Familial Hypercholesterolaemia : An Updated Overall Management

Familial hypercholesterolaemia (FH), the commonest and serious but potentially treatable form of inherited dyslipidaemias, is characterised by severely elevated plasma low-density lipoprotein-cholesterol (LDL-C) level, which subsequently leads to premature coronary artery disease (pCAD). Effectiveness of FH early detection and treatment is supported by the outcome of several international cohort studies. Optimal FH management relies on prescription of statins either alone or together with other lipid-lowering therapies (LLT). Intensive lifestyle intervention is required in parallel with LLT, which should be commenced at diagnosis in adults and childhood. Treatment with high intensity statin should be started as soon as possible. Combination with ezetimibe and/or bile acid sequestrants is indicated if target LDL-C is not achieved. For FH patients in the very-high risk category, if their LDL-C targets are not achieved, despite being on maximally tolerated statin dose and ezetimibe, proprotein convertase subtilisin/kexin type1 inhibitor (PCSK9i) is recommended. In statin intolerance, ezetimibe alone, or in combination with PCSK9i may be considered. Clinical evaluation of response to treatment and safety are recommended to be done about 4-6 weeks following initiation of treatment. Homozygous FH (HoFH) patients should be treated with maximally tolerated intensive LLT and, when available, with lipoprotein apheresis. This review highlights the overall management, and optimal treatment combinations in FH in adults and children, newer LLT including PCSK9i, microsomal transfer protein inhibitor, allele-specific oligonucleotide to ApoB100 and PCSK9 mRNA. Family cascade screening and/or screening of high-risk individuals, is the most cost-effective way of identifying FH cases and initiating early and adequate LLT.


INTRODUCTION
The natural history of Familial Hypercholestrolaemia (FH) has changed with the use of statins, such that proper identification and treatment of FH subjects through cascade screening (NICE 2018) has resulted in normalisation of disease-free survival almost approaching that of an age-and gender-matched population [1]. Furthermore, coronary artery disease (CAD) risk may be significantly attenuated, if diagnosed early and properly treated.
Genetic analysis of a Northern European general population has recently discovered approximately 1/200 of the people were with heterozygous FH (HeFH). Less than 1% of HeFH are detected in most countries, taking into account a theoretical estimated global prevalence of 1/500. Albeit FH individuals have increased CAD risk by at least 10fold, many studies reported failure to achieve recommended LDL-C targets in a large proportion of these patients. Based on the prevalence of 1/200 and 1/500 [2,3], it is estimated that about 14 -35 million individuals worldwide are affected by FH [4,5]. If left untreated, HeFH individuals may develop premature CAD (pCAD) at ages of <55 and <60 years, in men and women respectively [5].
Therefore, individuals are recommended for FH screening, if a person or family member presents with either (i) FH, (ii) total plasma cholesterol level (TC) of ≥8 mmol/L (≥ 310 mg/dL), and/or LDL-C ≥ 5 mmol/L (≥ 195 mg/dL), in an adult; or TC ≥ 6 mmol/L (≥ 230 mg/dL) and/or LDL-C ≥ 4 mmol/L (≥ 155 mg/dL), in a child, (iii) tendon xanthoma(s) and/or (iv) pCAD or sudden premature cardiac death. Family cascade screening and/or screening of high-risk individuals, is the most cost-effective way of identifying FH cases and initiating early and adequate LLT.
This review highlights an updated overall management of FH, comprising of treatment targets, lifestyle measures, optimal treatment combinations in adults and children, as well as an overview on newer LLT including PCSK9i, microsomal transfer protein inhibitor, allele-specific oligonucleotide to ApoB100 and PCSK9 mRNA.

