Background and aims
Familial hypercholesterolemia (FH) is a common autosomal dominant disorder that can result in premature atherosclerotic cardiovascular disease (ASCVD). Limited data are available worldwide about the prevalence and management of FH. Here, we aimed to estimate the prevalence and management of patients with FH in five Arabian Gulf countries (Saudi Arabia, Oman, United Arab Emirates, Kuwait, and Bahrain).
The multicentre, multinational Gulf FH registry included adults (≥18 years old) recruited from outpatient clinics in 14 tertiary-care centres across five Arabian Gulf countries over the last five years. The Gulf FH registry had four phases: 1- screening, 2- classification based on the Dutch Lipid Clinic Network, 3- genetic testing, and 4- follow-up.
Among 34,366 screened patient records, 3713 patients had suspected FH (mean age: 49±15 years; 52% women) and 306 patients had definite or probable FH. Thus, the estimated FH prevalence was 0.9% (1:112). Treatments included high-intensity statin therapy (34%), ezetimibe (10%), and proprotein convertase subtilisin/kexin type 9 inhibitors (0.4%). Targets for low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol were achieved by 12% and 30%, respectively, of patients at high ASCVD risk, and by 3% and 6%, respectively, of patients at very high ASCVD risk (p <0.001; for both comparisons).
This snap-shot study was the first to show the high estimated prevalence of FH in the Arabian Gulf region (about 3-fold the estimated prevalence worldwide), and is a “call-to-action” for further confirmation in future population studies. The small proportions of patients that achieved target LDL-C values implied that health care policies need to implement nation-wide screening, raise FH awareness, and improve management strategies for FH.
Citation: Alhabib KF, Al-Rasadi K, Almigbal TH, Batais MA, Al-Zakwani I, Al-Allaf FA, et al. (2021) Familial Hypercholesterolemia in the Arabian Gulf Region: Clinical results of the Gulf FH Registry. PLoS ONE 16(6): e0251560. https://doi.org/10.1371/journal.pone.0251560
Editor: Xianwu Cheng, Nagoya University, JAPAN
Received: August 27, 2020; Accepted: April 28, 2021; Published: June 4, 2021
Copyright: © 2021 Alhabib et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the manuscript and its Supporting Information files.
Funding: This study received support from Sanofi-Aventis Groupe (https://www.sanofi.com) in the form of a grant (number DIREGL08183) awarded to KFA, KA, FA, WA, MA, and NA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study.
Competing interests: The authors have read the journal’s policy and the authors of this manuscript have the following competing interests: KA reports grants from Sanofi during the conduct of the study and other funs from Sanofi, Abbott, and MSD outside the submitted work; NA reports personal fees from Sanofi, Aegerion, Merck Sharp, Abbott, AstraZeneca, Pfizer, and Amgen outside the submitted work; HS reports personal fees from Sanofi and Amgen outside the submitted work. This does not alter our adherence to PLOS ONE policies on sharing data and materials. There are no patents, products in development or marketed products associated with this research to declare.
Familial hypercholesterolemia (FH) is a common, life-threatening genetic disorder. FH is characterized by impaired clearance of low-density lipoprotein cholesterol (LDL-C) from blood, due to mutations in one or more genes, which results in lifelong elevated LDL-C . The autosomal dominant inherited form is typically due to a mutation in the low-density lipoprotein receptor (LDLR), apolipoprotein B (ApoB), or proprotein convertase subtilisin/kexin type 9 (PCSK9). Mutations in the gene codes for the low-density lipoprotein receptor adaptor protein (LDLRAP1) results in the autosomal recessive form of FH . FH can be heterozygous (frequently less severe, due to a single mutated allele) or homozygous (commonly severe, due to mutations in both alleles). Less commonly, FH can also be double heterozygous (two different mutated alleles at two separate genetic loci) or compound heterozygous (two different mutated alleles at one particular gene locus) [3, 4]. In most studied populations, heterozygous FH (HeFH) affects one in 200–500 persons. Homozygous FH (HoFH) is rare; it affects one in 160,000–300,000 persons [5, 6].
Individuals with FH are at high risk of atherosclerosis and its consequences. In those cases, FH manifests as premature coronary artery disease (CAD), and patients are at increased risk of peripheral artery disease and stroke, which increases morbidity and mortality . Although the high CAD risk among patients with FH is well-established, the onset of cardiovascular events is variable; it depends on age, gender, and other risk factors, like hypertension, smoking, and high lipoprotein(a) levels. Previous studies reported that 50% of male patients and 30% of female patients with HeFH developed CAD by the age of 60 years . However, recent studies reported an even higher CAD prevalence at the same age .
