 3.6 ± 2.0
F: 4.1 ± 2.0	M: −50.0%
F: −45.3%	
Pérez-Calahorra35	2017	Spain	Cross-sectional analysis of registry data	HeFH	DLCN	2013–16	851	881	NR	NR	NR	NR	NR	
Ryzhaya7	2021	Canada	Retrospective longitudinal study using registry data	FH	DLCN	NR	275	304	Statins
M: 89.6%
F: 88.4%	Statins
Ezetimibe
PCSK9i	M: 6.93 ± 2.0
F: 6.83 ± 2.2	M: 2.71 ± 1.7
F: 3.09 ± 1.2	M: −60.9%
F: −54.8%	
Schreuder36	2023	Netherlands
Norway	Cross-sectional study	HeFH	DLCN
Genetic	2011–17	1465	1713	Per type of LLT Table 1	Statins
Ezetimibe
PCSK9i	M: 6.0 ± 1.7
F: 6.2 ± 1.6	M: 2.8 ± .9
F: 3.1 ± 1.0	M: −52.2%
F: −50.5%	
Vallejo-Vaz37	2018	UK	Retrospective study	HeFH	Phenotypic	NR	714	626	M: 65.5%
F: 65.5%	PCSK9i—Aliro 75/150mg	In mg/dL
M: 150.8 ± 54.1
F: 159.6 ± 62.5	NR	NR	
Vallejo-Vaz6	2021	Internationala	Retrospective cross-sectional—registry	HeFH	DLCN
Genetic
MEDPED
SB
Canadian
JAS	NR	19 031	21 999	M: 61.1%
F: 58.4%	Statins Ezetimibe
Fibrates
PCSK9i	NR	Median (IQR)
M: 4.18 (3.16–5.51)
F: 4.26 (3.24–5.75)	NR	
Vlad38	2021	Romania	Prospective cohort	FH	SB
DLCN
MEDPED	2016–17	22	39	Statins monotherapy at registration
M: 39.8%
F: 38.5%	Statins
Ezetimibe
Fibrates	NR	NR	NR	
Waluś-Miarka39	2017	Poland	Prospective cohort	FH	SB
Genetic	2011–13	63	91	NR	NR	NR	NR	NR	
Zamora8	2023	Spain	Cross-sectional	FH-phenotype	Phenotypic	2006–14	6747
CAD+:
1659
CAD−: 5088	7952
CAD+:
919
CAD−: 7033	Per type of statin Table 2	Statins
Ezetimibe	Overall
M: 7.35 ± .8
F: 7.35 ± .9
CAD +
M: 7.44 ± .90
F: 7.44 ± .93
CAD−
M: 7.31 ± .98
F: 7.34 ± .95	Overall
M: 4.23 ± 1.3
F: 4.50 ± 1.6
CAD +
M: 3.41 ± 1.24
F: 3.77 ± 1.29
CAD−
M: 4.62 ± 1.5
F: 4.65 ± 1.6	Overall
M: 42.4%
F: 38.6%
CAD +
M: −54.2%
F: −49.3%
CAD−
M: −36.8%
F: −36.6%	
Zhao40	2019	Canada	Bi-directional cohort	FH	Canadian
Genetic	NR	80	102	M: 10.0%
F: 6.9%	NR	M: 6.04 ± 1.2
F: 6.35 ± 1.53	M: 3.11 ± 1.41
F: 3.30 ± 1.48	M: −48.5%
F: −48.0%	
AHA, American Heart Association; Bile acid seq., bile acid sequestrants; CAD, coronary artery disease; DLCN, Dutch Lipid Clinic Network; F, females; FH, familial hypercholesterolaemia; HeFH, heterozygous familial hypercholesterolaemia; HoFH, homozygous familial hypercholesterolaemia; ICD code, International Classification of Diseases; IQR, interquartile range; JAS, Japanese Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; M, males; MEDPED, Making Early Diagnosis to Prevent Early Deaths; mg, milligrams; NR, not reported; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor; SB, Simon Broome; UK, United Kingdom; USA, United States of America.

Values are mean ± standard and units in mmol/L unless otherwise stated.

Heath et al.25: Detailed data on treatment of FH per sex in the full group were not available, but data on LDL-C measurements in a subgroup of 47 males vs. 39 females with tendon xanthomas were included in the analyses shown in Figures 4 and 5.

a56 countries (of 66) participating in the European Atherosclerosis Society's Familial Hypercholesterolaemia Studies Collaboration.

Country-specific estimates of sex differences in the treatment of FH with LLT showed heterogeneity in data, whereby in a majority of the 13 countries represented, with the exception of Argentina, Poland, Romania, and Russia, females were less likely to be treated than males (see Supplementary data online, Table S2 and Figure S3). However, in subgroup analyses of sex differences in treatment with LLT by WHO geographical location demonstrated that in all regions (Americas, Europe, Western Pacific, and International), females with FH were less likely to be on LLT compared with males with FH (see Supplementary data online, Figure S4). They were also less likely to be treated compared with males in studies where a majority of participants (>50%) were diagnosed using genetic testing vs. phenotypical/clinical diagnosis (see Supplementary data online, Figure S5). A subgroup analysis of sex differences in treatment was further performed by year of publication of studies included, using year 2016 as a cut-point. There were no significant sex disparities between pooled results obtained before and after 2016 (P = .06, Supplementary data online, Figure S6). Similar findings were obtained when stratifying by study sample size, with fewer vs. more than 1000 patients used as a cut-point (P = .23, Supplementary data online, Figure S7).

The impact of various types and doses of LLTs between sexes was investigated next (summary estimates in Supplementary data online, Table S3). Using random-effects estimates, comparable trends were observed for all medication classes and intensity, with females with FH less likely to be treated with statins [OR .79 (.69–.92)], particularly high-intensity statins [OR .66 (.57–.76)], ezetimibe [OR .67 (.57–.78)], statins and ezetimibe [OR .64 (.48–.86)], PCSK9 inhibitors [OR .70 (.54–.91)], and two or more LLTs [OR .67 (.53–.84)] (see Supplementary data online, Table S4 and Figures S8–S11). This observed trend seemed to diminish, however, with year of publication (see Supplementary data online, Figure S12).

In achievement of guideline-recommended lipid targets or thresholds, females were also less likely to reach ≥50% reduction in LDL-C from baseline [OR .78 (.54–1.13)], an LDL-C < 2.5 mmol/L [OR .85 (.74–.97)], or an LDL-C < 1.8 mmol/L [OR .64, (.43–.97)] (Figure 6 and Supplementary data online, Table S4).