RISK ESTIMATION
Recently confirmed new evidence suggests that retention of LDL-C and apolipoprotein B (ApoB) within the arterial wall is the key factor of atherogenesis [6]. Besides, lowering LDL-C and ApoB-containing lipoproteins reduces CV events. Furthermore, it has also been well documented that hypercholesterolaemia causes and is strongly linked to atherosclerotic cardiovascular disease (ASCVD). In tandem with these new findings, new targets for LDL-C and a revision of the CV risk stratification have been proposed by the new guidelines, particularly relevant to patients in the very-high and high-risk categories. For FH individuals, it is unnecessary to perform total risk estimation as they are already categorised as high or very-high risk individuals. Presence of ASCVD or one other major risk factor in FH patients, renders them to be in the veryhigh risk category, whilst those without are considered to be at high-risk (Figures 1, 2).
While the calculation for risk estimation scores is not needed for individuals who are already in proactive management for their risk factors, several groups of individuals have been identified to be in the high and very-high total CV risk categories. These include those with type 1 and type 2 DM, documented ASCVD, chronic kidney disease (CKD) or other highlevel individual risk factors such as severe hypercholesterolaemia.  Some individuals, without requiring risk scoring, are categorised in the high-or very-high cardiovascular disease (CVD) risk groups, demanding the immediate attention of all risk factors. These include individuals with known FH, CVD, chronic kidney disease (CKD), diabetes mellitus (DM) of long duration, as well as the presence of coronary artery calcium score (>100 Agatston), carotid or femoral plaques, or severely elevated serum Lp(a) levels. Lp(a), an LDL-C-like particle that contains a highly variable apolipoprotein(a), has been associated with increased CV risk [7]. Elevated Lp(a) has also been reported as an independent determinant for CVD risk [8]. Therefore, a single Lp(a) measurement may assist in identifying individuals who inherit very high Lp(a) levels, resulting in enhanced ASCVD lifetime risk. Subsequent risk stratification of some groups of patients such as those with high risk of ASCVD and a strong family history of premature CVD, can be further assisted by high Lp(a) level. Furthermore, Lp(a) may be useful in ascertaining treatment strategies among patients with borderline estimated risk categories.
In the presence of ASCVD or one other major risk factor, FH patients are considered to be at very-high risk, therefore, the recommended LDL-C targets are at least 50% reduction from baseline and to achieve <1.4 mmol/L (<55 mg/dL). In contrast, FH patients without ASCVD or another major risk factor, are grouped in the high-risk category, with LDL-C targets suggested at least 50% reduction from baseline and <1.8 mmol/L (<70 mg/dL). Similarly, using the Framingham Risk Score (FRS)-General CVD risk stratification tool, FH with and without ASCVD are classified as very-high and high-risk categories respectively. However, with this tool, the recommended LDL-C targets for those risk categories are higher at <1.8 and <2.6 mmol/L ( Figure  3).
Regardless of age, these targets are relevant for both HeFH and homozygous FH (HoFH). However, these targets are very challenging to accomplish in HoFH with current treatment, both in children and adults. Based on a community study in Malaysia, lipidlowering therapies (LLT) are prescribed to only 56.6% of potential (Definite and Probable) HeFH, according to the Dutch Lipid Clinic Network (DLCN) criteria [9]. Still, none of them achieved the therapeutic LDL-C target for high or very-high risk individuals as recommended by the Malaysian National Clinical Practice Guidelines for Management of Dyslipidaemia [9]. However, in a hospital-based FH cohort, an overall of 95.9% of the FH patients received statins, of whom only 9.8% achieved the LDL-C target of <1.8 mmol/L (Chua et al., 2019, unpublished).
Furthermore, our group reported that about 31% of the hypercholesterolaemic adults in the Malaysian community are in the high or very-high risk category according to the FRS-General CVD risk assessment tool. Of those, only 24.7% were on lipidlowering medication, of whom only a mere 16.3% achieved target LDL-C for the high and very-high risk categories [10].
Due to ethical reasons, randomised clinical trials of LLT against placebo in FH subjects have not been organised, thus, the lack of reports on the benefits of LLT. Nonetheless, treatment goals and benefits have been well reported in large-scale clinical trials among non-FH individuals [11]. It has been clearly established that with LDL-C as the main goal of treatment, its degree of decrement is proportional to the decline in both CV and all mortality. For every 1 mmol/L of decrement in LDL-C level, there is a corresponding decline in CV mortality and total mortality by 20% and 12% respectively, over 5 years [11]. Hence, all untreated FH individuals above 40 years of age, have been proposed to be regarded as very-high CV risk category, due to exposure to elevated LDL-C levels since birth [12].

