Familial Hypercholesterolaemia in the Asia-Pacific Region

Familial hypercholesterolaemia (FH) is a genetic disorder, characterised by elevated serum LDL cholesterol levels, and is the most common autosomal dominant disorder in humans.¹ Common pathogenic genetic variants involving the LDL receptor (LDLR), apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin 9 (PCSK9) genes have been linked to heterozygous and homozygous FH.²

The LDL receptor adapter protein 1 (LDLRAP1) gene, an autosomal recessive gene, also contributes to homozygous FH. The resulting disorder in LDL cholesterol catabolism causes abnormally high levels of LDL cholesterol in the serum from before birth, with a cumulative lifetime burden leading to clinical signs of hypercholesterolaemia, such as tendon xanthoma, corneal arcus and early-onset atherosclerotic cardiovascular disease (ASCVD).³

The clinical presentation is more severe in homozygous FH (HoFH) than in heterozygous FH (HeFH), with many HoFH patients showing clinical signs in childhood, but before the age of 20 years, and with cardiovascular (CV) events occurring from adolescence and most before age 30 years.⁴ Interventions, such as statin therapy and biological treatments, are available to lower LDL cholesterol in patients with FH, but most often are not appropriately started in childhood. FH remains underdiagnosed and undertreated worldwide.

The Asia-Pacific region, defined as the whole of Asia and Oceania, is home to almost 4.6 billion people or 58% of the world’s total population. Hence, it is expected that the majority of patients with FH reside in this region. However, most of the countries in the region are developing nations with resource limitations and conflicting priorities. This review aims to describe the current state of FH in this region, with a focus on gaps in care, practical barriers, strengths and potential solutions to increase the detection and improve CV outcomes throughout the region.

Epidemiology of FH in Asia-Pacific

The detection of FH throughout the Asia-Pacific region remains low, with even developed countries in the region reporting low detection rates at a fraction of those reported in Western countries.⁵ For example, in Australia, up to 90% of adults and 98% of children remain undiagnosed.^6,7 However, as interest in addressing FH grows, together with increasing treatment choices and the availability of secure open-source web-based digital infrastructure, several registries have been established in the Asia-Pacific region. Country-specific registries are already in place in Australia and New Zealand, India, Japan, Malaysia, Taiwan, Thailand, and Vietnam.^8–10

In 2015, the European Atherosclerosis Society FH Studies Collaboration was launched to establish a global FH registry to generate large-scale, robust data on the burden of FH worldwide.⁹ The collaboration now covers 69 countries, including 18 Asia-Pacific countries, namely Australia, China including Hong Kong, India, Iran, Iraq, Japan, Kyrgyzstan, Malaysia, Pakistan, the Philippines, Singapore, South Korea, Taiwan, Sri Lanka, Thailand, Turkey, Uzbekistan and Vietnam.^9,11 Middle East countries followed suit, and in 2020, Al-Rasadi et al. published the design and initial results of the Gulf FH Registry.¹² The registry enrolled only adult FH patients from Saudi Arabia, Oman, United Arab Emirates, Kuwait and Bahrain.

Prevalence

Based on data from previous studies, the prevalence of FH in Asia-Pacific ranges from one in 200 to one in 500 individuals.^9,13 A systematic review and meta-analysis reported a one in 526 prevalence of FH in Asia, based on two studies from Japan, a study from Korea and a study from China.¹⁴ Korea was over-represented in this meta-analysis (88%), with a reported prevalence of 1:909 individuals – this study included only patients with low serum cholesterol. In comparison, the prevalence of FH in both Europe and North America was one in 313.¹⁴

Table 1 summarises the published estimates of FH prevalence in 12 Asia-Pacific countries and regions: Australia, China, the Gulf region, India, Japan, Malaysia, New Zealand, the Philippines, Singapore, Sri Lanka, Taiwan and Vietnam. The Gulf region is notable for having an estimated prevalence of 0.9% (1 in 112), approximately triple the global estimated prevalence.¹⁵ The wide variation of reported local prevalence is due to several factors, such as true differences in epidemiology, differences in the study populations and variations in the definition of FH used. The use of varying diagnostic criteria between reports complicates comparisons between countries or even different studies in the same country.