Figure 6 Meta-analyses of sex differences in LDL cholesterol reduction target attainment. Panel (A) depicts sex differences in attainment of ≥50% reductions in LDL cholesterol. Panel (B) depicts sex differences in attainment of an LDL <2.5 mmol/L. Panel (C) depicts sex differences in attainment of an LDL <1.8 mmol/L. Small squares indicate study-level estimates of sex differences in treatment (odds ratios); large squares represent pooled odds ratio derived under random-effects models; horizontal lines represent 95% confidence intervals; vertical dashed line represents null effect. CI, confidence interval

From all 133 studies included in this systematic review of sex differences in the treatment of FH, 57 studies reported data on CVD outcomes and were included in a meta-analysis of MACE. Characteristics of patients from these studies (117 953 participants) are shown in Table 2.6,10,20,30,35,38,40–90 Studies followed participants from a range of 12 weeks to 15 years. Pooling these studies (Figure 7) with 20 575 events, males with FH were identified as having an upward of two-fold greater relative risk of MACE compared with females (OR 2.16 [1.89–2.47]) and a significantly stronger risk of myocardial infarction (MI) [OR 2.81 (2.54–3.12)], with little heterogeneity between studies (I2 = 0%, P = .76). Males also had greater relative risk of coronary heart disease [OR 2.22 (1.85–2.66)], ASCVD [OR 1.94 (1.71–2.19)], and cardiovascular mortality [OR 2.45 (1.47–4.08)]. There were no differences in risk of stroke or peripheral vascular disease between males and females, in 10 studies (72 479 participants; 1809 events) for stroke and nine studies (62 487 participants; 1569 events) for peripheral vascular disease.

Figure 7 Risk of major adverse cardiovascular events in males vs. females with familial hypercholesterolaemia. This figure depicts pooled estimates (circles) with 95% confidence intervals (horizontal lines) for comparisons of the risk of major adverse cardiovascular events in males vs. females with familial hypercholesterolaemia. All pooled estimates are derived using inverse-variance weighting incorporating random-effects. ASCVD, atherosclerotic cardiovascular diseases; CHD, coronary heart disease; CI, confidence interval; CV, cardiovascular; MACE, major adverse cardiovascular events; MI, myocardial infarction; PVD, peripheral vascular disease

Table 2 Characteristics of the 57 studies included in the meta-analysis of sex differences in major adverse cardiovascular events in risk of familial hypercholesterolaemia

First author	Year	Country	Study design	Participants	Diagnosis criteria	Recruitment period	Males, n	Females, n	CVD outcomes	Follow-up time	
Agarwala20	2023	USA	Retrospective cohort	HeFH	DLCN
SB
MEDPED
AHA
Genetic	NR	280	502	Premature ASCVD	NR	
Ahmad41	2016	USA	Retrospective cohort	HeFH	Genetic	NR	42	51	Premature CHD	NR	
Allard42	2014	Canada	Retrospective cohort	HeFH	DLCN	1970–2014	180	229	CVD	NR	
Alonso43	2014	Spain	Registry	HeFH	Genetic	NR	921	1039	CVD	NR	
Beaumont44	1976	France	Cross-sectional	FH	Phenotypic	NR	158	116	IVD: Angina, MI, PVD	NR	
Benn10	2012	Denmark	Cross-sectional	HeFH	DLCN Genetic	1977–2011	204	298	CAD	NR	
Berard45	2019	France	Retrospective cohort	HeFH	DLCN	1995–2005	35	32	Premature ASCVD	NR	
Bertolini46	2013	Italy	Retrospective cohort	HeFH
HoFH	DLCN
Genetic	NR	818	951	CHD	NR	
Besseling47	2014	Netherlands	Registry	HeFH	Genetic	1994–2013	6848	7435	CVD	NR	
Bhatnagar48	2000	UK	Retrospective cohort	HeFH	SB	1987–98	183	197	Angina, MI, CABG, Stroke, CHD, CVD	NR	
Bogsrud49	2019	Norway	Registry	HeFH	Genetic	2014–15	307	407	MI, CHD	11.1 ± 7.9 years	
Bowden50	1994	Canada	Retrospective cohort	HeFH	Phenotypic	NR	48	67	CAD	NR	
Carmena51	1996	Canada	Retrospective cohort	HeFH	Phenotypic	NR	45	53	ASCVD	NR	
Chan52	2015	Australia	Cross-sectional	HeFH	Phenotypic
Genetic	2007–14	171	219	CAD	NR	
De Sauvage Nolting53	2003	Netherlands	Cross-sectional	HeFH	DLCN
Genetic	NR	287	229	CVD	NR	
Doi54	2021	Japan	Retrospective cohort	HeFH	Genetic
JAS	2005–16	116	116	MI, revascularization	NR	
Duell55	2019	USA	Registry	HeFH	DLCN
Genetic
MEDPED
SB	NR	744	1156	ASCVD	20 ± 11 months	
Ershova56	2017	Russia	Retrospective cohort	HeFH	DLCN	2012–13	7	23	CAD, MI	NR	
Firth57	2008	South Africa	Retrospective cohort	HeFH	Phenotypic
Genetic	NR	488	581	Angina, MI, IHD, Stroke, TIA, PVD, Death	NR	
Hill58	1990	Canada	Cross-sectional	HeFH	Phenotypic	NR	CAD data: 115	CAD data: 173	Angina, CAD, MI, Stroke	NR	
Hirobe59	1982	Japan	Cross-sectional	HeFH	Phenotypic	NR	30	22	CAD	NR	
Holmes60	2005	Canada	Retrospective cohort	HeFH	SB	NR	173	215	CVD	NR	
Hoogerbrugge61	1999	Netherlands	Clinical trial	HeFH	Phenotypic	NR	20	20	CAD	12 weeks	
Hopkins62	2001	USA	Registry	HeFH	MEDPED	NR	112	150	Premature CAD	NR	
Iyen63	2019	UK	Retrospective cohorty—registry	FH	DLCN
SB	1999–2016	6578	7519	CVD	13.8 (8.4–17.7) years	
Jansen64	2004	Netherlands	Retrospective cohorty—registry	HeFH	DLCN
MEDPED
SB
Genetic	1989–99	1179	1221	CVD	CVD+: 4.7 (2.4–9.0) years
CVD−: 3.2 (1.2–6.5) years	
Khoury65	2021	Canada	Bi-directional cohort	FH	SB
Genetic	NR	891	888	CVE	NR	
Li30	2017	China	Retrospective cohort	FH	DLCN
Genetic	2011–16	162	119	CAD, Premature CAD	NR	
Mabuchi66	1977	Japan	Cohort	HeFH	Phenotypic	NR	IHD data: 37	IHD data: 46	IHD	NR	
Michikura67	2017	Japan	Cross-sectional	HeFH	Phenotypic	2013–16	53	77	CAD	NR	
Miettinen68	1988	Finland	Retrospective cohort	HeFH	Phenotypic	1968–70	48	48	CAD, CAD Mortality	15 years	
Miname69	2019	Brazil	Prospective study	HeFH	Genetic	NR	75	131	MACE	Median (IQR) 3.7 (2.7–6.8) years	
Mohrschladt70	2004	Netherlands	Retrospective cohort	FH	Phenotypic	NR	190	210	CVD	8 years	
Mundal71	2016	Norway	Registry	HeFH
HoFH	Genetic	1994–2009	2693	2845	CVD hospitalizations	Median (IQR)
5 (1–9) years	
Neil72	2008	UK	Cross-sectional study—registry	HeFH	SB	1980–2006	1650	1732	Angina, CHD, CVD mortality, MI	Median
M: 14.5 years
F: 14.1 years	
Nenseter73	2011	Norway	Retrospective cohort	HeFH	Genetic	2007–9	68	44	CHD	NR	
Panagiotakos74	2003	Greece	Prospective cohort	HeFH	MEDPED	1987–97	295	344	CHD	15 years	
Pang75	2018	South Africa Australia
Brazil	Retrospective cohort—registry	HeFH	Genetic	1990–2017	399	476	CAD	NR	
Perak76	2016	USA	Retrospective cohort	HeFH	AHA	1999–2010	1559	2291	ASCVD, CHD	≥10 years	
Pérez-Calahorra35	2017	Spain	Cross-sectional analysis of registry data	HeFH	DLCN	2013–16	851	881	CVD	NR	
Perez de Isla77	2017	Spain	Registry	HeFH	Genetic	2004–15	1087	1317	ASCVD	5.5 ± 3.2 years	
Perez Garcia78	2018	Spain	Retrospective cohort	HeFH
HoFH	Genetic	2001–17	67	66	CHD	NR	
Pisciotta79	2005	Italy	Prospective cohort	HeFH	Phenotypic	NR	103	146	CAD	NR	
Pitsavos80	2004	Greece
USA	Retrospective cohort	HeFH	Phenotypic	1987–2002	295	344	CHD	6 ± 3 years	
Ramos81	2020	Spain	Retrospective cohort	FH-phenotype	Phenotypic	2006–13	3047	4385	ASCVD	NR	
Sánchez-Ramos82	2021	Spain	Prospective cohort	HeFH	Phenotypic	2004–7	602	105	MACE	6.6 ± 3.6 years	
Seed83	1990	UK	Retrospective cohort	HeFH	SB	NR	61	54	CHD	12 months	
Silva84	2016	Brazil	Prospective cohort	FH	Genetic	NR	302	516	CVD	1 year	
Simonen85	1987	Finland	Retrospective cohort	HeFH	Phenotypic	1970s	49	48	Angina, CAD	NR	
Slack86	1969	UK	Retrospective cohort	HeFH	Phenotypic	NR	51	53	IHD, IHD mortality	NR	
Tada87	2023	Japan	Retrospective cohort	HeFH
HoFH	JAS
Genetic	2000–20	490	560	MACE	12.6 (9.1–17.4) years	
Vallejo-Vaz6	2021	Internationala	Retrospective cross-sectional—registry	HeFH	DLCN
Genetic
MEDPED
SB
Canadian
JAS	NR	19 031	21 999	CAD, PAD, Premature CAD, Stroke	NR	
Vlad38	2021	Romania	Prospective cohort	FH	SB
DLCN
MEDPED	2016–17	CHD data in 61	CHD data in 61	ASCVD, CHD, PAD, Stroke	2 years	
Vuorio88	1997	Finland	Registry	HeFH	Phenotypic
Genetic	1992–96	73	106	CHD, MI	NR	
Wierzbicki89	2000	UK	Retrospective cohort	HeFH	SB	NR	66	46	CHD	≥6 years	
Yaman90	2020	Turkey	Cross-sectional	HeFH	DLCN	2010–16	119	248	CHD	NR	
Zhao40	2019	Canada	Bi-directional cohort	FH	Canadian
Genetic	NR	80	102	Premature MI	≤1 year	
AHA, American Heart Association; ASCVD, atherosclerotic cardiovascular disease; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; CHD, coronary heart disease; CVD, cardiovascular disease; CVE, cardiovascular event; DLCN, Dutch Lipid Clinic Network; F, females; FH, familial hypercholesterolaemia; FU, follow-up; HeFH, heterozygous familial hypercholesterolaemia; HoFH, homozygous familial hypercholesterolaemia; IHD, ischemic heart disease; IQR, interquartile range; IVD, ischaemic vascular disease; JAS, Japanese Atherosclerosis Society; LDL-C, low-density lipoprotein cholesterol; M, males; MACE, major adverse cardiac events; MEDPED, Making Early Diagnosis to Prevent Early Deaths; MI, myocardial infarction; NR, not reported; PAD, peripheral arterial disease; PVD, peripheral vascular disease; SB, Simon Broome; UK, United Kingdom; USA, United States of America.