Various studies have reported that FH is underdiagnosed and undertreated. Among the estimated 34 million individuals with FH, only 1% are identified in most countries [10–12]. Therefore, a reduction in cardiovascular disease (CVD) risk requires early detection and management of FH, particularly in the presence of premature atherosclerotic cardiovascular disease (ASCVD). These measures are particularly important among high-risk populations, like those in the Arabian Gulf countries, where FH prevalence might be high, due to high consanguinity rates [13–15].
Although FH leads to fatal cardiovascular outcomes, data are currently limited worldwide; only 9% of countries in the world have reported the FH prevalence in the general population . Therefore, this study aimed to estimate the prevalence and management of patients with FH in five Arabian Gulf countries.
Study design and population
The study design and detailed methodology of the Gulf FH registry construction were previously published . Briefly, the Gulf FH registry study was a multicentre, multinational study with cross-sectional and prospective components. Participants were recruited from outpatient (primary care, cardiology, endocrinology, and lipid) clinics in 14 tertiary-care centres across five countries in the Arabian Gulf region: 7 centres in Saudi Arabia, 1 centre in Oman, 2 centres in the United Arab Emirates, 2 centres in Kuwait, and 2 centres in Bahrain. The registry had four phases: 1- screening, 2- classification based on the Dutch Lipid Clinic Network (DLCN), 3- genetic testing, and 4- follow-up (S1 Appendix). The present study focused on the first two phases. Results from the follow-up and genetic testing will be reported separately.
Inclusion criteria for enrolment in the Gulf FH registry were: age ≥18 years; Arabian Gulf national; either LDL-C ≥4.9 mmol/L (≥190 mg/dL) or total cholesterol (TC) ≥7.5 mmol/L (≥290 mg/dL); either not taking lipid-lowering treatments or a corrected LDL-C ≥4.9 mmol/L (≥190 mg/dL); and a previous genetic diagnosis of FH. Lipid results were collected retrospectively from hospital medical records over the last five years. Therefore, fasting status was unknown, though most laboratories typically collected lipid samples under fasting conditions. Exclusion criteria were: triglycerides >5 mmol/L (442 mg/dL), history of untreated hypothyroidism, proteinuria ≥1 g/L, obstructive liver disease, chronic kidney disease, human immune deficiency virus infection, and the use of immunosuppressants, steroids, or psychiatric medications.
Study objectives and definitions
The main objectives of the present Gulf FH registry-based study were to estimate the prevalence and management of patients with FH in five Arabian Gulf countries. The DLCN criteria were used to categorize the patients into one of four FH groups: definite FH (DFH), probable FH (PrFH), possible FH (PoFH), or unlikely FH  (S2 Appendix). To calculate the FH prevalence, we merged data for patients with DFH and PrFH and excluded 132 patients with confirmed genetic mutations as these patients were recruited from highly specialized lipid clinics in only two countries in the Gulf region (Saudi Arabia and Oman). Patients had a family history of premature CVD when a first-degree relative had premature CVD (male <55 years old or female <65 years old) . Statin therapy was classified as: high-intensity, moderate-intensity, or low-intensity statin  (S3 Appendix). Based on the 2016 guidelines established by the European Society of Cardiology and the European Atherosclerosis Society (ESC/EAS), lipid targets for LDL-C were <2.6 mmol/L (<100 mg/dL) and <1.8 mmol/L (<70 mg/dL), for those at high and very-high ASCVD risk, respectively. The 2016 lipid targets for non-HDL-C were <3.4 mmol/L (<130 mg/dL) and <2.6 mmol/L (<100 mg/dL) for those at high and very-high ASCVD risk, respectively . In the updated, 2019 version of the ESC/EAS dyslipidaemia guidelines, lipid targets for LDL-C were <1.8 mmol/L (<70 mg/dL) and <1.4 mmol/L (<55 mg/dL) for those at high and very-high ASCVD risk, respectively. The 2019 lipid targets for non-HDL-C were <2.6 mmol/L (<100 mg/dL) and <2.2 mmol/L (<85 mg/dL) for those at high and very-high ASCVD risk, respectively .
