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Atherosclerosis 393 (2024) 117516
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0021-9150/© 2024 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
Improved lipid-lowering treatment and reduction in cardiovascular disease 
burden in homozygous familial hypercholesterolemia: The SAFEHEART 
follow-up study 
Rodrigo Alonso a,b,1,*, Raquel Arroyo-Olivares a,1, Jose Luis Díaz-Díaz c, 
Francisco Fuentes-Jiménez d, Francisco Arrieta e, Raimundo de Andrés f, 
Pablo Gonzalez-Bustos g, Rosa Argueso h, Mercedes Martin-Ordiales i, Ceferino Martinez-Faedo j, 
Fátima Illán k, Pedro Saenz l, José María Donate m, Juan F. Sanchez Muñoz-Torrero n, 
Sergio Martinez-Hervas o, Pedro Mata a,** 
a Fundación Hipercolesterolemia Familiar, Madrid, Spain 
b Center for Advanced Metabolic Medicine and Nutrition, Santiago, Chile 
c Department of Internal Medicine, Hospital Abente y Lago, A Coruña, Spain 
d Maimonides Biomedical Research Institute of Cordoba (IMIBIC), University of Cordoba, Reina Sofia University Hospital, CIBERObn, Córdoba, Spain 
e Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain 
f Department of Internal Medicine, Fundación Jimenez Díaz, Madrid, Spain 
g Department of Internal Medicine, Hospital Universitario Virgen de Las Nieves, Granada, Spain 
h Department of Endocrinology, Hospital Universitario de Lugo, Lugo, Spain 
i Department of Internal Medicine, Complejo Asistencial de Salamanca, Salamanca, Spain 
j Department of Endocrinology, Hospital Central de Asturias, Oviedo, Spain 
k Department of Endocrinology, Hospital Morales Meseguer, Murcia, Spain 
l Department of Internal Medicine, Hospital de Mérida, Mérida, Spain 
m Department of Pediatric Endocrinology, Hospital General Universitario Santa Lucía, Murcia, Spain 
n Department of Internal Medicine, Hospital San Pedro de Alcántara, Caceres, Spain 
o Department of Endocrinology, Hospital Clínico Universitario de Valencia INCLIVA, CIBER de Diabetes, Spain 
A R T I C L E I N F O 
Keywords: 
Homozygous familial hypercholesterolemia 
Cardiovascular disease 
Aortic valve disease 
Statins 
Ezetimibe 
Lomitapide 
PCSK9 inhibitors 
Lipoprotein-apheresis 
A B S T R A C T 
Aim: We aimed to describe clinical and genetic characteristics, lipid-lowering treatment and atherosclerotic 
cardiovascular disease (ASCVD) outcomes over a long-term follow-up in homozygous familial hypercholester-
olemia (HoFH). 
Methods: SAFEHEART (Spanish Familial Hypercholesterolaemia Cohort Study) is a long-term study in molecu-
larly diagnosed FH. Data analyzed in HoFH were prospectively obtained from 2004 until 2022. ASCVD events, 
lipid profile and lipid-lowering treatment were determined. 
Results: Thirty-nine HoFH patients were analyzed. The mean age was 42 ± 20 years and nineteen (49%) were 
women. Median follow-up was 11 years (IQR 6,18). Median age at genetic diagnosis was 24 years (IQR 8,42). At 
enrolment, 33% had ASCVD and 18% had aortic valve disease. Patients with new ASCVD events and aortic valve 
disease at follow-up were six (15%), and one (3%), respectively. Median untreated LDL-C levels were 555 mg/dL 
(IQ 413,800), and median LDL-C levels at last follow-up was 122 mg/dL (IQR 91,172). Most patients (92%) were 
on high intensity statins and ezetimibe, 28% with PCSK9i, 26% with lomitapide, and 23% with lipoprotein- 
apheresis. Fourteen patients (36%) attained an LDL-C level below 100 mg/dL, and 10% attained an LDL-C 
below 70 mg/dL in secondary prevention. Patients with null/null variants were youngers, had higher un-
treated LDL-C and had the first ASCVD event earlier. Free-event survival is longer in patients with defective 
variant compared with those patients with at least one null variant (p=0.02). 
* Corresponding author. Fundación Hipercolesterolemia Familiar, General Alvarez de Castro 14, 28010, Madrid, Spain. 