From the 133 studies included in the qualitative synthesis, i.e. in studies that were found to have data on sex differences in the treatment of FH, 57 were found to have quantitative data on the risk of MACE outcomes for meta-analysis.

a56 countries (of 66) participating in the European Atherosclerosis Society’s Familial Hypercholesterolaemia Studies Collaboration.

Discussion

In the present study, important sex disparities in treatment and lipid target achievement in patients with FH were observed and should be taken into consideration. With data in more than 129 000 patients, this is the largest systematic review performed to date providing evidence for sex differences in treatment with LLT among individuals with FH. These results emphasize the importance of considering sex in risk-stratifying patients with FH and highlight the need for sex-specific strategies for CVD prevention.

In clinical trials using fixed doses of LLTs, males and females with FH displayed similar response to LDL-C lowering medications. Despite this, in observational studies, females were treated less intensively and were less likely to reach guideline-recommended LDL-C targets (see Structured Graphical Abstract). This was independent of WHO geographical location and the proportion of females studied, although the observed trend seemed to diminish with year of publication, suggesting that initiatives by national registries as well as international organizations such as the Family Heart FH Foundation and the FHSC led by the European Atherosclerosis Society may be having an impact to lessen these sex disparities.91,92 Further research is nevertheless needed to identify causes underlying these disparities.

The reasons behind these sex differences are not fully understood but are likely multifactorial. In terms of direct care, one possibility could be that females are reluctant to be treated with LLTs or under-estimate their own health risk with FH. However, our group has previously shown that females do not appear to minimize this risk associated with FH or CVD.5 Other reasons include adverse effects. It has been well described that in general, females report a significantly higher number of side events with LLT than males which may impede up-titration to optimal LLT.36 Healthcare providers might also play a role. In a nationwide multicentre Spanish registry with 3361 adult patients with FH, females had a 49% lower chance of being prescribed a PCSK9 inhibitor than males.27 However, prior studies on FH report no sex differences in adherence to LLT.93,94

In FH, LLT is recommended to reduce the risk of ASCVD without differences according to sex. Evidence from clinical trials of LLT in patients with FH indicates that statins are equally effective in both males and females in the prevention of ASCVD in high-risk populations. In the present meta-analysis, however, we confirm that males and females with FH are less likely to reach guideline-mandated therapeutic thresholds for primary and secondary prevention, with females being treated less intensively than males. These findings support recent studies where females received less high-potency statins and fewer females reached lipid targets of LDL <2.0 mmol/L.7 This lower intensity LLT was especially evident for females in secondary prevention. The differences in goal achievement can be partly explained by the finding that females with FH have higher LDL-C levels from an earlier age,95 are diagnosed 3–7 years later than males, and seldom use maximally tolerated statin doses or combination LLT.6 As a result, achievement of recommended LDL-C treatment goals is subsequently lower. These disparities in FH care impact ASCVD risk, with registry data showing the highest excess risk among younger females with FH.11,96

In the present study, even though females with FH were treated less intensively and reached their LDL-C goals less frequently, males had more than two-fold greater cardiovascular risk. This disparity was consistent across various subgroups and outcomes, including MI, ASCVDs, and cardiovascular death. The association between FH and ASCVD is widely recognized, but there has been uncertainty regarding equality of this excess risk in males and females. While an early report from the Copenhagen General Population Study found no meaningful difference in risk estimates between sexes,10 the UK Simon Broome and Norwegian registries have since documented greater cardiac morbidity and mortality among females.11,96 More recently, a multi-national cross-sectional study of FH registries demonstrated a greater risk of prevalent CAD in males.6 Part of the uncertainty in the evidence may be attributed to disharmony in outcomes examined by previous individual studies and the referral bias seen in disease-specific registries compared with general population settings. Further, females are generally underrepresented in FH and CVD literature, resulting in a lack of statistical precision in risk estimates. Finally, absence of direct comparisons between males and females with FH has made interpreting the limited available data challenging. In this meta-analysis, we aimed to address these shortfalls in the literature.