A few studies have also investigated the prevalence of FH among high-risk groups, particularly those with early-onset ASCVD. In New Delhi, India, the prevalence of FH among patients with premature coronary artery disease was 4% (definite FH) and 11% (probable FH).¹⁶ In Japan, the prevalence of HeFH among hospitalised acute coronary syndrome patients was 5.7% overall, increasing to 7.8% among patients aged <60 years.¹⁷ Another Japanese study found that the prevalence of FH in those with premature acute coronary syndrome (aged <55 years for men, <65 years for women) was 4.7%.¹⁸ In Beijing, China, the prevalence of FH diagnosed by genetic testing among patients with premature MI was 4.4%, and definite/probable FH diagnosed by the modified Dutch Lipid Clinic Network (DLCN) criteria was 23.6%.¹⁹ Another study in China found that 6.5% of patients aged ≤35 years with MI had definite/probable FH based on the DLCN criteria.²⁰ Based on these reports, the prevalence of diagnosed FH increases as the age of onset of ASCVD decreases and as the severity of ASCVD worsens.

As previously mentioned, the prevalence of FH in countries in the Asia-Pacific is complicated by the use of different diagnostic criteria in each country. The most commonly used criteria are the DLCN, Simon Broome Register Group, MEDPED and other self-developed criteria.¹³ The DLCN criteria calculates a score that helps determine the likelihood of FH.²¹ This scoring system incorporates genetic testing and other clinical elements, including family history, personal history, physical examination findings related to hypercholesterolaemia such as tendon xanthomas and corneal arcus, and LDL cholesterol levels. A total point score >8 (or a positive genetic test, even with low LDL cholesterol) is considered ‘definite’ FH, 6–8 is ‘probable’ FH and 3–5 is ‘possible’ FH. The Simon Broome Register Group diagnostic criteria are comparable and also integrate similar variables including genetic testing.²² In contrast, the US MEDPED criteria are based only on age-specific cholesterol thresholds.²³

These aforementioned diagnostic criteria were developed from Western cohorts; hence, their accuracy in Asian populations is unclear. Given that Asian populations have lower overall LDL cholesterol levels, some patients with FH may be missed with the use of Western criteria. In China, a modified DLCN scoring system uses lower LDL cholesterol thresholds, and excludes physical examination findings and DNA analysis, due to the absence of widespread availability of genetic testing.^24,25

The Japanese Familial Hypercholesterolaemia Management Criteria indicated in the guidelines of the Japan Atherosclerosis Society defines the diagnosis of homozygous FH as the genetic diagnosis of homozygous FH or reduced LDL receptor activity (definite HoFH); and the presence of cutaneous or tendon xanthomas during childhood associated with serum total cholesterol (TC) ≥450 mg/dl (11.6 mmol/l) or LDL−c ≥370 mg/dl (9.6 mmol/l), and shows resistance to LDL-lowering therapies (probable HoFH).²⁶ The criteria of HeFH in Japan are as follows: LDL cholesterol level of ≥180 mg/dl (4.6 mmol/l); tendon xanthoma on the back of the hands, elbows, knees or other areas, Achilles tendon hypertrophy or Achilles tendon thickness (≥8.0 mm in men, ≥7.5 mm in women on radiography; ≥6.0 mm in men, ≥5.5 mm in women on ultrasound) or xanthoma tuberosum; and family history of FH or premature coronary artery disease diagnosed in a first-degree relative.^27,28

A Malaysian study compared the performance of the Simon Broome Register Group, US MEDPED and Japanese Familial Hypercholesterolaemia Management Criteria with the DLCN criteria (considered the gold standard). The study found that the Simon Broome Register Group criteria had a sensitivity of 51% and a positive predictive value of 98.8%; the Japanese Familial Hypercholesterolaemia Management Criteria had a sensitivity of 47% and a positive predictive value of 97.9%. The US MEDPED criteria had the lowest sensitivity of 25.3%.²⁹

Korean researchers compared the sensitivity and specificity of several well-known diagnostic criteria using individuals with confirmed pathogenic variants identified in gene tests as a gold standard of FH. This study highlighted that Japan’s diagnostic criteria had higher sensitivity for identifying individuals with LDLR, APOB, PCSK9 and LDLRAP1 pathogenic variants.³⁰ The combined criteria of definite and probable FH based on the DLCN criteria could have 65% sensitivity and 65% specificity. The Simon Broome Register Group criteria had a maximum sensitivity of 94%, but only 21% specificity, and in contrast, the MEDPED criteria had a sensitivity of 39%, but a specificity of 94%. This study reported that the cutoff values for LDL cholesterol of 5.8 mmol/l or TC 8.0 mmol/l were of the best capacity to detect pathogenic variants in Korean patients.

