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Journal of Atherosclerosis and Thrombosis  Vol. 23, No. 5

Review

Management of Familial Hypercholesterolemia in Hong Kong Miao Hu 1, Amanda J Hooper 2, Frank M van Bockxmeer 3, Gerald F Watts 4, Juliana CN Chan 1 and Brian Tomlinson 1 1

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, Hong Kong SAR Department of Core Clinical Pathology & Biochemistry, Royal Perth Hospital; School of Medicine and Pharmacology, University of Western Australia; School of Pathology & Laboratory Medicine, University of Western Australia, Western Australia, Australia 3 School of Surgery, University of Western Australia, Western Australia, Australia 4 School of Medicine and Pharmacology, University of Western Australia; Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, Western Australia, Australia 2

Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic coronary heart disease (CHD). Patients with FH in Hong Kong were found by the identification of potential probands with primary hypercholesterolemia manifesting total cholesterol levels greater than 7.5 mmol/L or LDL-C levels greater than 4.9 mmol/L and undertaking cascade screening of available relatives in the Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong since the early 1990s. Our previous study in a group of 252 subjects from 87 pedigrees clinically diagnosed as having heterozygous FH reported the mean plasma LDL-C level as 7.2±1.5 mmol/L. Xanthomata were present in 40.6% of males and 54.8% of females. The prevalence of known CHD was relatively low at 9.9% in males and 8.5% in females. All FH patients were offered treatment with statins and many of them reached the LDL-C goal with a moderate or high dose of potent statin alone. Ezetimibe is usually added for patients who have not achieved target LDL-C levels on statin alone, particularly in patients with established CHD. Some FH patients who have not achieved the LDL-C targets with this combination have entered into clinical trials with new cholesterol-modifying agents such as the monoclonal antibodies to proprotein convertase subtilisin-kexin type 9. Increased awareness, early identification, and optimal treatment are essential to reduce the risk of CHD, increase life expectancy, and improve the quality of life of patients with FH. J Atheroscler Thromb, 2016; 23: 520-531. Key words: Familial hypercholesterolemia, Chinese, Hong Kong, Genetics, Low-density lipoprotein cholesterol

Introduction Familial hypercholesterolemia (FH) is an autosomal-dominant genetic disease characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of premature atherosclerotic coronary heart disease (CHD) 1, 2). It is generAddress for correspondence: Brian Tomlinson, Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR E-mail: [email protected] Received: December 2, 2015 Accepted for publication: January 13, 2016

ally caused by mutations in the genes affecting the metabolic clearance of LDL particles, e.g., loss-of-function mutations in the low-density lipoprotein receptor (LDLR) or apolipoprotein B (APOB) genes or gain-offunction mutations in the proprotein convertase subtilisin-kexin type 9 (PCSK9) gene 3-5). Recent investigations have discovered additional genetic loci associated with autosomal dominant hypercholesterolemia 3-6). Heterozygous FH affects around 1 in 200 – 500 individuals in unselected general populations or higher numbers in founder populations ( ＞1%) 7-10). The prevalence of homozygous FH has been estimated at 1 in a million on the basis of the frequency of 1 in 500

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for the heterozygotes 1, 11). Recent data from the Netherlands have shown that the prevalence of molecularly defined homozygous FH, which is either caused by homozygosity or compound heterozygosity for mutations in LDLR, APOB, or PCSK9, is around 1:300,000 9). Patients with homozygous FH usually have a more severe clinical phenotype with plasma cholesterol levels ＞13 mmol/L and extensive xanthomas and suffer from cardiovascular disease (CVD) at a very early age 11, 12); however, sometimes there is an overlap in the clinical features of patients with heterozygous and homozygous FH 9). If left untreated, patients with heterozygous FH typically develop CHD before age 55 and 60 for men and women respectively, whereas homozygotes may develop CHD very early in life 1). Early identification of patients with FH and effective treatment to lower LDL-C levels may prevent or delay future cardiovascular events in this group of high-risk individuals. However, FH remains underdiagnosed and undertreated in most countries 1). Recent guidelines and consensus statements highlight the need for early identification of FH and improving the awareness and management of this condition 1, 8, 11, 13, 14). The prevalence of FH in the Chinese populations appears to be comparable to that in Western countries 10). As the most populous country in the world, China may bear a heavy health burden because of this genetic disease and the associated cardiovascular complications. However, most of the FH patients in Mainland China are undiagnosed and untreated. As with other Asian countries 15), there are significant gaps in the awareness of FH among physicians and the general public in the Chinese populations. This article reports our experience in cascade screening and management of FH in Hong Kong Chinese patients in the past 20 years in the Prince of Wales Hospital in Hong Kong. Cascade Screening of Familial Hypercholesterolemia in Hong Kong The Hong Kong FH cascade screening was initiated in the early 1990s in the Department of Medicine & Therapeutics, Prince of Wales Hospital, which is a teaching hospital of the Chinese University of Hong Kong. Adult subjects were considered as potential probands if plasma total cholesterol level was greater than 7.5 mmol/L and/or LDL-C level was greater than 4.9 mmol/L without secondary causes. The probands and their close relatives (parents, offspring, and siblings) were screened. Other first-degree relatives of the family members found to be affected were subsequently screened whenever possible. During