** Corresponding author. 
E-mail addresses: rodrigoalonsok@gmail.com, ralonso@cammyn.cl (R. Alonso), pmata@colesterolfamiliar.org (P. Mata). 
1 These authors contributed equally to this work. 
Contents lists available at ScienceDirect 
Atherosclerosis 
journal homepage: www.elsevier.com/locate/atherosclerosis 
https://doi.org/10.1016/j.atherosclerosis.2024.117516 
Received 18 December 2023; Received in revised form 7 March 2024; Accepted 8 March 2024 
mailto:rodrigoalonsok@gmail.com
mailto:ralonso@cammyn.cl
mailto:pmata@colesterolfamiliar.org
www.sciencedirect.com/science/journal/00219150
https://www.elsevier.com/locate/atherosclerosis
https://doi.org/10.1016/j.atherosclerosis.2024.117516
https://doi.org/10.1016/j.atherosclerosis.2024.117516
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Atherosclerosis 393 (2024) 117516
2
Conclusions: HoFH is a severe life threating disease with a high genetic and phenotypic variability. The 
improvement in lipid-lowering treatment and LDL-C levels have contributed to reduce ASCVD events. 
1. Introduction 
Homozygous familial hypercholesterolemia (HoFH) is a rare and 
severe genetic disease, caused by loss-of-function pathogenic variants in 
both alleles of the low-density lipoprotein receptor (LDLR) gene, 
involved in the receptor-mediated LDL particles uptake. Pathogenic 
variants in the apolipoprotein B (ApoB) and the proprotein convertase 
subtilisin/kexin type 9 (PCSK9) genes are also causative of HoFH, but 
are less frequently found [1]. Variants in the gene encoding LDL receptor 
adaptor protein 1 (LDLRAP1) produce a very rare condition known as 
autosomal recessive hypercholesterolemia (ARH) with a similar 
phenotypic expression than HoFH. Current prevalence of HoFH has been 
estimated in approximately one case in 300,000 to 400,000 persons in 
the general population [2]; therefore, it is expected to have 120 to 160 
cases with HoFH in Spain. 
Clinically, patients with HoFH have severe hypercholesterolemia 
since birth, cutaneous xanthomas and very early-onset of aortic valve 
stenosis and atherosclerotic coronary artery disease (ASCVD) can occur 
in adolescence [1,3,4]. Therefore, these patients should be treated early 
and intensively with statins, ezetimibe, and PCSK9 inhibitors (PCSK9i) 
that have shown some efficacy in some HoFH patients depending on 
their genetic background [1,5,6]. Due to the difficulty to control LDL-C 
levels specially those patients carrying more severe pathogenic variants, 
most of them will require therapies that decrease LDL-C levels irre-
spective of residual LDL receptor function as lomitapide or evinacumab, 
both drugs with a mechanism of action independent of the activity of 
LDLR, and/or LDL-apheresis if available, and exceptionally, a liver 
transplant [1,7–11]. In the last year, different cohorts have been pub-
lished showing the difficulties in the diagnosis and management of this 
disorder [12–14]. 
Previous report of HoFH patients included in the SAFEHEART 
(Spanish Familial Hypercholesterolemia Cohort Study) with a median 
follow-up of 6.9 years showed that most patients do not attain the LDL-C 
treatment goals with high intensity statins plus ezetimibe. In addition, 
few patients were under lipoprotein-apheresis [3]. Since then, more 
patients have been included in this registry, and the availability of 
PCSK9i and Lomitapide in Spain with the indication of HoFH has 
allowed that patients may be treated more intensively. 
Our aim in this study was to describe the clinical and genetic char-
acteristics, changes in lipid-lowering treatments (LLT), LDL-C goals 
attainment and ASCVD outcomes over a longer period of follow-up in a 
well-defined HoFH population with genetic diagnosis. 
2. Patients and methods 
2.1. Study design and subjects recruitment 
The Spanish HoFH Registry is a subset of the SAFEHEART registry 
that hasbeen previously described [3,15]. Briefly, patients with genetic 
diagnosis of FH and their non-affected relatives are registered and 
followed-up every year through a standardized phone call to record 
changes in LLT, lipid levels, development of ASCVD events, and other 
variables. Data from HoFH cases with genetic diagnosis registered be-
tween 2004 and December 2022 were included in this study. ASCVD at 
enrolment and during follow-up was documented. Clinical characteris-
tics, lipid profile, lipid lowering medication and duration of treatment 
were analyzed. 