Genotypes

Currently, four genes have been identified, including LDLR, APOB, PCSK9 and LDLRAP1.^1,13,31,32 For LDLR mutations, >2,000 mutation types are already housed in the UK LDLR mutation database (https://databases.lovd.nl/shared/genes/LDLR). Most are point mutations or small deletion and insertion mutations, and a minority are large fragment rearrangements. Almost half of the mutations have been reported in only one patient.

The characterisation of FH genotypes among Asian individuals is an evolving process, with most studies focusing on LDLR variants and less on PCSK9 and APOB variants prior to 2015.³² A systematic review that examined literature from 1950 to 2019 reported genetic variants of FH in Asia. The studies encompassed 8,994 FH families from 48 Asian countries. A total of 20 countries have studied LDLR variants. A total of 629 mutations were reported, and 20 variants were found to be commonly present. China, Japan, India and Taiwan constituted 68% of published articles. The most frequent mutation was reported in Japan, but was not common in other countries. Other missense variants accounted for 50% of the mutations, frameshifts in 19% and nonsense in 11%.³³

Looking at LDLR mutations first, a systematic review found that the frequent variants in southeast Asia are c.301G>A (p.Glu101Lys; 11 of 43), c.763T>A (p.Cys255Ser; 10 of 43) and c.601G>A (p.Glu201Lys; 9 of 43) in Malaysia, and c.1747C>T in Singapore.³³ Vietnam and the Philippines had no frequent variants. In south and central Asia, no frequent variant was found for India, Sri Lanka and Pakistan. In west Asia, the frequent variants found were c.1,729T>C (p.Trp577Arg; 3 of 10) in Iran, c.2027delG (p.Gly676Alafs*33; 7 of 17) in Arabia, c.del197 (p. Val66Hisfs*63; 35 of 103) in Israel, and c.2043C>A (p.Cys681Ter; 103 of 183) and c.1171G>A (p.Ala391Thr; 10 cases) in Lebanon. In east Asia, 408 mutations were found, accounting for 65% of the total reported mutations. The frequent mutations in Japan were c.2431A>T (p.Lys811Ter; 30%), c.2312−3C>A (6%), c.1845+2T>C (4%), c.1012T>A (p.Cys338Arg; 3%) and c.1297G>C (p.Asp433His; 3%). The frequent variant in China is c.1448G>A. The frequent variant in Taiwan is c.1747C>T (p.His583Tyr). In South Korea, the frequent variant is c.661G>A.

Looking at APOB and PCSK9 mutations, the systematic review found that APOB had 58 variants in Taiwan, 47 in China, 27 in Vietnam, 17 in Arab countries, and the rest were found in Singapore, Korea, Israel and Japan.³³ The most common variant was p.Arg3527Trp, accounting for 78 of 184 heterozygous variants. PCSK9 had 20 variants. The most common variant was p.Glu32Lys seen in Japan.

Finally, a rare cause of FH via LDLRAP1 mutations called autosomal recessive hypercholesterolaemia have also been identified in Japanese FH patients.^34,35 It is interesting to note that this situation is rather frequent in Sardinia, Italy.

Clinical Characteristics Including LDL Levels

Asian individuals tend to have lower serum cholesterol levels compared with Western populations.³⁶ However, LDL cholesterol levels also differ between Asian countries. For example, Singapore, Qatar and Japan all have a mean TC level >5.2 mmol/l. In contrast, Myanmar, Cambodia, India, Bangladesh, Timor-Leste, North Korea and Nepal all have mean TC levels <4.5 mmol/l.¹³ In terms of LDL cholesterol, some studies have suggested that China and Hong Kong had lower levels compared with Japan and southeast Asia.³⁷

The risk of CV events also seems to be more elevated among Asian individuals than westerners with the same LDL cholesterol level, most likely due to a higher atherogenic potential of small LDL cholesterol particles, which are also more prevalent among some Asian populations, such as those in the Indian subcontinent.³⁸

There will be distinct polygenic risk profiles that form a significant proportion of the regional specific CV risk – unlike the large studies based on the UK Biobank data, which have been used to create polygenic risk score profiles to predict CV risk, data sets from Asian populations are yet to be formally created. Furthermore, the understanding of the monogenic causes of FH in many Asian countries is limited, with large proportions of individuals with high LDL cholesterol and family history of early-onset ASCVD not having an identifiable pathogenic change in LDLR, APOB, PCSK9 or LDLRAP1.