the screening, patients were examined for the typical signs of FH including corneal arcus, xanthomata, and xanthelasmata. Demographic data, medical history, and evidence of CHD were recorded for all patients. It is likely that on the basis of the clinical diagnostic criteria used in this study, some patients with mild phenotypes may be missed. Since 2011, we have been offering cascade screening for those subjects with a mildly elevated LDL-C levels ( ＞ 4.5 mmol/L) but a strong family history of hypercholesterolemia at the Lipid Clinic in the Prince of Wales Hospital to maximize the chance of identifying potential cases. For young patients with elevated LDL-C levels aged below 18 years, family history was collected and first-degree relatives of the family members were screened. Clinical Diagnosis of Familial Hypercholesterolemia It was previously reported that Chinese patients with FH living in China have lower LDL-C levels (4.4±1.1 mmol/L vs. 7.5±1.3 mmol/L), prevalence of xanthomata (0% vs. 37.5%), and premature CHD (0% vs. 25%) than those living in Canada with equivalent LDLR gene mutations 16, 17), demonstrating the importance of environmental factors in determining the phenotypes of FH. With the rapid socioeconomic development in China, there have been significant changes in lifestyle and diet, which has led to an increased total cholesterol level in Mainland China in the past 30 years 18). The phenotype of FH in China is very likely to become more evident in relation to increased urbanization and increased background LDL-C levels. The lifestyle in Hong Kong has been in a transition between Mainland China and Western countries for several decades. The plasma cholesterol levels in the Hong Kong general population were comparable to those in Western countries 19). The criteria for the clinical diagnosis of FH in our patients were described previously 19). In brief, we adopted the MedPed (Make Early Diagnosis to Prevent Early Death in Medical Pedigrees) Program criteria. Both elevated LDL-C levels and evidence of dominant inheritance were required to verify the clinical diagnosis of FH for the index case. The presence of tendon xanthomata in the family was important, but not essential, evidence. First-degree relatives of diagnosed FH patients were classified as FH if LDL-C levels exceeded the age-specific cut-off points, for example, LDL-C levels of 4.0, 4.4, 4.9, and 5.3 mmol/L for ages ＜ 20, 20 – 29, 30 – 39, and ≥ 40 years, respectively. For patients who had no relatives available for screening, substantially elevated LDL-C levels, and

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Table 1. Characteristics of Hong Kong Chinese patients with familial hypercholesterolaemia 19) Characteristics

All

Males

Females

Age ＜18 Age (years) Body weight (kg) Body mass index (kg/m2) TC (mmol/L) TG (mmol/L) HDL- C (mmol/L) LDL-C (mmol/L) Corneal arcus Y/N (%) a Xanthelasmata Y/N ((%) a Xanthomata Y/N (%) a

(n = 43) 12.2±4.0 41.0±12.5 18.7±3.3 8.09±1.48 1.00±0.40 1.31±0.23 6.23±1.32 21/13 (61.8) 2/34 (5.6) 4/32 (11.1)

(n = 26) 10.8±3.9 36.0±12.0 21.1±2.9 8.13±1.43 0.95±0.40 1.33±0.24 6.21±1.15 12/7 (63.2) 2/19 (9.5) 3/18 (14.3)