The sex differences reported here potentially reflect a culmination of genetic and hormonal factors, sex-specific health behaviours, and some systemic determinants. For example, our findings might suggest that other cardio-protective factors, such as pre-menopausal status, higher HDL cholesterol levels, lower prevalence of other cardiovascular risk factors, such as tobacco, or higher levels of triglycerides and remnant lipoprotein cholesterol in males might play a role. In fact, males in the present study may have had more cardiovascular risk factors than their female counterparts,38 which have been shown to exert cumulative97 and sex-specific impacts on CVD risk among those with FH. While some risk estimates included in our analyses accounted for these factors, it is likely that some were not fully adjusted for. Excess risk observed in males may have also been due to differences in treatment with LLT, as we were not able to account for treatment intensity, efficacy, or duration in our analyses. This explanation may be less likely, however, given our current results suggesting that males with FH are treated earlier98 and more aggressively than female counterparts and are more likely to reach cholesterol reduction targets.27 Finally, it may be possible that a greater proportion of females included in studies represented non-index cases given the earlier onset of cardiovascular events in males. Studies have demonstrated that affected relatives are detected several years earlier, with fewer cardiovascular risk factors and improved cardiovascular outcomes.6

Interestingly, no difference between males and females was found in the risk of stroke and peripheral vascular disease, contrasting patterns seen in the general population.99–101 A potential explanation for this may be similar rates of predisposing factors such as atrial fibrillation and heart failure among males and females with FH.102 Alternatively, it is possible that factors such as age, socioeconomic status, and lifestyle behaviours interact with sex and gender to impact the likelihood of stroke and peripheral vascular disease.103 If that were the case, uncovering these potentially protective determinants would present an important priority for future research.

This study has some strengths and limitations that merit consideration. Among its strengths are its exhaustive search, large sample size, diversity of study populations, extensive sensitivity investigations, and the important information it brings to the field. In terms of limitations, first omission of relevant reports cannot be ruled out despite extensive search efforts. However, the large number of studies included in our primary analysis made these results robust to the inclusion of any single investigation. Second, studies reporting significant associations between sex and cardiovascular outcomes might be more likely to be published. Third, it is recognized that the trim-and-fill method may not be valid in the presence of excess heterogeneity between studies.19 A high degree of heterogeneity (I2 > 70%) was observed for several analyses, likely explained by difference in studies design, diagnostic criteria, and endpoint definitions, suggesting bias between studies (see Supplementary data online, Figure S13). This is consistent with the meta-analysis being a study-level rather than a patient-level meta-analysis, with both retrospective and prospective studies included. We anticipated and accounted for this heterogeneity using random-effects models. Finally, while our study evaluated sex differences in outcomes in patients with FH, we were unable to account for gender identity and other important aspects of intersectionality in our analyses. Accordingly, these present pressing areas for future research.

Conclusions

The present study found than males and females with FH show similar response to LDL-C lowering medications. Despite this, females seemed less likely to be treated intensively and to reach guideline-recommended LDL-C targets. A better understanding of drivers of sex-related disparities in FH treatment is needed. Identifying these imbalances will allow us to reduce barriers to care and improve survival in individuals with FH.

Supplementary data

Supplementary data are available at European Heart Journal online.

Supplementary Material

ehae417_Supplementary_Data

Declarations

Disclosure of Interest

J.G. leads the Canadian Registry on FH (www.fhcanada.net). L.R.B. sits on advisory boards for Novartis, Amgen, Ultragenyx, and Novo Nordisk. All other authors have declared that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data Availability

The Rayyan file containing the studies reviewed and included in the systematic review is available from the corresponding author on reasonable request.

Funding

This research was supported by a project grant from the Canadian Institutes of Health Research (Grant PJT-168886 to J.G., T.C., and L.R.B.). The funder of the study had no role in study design, collection and interpretation of data, writing the report, or the decision to submit for publication.

Ethical Approval

Ethical approval was not required.