Lipoprotein (a) (Lp[a]) elevation is also a risk factor for ASCVD in patients with FH.³⁹ However, data on Lp(a) levels in FH patients in the Asia-Pacific region are scarce. In one Chinese study that included 393 HeFH patients, higher Lp(a) levels were associated with a significantly lower event-free survival rate, each unit increase in logarithmically transformed Lp(a) levels was associated with a doubling of CV event risk.⁴⁰ Studies in other countries are lacking.

The rates of clinical signs of FH in Asia-Pacific vary widely across studies.³² The proportion of FH patients with corneal arcus ranged from 38% in Japan to 72% in China. The proportion of patients with xanthoma ranged from <10% in China to 20% in Korea and 87% in Japan. The reported proportions with early-onset ASCVD were 9% in Hong Kong, 68% in Malaysia and 82% in China. The reasons for these discrepancies are unclear, but may be related to variations in FH definitions, the LDL cholesterol levels of included patients, and the definitions and methods of assessment of the outcomes. Clinical presentation of FH is likely more related to LDL cholesterol levels rather than to ethnicity alone.³² Hence, environmental, lifestyle and dietary differences that affect LDL cholesterol have an impact on the clinical presentations of FH in Asia, from lipid deposits, such as xanthomas, to overt ASCVD. Factors, such as the rapid socioeconomic growth and urbanisation seen in many Asian countries, may play a role in the evolution of FH epidemiology and clinical presentation in the region.

Clinical Care of Patients with FH in Asia-Pacific

The majority of countries in the Asia-Pacific region have no formal guidance on the management of FH, although India, Indonesia, Malaysia, the Philippines, South Korea, Singapore, Taiwan and Thailand provide some direct or indirect guidance within their general dyslipidaemia guidelines. Only a handful of regions or countries, namely Australia and New Zealand, China, Hong Kong, and Japan, have separate FH guidelines. The recommendations of these guidelines are summarised in Tables 2 and 3.

Diagnosis

Diagnosis rates were estimated to vary from 0.1% in China to 4% in Australia, compared with 10–20% in the UK.⁴¹ Given these low detection rates with regard to the positive clinical impact of early detection, systematic screening at different times of the lifecycle is advocated through genomic newborn screening, universal childhood screening integrated as part of child health assessment or national vaccination schedules, targeted assessment/diagnostic testing of individuals with early-onset acute coronary syndrome, adult population genomic screening and identification of FH in the primary care setting. Regardless of the choice, subsequent cascade screening is required to identify and contact biological relatives of a person diagnosed with FH (the index case), and then systematically test these relatives to maximise the impact, and improve the cost-effectiveness and impact of screening.⁴²

The less commonly used strategy of reverse screening includes a child–parent screening approach, where children are screened and deemed positive in the presence of elevated cholesterol and an FH mutation or elevated cholesterol on a repeat measurement taken 3 months later.⁴³ Parents are then screened and deemed positive if the same mutation is also present, or if no mutation is evident and they also have elevated cholesterol. Table 2 shows the guideline recommendations for screening and diagnosis in Australia and New Zealand, China, Hong Kong, and Japan.

FH screening in childhood is an important aspect of early FH detection. In 2011, the US National Heart, Lung and Blood Institute Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents recommended universal screening for dyslipidaemia by the age of 9–11 years, and subsequently at age 17–21 years.⁴⁴ The ‘Ten Countries Study’ found that none of the participating countries were implementing universal screening among children.⁴¹ Of these countries, nine are considered part of the Asia-Pacific region (i.e. Australia, China, Hong Kong, Japan, Malaysia, New Zealand, the Philippines, Taiwan and Vietnam). In Australia, research groups are trialling genomic newborn screening and universal childhood screening in primary practice.⁴⁵ In Japan, universal screening for paediatric FH (age 9–10 years) has been implemented in some areas, but has not led to a sustained population screening program on a national level on an ongoing basis.⁴⁶