LIFESTYLE MEASURES
In parallel with lowering the elevated LDL-C levels, lifestyle intervention has to be intensified and all other major risk factors have to be diligently managed according to expert recommendations ( Figure 4). A healthy diet needs to be emphasised, consisting of low cholesterol, saturated fats, trans-fat and carbohydrates whilst focussing on whole grain products, fish, vegetables and fruits, gearing towards ideal body weight and waist circumference. Intensive health education focussing on lifestyle intervention including smoking, physical activity and diet, need to be given to all FH patients and their families [13]. A healthy diet should be implemented and individualised, with the involvement of the whole family and support by a certified dietitian. Plant sterols and stanols have been reported to lower LDL-c levels to a certain extent, hence can be considered as functional foods.  Smoking cessation is extremely important for smokers, and where necessary such patients should be referred to a specialised anti-smoking programme. It is imperative to advise children and young adults to abstain from smoking and not be subjected to passive smoking. Implementation of regular physical activities is crucial. However, assessment of CV function is advisable in adults with FH, before starting any strenuous exercise programme. Despite the benefits of lifestyle intervention, including healthy diets, almost all FH patients require LLT to reduce elevated LDL-C.

PHARMACOTHERAPY
In adults, treatment with LLT should be started as soon as possible, after a diagnosis of FH has been made, in tandem with lifestyle intervention. The utilisation of imaging techniques such as coronary calcium scoring and carotid/femoral plaques assessment is recommended to detect asymptomatic atherosclerosis, for subsequent improvement of risk assessment.
The priority of pharmacotherapy for adults is as follows: (i) maximal potent statin dose, (ii) ezetimibe, (iii) bile acid sequestrant, (iv) PCSK9i, (v) lipoprotein apheresis in HoFH and treatment-resistant HeFH with CAD. Treatment with high-intensity statin, in combination with ezetimibe in most instances, should be initiated as soon as possible. For FH patients in the very-high risk category (presence of ASCVD or one other major risk factor), if the LDL-C targets are not reached despite being on maximally tolerated statin dose and ezetimibe, proprotein convertase subtilisin/kexin type1 inhibitor (PCSK9i) is recommended. If the LDL-target is still not achieved, combination of statin with a bile acid sequestrant may be considered ( Figure 5 and Figure 6). For patients with statin intolerance at any dosage (even after rechallenge), either ezetimibe alone, or in combination with a PCSK9i should be considered.   High-intensity statin at maximal dose, including either rosuvastatin 40 mg, atorvastatin 80 mg, or pitavastatin 4 mg, should be commenced in adults at the first consultative visit (Figure 7). However, due to the association with elevated risk for myositis and rhabdomyolysis, simvastatin 80 mg is not recommended as this dose. There are several justifications for the recommendation to initiate treatment with maximal dose of a high intensity statin. Firstly, while most FH patients need at least 50% LDL-C reduction, only less than 5% (1/20) of FH individuals achieve the targeted LDL-C levels. Secondly, high percentage FH patients receive inadequate doses to reach LDL-C goals. Thirdly, many clinicians despite not achieving treatment targets, fail to increase statin doses.
In children, it is highly recommended to initiate LLT at about the age of 6 -10 years, in parallel with lifestyle intervention. The priority for pharmacotherapy in children is as follows; (i) statin, (ii) ezetimibe, (iii) bile acid sequestrant, and (iv) lipoprotein apheresis in HoFH. For children, statins to be used should only be amongst those licensed statins in this age group, usually simvastatin or pravastatin [14,15].
Clinical evaluation of response to treatment and safety are recommended to be done about 4-6 weeks following initiation of therapy. Numerous evidences have shown substantial reduction in major CV events with statin treatment in observational studies. Thus, statins are the main drugs of choice [11,16,17]. Furthermore, the introduction of statin treatment has also resulted in the decline of CAD events in FH patients [18,19]. Moreover, FH individuals who have had treatment initiated prior to onset of CAD, have the potential benefit of CAD event-free period as good as those in the general population ( Figure 8).
Statins are first-line drugs for patients in the high and very-high risk categories, as they have been overwhelmingly proven to reduce CV events and safe to use by numerous randomised controlled trials.
However, in some high-risk individuals such as FH patients or those with statin intolerance, the targeted LDL-C levels are not achieved despite maximally tolerated statin. The use of non-statin therapies, such as ezetimibe and the newer PCSK9i have been previously reviewed [20]. Most FH patients are unable to achieve the targeted LDL-C level with statin alone, albeit commencement of the maximal doses of high intensity statin. In such situation, ezetimibe can be combined with statin therapy with high compliance and minimal side effects. Generally, statin-ezetimibe combination will result in 60-70% LDL-C reduction. Bile acid sequestrants such as cholestyramine, colestipol, or colesevelam, is suggested as a third drug for very-high risk patients when the LDL-C levels exceeding recommended targets of <1.8 mmol/L (<70 mg/dL). Addition of pure niacin (up to 3 g/day) on top of the above-mentioned medications, in some FH patients, as practised in some countries, is another possible option to reduce LDL-C and Lp(a) further. Combination of maximal dose of high-intensity statin with fibrates can be considered in FH patients with hypertriglyceridaemia and low HDL-C, or TG >5.7 mmol/L (>500 mg/dL). This statin combination is particularly with fenofibrate, due to its favourable drug interaction report [21] and effect on LDL-C reduction in FH [22]. Fenofibrate is also an option if there is intolerance or unavailability to other LLT, as it is capable of reducing LDL-C levels even when TG is normal. Further information on management, safety, as well as efficacy of LLT have been previously eluded [23].
Specialised clinical management is needed for statin intolerance in FH patients. This is to ascertain that wherever possible, the FH patients have been challenged with the various types of statins, in addition to considering, depending on appropriate cases, combination therapy of low dose of statin, ezetimibe, and resins.