Pre-registered Clinical Trial Number

Not applicable.
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References

1 Hu  P, Dharmayat  KI, Stevens  CAT, Sharabiani  MTA, Jones  RS, Watts  GF, et al  Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation  2020;141 :1742–59. 10.1161/CIRCULATIONAHA.119.044795 32468833
2 Nordestgaard  BG, Chapman  MJ, Humphries  SE, Ginsberg  HN, Masana  L, Descamps  OS, et al  Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J  2013;34 :3478–3490a. 10.1093/eurheartj/eht273 23956253
3 Ademi  Z, Watts  GF, Juniper  A, Liew  D. A systematic review of economic evaluations of the detection and treatment of familial hypercholesterolemia. Int J Cardiol  2013;167 :2391–6. 10.1016/j.ijcard.2013.01.280 23490080
4 Akioyamen  LE, Genest  J, Shan  SD, Inibhunu  H, Chu  A, Tu  JV. Anxiety, depression, and health-related quality of life in heterozygous familial hypercholesterolemia: a systematic review and meta-analysis. J Psychosom Res  2018;109 :32–43. 10.1016/j.jpsychores.2018.03.170 29773150
5 Alshibani  B, Iatan  I, Guerin  A, Ruel  I, Cermakova  L, Ramanakumar  AV, et al  Sex differences in the perception of cardiovascular risk in familial hypercholesterolemia. J Clin Lipidol  2024;18 :e97–104. 10.1016/j.jacl.2023.10.007 37926591
6 EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) . Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Lancet  2021;398 :1713–25. 10.1016/S0140-6736(21)01122-3 34506743
7 Ryzhaya  N, Cermakova  L, Trinder  M, Ruel  I, Coutinho  T, Genest  J, et al  Sex differences in the presentation, treatment, and outcome of patients with familial hypercholesterolemia. J Am Heart Assoc  2021;10 :e019286. 10.1161/JAHA.120.019286 34032141
8 Zamora  A, Ramos  R, Comas-Cufi  M, Garcia-Gil  M, Marti-Lluch  R, Plana  N, et al  Women with familial hypercholesterolemia phenotype are undertreated and poorly controlled compared to men. Sci Rep  2023;13 :1492. 10.1038/s41598-023-27963-z 36707646
9 European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration . Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study. Lancet  2024;403 :55–66. 10.1016/S0140-6736(23)01842-1 38101429
10 Benn  M, Watts  GF, Tybjaerg-Hansen  A, Nordestgaard  BG. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab  2012;97 :3956–64. 10.1210/jc.2012-1563 22893714
11 Mundal  L, Sarancic  M, Ose  L, Iversen  PO, Borgan  J-K, Veierod  MB, et al  Mortality among patients with familial hypercholesterolemia: a registry-based study in Norway, 1992–2010. J Am Heart Assoc  2014;3 :e001236. 10.1161/JAHA.114.001236 25468658
12 Iyen  B, Qureshi  N, Weng  S, Roderick  P, Kai  J, Capps  N, et al  Sex differences in cardiovascular morbidity associated with familial hypercholesterolaemia: a retrospective cohort study of the UK Simon Broome register linked to national hospital records. Atherosclerosis  2020;315 :131–7. 10.1016/j.atherosclerosis.2020.10.895 33187671
13 Page  MJ, McKenzie  JE, Bossuyt  PM, Boutron  I, Hoffmann  TC, Mulrow  CD, et al  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ  2021;372 :n71. 10.1136/bmj.n71 33782057
14 Stroup  DF, Berlin  JA, Morton  SC, Olkin  I, Williamson  GD, Rennie  D, et al  Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group. JAMA  2000;283 :2008–12. 10.1001/jama.283.15.2008 10789670
15 Heidari  S, Babor  TF, De Castro  P, Tort  S, Curno  M. Sex and gender equity in research: rationale for the SAGER guidelines and recommended use. Res Integr Peer Rev  2016;1 :2. 10.1186/s41073-016-0007-6 29451543
16 Thomas  BH, Ciliska  D, Dobbins  M, Micucci  S. A process for systematically reviewing the literature: providing the research evidence for public health nursing interventions. Worldviews Evid Based Nurs  2004;1 :176–84. 10.1111/j.1524-475X.2004.04006.x 17163895
17 DerSimonian  R, Laird  N. Meta-analysis in clinical trials. Control Clin Trials  1986;7 :177–88. 10.1016/0197-2456(86)90046-2 3802833
18 Egger  M, Davey Smith  G, Schneider  M, Minder  C. Bias in meta-analysis detected by a simple, graphical test. BMJ  1997;315 :629–34. 10.1136/bmj.315.7109.629 9310563
19 Peters  JL, Sutton  AJ, Jones  DR, Abrams  KR, Rushton  L. Performance of the trim and fill method in the presence of publication bias and between-study heterogeneity. Stat Med  2007;26 :4544–62. 10.1002/sim.2889 17476644
20 Agarwala  A, Deych  E, Jones  LK, Sturm  AC, Aspry  K, Ahmad  Z, et al  Sex-related differences in premature cardiovascular disease in familial hypercholesterolemia. J Clin Lipidol  2023;17 :150–6. 10.1016/j.jacl.2022.11.009 36470719
21 Amrock  SM, Duell  PB, Knickelbine  T, Martin  SS, O'Brien  EC, Watson  KE, et al  Health disparities among adult patients with a phenotypic diagnosis of familial hypercholesterolemia in the CASCADE-FH TM patient registry. Atherosclerosis  2017;267 :19–26. 10.1016/j.atherosclerosis.2017.10.006 29080546
22 Arnesen  K-E, Phung  AV, Randsborg  K, Mork  I, Thorvall  M, Langslet  G, et al  Risk of recurrent coronary events in patients with familial hypercholesterolemia; a 10-years prospective study. Front Pharmacol  2020;11 :560958. 10.3389/fphar.2020.560958 33737874
23 Beliard  S, Carreau  V, Carrie  A, Giral  P, Duchene  E, Farnier  M, et al  Improvement in LDL-cholesterol levels of patients with familial hypercholesterolemia: can we do better? Analysis of results obtained during the past two decades in 1669 French subjects. Atherosclerosis  2014;234 :136–41. 10.1016/j.atherosclerosis.2014.02.021 24637413
24 Gallo  A, Giral  P, Carrie  A, Carreau  V, Beliard  S, Bittar  R, et al  Early coronary calcifications are related to cholesterol burden in heterozygous familial hypercholesterolemia. J Clin Lipidol  2017;11 :704–711.e2. 10.1016/j.jacl.2017.03.016 28456681
25 Heath  KE, Gudnason  V, Humphries  SE, Seed  M. The type of mutation in the low density lipoprotein receptor gene influences the cholesterol-lowering response of the HMG-CoA reductase inhibitor simvastatin in patients with heterozygous familial hypercholesterolaemia. Atherosclerosis  1999;143 :41–54. 10.1016/S0021-9150(98)00274-3 10208479
26 Jackson  CL, Deng  Y, Yao  X, Van Houten  H, Shah  ND, Kopecky  S. Proprotein convertase subtilisin/kexin type 9 inhibitor utilization and low-density lipoprotein-cholesterol control in familial hypercholesterolemia. J Clin Lipidol  2021;15 :339–46. 10.1016/j.jacl.2020.12.009 33419720
27 Jimenez  A, Vinals  C, Marco-Benedi  V, Gonzalez  P, Domenech  M, Suarez-Tembra  M, et al  Sex disparities in familial hypercholesterolemia. J Am Coll Cardiol  2023;81 :203–5. 10.1016/j.jacc.2022.10.023 36631212