Cascade screening is recommended as a cost-effective method of detecting patients with FH.^6,7,42 Table 2 shows some recommendations on cascade screening among the four countries or regions in Asia-Pacific with FH guidelines. This approach has been successfully implemented in several Asian countries.⁹ In Hong Kong, cascade screening enabled the identification of two relatives with heart failure for every one index patient. Furthermore, 50–60% of screened relatives were diagnosed with FH.⁴⁷ Cascade screening in India and Vietnam diagnosed FH in 54 and 52%, respectively, of all relatives screened, with 14 and 32% of diagnosed cases being aged <18 years.^48,49 The prognosis of patients with FH identified via cascade screening appeared to be much better than the proband who sought medical care for FH.⁵⁰ The earlier the initiation of preventative health strategies, the better the lifetime outcomes for individuals, with the potential to both gain decades of life and reduce cost to health systems.⁴²

While recommended, cascade testing is often limited by resource challenges, low awareness among patients and healthcare professionals, and the potential stigma and insurance implications associated with genetic conditions.³² Furthermore, many patients in Asia who have been diagnosed via cascade screening face challenges with treatment initiation. One strategy to improve uptake of cascade screening among relatives includes direct notification of relatives, together with mobile phone applications and online counselling.⁵¹ There is also the possibility of further aspects of genetic discrimination without government policy to prevent it.

Reverse screening is only beginning to gain interest in the Asia-Pacific region. A reverse screening programme in China tested 41 children with severe hypercholesterolaemia, and 12 were found to have HoFH and 29 had compound HeFH. Based on these initial findings, 81 first-degree family members were screened, all of whom were genotypically diagnosed with FH. Among 37 second-degree relatives, 92% were diagnosed with FH. These rates translated to the detection of 2.8 new cases among family members for every child with FH found.⁵²

Finally, several approaches to screening for FH in primary care have been proposed in the Asia-Pacific region, but have only been thoroughly investigated in Australia.^6,7,53 Their experience showed that success was largely dependent on two main factors: the accessibility of community-based laboratories to enable opportunistic screening, and the use of electronic extraction tools to streamline detection in general practice.⁵³ The feasibility of this approach should be more thoroughly investigated in other countries in the region, including developing countries. However, the absence of accessible primary care services in remote and regional areas of Asian countries needs to be addressed to improve equity of access across the region.

Ultrasound, CT or MRI may be used as accessories to diagnosis by being able to identify tendon xanthomata that may not be clinically apparent. However, their use is rarely seen in routine clinical practice.⁵⁴ The Japanese Atherosclerosis Society guidelines recommend the use of Achilles tendon thickness measured by imaging as an objective and quantitative mode of identifying tendon xanthomas.⁵⁵ The cut-off of Achilles tendon thickness ≥8.0 mm in men and ≥7.5 mm in women by X-ray, and Achilles tendon thickness ≥6.0 mm in men and ≥5.5 mm in women by ultrasound is proposed. Given that tendon xanthomas may resolve with lipid-lowering treatment, it should be correlated with the patient’s medication history and blood lipid levels. Carotid artery intima-medial thickness is considered by Australian guidelines as recommended, but is largely not available in clinical practice in many centres.^6,7

Regarding risk assessment and the use of risk enhancers, there is currently limited evidence available to guide the optimum CV risk stratification of patients with FH. Traditional risk factors are insufficient for risk prediction in these typically younger groups of patients.⁵⁶ The presence of a pathogenic variant, especially a null variant in LDLR, has been associated with high risk among patients with FH.⁵⁷ PCSK9 and APOB variants cause lower LDL cholesterol levels compared with LDLR variants overall.

For ASCVD risk stratification, the International Atherosclerosis Society (IAS) released an expert consensus in 2016 suggesting that FH patients be further characterised specifically as severe and non-severe FH. In those untreated and at first presentation, ssevere FH is defined by the IAS as either LDL cholesterol >10 mmol/L, LDL cholesterol >8.0 mmol/L with one high-risk feature, or LDL cholesterol >5.0 mmol/L with two or more high-risk features (e.g., age >40 years without treatment, smoking, male sex, lipoprotein (a) >75 nmol/L, HDL cholesterol <1 mmol/L). Additional inclusion criteria for severe FH are advanced subclinical ASCVD (defined as a coronary artery calcium score >100 Agatston units and/or >75th percentile, or CT angiography with at least 1 >50% obstructive lesion or multivessel lesions <50%) or clinical ASCVD (defined as a previous cardiac event, transient ischaemic attack, stroke or intermittent claudication).⁵⁸ While the IAS recommendations have been challenged as being validated only by cross-sectional and retrospective studies, the applicability of the IAS definition using the large Simon Broome Register Group found that it can be useful as a risk stratification tool.⁵⁹