The presence of ASCVD was defined as fatal or non-fatal myocardial 
infarction (MI), angina pectoris diagnosed by classic symptoms in 
combination with at least one result of exercise test, nuclear scintigram 
or >70% stenosis on a coronary angiogram, fatal or non-fatal ischemic 
stroke, coronary revascularization, aortic valve stenosis with valve 
replacement, peripheral artery disease and cardiovascular death well 
documented in the medical report [3]. Local ethics committees 
approved this study and all eligible subjects or legal representatives gave 
written informed consent. 
2.2. Genetic testing 
In the last 10 years, next-generation sequencing including promoter, 
exons, and intron–exon boundaries of LDLR, PCSK9 and LDLRAP1 genes; 
and APOB binding domain to LDLR has been used for the molecular 
diagnosis of FH in Spain. Before 2012, the complete sequencing of LDLR 
gene including exons, and intron–exon boundaries, and of the APOB 
binding domain was used, as well a specific microarray performed to 
examine the most frequent LDLR and APOB variants found in Spanish 
population. In this later case, when no variant was identified, a complete 
sequencing was conducted of the LDLR gene as well as the APOB binding 
domain [16]. 
2.3. LDLR gene mutations classification 
DNA analysis was performed as previously described [17]. According 
to the recent European statement, Simple or True Homozygous FH are 
those cases with bi-allelic identical variants, and compound heterozy-
gous FH (CHeFH) are those cases with bi-allelic different variants [1]. 
All variants that have been proven by in vitro functional assays or 
computed simulated analysis that lead toLDL-C before starting PCSK9i treatment in 21 patients was 
303 mg/dL (IQR 242,360) [7.82 mmol/L (6.24, 9.29)], with no differ-
ences among the severity of the variants. Patients with defective/ 
defective variants treated with PCSK9i (n = 10) achieved the lowest 
LDL-C (121 mg/dL, IQR 89,187) [3.12 mmol/L (2.30, 4.83)]compared 
with those patients with null/null, and null/defective variants (P=0.04) 
(Table 3). Median LDL-C percent reduction with PCSK9i was 38%, being 
Table 1 
Clinical and biochemical data at inclusion in the whole population and according the severity of the pathogenic variants. 
Variable Total (N = 39) Null/Null (N = 14) Null/Defective (N = 7) Defective/Defective (N = 18) p 
Sex (female) 19 (49) 7 (50) 5 (71) 7 (39) 0,40 
Current age 42 (24,57) 26 (19,30) 44 (11,56) 57 (47,64) 0.0007 
Age at time of genetic diagnosis 24 (8,42) 10 (8,23) 16 (7,42) 37 (34,47) 0,0007 
Single HoFH (Bi-allelic identical variants)a 26 (67) 11 (79) 0 15 (83) C 17,11 p. [Asn564His] 
p. [Val800_Leu802del] 
DD 1 
c.1199_1207del 9 p. [Tyr400_Phe402del] DD 1 
c.313+2 dup 3i p. [Leu64_Pro105delinsSer] NN 4 
c.1618G > A; c.451_453delGCC 11,4 p. [Ala519Thr; p.Ala130del] DD 2 
c.953G > T 7 p. [Cys297Phe] DD 1 
c.902A > G; c.1646G > T 6,11 p. [Asp301Gly]; p. [Gly549Val] DN 1 
c.800A > C 5 p. [Glu246Ala] DD 1 
c.1027G > A 7 p. [Gly322Ser] DD 1 
c.1775G > A 12 p. [Gly592Glu] DD 2 
c.2475C > A 17 p. [Asn804Lys] DD 1 
c.97C > T 2 p. [Gln 12*] NN 1 
c.460C > T; c.418G > A 4,4 p. [Gln 154*]; p. [Glu119Lys] ND 1 
c.1342C > T 9 p. [Gln 448*] NN 2 
c.1783C > T 12 p. [Arg574Trp] DD 3 
c.1897C > T 13 p. [Arg633Cys] DD 2 
c.12G > A; c.677C > G 1,14 p. [Trp (-18)X]; p. [Ser226Cys] ND 1 
c.826T > G; c.1246C > T 6,9 p. [Cys255Gly]; p. [Arg395Trp] DD 1 
c.1646G > A 11 p. [549G > D] NN 1 
c.1048C > T 7 p. [Arg329X] NN 1 
c.313+5G > A 3i p. [?] NN 1 
c.898A > G 6 p. [Arg300Gly] DD 1 
c.862G > A; c.1-?_67+?del 6,1P-1i p. [Glu267Lys]; p. [?] DN 1 
c.1162_1173del 8 p. [His388_Ala391del] DD 1 
c.2390-?_2547+?del; c.1775G > A 17,12 p. [?]; p. [Gly571Glu] ND 1 
c.2390-?_2583+?del; c.1898G > A 17-18, 13 p. [?]; p. [Arg612His] DN 2 
c.1706-?_1845+?del 12 p. [? ] NN 1 
Mutation LDLRAP gene 
c.344-?_694 + ¿del 4 p. [? ] NN 2 
c.207delC 2 p. [Ala70ProfsX19] NN 1 
N, Null; D, Defective; ND, Null/Defective; DN, Defective/Null variants. 