LIPOPROTEIN APHERESIS
For severely hypercholesterolaemic individuals with very-high CV risk despite already under LLT, lipoprotein apheresis (LA) is recommended, especially for HoFH children. Up to 50-75% of LDL-C and Lp(a) reduction can be achieved with weekly or biweekly lipoprotein apheresis session [24][25][26][27]. LA is available at specialised lipid clinics, haemodialysis centres and blood transfusion centres. Different countries may have different clinical criteria for initiation of lipoprotein apheresis.
It is important to identify the HoFH in young age, and critical to initiate intensive LLT by lipid specialists, and, when available, with lipoprotein apheresis. These early and extensive treatment can lead to a 5 -70% decrement in plasma LDL-C levels, if maximally tolerated pharmacological therapy is maintained [28]. The detailed guidelines on HoFH management is discussed in EAS consensus statements [28,29].

Case 1 -Homozygous FH with severe xanthelasma
Our group has previously reported 3 cases of HoFH. The first case was a rare case of HoFH in a 22-year-old Malay woman with severe hypercholesterolaemia (LDL-C 13.9 mmol/L) and the presence of gross xanthelasma [30]. Upon her referral to a Specialist Lipid Clinic, she was clinically diagnosed as FH, but without personal history of CAD or other major risk factors. However, three of her siblings died due to sudden cardiac death at young age (20 -40 years old). Her parents have marital consanguinity, where they are related (cousins). Genetic testing was done and she was confirmed to inherit a homozygous pathogenic variant, C255S (c.763T>A) in Exon 5 of the her LDLR gene. Family cascade screening was performed on her affected family members and confirmed the presence of the same disease-causing variant. She was treated with high-intensity statins (atorvastatin 40 -80 mg) and ezetimibe, which managed to reduce her LDL-C by more than 50% from baseline, although targeted LDL-C of <2.6 mmol/L was not achieved.

Case 2 -Homozygous FH with successful pregnancy outcome
Our second case of HoFH, was first seen with complications of severe ASCVD including supravalvular aortic stenosis. Despite genetic counselling, she decided to proceed on with the pregnancy, with subsequent successful pregnancy outcome [31]. Pregnancy in HoFH may pose the risk of early coronary morbidity and mortality to both foetus and mother. Hence, the combination of HoFH and pregnancy can be a potentially fatal condition. The difficulty of her LDL-C management was exacerbated by the fact that statins are contraindicated in pregnancy, thus, the choice of LLT was limited. In contrast, LA is an alternative effective treatment to control cholesterol level during pregnancy. However, the procedure is not widely available in the Asian region, especially in economically deprived countries. Despite being counselled, this patient refused to undergo LA, hence, was continued on LLT. Her LDL-C level peaked to above 20 mmol/L in the second trimester, during which she developed angina symptoms and underwent angioplasty. To date, there are scarce documented case reports of HoFH in pregnancy, the majority of whom underwent LA through-out their pregnancy. This case report illustrates a rare but successful pregnancy outcome of a HoFH patient, managed by a multidisciplinary team, treated with LLT during pregnancy.