Based on the ESC/EAS 2019 dyslipidaemia guidelines, patients with FH were considered at very high risk of ASCVD, when ASCVD was documented, or when another major risk factor was present; patients with FH were considered at high risk of ASCVD, when no other major CVD risk factors were present. ASCVD was diagnosed (either based on clinical or unequivocal imaging evidence) when patients had previous evidence of acute coronary syndrome (i.e., myocardial infarction or unstable angina), stable angina, coronary revascularization (percutaneous coronary intervention [PCI], coronary artery bypass graft, or other arterial revascularization procedures), stroke or transient ischaemic attack, or peripheral artery disease. Unequivocal imaging evidence of ASCVD included findings known to be predictive of clinical events, such as a significant plaque (i.e., multivessel coronary disease, with two major epicardial arteries >50% stenotic) detected with coronary angiography, computerized tomography (CT), or carotid ultrasound .
Study organization and ethical approval
The study was organized by the co-principal investigators, national leaders, co-investigators, and study manager of the five included countries in the Arabian Gulf region. The study was approved by the following ethical commettees and institutional review boards:
- King Saud University Medical City IRB.
- King Abdullah International Medical Research Center IRB.
- Cardiac Research Department, Prince Sultan Cardiac Center.
- Saud Albabtain Cardiac Center IRB.
- King Abdulaziz University Ethics Committee.
- Sheikh Khalifa Medical City IRB.
- Alain Hospital Research and Ethics Governance Committee.
- Gulf Diabetes Specialist Center Ethics Committee.
- Kuwait MOH Research Ethics Committee.
- Research Ethics Committee Royal Medical Services, Bahrain Defence Force.
- Sultan Qaboos University Hospital Ethics Committee.
The sample size was calculated, based on a conservative estimate that the HeFH prevalence would be 1:500  (S4 Appendix). We estimated a 10% snap-shot sample of the expected HeFH proportion of the populations in each of the five Arabian countries. The final calculated sample size was 5179. The study steering committee considered that at least 70% of the calculated sample size (n = 3625) would be sufficient, in view of the expected missing or unclear data.
Descriptive statistics are expressed as the frequency and percentage for categorical variables. Differences between the FH groups were analysed with Pearson’s χ2 test (or Fisher’s exact test for <5 expected cells). Continuous variables are expressed as the mean and standard deviation (±SD). Statin daily doses are expressed as the median and interquartile range (IQR). Differences between groups were analysed with the Kruskal-Wallis test. An a priori two-tailed level of significance was set at 0.05. Statistical analyses were performed with STATA version 13.1 (STATA Corporation, College Station, TX, USA).
Prevalence of FH
Among 34,366 participants screened and was filtered further based on the inclusion/exclusion criteria and the missing essential data for the DLCN criteria (Fig 1) Schematic diagram of patient flow of Gulf FH study, the final data consisted of 3,713 patients which was higher than the cohort in the initial published Gulf FH design paper as more patients have been included . After stratifying the cohort, based on the DLCN criteria, there were 195 (5.3%) patients with DFH, 243 (6.5%) patients with PrFH, 2801 (75.4%) patients with PoFH, and 474 (12.8%) patients with unlikely FH. Thus, among all screened participants, the FH prevalence (including both PrFH and DFH groups) was 0.9% (306/34,234, i.e., 1:112).
Patient demographics and clinical characteristics
The overall mean age±SD of the patients was 49±15 years, and 1948 (52%) were women (Table 1). A positive history of FH was documented in the hospital medical records of 1181 (32%) patients, based on either clinical or genetic results. The prevalence of diabetes mellitus was higher among patients with PoFH (28%) or unlikely FH (28%), compared to those with PrFH/DFH (23%; p <0.001). However, compared to those with PoFH or unlikely FH, more patients with PrFH/DFH had histories of premature CAD (33% vs. 8.4% and 6.3%, respectively; p <0.001), angina (19% vs. 5.5% and 3.4%, respectively; p <0.001), myocardial infarction (14% vs. 4.1% and 3.4%, respectively; p <0.001), premature cerebrovascular diseases (3.9% vs. 1.5% and 1.5%, respectively; p = 0.001), and premature peripheral artery disease (1.4% vs. 0.4% and 0.2%, respectively; p = 0.032). Smoking was reported by 278 (7.5%) patients. Tendon xanthomas were present in 55 (13%) patients with PrFH/DFH and absent in all individuals with PoFH or unlikely FH. Histories of cardiac procedures and investigations (i.e., PCI, coronary artery bypass graft, CT angiogram, CT coronary calcium score, and echocardiography) were found more frequently among patients with PrFH/DFH than among patients with PoFH or unlikely FH (Table 1).