28 Korneva  V, Kuznetsova  T, Julius  U. Efficiency and problems of statin therapy in patients with heterozygous familial hypercholesterolemia. Atheroscler Suppl  2019;40 :79–87. 10.1016/j.atherosclerosissup.2019.08.029 31818452
29 Krogh  HW, Mundal  L, Holven  KB, Retterstol  K. Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death. Eur Heart J  2016;37 :1398–405. 10.1093/eurheartj/ehv602 26586781
30 Li  J-J, Li  S, Zhu  C-G, Wu  N-Q, Zhang  Y, Guo  Y-L, et al  Familial hypercholesterolemia phenotype in Chinese patients undergoing coronary angiography. Arterioscler Thromb Vasc Biol  2017;37 :570–9. 10.1161/ATVBAHA.116.308456 27932355
31 Matta  MG, Saenz  B, Schreier  L, Corral  A, Sarobe  A, Corral  P. Use and persistence of lipid-lowering therapy in patients with severe hypercholesterolemia: a prospective study. Clin Investig Arterioscler  2021;33 :308–13. 10.1016/j.arteri.2021.07.003
32 Mattina  A, Giammanco  A, Giral  P, Rosenbaum  D, Carrie  A, Cluzel  P, et al  Polyvascular subclinical atherosclerosis in familial hypercholesterolemia: the role of cholesterol burden and gender. Nutr Metab Cardiovasc Dis  2019;29 :1068–76. 10.1016/j.numecd.2019.06.015 31378630
33 Neil  HAW, Seagroatt  V, Betteridge  DJ, Cooper  MP, Durrington  PN, Miller  JP, et al  Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart  2004;90 :1431–7. 10.1136/hrt.2003.022764 15547022
34 Pang  J, Sullivan  DR, Hare  DL, Colquhoun  DM, Bates  TR, Ryan  JDM, et al  Gaps in the care of familial hypercholesterolaemia in Australia: first report from the National registry. Heart Lung Circ  2021;30 :372–9. 10.1016/j.hlc.2020.07.012 32873489
35 Perez-Calahorra  S, Sanchez-Hernandez  RM, Plana  N, Marco-Benedi  V, Pedro-Botet  J, Almagro  F, et al  Value of the definition of severe familial hypercholesterolemia for stratification of heterozygous patients. Am J Cardiol  2017;119 :742–8. 10.1016/j.amjcard.2016.11.025 28081939
36 Schreuder  MM, Hamkour  S, Siegers  KE, Holven  KB, Johansen  AK, van de Ree  MA, et al  LDL cholesterol targets rarely achieved in familial hypercholesterolemia patients: a sex and gender-specific analysis. Atherosclerosis  2023;384 :117117. 10.1016/j.atherosclerosis.2023.03.022 37080805
37 Vallejo-Vaz  AJ, Ginsberg  HN, Davidson  MH, Eckel  RH, Cannon  CP, Lee  LV, et al  Lower on-treatment low-density lipoprotein cholesterol and Major adverse cardiovascular events in women and men: pooled analysis of 10 ODYSSEY phase 3 alirocumab trials. J Am Heart Assoc  2018;7 :e009221. 10.1161/JAHA.118.009221 30371190
38 Vlad  CE, Foia  L, Florea  L, Costache  II, Covic  A, Popescu  R, et al  Evaluation of cardiovascular risk factors in patients with familial hypercholesterolemia from the North-Eastern area of Romania. Lipids Health Dis  2021;20 :4. 10.1186/s12944-020-01428-y 33430859
39 Walus-Miarka  M, Czarnecka  D, Kloch-Badelek  M, Wojciechowska  W, Kapusta  M, Malecki  MT. Carotid artery plaques—are risk factors the same in men and women with familial hypercholesterolemia?  Int J Cardiol  2017;244 :290–5. 10.1016/j.ijcard.2017.06.076 28663044
40 Zhao  PJ, Ban  MR, Iacocca  MA, McIntyre  AD, Wang  J, Hegele  RA. Genetic determinants of myocardial infarction risk in familial hypercholesterolemia. CJC Open  2019;1 :225–30. 10.1016/j.cjco.2019.06.001 32159113
41 Ahmad  Z, Li  X, Wosik  J, Mani  P, Petr  J, McLeod  G, et al  Premature coronary heart disease and autosomal dominant hypercholesterolemia: increased risk in women with LDLR mutations. J Clin Lipidol  2016;10 :101–108.e1–3. 10.1016/j.jacl.2015.09.003 26892126
42 Allard  MD, Saeedi  R, Yousefi  M, Frohlich  J. Risk stratification of patients with familial hypercholesterolemia in a multi-ethnic cohort. Lipids Health Dis  2014;13 :65. 10.1186/1476-511X-13-65 24712315
43 Alonso  R, Andres  E, Mata  N, Fuentes-Jimenez  F, Badimon  L, Lopez-Miranda  J, et al  Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J Am Coll Cardiol  2014;63 :1982–9. 10.1016/j.jacc.2014.01.063 24632281
44 Beaumont  V, Jacotot  B, Beaumont  JL. Ischaemic disease in men and women with familial hypercholesterolaemia and xanthomatosis. A comparative study of genetic and environmental factors in 274 heterozygous cases. Atherosclerosis  1976;24 :441–50. 10.1016/0021-9150(76)90136-2 971346
45 Berard  E, Bongard  V, Haas  B, Dallongeville  J, Moitry  M, Cottel  D, et al  Prevalence and treatment of familial hypercholesterolemia in France. Can J Cardiol  2019;35 :744–52. 10.1016/j.cjca.2019.02.013 31151710
46 Bertolini  S, Pisciotta  L, Rabacchi  C, Cefalu  AB, Noto  D, Fasano  T, et al  Spectrum of mutations and phenotypic expression in patients with autosomal dominant hypercholesterolemia identified in Italy. Atherosclerosis  2013;227 :342–8. 10.1016/j.atherosclerosis.2013.01.007 23375686
47 Besseling  J, Kindt  I, Hof  M, Kastelein  JJP, Hutten  BA, Hovingh  GK. Severe heterozygous familial hypercholesterolemia and risk for cardiovascular disease: a study of a cohort of 14,000 mutation carriers. Atherosclerosis  2014;233 :219–23. 10.1016/j.atherosclerosis.2013.12.020 24529147
48 Bhatnagar  D, Morgan  J, Siddiq  S, Mackness  MI, Miller  JP, Durrington  PN. Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. BMJ  2000;321 :1497–500. 10.1136/bmj.321.7275.1497 11118175
49 Bogsrud  MP, Graesdal  A, Johansen  D, Langslet  G, Hovland  A, Arnesen  KE, et al  LDL-cholesterol goal achievement, cardiovascular disease, and attributed risk of Lp(a) in a large cohort of predominantly genetically verified familial hypercholesterolemia. J Clin Lipidol  2019;13 :279–86. 10.1016/j.jacl.2019.01.010 30910667
50 Bowden  JF, Pritchard  PH, Hill  JS, Frohlich  JJ. Lp(a) concentration and apo(a) isoform size. Relation to the presence of coronary artery disease in familial hypercholesterolemia. Arterioscler Thromb  1994;14 :1561–8. 10.1161/01.ATV.14.10.1561 7918305
51 Carmena  R, Lussier-Cacan  S, Roy  M, Minnich  A, Lingenhel  A, Kronenberg  F, et al  Lp(a) levels and atherosclerotic vascular disease in a sample of patients with familial hypercholesterolemia sharing the same gene defect. Arterioscler Thromb Vasc Biol  1996;16 :129–36. 10.1161/01.ATV.16.1.129 8548413
52 Chan  DC, Pang  J, Hooper  AJ, Burnett  JR, Bell  DA, Bates  TR, et al  Elevated lipoprotein(a), hypertension and renal insufficiency as predictors of coronary artery disease in patients with genetically confirmed heterozygous familial hypercholesterolemia. Int J Cardiol  2015;201 :633–8. 10.1016/j.ijcard.2015.08.146 26340131