Case 3 -Homozygous FH with good response and unique legacy effect of PCSK9 Inhibitor
In this third case of HoFH, our group report a good response and a unique prolonged effect of short-term alirocumab treatment on a clinically and genetically confirmed young HoFH patient, who suffered from ACS. The patient was initially treated with a combination of high intensity statin and ezetimibe for 12 weeks. Subsequently, alirocumab was added to the lipid-lowering regime, which managed to achieve guideline recommended LDL-C target within 10 weeks. However, due to financial constraints, alirocumab was stopped after 32 weeks of the triple drug combination therapy. Interestingly, despite cessation of PCSK9 inhibitor therapy for period of subsequent 30 weeks, LDL-C level only increased slightly, but not returning to pre-alirocumab baseline level, and more importantly, managed to maintain target LDL-C levels [32]. This suggests HoFH patients with residual LDL receptor expression as in this case, can benefit from PCSK9 inhibitor therapy. This case illustrates the hypothesised legacy effect of PCSK9 inhibitor, where LDL-C reduction may persist for a long time even after cessation of the medication. However, the long-term clinical benefit is still unclear.

FAMILIAL HYPERCHOLESTEROLAEMIA IN CHILDREN
Children with FH can be effectively diagnosed based on clinical features such as severe hypercholesterolaemia, a positive family history of hypercholesterolaemia, pCAD, and/or genetically confirmed FH mutations [33] . LDL-C in childhood can be used for optimal discrimination between FH and non-FH due to the lack of exposure to secondary causes of hyperlipidaemia. The threshold limit of hypercholesterolaemia in children with a positive family history of hypercholesterolaemia and pCAD is LDL-C of >4.0 mmol/L (>155 mg/dL). If FH gene mutation is detected in a parent, the child LDL-C threshold level is >3.5 mmol/L (>130 mg/dL). Genetic analysis in children can be initiated at 5 years old or even at younger age in suspected HoFH cases. Children of mutation-confirmed parents have 50% chance of inheriting the gene mutation, hence are also recommended to undergo genetic testing. [34].
Several observational studies in FH children have suggested that earlier initiation of LLT can lead to LDL-C reduction and improvement in endothelial function, better than starting the LLT in later age, where the early reduction of LDL-C will subsequently reduce coronary outcomes in later years [15,33,35,36]. Therapeutic lifestyle changes and statin treatment are therapies for FH children, which should be initiated at the age of about 6 -10 years. Ten years old children should be screened for FH and treated with statins such as simvastatin or pravastatin, which are licensed for this age group. [14,15]. The LLT can be started with lowdose statin, and gradually increased until the LDL-C goal is achieved [37]. For proven FH cases, on a suitable diet and LDL >4.0 mmol/L on two occasions, the initial aim of the LLT is to achieve a reduction in plasma LDL-C by 50%, and subsequent target LDL of <4.0 mmol/L in children between the ages of 8 and 10 years. For children older than 10 years, an LDL-C goal of <3.5 mmol/L (<135 mg/dL) should be targeted.
Our group has recently reported a rare case of FH in a pair of 8-year old identical twins, who were identified in a family cascade screening [38]. Their baseline LDL-C levels were 8.8 mmol/L and 8.6 mmol/L respectively, with absence of lipid stigmata manifestation. Their father was the index case who initially presented with severe hypercholesterolaemia, pCAD, positive family history of pCAD, and subsequently clinically diagnosed and molecularly confirmed as FH. Besides the twins and the father, the family cascade screening also managed to clinically identify the paternal grandfather, another elder brother, aged ten years, a paternal uncle and a cousin as FH patients. Genetic analysis by targeted next-generation sequencing (NGS) revealed that all these individuals were carrying a heterozygous LDLR gene variant which was previously described as pathogenic missense mutation (c.530C>T). The twins and their elder brother were counselled on lifestyle intervention, including healthy diet and were started on low dose statin to target for at least 50% LDL-C reduction.

NEW TREATMENT MODALITY i. PCSK9 Inhibitors
PCSK9 monoclonal antibodies (mAbs) are the newly approved medications for FH therapy which are recommended in FH patients in the very-high-risk category, if the targeted LDL-C goal is not acquired by statin and ezetimibe. Currently, there are only two mAbs approved by the Food and Drug Administration (FDA): alirocumab and evolocumab. PCSK9i can minimise LDL-C levels by up to 60% when coadministered with statin. Two randomised controlled trials recorded promising therapeutic effect of PCSK9 treatment in non-FH ASCVD patients [39,40]. PCSK9i. PCSK9i monotherapy is also indicated for FH patients who are unable to tolerate statin [29,41,42] (Figure 6 A).