(n = 17) 14.3±3.1 48.4±9.6 17.1±2.5 8.03±1.59 1.06±0.40 1.29±0.21 6.25±1.58 9/6 (60.0) 0/15 1/14 (6.7)

Age ≥ 18 Age (years) Body weight (kg) Body mass index (kg/m2) TC (mmol/L) TG (mmol/L) HDL- C (mmol/L) LDL-C (mmol/L) Corneal arcus Y/N (%) a Xanthelasmata Y/N ((%) a Xanthomata Y/N (%) a Smokers Y/N (%) a Hypertension Y/N (%) a Type 2 diabetes Y/N (%) a CHD Y/N (%) a

(n = 209) 41.9±13.4 58.1±10.1 23.2±3.4 9.36±1.43 1.30±0.74 1.35±0.39 7.42±1.47 139/54 (72.0) 25/167 (13.0) 97/98 (49.7) 21/165 (11.3) 28/156 (15.2) 11/174 (5.9) 18/182 (9.0)

(n = 74) 38.8±11.5 64.7±8.8 23.1±3.6 9.31±1.48 1.58±0.89 1.17±0.37 7.39±1.50 56/13 (81.2) 7/60 (10.4) 28/41 (40.6) 15/50 (23.1) 7/57 (10.9) 4/61 (6.2) 7/64 (9.9)

(n = 135) 43.5±14.0 54.7±9.1 23.6±2.7 9.39±1.41 1.14±0.59 1.45±0.37 7.44±1.45 83/41 (66.9) 18/107 (14.4) 69/57 (54.8) 6/115 (5.0) 21/99 (17.5) 7/113 (5.8) 11/118 (8.5)

P 0.003 0.006 ＜ 0.001 0.829 0.376 0.603 0.932 0.851 0.5 0.626 0.009 ＜ 0.001

0.162 0.67 ＜ 0.001 ＜ 0.001 0.816 0.035 0.506 0.058 ＜ 0.001 0.238 0.999 0.753

Abbreviations: CHD, coronary heart disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides. Quantitative variables are expressed as mean±standard deviation (S.D.). a Data were missing in some patients. Permission is obtained.

presence of tendon xanthomata were needed to support the diagnosis of FH. We previously reported the clinical characteristics of 252 patients from 87 pedigrees clinically diagnosed as FH during 1990 – 2000 (Table 1) 19). The mean (±SD) age of the 252 patients with heFH was 37±17 (range from 2 to 80) years including 43 subjects aged below 18 years 19). The mean plasma LDL-C level was 7.2±1.5 mmol/L. Tendon xanthomata were present in 40.6% of males and 54.8% of females. The prevalence of known CHD was relatively low at 9.9% in males and 8.5% in females. Multiple logistic regression analysis showed that the risk of CHD was related to age (per year) [odds ratios (OR) 1.07; 95% confidence interval (CI) 1.01,−1.14; p = 0.02) and the presence of xanthelasmata (OR 10.72; 95% CI 2.28, −50.42; p ＜ 0.001) 19). During the family screening of FH, we identified

two index cases with sitosterolemia, a rare autosomal recessive disease showing similar clinical manifestations as FH (e.g., elevated LDL-C levels, tendon xanthomata, and premature CHD). The intestinal sterol/ cholesterol absorption is governed by the two ATPbinding cassette (ABC) half-transporters, ABCG5 and ABCG8, which heterodimerize to form a sterol efflux transporter in the liver and intestine to transport sterols (cholesterol and plant sterols) out of the body, and the Niemann-Pick C1-like 1 (NPC1L1) transporter, which mediates intestinal absorption of cholesterol and sterols 20). Sitosterolemia is caused by mutations in either ABCG5 or ABCG8 21). We previously reported the potential role of NPC1L1 polymorphisms in determining the clinical manifestation of sitosterolemia in one of the cases and her genetically affected sibling 22). Sitosterolemia can be diagnosed on the basis of demonstration of elevated plasma levels of plant

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Table 2. Mutations identified in 19 subjects with clinical diagnosis of familial hypercholesterolaemia No 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17