A total of 3192 (86%) participants used lipid-lowering medications. Atorvastatin, rosuvastatin, simvastatin, and pravastatin were prescribed for 1426 (45%), 777 (24%), 237 (7.4%), and 2 (0.1%) patients, respectively. Patients with PrFH/DFH were more likely (62%) to be treated with high-intensity statin treatments than those with PoFH (30%) or unlikely FH (28%; p <0.001; (Fig 2) Intensity of statin therapy among the Gulf familial hypercholesterolemia cohort stratified by the Dutch Lipid Clinic Network (DLCN). Among patients with PrFH/DFH that were managed with lipid-lowering treatments, almost one-third (33%) were treated with ezetimibe, 6 (1.4%) were treated with PCSK9 inhibitors, and 12 (2.8%) underwent LDL-apheresis (Table 2).
**High-intensity statin therapy was defined as those on atorvastatin 40–80 mg and rosuvastatin 20–40 mg while medium-intensity statin therapy was defined as those on atorvastatin 10–20 mg, rosuvastatin 5–10 mg, simvastatin 20–40 mg and pravastatin 40–80 mg. Low intensity statin therapy was defined as those on simvastatin 10 mg or pravastatin 10–20 mg.
Patient lipid profiles
Mean TC levels at baseline and post-treatment, respectively, were: PrFH/DFH: 9.54 and 7.12 mmol/L, PoFH: 7.67 and 5.84 mmol/L, and unlikely FH: 6.71 and 5.33 mmol/L (Table 3). Mean LDL-C levels at baseline and post-treatment, respectively, were: PrFH/DFH: 7.61 and 5.96 mmol/L, PoFH: 5.68 and 4.09 mmol/L, and unlikely FH: 4.70 and 3.54 mmol/L. All of these differences between baseline and post-treatment levels were statistically significant (p <0.001).
LDL-C and non-HDL-C target achievements
Most patients did not achieve the lipid targets. LDL-C and non-HDL-C targets were achieved by 12% and 30%, respectively, in the high ASCVD risk group, and by 3% and 6%, respectively, in the very-high ASCVD risk group (between-group differences: p <0.001 for both targets; (Fig 3) . LDL and non HDL cholesterol goal attainments in the Gulf FH cohort, stratified by ASCVD risk. (A) Percentages of subjects that achieved the ESC/EAS-2016 lipid targets. LDL-cholesterol targets were <2.6 mmol/L and <1.8 mmol/L, for the high and very high ASCVD risk groups, respectively; non HDL-cholesterol targets were 3.4 mmol/L and 2.6 mmol/L, for the high and very high ASCVD risk groups, respectively. (B) Percentages of subjects that achieved the ESC/EAS-2019 lipid targets. LDL-cholesterol targets were <1.8 mmol/L and <1.4 mmol/L, for the high and very high ASCVD risk groups, respectively; non HDL-cholesterol targets were <2.6 mmol/L and <2.2 mmol/L, for the high and very high ASCVD risk groups, respectively.
(A) Percentages of subjects that achieved the ESC/EAS-2016 lipid targets. LDL-cholesterol targets were <2.6 mmol/L and <1.8 mmol/L, for the high and very high ASCVD risk groups, respectively; non HDL-cholesterol targets were 3.4 mmol/L and 2.6 mmol/L, for the high and very high ASCVD risk groups, respectively. (B) Percentages of subjects that achieved the ESC/EAS-2019 lipid targets. LDL-cholesterol targets were <1.8 mmol/L and <1.4 mmol/L, for the high and very high ASCVD risk groups, respectively; no HDL-cholesterol targets were <2.6 mmol/L and <2.2 mmol/L, for the high and very high ASCVD risk groups, respectively.
This Gulf FH registry-based study was the first multinational study to estimate the prevalence and management of FH in adult patients in the Arabian Gulf region. We revealed a high prevalence of FH (1:112) in a snap-shot sample taken from various specialized and non-specialized out-patient clinics in the region. Most participants with PrFH/DFH had a history of FH and a history of ASCVD. In addition, patients with PrFH/DFH could not adequately achieve LDL-C or non-HDL-C targets.