53 de Sauvage Nolting  PRW, Defesche  JC, Buirma  RJA, Hutten  BA, Lansberg  PJ, Kastelein  JJ. Prevalence and significance of cardiovascular risk factors in a large cohort of patients with familial hypercholesterolaemia. J Intern Med  2003;253 :161–8. 10.1046/j.1365-2796.2003.01070.x 12542556
54 Doi  T, Hori  M, Harada-Shiba  M, Kataoka  Y, Onozuka  D, Nishimura  K, et al  Patients with LDLR and PCSK9 gene variants experienced higher incidence of cardiovascular outcomes in heterozygous familial hypercholesterolemia. J Am Heart Assoc  2021;10 :e018263. 10.1161/JAHA.120.018263 33533259
55 Duell  PB, Gidding  SS, Andersen  RL, Knickelbine  T, Anderson  L, Gianos  E, et al  Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: the CASCADE FH registry. Atherosclerosis  2019;289 :85–93. 10.1016/j.atherosclerosis.2019.08.007 31487564
56 Ershova  AI, Meshkov  AN, Bazhan  SS, Storozhok  MA, Efanov  AY, Medvedeva  IV, et al  The prevalence of familial hypercholesterolemia in the West Siberian region of the Russian Federation: a substudy of the ESSE-RF. PLoS One  2017;12 :e0181148. 10.1371/journal.pone.0181148 28719663
57 Firth  JC, Marais  AD. Familial hypercholesterolaemia: the Cape Town experience. S Afr Med J  2008;98 :99–104.18350202
58 Hill  JS, Hayden  MR, Frohlich  J, Pritchard  PH. Genetic and environmental factors affecting the incidence of coronary artery disease in heterozygous familial hypercholesterolemia. Arterioscler Thromb  1991;11 :290–7. 10.1161/01.ATV.11.2.290 1998646
59 Hirobe  K, Matsuzawa  Y, Ishikawa  K, Tarui  S, Yamamoto  A, Nambu  S, et al  Coronary artery disease in heterozygous familial hypercholesterolemia. Atherosclerosis  1982;44 :201–10. 10.1016/0021-9150(82)90114-9 7138620
60 Holmes  DT, Schick  BA, Humphries  KH, Frohlich  J. Lipoprotein(a) is an independent risk factor for cardiovascular disease in heterozygous familial hypercholesterolemia. Clin Chem  2005;51 :2067–73. 10.1373/clinchem.2005.055228 16141286
61 Hoogerbrugge  N, Jansen  H. Atorvastatin increases low-density lipoprotein size and enhances high-density lipoprotein cholesterol concentration in male, but not in female patients with familial hypercholesterolemia. Atherosclerosis  1999;146 :167–74. 10.1016/S0021-9150(99)00125-2 10487500
62 Hopkins  PN, Stephenson  S, Wu  LL, Riley  WA, Xin  Y, Hunt  SC. Evaluation of coronary risk factors in patients with heterozygous familial hypercholesterolemia. Am J Cardiol  2001;87 :547–53. 10.1016/S0002-9149(00)01429-6 11230837
63 Iyen  B, Qureshi  N, Kai  J, Akyea  RK, Leonardi-Bee  J, Roderick  P, et al  Risk of cardiovascular disease outcomes in primary care subjects with familial hypercholesterolaemia: a cohort study. Atherosclerosis  2019;287 :8–15. 10.1016/j.atherosclerosis.2019.05.017 31181417
64 Jansen  ACM, van Aalst-Cohen  ES, Tanck  MW, Trip  MD, Lansberg  PJ, Liem  AH, et al  The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients. J Intern Med  2004;256 :482–90. 10.1111/j.1365-2796.2004.01405.x 15554949
65 Khoury  E, Brisson  D, Roy  N, Tremblay  G, Gaudet  D. Identifying markers of cardiovascular event-free survival in familial hypercholesterolemia. J Clin Med  2021;10 :64. 10.3390/jcm10010064
66 Mabuchi  H, Haba  T, Ueda  K, Ueda  R, Tatami  R, Ito  S, et al  Serum lipids and coronary heart disease in heterozygous familial hypercholesterolemia in the Hokuriku District of Japan. Atherosclerosis  1977;28 :417–23. 10.1016/0021-9150(77)90068-5 597349
67 Michikura  M, Ogura  M, Yamamoto  M, Sekimoto  M, Fuke  C, Hori  M, et al  Achilles tendon ultrasonography for diagnosis of familial hypercholesterolemia among Japanese subjects. Circ J  2017;81 :1879–85. 10.1253/circj.CJ-17-0041 28652530
68 Miettinen  TA, Gylling  H. Mortality and cholesterol metabolism in familial hypercholesterolemia. Long-term follow-up of 96 patients. Arteriosclerosis  1988;8 :163–7. 10.1161/01.ATV.8.2.163 3348758
69 Miname  MH, Bittencourt  MS, Moraes  SR, Alves  RIM, Silva  PRS, Jannes  CE, et al  Coronary artery calcium and cardiovascular events in patients with familial hypercholesterolemia receiving standard lipid-lowering therapy. JACC Cardiovasc Imaging  2019;12 :1797–804. 10.1016/j.jcmg.2018.09.019 30448145
70 Mohrschladt  MF, Westendorp  RGJ, Gevers Leuven  JA, Smelt  AHM. Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia. Atherosclerosis  2004;172 :329–35. 10.1016/j.atherosclerosis.2003.11.007 15019543
71 Mundal  L, Veierod  MB, Halvorsen  T, Holven  KB, Ose  L, Iversen  PO, et al  Cardiovascular disease in patients with genotyped familial hypercholesterolemia in Norway during 1994–2009, a registry study. Eur J Prev Cardiol  2016;23 :1962–9. 10.1177/2047487316666371 27558979
72 Neil  A, Cooper  J, Betteridge  J, Capps  N, McDowell  I, Durrington  P, et al  Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J  2008;29 :2625–33. 10.1093/eurheartj/ehn422 18840879
73 Nenseter  MS, Lindvig  HW, Ueland  T, Langslet  G, Ose  L, Holven  KB, et al  Lipoprotein(a) levels in coronary heart disease-susceptible and -resistant patients with familial hypercholesterolemia. Atherosclerosis  2011;216 :426–32. 10.1016/j.atherosclerosis.2011.02.007 21376325
74 Panagiotakos  DB, Pitsavos  C, Skoumas  J, Chrysohoou  C, Toutouza  M, Stefanadis  CI, et al  Importance of LDL/HDL cholesterol ratio as a predictor for coronary heart disease events in patients with heterozygous familial hypercholesterolaemia: a 15-year follow-up (1987–2002). Curr Med Res Opin  2003;19 :89–94. 10.1185/0300799039117034 12755140
75 Pang  J, David Marais  A, Blom  DJ, Brice  BC, Silva  PR, Jannes  CE, et al  Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: importance of early detection and lifestyle advice. Atherosclerosis  2018;277 :470–6. 10.1016/j.atherosclerosis.2018.06.822 30270087
76 Perak  AM, Ning  H, de Ferranti  SD, Gooding  HC, Wilkins  JT, Lloyd-Jones  DM. Long-term risk of atherosclerotic cardiovascular disease in US adults with the familial hypercholesterolemia phenotype. Circulation  2016;134 :9–19. 10.1161/CIRCULATIONAHA.116.022335 27358432
77 Perez de Isla  L, Alonso  R, Mata  N, Fernandez-Perez  C, Muniz  O, Diaz-Diaz  JL, et al  Predicting cardiovascular events in familial hypercholesterolemia: the SAFEHEART registry (Spanish Familial Hypercholesterolemia Cohort Study). Circulation  2017;135 :2133–44. 10.1161/CIRCULATIONAHA.116.024541 28275165
78 Perez Garcia  L . Familial hypercholesterolemia: experience in the lipid clinic of Alava. Clin Investig Arterioscler  2018;30 :224–9. 10.1016/j.arteri.2018.04.007