Mutation LDLR c.1241T ＞ G (Leu414Arg, exon 9) LDLR c.1474G ＞ A (Asp492Asn, exon 10) LDLR in-frame deletion (exon 5) LDLR c.298G ＞ A (Asp100Asn, exon 3) LDLR c.442T ＞ G (Cys148Gly, exon 4) LDLR c.1055G ＞ C (Cys352Ser, exon 7) LDLR c.660delC (Asp221Thrfs*44, exon 4) LDLR c.682G ＞ A (Glu228Lys, exon 4) LDLR c.1048C ＞ T (Arg350X, exon 7) LDLR c.1285G ＞ A (Val429Met, exon 9) LDLR c.817＋1G ＞ A (intron 5) LDLR 1187-10G ＞ A (intron8) LDLR c.1706-1G ＞ A (intron 11) LDLR c.769C ＞ T (Arg257Trp, exon 5) LDLR c.1765G ＞ A (Asp589Asn, exon 12) LDLR c.1747C ＞ T (His583Tyr, exon 12) APOB R3500W (exon 26)

Number of Subjects

LDLR database＊

4 2 (including 1 homozygous) 1 1 1 1 1 1 1 1 1 1 1 1 (Compound homozygous with #15) 1 (Compound homozygous with #14) 1 (Compound heterozygous with #17) 1 (Compound heterozygous with #16)

LDLR_00372 LDLR_00548 LDLR_00121 Novel Novel Novel LDLR_00865 LDLR_00039 LDLR_00215 LDLR_00066 LDLR_01218 LDLR_00882 LDLR_01159 LDLR_00712 LDLR_01066 LDLR_00263

＊

www.ucl.ac.uk/ldlr

sterols, particularly sitosterol and campesterol, the two major plant-derived sterols 23, 24). However, as plasma levels of plant sterols were not routinely checked, these patients sometimes may be misdiagnosed as having FH. Patients with sitosterolemia usually have a poor LDL-C response to statin therapy but a very good response to ezetimibe, the NPC1L1 inhibitor, and this feature can be used to help distinguish these patients from those with FH. Genetic Testing Genetic Testing in Familial Hypercholesterolemia Patients with Severe Phenotypes in Hong Kong As the clinical phenotype of FH is highly variable in terms of severity, the presence of tendon xanthomata, and the age of onset and severity of CHD because of a combination of genetic and environmental factors, diagnosing FH on the basis of clinical criteria alone may not be very reliable and may overlook a substantial proportion of FH, particularly for those cases with no family member or family history available. Genetic testing can give an unequivocal diagnosis of this genetic lipid disorder. However, genetic causes of FH in Chinese patients are not well known. In Hong Kong, genetic testing was performed in some selected cases but not in all cases. We previously performed direct DNA sequencing in 73 DNA samples from 30 families for the detection of mutations in the promoter and 18 coding

exons of LDLR using a double-strand DNA cycle sequencing kit (GIBCO-BRL). A total of 18 different mutations were identified in LDLR in 63 subjects from 21 families as previously described 25). More recently, we performed sequencing for mutations in the coding region and splice sites of LDLR and for known mutations in APOB exon 26 in 20 probands with a clinical diagnosis of FH who had very high LDL-C levels (baseline LDL-C: 9.5±1.7 mmol/L). A total of 17 mutations in LDLR or APOB were identified in 19 subjects with 3 patients being homozygous FH or compound heterozygotes (Table 2). The remaining subject was confirmed to have sitosterolemia but was previously misdiagnosed as FH as her first-degree family member also had high plasma lipid levels. There were three novel mutations identified in LDLR (Table 2). LDLR 1241T ＞ G occurred in 4 patients representing the most common mutation responsible for the severe phenotypes of FH in Chinese patients. Genotyping of the variant identified in each proband was performed in the family members who previously provided written consent for genetic testing for the 19 FH families. In the 94 family members of the 19 probands, there was a high degree of agreement in the clinical diagnosis and the molecular diagnosis of FH. A genetic diagnosis of FH was established in 49 subjects, of which 2 patients who had previously not been diagnosed with FH were found to have this disorder (false negative rate: 6%). However, the diagnosis of FH was rejected by the genetic test in