A review of the current literature showed that studies describing the risk stratification strategies in the Asia-Pacific region are lacking. A small study in Japan found that the IAS definitions could be used to predict risks of both first and subsequent ASCVD, and may be used to identify those who require further stringent anti-atherosclerotic management.⁶⁰ In the lack of other more robustly validated risk stratification tools, the IAS stratification may be used to guide treatment and as a foundation for future guidelines.

There are several gaps in the optimal diagnosis of FH in the Asia-Pacific region. Foremost, many physicians, especially those in primary care (paediatricians, family physicians and general practitioners), have significant gaps in the awareness, knowledge and practices related to FH.^61,62 Hence, there is a need for more extensive educational programmes regarding the screening, diagnosis and management of FH.

Aside from the documented low rates of diagnosis and screening, the authors underscore that there is an imbalance in the availability of diagnostic infrastructure in many Asia-Pacific countries, especially in developing countries. Laboratories and health facilities with imaging technologies are largely concentrated in urbanised areas with higher costs of healthcare.

Treatment of Familial Hypercholesterolaemia

Table 3 shows the guideline recommendations for treatment in countries with standalone FH guidelines, specifically Australia and New Zealand, China, Hong Kong, and Japan.

Due to the substantial increase in the CV risk of patients with FH, guidelines recommend lowering LDL cholesterol levels as low as possible. The Japanese guidelines recommend <2.7 mmol/l for adults and <3.6 mmol/l for children. The Hong Kong guidelines recommend <2.5 mmol/l for primary prevention and <1.8 mmol/l for those with very high risk.⁶³ The China guidelines recommend similar targets and <3.4 mmol/l for children.⁶⁴ In Australia and New Zealand, LDL cholesterol targets for low-, moderate-, high- and very high-risk groups in adults are <3, <2.6, <1.8 and <1.4 mmol/l, with paediatric recommendations dependent on genetic status and family history.^6,7,65 However, it is difficult to achieve target LDL cholesterol levels for FH in clinical practice with treatment to target only achieved in <25% of individuals.²⁵ Target attainment is achieved in 44% with moderate-intensity statin monotherapy, 38% with high-intensity monotherapy, a further 9% when used in combination with ezetimibe with 9% requiring further therapeutic agents. However, the option of dual or triple therapy at a lower dose or the usage of novel agents may be considered to reduce side-effects and improve adherence to therapy.

As shown in Table 3, the main treatment modalities are most commonly statins and ezetimibe. PCSK9 inhibitors have in many countries become the third-line therapy. New agents, including bempedoic acid, small interfering RNA therapies against PCSK9 (including inclisiran), APOC3/ angiopoietin-like 3 inhibitors, APOB antisense oligonucleotide therapies (e.g. mipomersen), microsomal triglyceride transfer protein inhibitor (e.g. lomitapide) and Lp(a) agents (e.g. olpasiran), may be required when statins that are administered at the highest tolerated dose in combination with other medications do not achieve target LDL cholesterol levels, especially in homozygous or compound heterozygous FH patients. Bile acid sequestrants (e.g. cholestyramine) may be appropriate in some patients.⁶⁶ Furthermore, these treatments also lower levels of Lp(a), albeit modestly (no greater than a 30% reduction).⁶⁷ Finally, gene editing trials will be coming to the Asia-Pacific in greater numbers, with a necessity of including Asia-Pacific individuals to ensure similar responsiveness and safety, as well as region-specific implementation strategies to ensure access.