Mechanism of Action
PCSK9i exert their therapeutic effect by targeting PCSK9 protein which is involved in the control of the LDL receptor [43]. Physiologically, PCSK9 in plasma binds to the LDL receptor and decreases the expression of the LDL receptor by fostering lysosomal catabolism of the LDL receptor. Consequently, the plasma LDL-C level increases. Therefore, a decrease in PCSK9 concentration or would reduce plasma LDL-C levels [44]. PCSK9i reduces the amount of PCSK9 in plasma, which in turn decreases its ability to bind to LDL receptors. As this association causes intracellular degradation of the LDL receptor, reducing circulating PCSK9 will increase LDL receptor expression on the cell surface. Thus, more circulating LDL-C levels will be absorbed by the cells [44]. The optimal effects of PCSK9i has been reported when administered together with statins, as serum level of PCSK9 is elevated with statin treatment [45].

Low-density lipoprotein cholesterol
Alirocumab and evolocumab, either alone or in combination with statins and/or other LLTs, in several clinical trials, have been reported to dramatically result in reduction in LDL-C levels by an average of 60 percent. If combined with high-intensity or maximally tolerated statins, alirocumab and evolocumab lead to 46-73 percent LDL-C reduction, compared to placebo, and 30 percent more than ezetimibe. PCSK9i plus ezetimibe decreased LDL-C, even in patients who do not tolerate statins [46]. Alirocumab and evolocumab have also been reported to attenuate LDL-C levels in patients at increased CV risk, especially those with DM. [47]. PCSK9i is effective in lowering LDL-C in a wide variety of hypercholesterolaemic patients, due to its primary action on LDL receptor, as long as patients are capable of producing LDL receptors. Patients who may benefit from PCSK9i are those with HeFH, and to a lesser degree, HoFH patients with residual LDL receptor expression. HoFH with receptor deficiency responds poorly to therapy [48].

Triglycerides and high-density lipoprotein cholesterol
In addition to being potent in LDL-lowering, PCSK9i also decrease TG levels and elevate both HDL-C and ApoA-I levels. Treatment with evolocumab results in 26 percent TG reduction, and 9 percent and 4 percent increment in HDL-C and ApoA respectively, in phase II studies; similar results have been reported for alirocumab [23,49]. However, the TG lowering effect must be confirmed.in populations with higher initial blood TG concentrations.

Lipoprotein(a)
Contrary to statins, anti-PCSK9 mAB also lowers plasma levels of Lp(a) Pooled findings from phase II studies have demonstrated that PCSK9i treatment resulted in 30-40% reduction in Lp(a) [50,51]. Whist recent research has attempted to understand the different mechanisms, the underlying process remains unclear. However, it seems to be dissimilar to statins, which also enhance the activity of the LDL receptor but do not reduce the levels of circulating Lp(a) in humans. Furthermore, in properly designed experiments, the relative input of this effect to reduction in cardiovascular risk continues to be discussed.