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8 patients who had previously been clinically diagnosed with FH (false positive rate: 18.2%). These findings suggest the importance of genetic testing in the diagnosis of FH. The effectiveness of genetic cascade screening for FH has been proven in Australia and in some other Western countries 26). Other Genetic Factors Contributing to the Phenotypes of Familial Hypercholesterolemia In this small group of FH patients with severe phenotypes, the plasma lipid levels were highly variable within the affected family members who carried the same mutations. Other genetic variants and environmental factors may also contribute to the diverse phenotypes. Talmud et al tested the hypothesis that FH can be caused by an accumulation of common small-effect LDL-C-raising alleles 27). They compared the gene score distribution among patients with FH with no known confirmed mutation (baseline LDL-C level: 5.87±1.57 mmol/L), those with an identified mutation (7.03±1.49 mmol/L), and controls (4.4± 1.0 mmol/L). A total of 12 common LDL-C-raising polymorphisms in 11 genes were genotyped and were used to construct a weighted LDL-C-raising gene score. The mean weighted LDL-C gene score of the controls was strongly associated with LDL-C level (p = 1.4×10−77; R2 = 0.11). Mutation-negative patients had a significantly higher mean weighted LDL-C score than the controls (p = 4.5×10−16) 27). The score was also higher in the mutation-positive patients than in the controls. This study suggested that the raised LDL-C levels in patients with FH without a known mutation have a polygenic cause, whereas those in patients with a detected mutation, a substantial polygenic contribution, add to the variable penetrance of the disease 27). It has been reported that mutations in LDLR, APOB, and PCSK9 can be detected in approximately 60% – 80% of definite FH patients 28, 29). A recent study showed that in 125 patients with a clinical diagnosis of definite FH but no detectable mutation in LDLR, APOB, and PCSK9, whole exome sequencing failed to identify any major novel locus for FH in these patients, suggesting that the genetic cause of FH in these unexplained cases is likely to be heterogeneous. Fouchier et al performed parametric linkage analysis combined with exome sequencing in a family with autosomal-dominant hypercholesterolemia and identified a variant in signal-transducing adaptor family member 1 (STAP1) associated with the disease 6). Further Sanger sequencing of STAP1 in 400 additional unrelated autosomal-dominant hypercholesterolemia probands identified 3 additional missense vari-

ants 6). Those STAP1 variant carriers (n = 40) showed significantly higher plasma LDL-C levels compared with nonaffected relatives (n = 91). The study provided strong genetic evidence for involvement of STAP1 in controlling cholesterol homeostasis, but the molecular mechanism behind this remains to be determined. It is still unclear whether the mutations in STAP1 are associated with the phenotypes of FH in the Chinese patients with a clinical diagnosis of FH who do not carry mutations in the established genes. Recent data from 97 Korean FH patients revealed conventional clinical criteria (Simon Broome or Dutch Lipid Clinic) showed limited mutation detection power (35% – 37%), but the mutation detection rate by MEDPED criteria was as high as 67% – 75%, and the best LDL-C threshold for putative mutations in LDLR, APOB or PCSK9 genes was 225 mg/dl (5.8 mmol/L) in this group of patients 30). However, whole-exome sequencing analysis did not identify any other novel genes accounting for the genetic cause of FH 31). Our initial genetic testing was only performed in those probands with severe phenotypes and their family members and this may contribute to the high detection rate (100% after excluding the case with sitosterolemia). Future studies will be performed to examine the genetics of FH in patients with a clinical diagnosis of FH with relatively mild phenotypes. Clinical Management of Familial Hypercholesterolemia Lifestyle and Behavior Modification All patients with a clinical diagnosis of FH (definite, probable, and possible) were advised to improve their lifestyles, particularly healthy eating, regular exercise, and physical activity and stop smoking if they had such a habit. The importance of lifestyle modification has been emphasized at each follow-up in the clinic. They were also advised that lifestyle changes could help with the plasma lipid levels to some extent, but would not cure this genetic disease, and pharmacotherapies are still needed in almost all patients with FH. Pharmacotherapy Statins The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR) inhibitors or statins are the cornerstone of lipid-lowering therapy to reduce the risk of CHD. Large randomized clinical trials have demonstrated that statins significantly reduce the morbidity and mortality of CVD, with every 1 mmol/L reduction in LDL-C level with statin