Table 3 
Lipid levels according PCSK9 inhibitors and lomitapide treatment during the follow-up. 
Treatment Null/Null (n = 14) Null/Defective (n = 7) Defective/Defective (n = 18) Total (n = 39) p 
PCSK9ia 5 (36) 6 (86) 10 (56) 21 (54) 0.11 
LDL-C pre mg/dL 
mmol/L 
330 (312,360) 
8.52 (8.05,9.29) 
337 (303,420) 
8.69 (7.82,10.84) 
244 (170,300) 
6.29 (4.39,7.74) 
303 (242,360) 
7.82 (6.24,9.29) 
0.06 
LDL-C post mg/dL 
mmol/L 
215 (207,274) 
5.54 (5.34,7.07) 
199 (113,304) 
5.13 (2.91,7.84) 
121 (89,187) 
3.12 (2.30,4.83) 
172 (112,220) 
4.44 (2.89,5.68) 
0.04 
LDL-C % reduction 24 (18,35) 39 (28,53) 41 (35,58) 38 (28,48) 0.19 
Discontinuation 5 (100) 2 (33) 3 (30) 10 (48) 0.68 
Lomitapide 5 (36) 2 (29) 3 (17) 10 (26) 0.72 
Median dose mg/day 40 30 30 30 
LDL-C pre mg/dL 
mmol/L 
334 (274,366) 
8.62 (7.07,9.44) 
320 (249,391) 
8.26 (6.43,10.09) 
310 (187,347) 
8.0 (4.83,8.95) 
322 (266,366) 
8.31 (6.86,9.44) 
0.70 
LDL-C post mg/dL 
mmol/L 
117 (79,163) 
3.02 (2.04,4.21) 
153 (129,186) 
3.95 (3.33,4.80) 
86 (68,121) 
2.22 (1.75,3.12) 
119 (79,163) 
3.07 (2.04,4.21) 
0.34 
LDL-C % reduction 68 (39,71) 50 (48,52) 72 (35-,0) 60 (39,72) 0.79 
a PCSK9i, PCSK9 inhibitor. Values expressed as n (%), median (IQR). PCSK9 inhibitors include: alirocumab 75 mg Q2W (n = 1), alirocumab 150 mg Q2W (n = 1), 
evolocumab 140 mg Q2W (n = 9), evolocumab 420 mg Q2W (n = 5), evolocumab 420 mg Q4W (n = 5), and all patients who received PCSK9i during the follow-up are 
included in this table. 
R. Alonso et al.Atherosclerosis 393 (2024) 117516
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3.3. Follow-up and outcomes 
During the follow-up, median 11 years (IQR 6,18), six patients 
developed new ASCAD event (15%), and one case was diagnosed with 
aortic valve disease (3%). Out of them, three cases had history of prior 
events: acute coronary syndrom (1 case), myocardial infarction (1 case), 
and aortic valve replacement (1 case). The numbers of total events 
during the follow up was 8, 70% less than the total number of events 
known at inclusion. There were no differences between male and fe-
males (P=0.57). Three patients died during the follow-up. Two related 
to CVD (post-surgery of valve replacement, and heart failure) and one 
under immunosuppression therapy by septicemia. Two of them carried 
defective/defective variants, they had history of ASCVD and aortic valve 
stenosis, and median baseline LDL-C was 535 mg/dL. One case had a 
heart and liver transplant in childhood, and the other two cases were 
treated with high intensity statins and ezetimibe for more than 15 years 
respectively. Median follow-up since birth was 40 years (IQR 20–56) and 
ASCVD free-event survival was lower in patients with at least one null 
variant compared with those patients with defective variants (35 years 
and 56 years, respectively; p=0.02, Fig. 1). 