Statins remain the cornerstone of lipid-lowering therapy for FH patients in guidelines in the Asia-Pacific region. A Cochrane review found that among nine included randomised controlled trials comprising 1,177 children, statins effectively reduced the mean LDL cholesterol concentration at all time points and was well tolerated (Table 4).⁶⁸ Response to lipid-lowering therapy including statins among Asian individuals has been shown to differ from other ethnic groups. For example, a smaller statin dose has been shown to lower CV risk in Japanese patients to a comparable level as Western patients.⁶⁹ Similar findings were demonstrated among multi-ethnic populations.⁷⁰

The development of PCSK9 inhibitors is a milestone in the treatment of FH due to their profound ability to lower LDL cholesterol. PCSK9 inhibitors have shown their ability to reduce LDL cholesterol by approximately 50–70% in HeFH patients without serious adverse events.^27,63 However, Asian studies on the benefit of PCSK9 inhibitors in patients with FH are limited. The RAMAN study was an open-label, Phase IV study that evaluated the safety and tolerability of evolocumab in patients with homozygous FH in India. It included patients aged 12–80 years on stable lipid-lowering therapy with fasting LDL cholesterol >3.4 mmol/l receiving evolocumab 420 mg subcutaneously monthly (every 2 weeks if on apheresis). Of the 30 enrolled patients, 13 were aged <18 years. At week 12, LDL cholesterol, APOB and Lp(a) were reduced by −6.4 ± 4.2%, −6.0 ± 3.7% and −0.2 ± 4.9%, respectively. Reductions in LDL cholesterol were greatest in patients aged ≥18 years and those with baseline LDL cholesterol <13 mmol/l.⁷¹ A Japanese subgroup analysis of ODYSSEY, in which 18% of patients had HeFH, demonstrated that alirocumab treatment resulted in a greater reduction in LDL cholesterol compared with placebo (a least squares mean difference of −64.1 ± 2.2%; 95% CI [−68.5, −59.8%]; p<0.000). However, the response for the HeFH was not specifically reported.⁷²

Studies in children and young adults are emerging with evidence of alirocumab and evolocumab, respectively, from the ODYSSEY KIDS and HAUSER studies, showing approximately 45% reductions in LDL, with up to 75% of children achieving their LDL targets.^73,74 Inclisiran efficacy and tolerability in children will soon be reported, with these trials including patients from the Asia-Pacific region.⁷⁵

A few studies reported the efficacy of lipoprotein apheresis on Asian patients with FH. A 6-year study in Japan found that among 130 HeFH patients, lipid apheresis in addition to drug therapy reduced LDL cholesterol by 58% versus 28% with drug therapy alone. This was associated with a 72% reduction in CV events.⁷⁶ In Malaysia, a small study (n=10 HoFH and n=5 HeFH) with a 10-year follow-up found that apheresis plus intensive medical therapy reduced LDL cholesterol by 55.6% versus baseline in HoFH and 57.8% in HeFH.⁷⁷ Table 4 summarised some of the ^key studies on the treatment of FH.^{68,72,76–79}

There are several gaps in the treatment of FH patients in Asia-Pacific. The ‘Ten Countries Study’ found that <5% of patients in China, Japan, Malaysia and Vietnam were reported as achieving an LDL cholesterol treatment goal of <1.8 mmol/l.⁴¹ Experience from Vietnam found that the main challenges to patient treatment were poor knowledge of either or both the patient and primary physician, and access to treatment.⁴⁹ For example, PCSK9 inhibitors have been approved and are available in many countries in Asia-Pacific, but are not yet available in Sri Lanka and Vietnam.

Like LDL cholesterol levels, other traditional risk factors also impact outcomes in patients with FH. A study from Japan demonstrated that hypertension status and smoking were significantly associated with cardiovascular events, regardless of LDL cholesterol and FH mutation status, in patients with FH.⁸⁰ Another study from Japan showed that healthy lifestyle (healthy dietary patterns, regular exercise, not smoking and absence of obesity) was associated with reduced risk of major CV events among patients with FH.⁸¹ These findings highlight the importance of management of traditional risk factors in addition to LDL cholesterol levels in patients with FH.

Published information on patient advocacies in the Asia-Pacific region is also scarce. The authors identified educational initiatives only in Australia, China, Japan, Taiwan and Vietnam.⁸ Hence, the authors advocate for the establishment of patient advocacies and lay educational programmes to improve detection rates and genetic counselling services, address misconceptions about treatments and push for greater treatment reimbursements, especially for the newer agents, such as PCSK9 inhibitors that are able to reduce lipid levels to much lower levels compared with statin therapy.