FH in Hong Kong

therapy being associated with approximately 20% reduction in major vascular events in a wide range of subjects 32-34). A long-term cohort study in over 2000 patients with FH without prevalent CHD in the Netherlands has shown that the absolute risk of first onset of CHD was 11/1000 person years in statintreated patients compared with 119/1000 person years in untreated patients 35). Statin-treated patients had an overall risk reduction of 76% [hazard ratio 0.24 (95% confidence interval 0.18 – 0.30), p ＜ 0.001] compared with the untreated patients 35). In patients with homozygous FH, statin-treated patients had a 66% reduction in total mortality and a 51% reduction in major cardiovascular events compared with statin-naïve patients, although the mean reduction in LDL-C level was only 26.4% with lipidlowering therapy 36). In another large long-term prospective registry study of 3382 patients with heterozygous FH in the UK, CHD mortality fell significantly by 37% because of the widespread use of statins 37), although patients were still at a higher risk (from 3.4- to 2.1-fold higher risk) than the general population, which is in line with the observation from Norway 38). Primary prevention resulted in a 48% reduction in CHD mortality from 2.0-fold excess to none, with a smaller reduction of nearly 25% in patients with established CHD 37). In patients without known CHD at registration, allcause mortality from 1992 was 33% lower than in the general population, mainly because of a 37% lower risk of fatal cancer 37). These results emphasized the importance of early identification of FH and early treatment with statins. A recent Mendelian randomization analysis also suggested that prolonged exposure to lower LDL-C levels, beginning early in life, is associated with a 3-fold greater reduction in the risk of CHD for each unit of lower LDL-C level than the current practice of lowering LDL-C level later in life 39). Although recent studies have suggested that high doses of statins can increase the risk of developing type 2 diabetes 40, 41), the cardiovascular benefits of statin therapy clearly outweigh the risk of developing diabetes in this group of high-risk patients. Recent data from a large prospective cohort of FH patients treated with statins and their unaffected relatives showed that in patients with FH, long-term treatment with high doses of statins did not increase the risk of developing type 2 diabetes 42). The best predictors for the development of type 2 diabetes in patients with FH were increasing age (range 50 – 75 years) and the presence of metabolic syndrome at entry, with the plasma glucose levels being the only component of the

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metabolic syndrome that predicted increased risk of new-onset of type 2 diabetes in FH 42). Similar findings were reported by others 43). These studies suggest that FH patients on high dose statins are not at increased risk of developing diabetes, particularly if they avoid obesity and metabolic syndrome through preventive measures. In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with FH was significantly lower than among unaffected relatives, suggesting the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes 44). In Hong Kong, all our adult FH patients have been offered treatment with statins and many of them reach the LDL-C goal with a moderate or high dose of potent statin alone (e.g., simvastatin 40 mg, atorvastatin 20 – 40 mg, and rosuvastatin 10 – 20 mg). Ezetimibe is usually added for patients not achieving target LDL-C levels ( ＜ 2.6 mmol/L or ＜ 1.8 mmol/L for those with very high risk of CHD) on statin alone, particularly in patients with established CHD. Some young patients were given lipid-lowering drugs from childhood ( ＞10 years old). The European Atherosclerosis Society Consensus Panel recommended early detection (from age of 5 years or earlier if homozygous FH is suspected) in children and to treat the children with FH as early as age 8 – 10 years by lifestyle modification and statin therapy 14). Statins are very effective in reducing LDL-C levels in the general populations, and the percentage changes in LDL-C level in response to statins are largely independent of baseline values. There is no direct comparison for the lipid-lowering effect of statins in patients with and without heterozygous FH. In our previous pharmacogenetic study with rosuvastatin in nearly 400 Chinese patients with hypercholesterolemia, rosuvastatin 10 mg daily reduced the LDL-C level by 52% 45). This study included 166 patients with heterozygous FH who had a 2.6% smaller reduction in LDL-C levels (p ＜ 0.05) in response to rosuvastatin, compared with patients without FH, and this may be related to the impaired LDLR function in patients with FH 45). Other genetic and lifestyle factors may also contribute to the variability in the LDL-C response to statins. Ezetimibe Ezetimibe has recently been shown to modestly reduce cardiovascular events when added to background statin therapy in the IMPROVE-IT trial 46). This corresponds well with the finding that mutations that disrupt NPC1L1 function are associated with