4. Discussion 
This study reports an update of the characteristics, management and 
ASCVD outcomes of patients with HoFH enrolled in the HoFH- 
SAFEHEART registry, with a median follow-up of 11 years represent-
ing the real-life management of these patients with severe hypercho-
lesterolemia. The main findings of this study are: 1) high prevalence of 
premature ASCVD and AVS, 33% and 18% respectively; 2) those pa-
tients carrying at least one null allele have a severe phenotype and worse 
prognosis in the follow-up; 3) an improvement in lipid-lowering man-
agement with the availability of new drugs such-us PCSK9i and lomi-
tapide have allowed a greater number of patients to attain significant 
reductions in LDL-C levels, reflecting substantial progress in the treat-
ment and improving prognosis with reduction in number of patients 
with ASCVD events (Fig. 2). 
Patients with HoFH in the SAFEHEART represent a substantial pro-
portion of cases managed by specialists, and patients are included with 
genetic diagnosis confirming the bi-allelic variants in related genes. In 
our study, most of them where true homozygous (72%) showing iden-
tical bi-allelic variants in LDLR gene, similar to other series [14]. This is 
also consistent with global experience data in which less than 2% of 
cases are caused by variants in ApoB gene and homozygous cases for 
PCSK9 variants were very rare [12]. There is a high molecular hetero-
geneity reflected in the great variety of variants, most of them classified 
as defective. The phenotypic expression of the disorder depends in part 
in the type on the causal variant [3,4,19]. Based on this, patients with at 
least one null variant are diagnosed younger, and show a more severe 
phenotype with higher LDL-C levels, more aortic valve disease, and 
Fig. 1. Kaplan-Meier curves for CVD-free survival from birth in HoFH patients 
according the type of mutation. 
Red line, cases with at least one null variant; Blue line are cases with defective/ 
defective variants. p=0.02 
Fig. 2. Thirty-nine patients with genetic diagnosis of Homozygous Familial Hypercholesterolemia enrolled in the SAFEHEART registry were analyzed after a media 
of 11 years follow-up. 
An improvement in lipid-lowering therapies was observed with 90% of patients receiving high intensity statins with ezetimibe, and 21 (54%) patients on treatment 
with lomitapide or PCSK9i in the last contact. Three patients died during the follow-up. ASCVD event-free survival was significantly different according the genotype 
(35 vs. 56 years, in patients with at least one null allele variants or defective variants, respectively; p=0.02). 
R. Alonso et al. 
Atherosclerosis 393 (2024) 117516
6
earlier onset of ASCVD. Interestingly, the null/null group showed a 
non-significant lower prevalence of ASCVD, and this can be explained in 
part because current age is 30 years younger than those in the defecti-
ve/defective group, and the more severe phenotype made that age of 
detection and starting treatment were earlier in the severe group. This 
high phenotypic variability according the severity of the pathogenic 
variants was also observed in other cohorts, showing LDL-C levels 
varying widely among homozygous patients [19–22]. 
As shown recently in the large retrospective worldwide study [12], 
most cases are diagnosed during childhood, but it is not infrequent to 
make the diagnosis in adults. In our study, cases confirmed before age 15 
years had significantly higher LDL-C levels than those confirmed later 
(data not shown), and those cases with less severe variants (defecti-
ve/defective) were diagnosed genetically later compared to those cases 
carrying null variants, in part because the lipid levels sometimes overlap 
with those observed in heterozygous FH. ASCVD and aortic valve ste-
nosis are the main life threating in HoFH [1]. Different cohort studies 
have shown that ASCVD occurs earlier in HoFH than heterozygous FH 
due to the extremely high levels of LDL-C and great cumulative expo-
sure, and recurrence of cardiovascular events is also frequent [12–14, 
19]. In this study, 33% had history of at least one ASCVD event, and 18% 
had history of aortic stenosis with a median age of 32 years. Comparing 
with the recent published Canadian registry, having approximately the 
same number of cases but 88% genetically confirmed, the age of onset 
ASCVD and the percentage of MI were similar in both cohorts; however, 
the prevalence of severe AVS and the age of diagnosis were lower in our 
cohort [14]. Furthermore, despite patients with at least one severe 
variant started treatment at a younger age (4 years vs. 33 years in 
defective variants patients), onset of ASCVD was earlier, and had higher 
prevalence of aortic valve stenosis. Therefore, it is important to actively 
search aortic valve disease and ASCVD using imaging technique starting 
at the moment of the diagnosis of the disorder [1]. 