Our study results, and the results of other recent international registries, supported the notion that the true FH prevalence is most likely higher than the previously reported prevalence of 1:250–500 [22, 23]. The FH prevalence (1:112) we found in the Gulf FH registry was about 3-fold of the estimated worldwide FH prevalence recently published in two meta-analyses that included 11 million (1:313) and over 7.3 million individuals (1:311) [16, 24]. Although there is a high consanguinity rate in the Gulf region (as high as 50%) [13–15], the high prevalence of FH is likely due to founder effect . Furthermore, recruiting patients from tertiary-care centres might have led to including a population with FH that was in relatively worse health than the general population; hence, a relatively high FH prevalence could be expected. Despite these caveats, FH has been underdiagnosed and undertreated worldwide, as shown by previous findings from other registries . This oversight could be due to a lack of national registries, difficulty in performing genetic analyses, due to either unavailability and/or prohibitive costs, a lack of specialized lipid clinics, and a paucity of educational programs to raise physician awareness of FH. A recent Saudi study that investigated physician FH awareness, practices, and knowledge showed that 93% of participants had poor knowledge of FH . However, several courses and symposia have been conducted recently in the Arabian Gulf region in collaboration with the International Atherosclerosis Society. That endeavour aimed to raise awareness of the diagnosis and management of patients with FH [28, 29].
The prevalences of diabetes mellitus, hypertension, and smoking were 23%, 22%, and 16%, respectively, among patients with PrFH/DFH. These results were similar to the high prevalences of these modifiable CVD risk factors in the general population of the Arabian Gulf region [30–32]. Although these findings were generally similar to those in other international FH registries, few studies have reported that the prevalence of these modifiable CVD risk factors was lower among patients with FH than among the general population. For example, a large-scale observational study, conducted as part of the national Dutch screening program, reported a 50% lower risk of diabetes mellitus among individuals with FH compared to the general population . A plausible explanation could be that patients with FH might adopt relatively healthier lifestyles to minimize CVD risk .
The reported CAD prevalence among those with PrFH/DFH in our study (33%) was consistent with the prevalence rates of CAD in patients with FH in other international registries [35, 36]. For example, CAD prevalences among patients with FH were 35.9%, in the US CASCADE-FH Registry, and 38.8% in a UK study [37, 38]. Moreover, patients with FH are at high risk of ASCVD and require intensive management with lipid-lowering treatments .
Large LDL-C reductions in patients with FH have been associated with reduced CAD progression and reductions in CVD events and mortality rates [40–43]. The lipid target achievements in our study were poor. Only 12% and 3% of patients achieved the 2016 LDL-C targets (<2.6 mmol/L and <1.8 mmol/L) in the high ASCVD risk and very-high ASCVD risk groups, respectively. Although the majority (86.8%) of patients with PrFH/DFH in our study received statins, only about two-thirds (62%) received high-intensity doses; 33% received ezetimibe, 2.8% underwent LDL apheresis, and 1.4% received PCSK9 inhibitors. These results were similar to those reported in other registries, with only slight differences. In the American CASCADE-FH registry, only 25% of adult subjects with FH achieved the LDL-C target (LDL-C <2.6 mmol/L); 75% received statins, 42% received high-intensity statins, and 34% received statins and ezetimibe . In the Netherlands, another FH registry study showed that 21% of the cohort achieved the LDL-C target (LDL-C <2.6 mmol/L), 96% received statins, 34% received high-intensity statins, and 53% received statins and ezetimibe .
The low rates of achieving the target LDL-C could have been due to inadequate prescribing, and/or the use of high-intensity statins, ezetimibe, or PCSK9 inhibitors (individually or in combination, due to cost and/or side effects), and/or low compliance with a healthy lifestyle [45, 46]. Adding ezetimibe to statin therapy can decrease LDL-C levels by 60–70% in individuals with FH . LDL-C can be reduced by 50–70% with lipoprotein apheresis, but that therapy is expensive, and it is only available in very few centres in the Arabian Gulf region . Recently, PCSK9 inhibitors (alirocumab and evolocumab) were shown to lower LDL-C by around 60% (when added to lipid lowering therapies, mainly statins), and they improved CVD outcomes in patients with FH [49–51]. Nevertheless, the rate of PCSK9 inhibitor use remains low in our region, mainly due to the high cost. However, studies have shown that these medications were cost-effective, at a threshold of $100,000 per quality-adjusted life-year (QALY), when the annual price was ≤$4536 (45). Currently, the annual price in the Arabian Gulf region remains above the cost-effective price, at $5962 .