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reduced plasma LDL-C levels and a reduced risk of CHD 47). Co-administration of ezetimibe with a statin provides addition reductions in LDL-C level by about 15% to 20% compared with statin monotherapy because of their complementary mechanisms of actions 48, 49), and this may be more cost-effective than doubling the dose of statins, which can only further reduce LDL-C level by an additional 6%. The results of the IMPROVE-IT trial may encourage the use of ezetimibe in patients with FH having uncontrolled LDL-C levels with statin monotherapy. PCSK9 Inhibitors Lipoprotein apheresis is not generally available in the public hospitals in Hong Kong. Some FH patients with a very high cardiovascular risk who have not achieved the LDL-C targets with the combination of statin and ezetimibe have entered into clinical trials with the new cholesterol-modifying agents such as the monoclonal antibodies to PCSK9. This class of agents given by subcutaneous injection once or twice per month resulted in a further reduction in the LDL-C levels by over 50% in patients receiving statins with or without ezetimibe, and this is consistent with the data in the clinical trials 50). Two PCSK9 inhibitors, alirocumab and evolocumab, have recently been approved by FDA and EMA on the basis of their ability to lower LDL-C levels, and their effects on other lipid fractions in patients at risk for CVD. No efficacy data on cardiovascular outcomes are available at present, except for encouraging but preliminary analyses of cardiovascular adverse events with evolocumab 51). Ongoing outcome studies with the PCSK9 inhibitors will elucidate the true clinical benefits and possible risks of this class of drugs. Currently, the PCSK9 monoclonal antibodies are only available in the clinical trials in Hong Kong. Niacin Nicotinic acid or niacin is an old drug which has been used for the treatment of dyslipidemia for over 50 years 52). It has favorable effects on all traditionally measured lipid parameters, e.g., reducing LDL-C levels, triglycerides and lipoprotein(a) [Lp(a)] levels and raising high-density lipoprotein cholesterol 53). Several lines of evidence suggest Lp(a) is causally related to premature CHD 54), and niacin is the only lipid-modifying drug currently available (except for PCSK9 inhibitors) to reduce plasma lipoprotein(a) levels. Levels of Lp(a) are genetically determined and differ significantly among ethnic groups, with Japanese and Chinese generally having a lower level of Lp(a) than Caucasians and Blacks 54). Patients with FH usually

have a higher plasma level of Lp(a) than the general population or patients with nonfamilial hypercholesterolemia. Elevated Lp(a) level has been found to be an independent predictor of CHD in FH after adjusting for other modifiable risk factors 55, 56). In a small cohort of study with niacin, we found Chinese patients with FH had a higher level of Lp(a) than those without FH [median(interquartile range): 12.5 (5.2, 23.3) mg/dL (n = 30) vs. 5.4 (2.3, 16.2) mg/dL (n = 91), p ＜ 0.01]. There were 16.7% and 11% of patients with an elevated Lp(a) level of ＞ 50 mg/dL in FH and non-FH patients, respectively. Niacin 2 g daily significantly (p ＜ 0.001) reduced the Lp(a) level by 39.6% and 37.2% in FH and non-FH patients, respectively. The clinical use of niacin in the statin era has been challenged after two outcome studies (the AIMHIGH trial and the HPS2-THRIVE trial), which showed that niacin or a combination of niacin and laropiprant (a selective antagonist of PGD2 at the DP1 receptor to reduce niacin-induced flushing) did not reduce cardiovascular event in patients receiving intensive statin therapy 57, 58). In our previous studies with niacin and niacin/laropiprant, we found the LDL-C response to niacin was significantly associated with baseline LDL-C levels 59, 60). This is in line with the observation in the HPS2-THRIVE study where the percentage reduction in LDL-C levels was dependent on the baseline values and this influenced the cardiovascular outcome with those with baseline LDL-C level of ＞ 2 mmol/L having the best outcome and those with LDL-C level of ＜1.5 mmol/L the worst outcome 58). This feature differs from the LDLC-lowering effects of statins for which the percentage changes in LDL-C levels are largely independent of baseline values. Indeed, we found that patients with FH had greater reductions in LDL-C levels with niacin/laropiprant than those without FH because of high baseline LDL-C levels 60). In some FH patients with high pretreatment LDL-C levels, the LDL-C reduction with niacin was similar in magnitude (~50%) to the effects of PCSK9 inhibitors. On the basis of these findings, we believe niacin may still have a role in some selected patients who do not reach their LDL-C targets with statin therapy, such as patients with FH. Challenges in the Care of Familial Hypercholesterolemia Chinese patients with FH remain underdiagnosed and undertreated in the community setting in Hong Kong as well as in the other parts of the world.