Considering that median age in our population is 42 years, and that 
they started any lipid lowering treatment at a median age of 13 years, 
most of them have been treated initially only with statins and then in 
combination with ezetimibe. New drugs like PCSK9i and lomitapide 
have begun to be used in Spain during the last 7 and 5 years, respec-
tively. An important striking finding in this study is that survival in 
patients carrying null variants was delayed compared to our previous 
study, in part due to a better and intensive management of the disorder 
with more potent statins in combination with ezetimibe and the new 
drugs [3], highlighting that on-treatment LDL-C levels are a major 
determinant of event-free survival for HoFH patients [23]. Despite the 
persistence of very high LDL-C levels with statins, they have showed to 
reduce mortality and delay cardiovascular outcomes in HoFH [5]. These 
results are consistent with a recent publication and a systematic-review 
that showed a delayed by more than a decade in the onset of ASCVD in 
HoFH patients from pre-statin to statin era in part attributable to 
widespread use of high intensity statins and other news LLT [24,25]. 
According the recent European consensus statement for the man-
agement of HoFH, LDL-C goals in HoFH are the same as recommended 
for high-risk patients in adults, and in children and adolescents, the goal 
isother patients with elevated LDL-C and high-risk conditions, is a chal-
lenging in HoFH. Most patients often have untreated LDL-C levels over 
500 mg/dL (12.9 mmol/L) and they do not achieve LDL-C goals, and it 
could be very difficult to attain even with the new medications [12]. 
LDL-C reduction with PCSK9i is dependent of the degree of residual 
activity of the LDL-R, so it is expected that in those patients with null 
variants, the response will be very low or without effect [26,27]. In our 
study, patients with null/null variants had the lowest reduction with 
PCSK9i on top of statin and ezetimibe and LDL-C remained far from the 
recommended goals. On the other hand, those patients with defecti-
ve/defective variants showed a greater LDL-C reduction, although 
LDL-C levels achieved were still far from the goals. 
Lomitapide has a mechanism of action independent of LDLR activity, 
and as expected, we observed in our patients an LDL-C reduction by 68% 
on top of statin and ezetimibe, attaining LDL-C levels very rarely seen in 
these patients, especially in those with null variants [7,8]. Furthermore, 
two patients that were on lipoprotein-apheresis discontinued apheresis 
maintaining a good LDL-C control. The percentage reduction in LDL-C 
with lomitapide in our study was higher compared to the 56% reduc-
tion observed in the retrospective analysis of the Lomitapide 
pan-European study and the 33% reduction in the LOWER registry, in 
part because our patients received a higher dose of the drug (30 mg/day 
vs. 20 mg/day and 10 mg/day, respectively) [28]. Evinacumab, a 
monoclonal antibody against angiopoietin-like 3, has recently emerged 
as a new option for HoFH and markedly reduces LDL-C levels up to 50% 
through an LDL-R independent mechanism [9,29]. It is important to 
highlight that the access and cost to PCSK9i, lomitapide and evinacumab 
are limitations to consider, specially the last two, and also 
lipoprotein-apheresis is not available at all sites and could worsen the 
quality of life of patients. We have observed a significant improvement 
in the treatment of HoFH patients in Spain in the last 5 years. In the 2016 
report, only four patient attained LDL-C levels below 100 mg/dL when 
they started lipoprotein-Apheresis. In the current analysis, one in three 
patients achieved an LDL-C below 100 mg/dL and one in ten achieved an 
LDL-C below 70 mg/dL (1.8 mmol/L). 
We would like to emphasize that a significant number of HoFH pa-
tients have been able to continue high-cost medications and procedures 
like PCSK9i, lomitapide, and lipoprotein-apheresis. This has been 
possible thanks to the commitment and support of the Spanish Familial 
Hypercholesterolemia Foundation, which managed to obtain reim-
bursement of different medications for the treatment of FH since 2004, 
permitting the global access to FH medication. Initially, statins and 
ezetimibe were included (2004 and 2009 respectively), and in recent 
years the use of lipoprotein-apheresis and PCSK9i (2011 and 2013 
respectively). Although lomitapide is still not included in the list, its 
compassionate use is covered by the hospital [30]. Moreover, the 
request and social support from the Spanish FH Foundation to the 
Ministry of Health has made it easier for genetic diagnosis to be financed 
in most regions of Spain. 