This study had various strengths, including the first-of-a-kind registry conducted in five Arabian Gulf counties. Moreover, we used standard DLCN criteria for diagnosing FH and well-defined exclusion criteria to avoid confounding with other potential causes of dyslipidaemia.
This study also had some limitations. First, its retrospective design had inherent limitations, such as missing data and uncertainties about compliance to medical therapies and healthy lifestyles. Data were not available for the time period between the measurements of baseline and post-treatment serum cholesterol levels. However, it was likely that most patients had been taking lipid-lowering therapies for several months and even years. Moreover, our study included only adults 18 years or older; hence, any inferences to FH prevalence or management would not be applicable to children. In addition, we might have overestimated the prevalence of FH, because participants were recruited from outpatient clinics in tertiary-care centres; thus, a potential referral bias could have resulted in a patient population with relatively poor health and more severe LDL-C levels than expected in the general population. However, the included centres were flagship hospitals from different health care sectors and geographic regions that had wide catchment areas, with referrals from the surrounding districts and even from outside their respective cities. Having said that, the results of our snap-shot study should be interpreted with caution, and to be viewed as a “call-to-action” for the Ministries of Health to confirm our findings in a nation-wide registry program in the Arabian Gulf population.
In conclusion, we showed that the Arabian Gulf region had a high estimated prevalence of adults with FH (3-fold the estimated prevalence worldwide), and a low proportion of patients achieved the target LDL-C. Our results have major implications for healthcare policy makers, with regard to establishing national programs and policies for nation-wide FH screening (index screening and cascade screening for first-degree relatives of patients with FH), raising FH awareness, and improving FH management. In future, the Gulf FH registry will report on detailed genetics and 1-year clinical follow-ups for patients with FH.
S1 Appendix. The four Gulf FH registry phases.
S2 Appendix. Dutch Lipid Clinic Network (DLCN) criteria.
S3 Appendix. Intensities of statin treatment.
S5 Appendix. Study coordinators for the Gulf FH registry.
We thank the study coordinators for their valuable work and commitment to the Gulf FH registry (S5 Appendix). We also thank our international research collaborators: Professor Raul D. Santos and Professor Kausik K. Ray (affiliations in S6 Appendix). This study was conducted under the auspices of the Gulf Heart Association and the Saudi Heart Association.
- 1. Migliara G, Baccolini V, Rosso A, D’Andrea E, Massimi A, Villari P. Familial hypercholesterolemia: a systematic review of guidelines on genetic testing and patient management. Front Public Health. 2017 Sep;5:252. pmid:28993804
- 2. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003 Jun;111(12):1795–803. pmid:12813012
- 3. Alnouri F, Athar M, Al-Allaf FA, Abduljaleel Z, Taher MM, Bouazzaoui A. Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia. Atherosclerosis. 2018 Oct;277:425–33. pmid:30270081
- 4. Al-Allaf FA, Alashwal A, Abduljaleel Z, Taher MM, Bouazzaoui A, Abalkhail H. Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient. Acta Biochim Pol. 2017;64(1):75–9. pmid:27878139
- 5. Parihar RK, Razaq M, Saini G. Homozygous familial hypercholesterolemia. Indian J Endocrinol Metab. 2012 Jul;16(4):643–5. pmid:22837934
- 6. Austin MA, Hutter CM, Zimmern RL, Humphries SE. Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol. 2004 Sep;160(5):407–20. pmid:15321837
- 7. Ungar L, Sanders D, Becerra B, Barseghian A. Percutaneous Coronary Intervention in Familial Hypercholesterolemia Is Understudied. Front Cardiovasc Med. 2018 Aug;5:116. pmid:30214904
- 8. Patel RS. The continuing challenge of familial hypercholesterolaemia. Oxford University Press; 2017.
- 9. Krogh HW, Mundal L, Holven KB, Retterstøl K. Patients with familial hypercholesterolaemia are characterized by presence of cardiovascular disease at the time of death. Eur Heart J. 2016 May;37(17):1398–405. pmid:26586781
- 10. Sjouke B, Kusters D, Kindt I, Besseling J, Defesche J, Sijbrands E. Homozygous autosomal dominant hypercholesterolemia in the Netherlands: prevalence, genotype-phenotype relationship and clinical outcome. J Am Coll Cardiol. 2014;63(12 Supplement):A2050.