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According to the experience from Australia, increasing awareness among primary care teams will optimize the detection and management of FH in the community 61-64). Cardiologists can also play a significant role in identification and management of FH as many index cases are identified when they have already developed symptomatic CHD and cardiologists may be the first clinicians to encounter the patients and their families 65), particularly in China, where primary care is not well developed and provided. Patients’ knowledge and perception of FH also have a significant impact on the management of FH. Although most of the index cases identified expressed positive attitudes toward the cascade screening, sometimes their relatives refuse to attend screening because of lack of knowledge of the disease and lack of motivation. It is important to improve the awareness of FH among the patients and the general public. Every effort should be made to detect FH and to initiate cascade testing of available family members to prevent the development of CHD in those who may be unaware that they also have the condition. Developing a model of care for FH in Hong Kong will help to bridge the gap in coronary prevention in FH patients. However, there are still lots of barriers, e.g., training primary care physicians, establishing population-specific clinical diagnostic criteria for FH, availability of a centralized FH care service, genetic testing, funding, and administration as well as support from the government and professionals, etc. Japan has developed the country-specific diagnosis criteria of FH on the basis of the population data 66) and has established its own guideline for the management of FH 67). FH Australasia Network has performed pioneer work in developing a model of care for FH in Australia and New Zealand 62, 65). These countries present good examples for the care of FH. Conclusion FH is a highly prevalent genetic lipid disorder causing premature atherosclerotic CHD, and the severity of FH is largely dependent on the degree and duration of exposure to high plasma LDL-C levels. However, FH remains underdiagnosed and inadequately treated worldwide. Increased awareness, early identification, and optimal treatment are essential to reduce the risk of CHD, increase life expectancy and improve the quality of life for patients with FH. There are significant gaps in awareness of FH among physicians and the general public. Registries and epidemiological studies are needed to better define the phenotypes of FH in the Chinese populations. Genetic stud-

ies are required to clarify the genetic features of FH and to improve diagnostic classification in Chinese. Acknowledgement We thank Ms Evelyn Chau for her excellent assistance. This paper is the first in a series to inform about the care of FH in the Asia-Pacific region, being a component of the 10-Countries Study supported by the IAS-Pfizer Grant (Grant ID: 10839501). Conflicts of Interest None. References 1) Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Boren J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR and Tybjaerg-Hansen A: 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. European heart journal, 2013; 34: 3478-3490a 2) Hovingh GK, Davidson MH, Kastelein JJ and O’Connor AM: Diagnosis and treatment of familial hypercholesterolaemia. European heart journal, 2013; 34: 962-971 3) Soutar AK and Naoumova RP: Mechanisms of disease: genetic causes of familial hypercholesterolemia. Nature clinical practice, 2007; 4: 214-225 4) Brautbar A, Leary E, Rasmussen K, Wilson DP, Steiner RD and Virani S: Genetics of familial hypercholesterolemia. Curr Atheroscler Rep, 2015; 17: 491 5) van der Graaf A, Avis HJ, Kusters DM, Vissers MN, Hutten BA, Defesche JC, Huijgen R, Fouchier SW, Wijburg FA, Kastelein JJ and Wiegman A: Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children. Circulation, 2011; 123: 1167-1173 6) Fouchier SW, Dallinga-Thie GM, Meijers JC, Zelcer N, Kastelein JJ, Defesche JC and Hovingh GK: Mutations in STAP1 are associated with autosomal dominant hypercholesterolemia. Circ Res, 2014; 115: 552-555 7) Benn M, Watts GF, Tybjaerg-Hansen A and Nordestgaard BG: Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab, 2012; 97: 3956-3964 8) Gidding SS, Ann Champagne M, de Ferranti SD, Defesche J, Ito MK, Knowles JW, McCrindle B, Raal F, Rader D, Santos RD, Lopes-Virella M, Watts GF and Wierzbicki AS: The Agenda for Familial Hypercholesterolemia: A Scientific Statement From the American Heart Associa-

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