The main strengths of this study is that it is a multicentre nation-wide 
study including a well-molecularly characterized HoFH cohort followed- 
up through a centralized standardized phone interview and interaction 
with treating physicians, their management in real life and the long-term 
time of follow. The limitations of this study is the relatively small sample 
size. 
4.1. Conclusions 
HoFH is a severe disease with a high burden of ASCVD, development 
of aortic stenosis and early mortality. In this study, the phenotypic 
expression is also variable, due to the high genetic heterogeneity. The 
improvement in treatment and the intense reduction in LDL-C levels 
with the new medications have contributed to reduce premature ASCVD 
events and increase free-event survival, especially in carriers of more 
severe variants. Early detection together with news drugs independent 
of LDLR activity show great promise for patients with HoFH, a difficult 
to treat and potentially life-threatening condition. 
Trial registration 
ClinicalTrials.gov number NCT02693548. 
Financial support 
This study was funded by the Fundación Hipercolesterolemia 
Familiar; grant G03/181 and FIS PI12/01289 of the Instituto de Salud 
Carlos III (ISCIII, Spain) and grant 08-2008 from the Centro Nacional de 
Investigaciones Cardiovasculares (CNIC, Spain). 
R. Alonso et al. 
Atherosclerosis 393 (2024) 117516
7
Data availability statement 
Fundacion Hipercolesterolemia Familiar provided the data under-
lying this article by permission. Data will be shared on request to the 
corresponding author with permission of Fundacion Hipercolester-
olemia familiar. 
CRediT authorship contribution statement 
Rodrigo Alonso: Formal analysis, have participated in the design, 
data analysis and interpretation of results. Raquel Arroyo-Olivares: 
Formal analysis, have participated in the design, data analysis and 
interpretation of results. Pedro Mata: Formal analysis, have partici-
pated in the design, data analysis and interpretation of results, All au-
thors have participated sufficiently in the work. Authors participated in 
the conception of the work and acquisition of data, reviewed critically 
the manuscript and given final approval of the version sent to publica-
tion. All authors agreed to be accountable to resolve any question 
related to the work. 
Declaration of competing interest 
RA reports personal fees and non-financial support from Tecnofarma 
Chile, NovoNordisk Chile, and personal fees from Novartis Chile, Amgen 
Spain, and Teva Chile, outside the submitted work. JLDD received 
honoraria for research activities from Merck Sharp and Dhome Spain, 
Amgen Spain, and Sanofi Spain. PM, received research grants from 
Amgen USA and Sanofi Spain. 
Acknowledgements 
We would like to thank the Spanish FH Foundation for its commit-
ment with patients, recruitment and follow-up, and to patients and their 
families for their valuable contribution and willingness to participate. 
Appendix A. Supplementary data 
Supplementary data to this article can be found online at https://doi. 
org/10.1016/j.atherosclerosis.2024.117516. 
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https://doi.org/10.1161/CIRCGENETICS.116.001545
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https://doi.org/10.1016/j.atherosclerosis.2017.04.002
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https://doi.org/10.1161/01.ATV.0000094410.66558.9A
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https://doi.org/10.1016/j.atherosclerosis.2016.03.009
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https://doi.org/10.1016/j.atherosclerosis.2018.08.020
	Improved lipid-lowering treatment and reduction in cardiovascular disease burden in homozygous familial hypercholesterolemi ...
	1 Introduction
	2 Patients and methods
	2.1 Study design and subjects recruitment
	2.2 Genetic testing
	2.3 LDLR gene mutations classification
	2.4 Statistical analysis
	3 Results
	3.1 Molecular characteristics and clinical expression according to pathogenic variant
	3.2 Lipid-lowering treatments and lipid levels in the follow-up
	3.3 Follow-up and outcomes
	4 Discussion
	4.1 Conclusions
	Trial registration
	Financial support
	Data availability statement
	CRediT authorship contribution statement
	Declaration of competing interest
	Acknowledgements
	Appendix A Supplementary data
	References