79 Pisciotta  L, Cortese  C, Gnasso  A, Liberatoscioli  L, Pastore  A, Mannucci  L, et al  Serum homocysteine, methylenetetrahydrofolate reductase gene polymorphism and cardiovascular disease in heterozygous familial hypercholesterolemia. Atherosclerosis  2005;179 :333–8. 10.1016/j.atherosclerosis.2004.10.016 15777550
80 Pitsavos  CH, Chrysohoou  C, Panagiotakos  DB, Kokkinos  P, Skoumas  J, Papaioannou  I, et al  Exercise capacity and heart rate recovery as predictors of coronary heart disease events, in patients with heterozygous Familial Hypercholesterolemia. Atherosclerosis  2004;173 :347–52. 10.1016/j.atherosclerosis.2003.12.027 15064112
81 Ramos  R, Masana  L, Comas-Cufi  M, Garcia-Gil  M, Marti-Lluch  R, Ponjoan  A, et al  Derivation and validation of SIDIAP-FHP score: a new risk model predicting cardiovascular disease in familial hypercholesterolemia phenotype. Atherosclerosis  2020;292 :42–51. 10.1016/j.atherosclerosis.2019.10.016 31759248
82 Sanchez-Ramos  A, Fernandez-Labandera  C, Vallejo-Vaz  AJ, Bonacho  EC, Quevedo-Aguado  L, Catalina-Romero  C, et al  Prevalence of familial hypercholesterolemia phenotype and ten-year risk of cardiovascular events in a working population in primary prevention: the ICARIA study. Atherosclerosis  2021;338 :39–45. 10.1016/j.atherosclerosis.2021.11.007 34785430
83 Seed  M, Hoppichler  F, Reaveley  D, McCarthy  S, Thompson  GR, Boerwinkle  E, et al  Relation of serum lipoprotein(a) concentration and apolipoprotein(a) phenotype to coronary heart disease in patients with familial hypercholesterolemia. N Engl J Med  1990;322 :1494–9. 10.1056/NEJM199005243222104 2139920
84 Silva  PRS, Jannes  CE, Marsiglia  JDC, Krieger  JE, Santos  RD, Pereira  AC. Predictors of cardiovascular events after one year of molecular screening for Familial hypercholesterolemia. Atherosclerosis  2016;250 :144–50. 10.1016/j.atherosclerosis.2016.05.023 27214396
85 Simonen  H, Miettinen  TA. Coronary artery disease and bile acid synthesis in familial hypercholesterolemia. Atherosclerosis  1987;63 :159–66. 10.1016/0021-9150(87)90116-X 3827979
86 Slack  J . Risks of ischaemic heart-disease in familial hyperlipoproteinaemic states. Lancet  1969;2 :1380–2. 10.1016/S0140-6736(69)90930-1 4188273
87 Tada  H, Nomura  A, Nohara  A, Usui  S, Sakata  K, Hayashi  K, et al  Attainment of the low-density lipoprotein cholesterol treatment target and prognosis of heterozygous familial hypercholesterolemia. Atherosclerosis  2023;371 :61–6. 10.1016/j.atherosclerosis.2023.03.005 36948965
88 Vuorio  AF, Turtola  H, Piilahti  KM, Repo  P, Kanninen  T, Kontula  K. Familial hypercholesterolemia in the Finnish north Karelia. A molecular, clinical, and genealogical study. Arterioscler Thromb Vasc Biol  1997;17 :3127–38. 10.1161/01.ATV.17.11.3127 9409302
89 Wierzbicki  AS, Lambert-Hammill  M, Lumb  PJ, Crook  MA. Renin-angiotensin system polymorphisms and coronary events in familial hypercholesterolemia. Hypertension  2000;36 :808–12. 10.1161/01.HYP.36.5.808 11082147
90 Yaman  S, Ozdemir  D, Akman  BT, Cakir  B, Ersoy  O. Awareness, treatment rates, and compliance to treatment in patients with serum LDL cholesterol higher than 250 mg/dL, and possible, probable, or definite familial hypercholesterolemia. Postgrad Med  2021;133 :146–53. 10.1080/00325481.2020.1805212 32744105
91 Family Heart FH Foundation. 2023. https://familyheart.org/cascade-fh-registry-clinical.
92 Familial Hypercholesterolaemia Studies Collaboration. 2023. https://eas-fhsc.org.
93 Langslet  G, Johansen  AK, Bogsrud  MP, Narverud  I, Risstad  H, Retterstol  K, et al  Thirty percent of children and young adults with familial hypercholesterolemia treated with statins have adherence issues. Am J Prev Cardiol  2021;6 :100180. 10.1016/j.ajpc.2021.100180 34327501
94 Galema-Boers  JMH, Lenzen  MJ, van Domburg  RT, Roeters van Lennep  J, van Bruchem-van de Scheur  GG, Sijbrands  EJ, et al  Predicting non-adherence in patients with familial hypercholesterolemia. Eur J Clin Pharmacol  2014;70 :391–7. 10.1007/s00228-013-1640-3 24449092
95 Holven  KB, Narverud  I, van Lennep  JR, Versmissen  J, Oyri  LKL, Galema-Boers  A, et al  Sex differences in cholesterol levels from birth to 19 years of age may lead to increased cholesterol burden in females with FH. J Clin Lipidol  2018;12 :748–755.e2. 10.1016/j.jacl.2018.02.021 29609857
96 Iyen  B, Qureshi  N, Roderick  P, Durrington  P, McDowell  I, Soran  H, et al  Characteristics and cardiovascular disease morbidity of men and women with familial hypercholesterolaemia (FH): a cohort study using data from the UK Simon Broome register linked with secondary care records. Atherosclerosis  2020;315 :e77. 10.1016/j.atherosclerosis.2020.10.239
97 Masana  L, Zamora  A, Plana  N, Comas-Cufi  M, Garcia-Gil  M, Marti-Lluch  R, et al  Incidence of cardiovascular disease in patients with familial hypercholesterolemia phenotype: analysis of 5 years follow-up of real-world data from more than 1.5 million patients. J Clin Med  2019;8 :1080. 10.3390/jcm8071080 31340450
98 Langslet  G, Bogsrud  MP, Halvorsen  I, Fjeldstad  H, Retterstol  K, Veierod  MB, et al  Long-term follow-up of young adults with familial hypercholesterolemia after participation in clinical trials during childhood. J Clin Lipidol  2015;9 :778–85. 10.1016/j.jacl.2015.08.008 26687698
99 Rexrode  KM, Madsen  TE, Yu  AYX, Carcel  C, Lichtman  JH, Miller  EC. The impact of sex and gender on stroke. Circ Res  2022;130 :512–28. 10.1161/CIRCRESAHA.121.319915 35175851
100 Leppert  MH, Burke  JF, Lisabeth  LD, Madsen  TE, Kleindorfer  DO, Sillau  S, et al  Systematic review of sex differences in ischemic strokes among young adults: are young women disproportionately at risk?  Stroke  2022;53 :319–27. 10.1161/STROKEAHA.121.037117 35073188
101 Pabon  M, Cheng  S, Altin  SE, Sethi  SS, Nelson  MD, Moreau  KL, et al  Sex differences in peripheral artery disease. Circ Res  2022;130 :496–511. 10.1161/CIRCRESAHA.121.320702 35175843
102 Hovland  A, Mundal  LJ, Igland  J, Veierod  MB, Holven  KB, Bogsrud  MP, et al  Increased risk of heart failure and atrial fibrillation in heterozygous familial hypercholesterolemia. Atherosclerosis  2017;266 :69–73. 10.1016/j.atherosclerosis.2017.09.027 28992466
103 Mauvais-Jarvis  F, Bairey Merz  N, Barnes  PJ, Brinton  RD, Carrero  JJ, DeMeo  DL, et al  Sex and gender: modifiers of health, disease, and medicine. Lancet  2020;396 :565–82. 10.1016/S0140-6736(20)31561-0 32828189