- 11. Béliard S, Rabès JP, Cariou B, Farnier M, Krempf M, Ferrières J. [Familial hypercholesterolemia: an under-diagnosed and under-treated disease. Survey of 495 physicians]. Presse Med. 2018 Sep;47(9):e159–67. pmid:30060905
- 12. Alnouri F, Al-Allaf FA, Athar M, Abduljaleel Z, Alabdullah M, Alammari D. Xanthomas Can Be Misdiagnosed and Mistreated in Homozygous Familial Hypercholesterolemia Patients: A Call for Increased Awareness Among Dermatologists and Health Care Practitioners. Glob Heart. 2020 Feb;15(1):19. pmid:32489792
- 13. al-Gazali LI, Bener A, Abdulrazzaq YM, Micallef R, al-Khayat AI, Gaber T. Consanguineous marriages in the United Arab Emirates. J Biosoc Sci. 1997 Oct;29(4):491–7. pmid:9881148
- 14. Al-Awadi SA, Moussa MA, Naguib KK, Farag TI, Teebi AS, el-Khalifa M. Consanguinity among the Kuwaiti population. Clin Genet. 1985 May;27(5):483–6. pmid:4006273
- 15. el-Hazmi MA, al-Swailem AR, Warsy AS, al-Swailem AM, Sulaimani R, al-Meshari AA. Consanguinity among the Saudi Arabian population. J Med Genet. 1995 Aug;32(8):623–6. pmid:7473654
- 16. Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol. 2020 May;75(20):2553–66. pmid:32439005
- 17. Al-Rasadi K, Alhabib KF, Al-Allaf F, Al-Waili K, Al-Zakwani I, AlSarraf A. The Gulf familial hypercholesterolemia registry (Gulf FH): Design, rationale and preliminary results. Curr Vasc Pharmacol. 2020;18(1):57–64. pmid:30289081
- 18. Civeira F; International Panel on Management of Familial Hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004 Mar;173(1):55–68. pmid:15177124
- 19. Berg AO, Baird MA, Botkin JR, Driscoll DA, Fishman PA, Guarino PD. National Institutes of Health State-of-the-Science Conference Statement: family history and improving health. Ann Intern Med. 2009 Dec;151(12):872–7. pmid:19884615
- 20. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H.; Authors/Task Force Members. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016 Oct;253:281–344. pmid:27594540
- 21. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L.; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan;41(1):111–88. pmid:31504418
- 22. Rubinsztein DC, van der Westhuyzen DR, Coetzee GA. Monogenic primary hypercholesterolaemia in South Africa. S Afr Med J. 1994 Jun;84(6):339–44. pmid:7740380
- 23. Vallejo-Vaz AJ, Kondapally Seshasai SR, Cole D, Hovingh GK, Kastelein JJ, Mata P. Familial hypercholesterolaemia: A global call to arms. Atherosclerosis. 2015 Nov;243(1):257–9. pmid:26408930
- 24. Hu P, Dharmayat KI, Stevens CA, Sharabiani MT, Jones RS, Watts GF. Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation. 2020 Jun;141(22):1742–59. pmid:32468833
- 25. Alhababi D, Zayed H. Spectrum of mutations of familial hypercholesterolemia in the 22 Arab countries. Atherosclerosis. 2018;279:62–72. pmid:30415195
- 26. Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS.; European Atherosclerosis Society Consensus Panel. 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 Dec;34(45):3478–90a. pmid:23956253
- 27. Batais MA, Almigbal TH, Bin Abdulhak AA, Altaradi HB, AlHabib KF. Assessment of physicians’ awareness and knowledge of familial hypercholesterolemia in Saudi Arabia: is there a gap? PLoS One. 2017 Aug;12(8):e0183494. pmid:28817709
- 28. Oman–Oman Society of Lipid and Atheorsclerosis. Available at: https://www.athero.org/about-ias/member-societies/oman-oman-society-of-lipid-and-atherosclerosis-osla/ Accessed on May 26, 2020.
- 29. International Atherosclerotic Society. https://www.athero.org/education-center/slide-library/1st-saudi-familial-hypercholesterolemia-symposium-3rd-severe-fh-master-class/ Accessed on May 26, 2020.