Future Perspective of Familial Hypercholesterolaemia in the Asia-Pacific Region

While gaps remain in the usage of conventional diagnostic and treatment strategies, clinicians should also be made aware that new treatments are under ongoing clinical development to potentially provide more treatment options and lower lipid levels further. Gene therapies and APOC3/angiopoietin-like 3 protein inhibitors are some of the most promising treatments in mid- to late-stage development.^82,83 More novel approaches, such as minicircle DNA vectors, microRNAs, long non-coding RNAs and CRISPR/Cas9 treatments, are still in preclinical development. Furthermore, various oral small-molecule Lp(a) inhibitors, antisense oligonucleotides or small interfering RNAs are under development to reduce plasma Lp(a) levels, which may also be useful in reducing CV events in patients with FH.^67,84

Importantly, more work is required to improve the health systems needed to effectively manage FH. A working group of 24 participants representing 15 research and academic institutions, nongovernment agencies, United Nations agencies, and governments identified priority areas for future health system improvements in the Pacific region. These areas include workforce development, risk communication, public health surveillance, laboratory capacity and localisation.⁸⁵ Applying these themes to FH, the authors suggest the following endeavours for future undertakings:

• Workforce development. Healthcare professionals should be trained on the screening, diagnosis and treatment of FH – not just new healthcare professionals, but also strengthen the capability and capacity of the current workforce. The goal is to provide competency to service the community, especially families from remote areas with poor healthcare access. This may require maximising digital technologies to reach healthcare professionals in these remote areas. A curriculum on FH should be developed that is appropriate to the local community.
• Risk communication. Given the high CV risk conferred by FH on young individuals, evidence-based messaging should be implemented and contextualised culturally, preferably in the local language, as well as the specific target demographic. These target audiences should include caregivers of children, as well as young and middle-aged adults and their relatives. The platforms used for communication should also be attuned to the target audience. Furthermore, counter-messaging misinformation regarding ASCVD, FH and lipid-lowering treatments should be implemented.
• Public health surveillance. As universal and cascade screening, as well as the implementation of registries, gain traction in the region, protocols should also be developed on the appropriate use of data to inform decision-making and improve standards of care. At the same time, data gaps should also be identified to further improve registries and screening programmes. Public health surveillance activities should also include vulnerable or marginalised populations. Finally, we recommend that public health action should be evidence-driven. Foundational to this evidence-based approach is the establishment of FH registries across the Asia-Pacific region. These registries should capture clinical outcomes to establish both burden and impact of disease, as well as the impact and efficiency of management.
• Laboratory capacity. While blood lipid measurements are available in most countries in the Asia-Pacific region, many developing countries have lower access in unurbanised areas. Many non-tertiary care hospitals in south Asian countries are only able to carry out total cholesterol and not the full lipid profile. Diagnostic modalities, such as ultrasound, also share similar uneven levels of availability. These imbalances should be addressed either through greater investments or improved systems of referral. Genetic testing, while not recommended by most guidelines in developing countries for diagnosis, may be strengthened if resources can be mobilised.
• Health policy modification. Despite FH being considered a public health priority globally, there is no standard FH screening programme in most countries in the region. Health policy including FH as a priority should be the starting point if any long-term changes are to be sustainable, and related programmes should be allocated resources, funding and support from governments.
• Localisation. The absence of engagement with the right stakeholders locally is a common reason for failures in public health programmes. It is important to ensure that actions furthering the four aforementioned priorities should be localised through partnerships and coordination with local community organisations to improve acceptability and promote sustainability.

Conclusion

The detection of FH is low throughout the Asia-Pacific region, even in developed countries, compared with the Western experience. Based on some registry data, the prevalence of FH in the region is estimated to be similar or slightly higher than in Europe or North America. Only four countries in the region have guidelines specific to FH, while a handful of countries provide direct or indirect guidance within their general dyslipidaemia guidelines. This review identified gaps in the optimal diagnosis of FH in the region, namely gaps in the awareness, knowledge, and practices related to FH among primary care physicians and low availability of diagnostic infrastructure. Regarding treatment, gaps include poor knowledge among patients and primary physicians, and low availability and accessibility of more advanced treatment. Hence, the authors call for more educational programs targeting both patients and physicians, as well as greater attention to the improvement of health systems to improve access to FH diagnostics and treatments. Interventions to improve the diagnosis and treatment of FH should be localised to each country’s scenario and supported by national policy.