- 30. Al-Nozha MM, Al-Mazrou YY, Arafah MR, Al-Maatouq MA, Khalil MZ, Khan NB. Smoking in Saudi Arabia and its relation to coronary artery disease. J Saudi Heart Assoc. 2009 Jul;21(3):169–76. pmid:23960568
- 31. Al-Nozha MM, Al-Maatouq MA, Al-Mazrou YY, Al-Harthi SS, Arafah MR, Khalil MZ. Diabetes mellitus in Saudi Arabia. Saudi Med J. 2004 Nov;25(11):1603–10. pmid:15573186
- 32. Al-Nozha MM, Abdullah M, Arafah MR, Khalil MZ, Khan NB, Al-Mazrou YY. Hypertension in Saudi Arabia. Saudi Med J. 2007 Jan;28(1):77–84. pmid:17206295
- 33. Besseling J, Kastelein JJ, Defesche JC, Hutten BA, Hovingh GK. Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus. JAMA. 2015 Mar;313(10):1029–36. pmid:25756439
- 34. 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 Jun;109:32–43. pmid:29773150
- 35. 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 Nov;97(11):3956–64. pmid:22893714
- 36. Allard MD, Saeedi R, Yousefi M, Frohlich J. Risk stratification of patients with familial hypercholesterolemia in a multi-ethnic cohort. Lipids Health Dis. 2014 Apr;13(1):65.
- 37. deGoma EM, Ahmad ZS, O’Brien EC, Kindt I, Shrader P, Newman CB. Treatment gaps in adults with heterozygous familial hypercholesterolemia in the United States: data from the CASCADE-FH registry. Circ Cardiovasc Genet. 2016 Jun;9(3):240–9. pmid:27013694
- 38. Neil HA, Seagroatt V, Betteridge DJ, Cooper MP, Durrington PN, Miller JP. Established and emerging coronary risk factors in patients with heterozygous familial hypercholesterolaemia. Heart. 2004 Dec;90(12):1431–7. pmid:15547022
- 39. Alonso R, Perez de Isla L, Muñiz-Grijalvo O, Diaz-Diaz JL, Mata P. Familial Hypercholesterolaemia diagnosis and management. Eur Cardiol. 2018 Aug;13(1):14–20. pmid:30310464
- 40. Versmissen J, Oosterveer DM, Yazdanpanah M, Defesche JC, Basart DC, Liem AH. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ. 2008 Nov;337:a2423. pmid:19001495
- 41. Neil A, Cooper J, Betteridge J, Capps N, McDowell I, Durrington P. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J. 2008 Nov;29(21):2625–33. pmid:18840879
- 42. Kane JP, Malloy MJ, Ports TA, Phillips NR, Diehl JC, Havel RJ. Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens. JAMA. 1990 Dec;264(23):3007–12. pmid:2243428
- 43. Raal FJ, Pilcher GJ, Panz VR, van Deventer HE, Brice BC, Blom DJ. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy. Circulation. 2011 Nov;124(20):2202–7. pmid:21986285
- 44. Pijlman AH, Huijgen R, Verhagen SN, Imholz BP, Liem AH, Kastelein JJ. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2010 Mar;209(1):189–94. pmid:19818960
- 45. Jackevicius CA, Mamdani M, Tu JV. Adherence with statin therapy in elderly patients with and without acute coronary syndromes. JAMA. 2002 Jul;288(4):462–7. pmid:12132976
- 46. Kazi DS, Moran AE, Coxson PG, Penko J, Ollendorf DA, Pearson SD. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016 Aug;316(7):743–53. pmid:27533159
- 47. Hamilton-Craig I, Kostner K, Colquhoun D, Woodhouse S. Combination therapy of statin and ezetimibe for the treatment of familial hypercholesterolemia. Vasc Health Risk Manag. 2010 Nov;6:1023–37. pmid:21127699
- 48. Cuchel M, Bruckert E, Ginsberg HN, Raal FJ, Santos RD, Hegele RA.; European Atherosclerosis Society Consensus Panel on Familial Hypercholesterolaemia. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014 Aug;35(32):2146–57. pmid:25053660
- 49. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015 Nov;36(43):2996–3003. pmid:26330422
- 50. Raal FJ, Stein EA, Dufour R, Turner T, Civeira F, Burgess L.; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015 Jan;385(9965):331–40. pmid:25282519
- 51. Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA.; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May;376(18):1713–22. pmid:28304224
- 52. Saudi Food & Drug Authority. https://www.sfda.gov.sa/en/drug/search/Pages/default.aspx Accessed on May 26, 2020.