Effect on Cardiovascular Morbidity and Mortality
Phase III studies preliminary results showed that CV events reduction was accomplished in tandem with LDL-C reduction [52][53][54]. Two important trials have been recently completed: More Cardiovascular Outcomes Study on PCSK9 Inhibition in Elevated Risk Subjects (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) studies [39,40]. The two trials were comparable with respect to the study design of secondary prevention and background treatment. However, the cohorts recruited had either stable CAD, peripheral arterial disease (PAD), or stroke; or a recent (median 2.6 months) ACS. The relative advantage was demonstrated in terms of primary endpoints risk reduction by 15-20 percent. The follow-up duration of both studies was relatively brief, hence, taking into account data from previous statin studies showing that LDL reduction could occur only after approximately one year [11], suggesting possible benefit of longer-term therapy may have been underestimated in these studies [40,54].
In the FOURIER study [39], 27,564 patients with atherosclerotic CVD, and LDL-C levels of > 1.8 mmol/L (70 mg/dL), who were on statin therapy, were randomly allocated to receive either evolocumab or placebo. Evolocumab at 48 weeks post-treatment, lowered the LDL-C median from 2.38 mmol / L (92 mg/dL) at baseline to 0.78 mmol / L (30 mg/dL). Evolocumab therapy decreased the primary outcome risk (composite CV mortality, MI, stroke, hospitalisation for unstable angina, or coronary revascularization) significantly, after a median followup period of 2.2 years, by 15%, [hazard ratio (HR) 0.85, 95 % CI 0.79-0.92]. The analysis conducted on the period to benefit also revealed a smaller benefit in the first year of trial compared to subsequent years, in parallel with the meta-analysis statin results reported in the Cholesterol Therapy Trialists [6]. The randomisation to evolocumab did not reduce CV mortality nor all-cause mortality risk in the FOURIER study.
The ODYSSEY Outcomes trial randomised 18,924 statin-treated patients, with LDL-C levels > 1.8 mmol / L (> 70 mg dL), non-HDL cholesterol > 2.6 mmol/L (> 100 mg dL) or ApoB > 80 mg/dL, following hospitalisation with acute MI or dysfunctional angina, to alirocumab or placebo injections. Alirocumab allocation lowered the baseline mean LDL-C at 12 months from 2.38 mmol/L (92 mg/dL) to 1.24 mmol/L (48 mg/dL). After a median follow-up of 2.8 years, there was a relative decline in the primary outcome (composite of CAD mortality, non-fatal MI, ischaemic stroke, or unstable angina involving hospitalisation) by 15% (HR 0.85, 95 percent CI 0.78-0.93) [40]. Although the ODYSSEY trial demonstrated a substantial decline in all-cause mortality, this was an exploratory result and was not accompanied by a significant impact on CV death.

Adverse Effects and Interactions
Anti-PCSK9 mAbs as PCSK9i are administered via subcutaneous injection, fortnightly or monthly, at different doses depending on the types of agent used.
There is absence of potential interaction with medications taken orally, as they do not exhibit pharmacokinetic or pharmacodynamic interference. Itching at the injection site and flu-like signs are among the most common reported side effects [55]. Increased patient-reported neurocognitive effects have been identified in several studies [56]. However, the results of a study specifically designed to monitor neurocognitive activity, the EBBINGHAUS trial [57], has been encouraging, as were the safety findings of both the FOURIER and ODYSSEY studies. Mendelian randomisation trials have also shown that inhibition of PCSK9 can increase the risk of LDL-C-related DM, as in the case with statins [58]. However, no signals have arisen from clinical trials to date [39,59,60]. While major long-term PCSK9i studies are essential to exclude these and other possible side effects of PCSK9i [61], the 7-year results from the IMPROVE-IT research showed that chronic low LDL-C levels are not correlated with any apparent adverse effects [62]. The occurrence of autoantibodies is a possible issue for long-term antibody therapy.
Evolocumab and alirocumab are both fully humanized antibodies and, therefore, theoretically are unlikely to activate autoantibodies. Up to now, very few anti-drug antibodies have been described, and there has been no diminished LDL-C lowering effect. However, long term treatment needs to be closely monitored. Recently, development for the third anti-PCSK9 mAB, a humanised antibody, bococizumab, was ceased due to presence of increased neutralizing antibodies resulting in diminished LDL-C-lowering effect over time, in addition to higher incidence of injection site reactions [42]. Furthermore, albeit PCSK9i are effective in attenuating LDL-C levels and CV events, in addition to statin and/or ezetimibe treatment, taking into account financial issues and limited long-term safety data, these medications are only probably likely to be considered cost-effective in patients in the very-high risk category. Hence, their utilisation in economically deprived countries may be limited.

ii. Lomitapide
In very low-density lipoprotein (VLDL) formation, the microsomal triglyceride transfer protein (MTP) transmits TGs and phospholipids from the endoplasmic reticulum to ApoB. The inhibition of MTP thus inhibits both VLDL formation in the liver, as well as chylomicrons in the intestines. Lomitapide. an inhibitor of MTP is an oral medication for HoFH. Lomitapide was evaluated as a supplementary treatment for statins with or without apheresis and a reduced-fat diet, in an open-label one-arm titration trial, [63]. At 26 and 56 weeks, LDL-C was reduced from baseline by 50% and 44% respectively. Lomitapide treatment has been demonstrated to reduce frequency of LDL-apheresis in patients with HoFH. However, the effect lomitapide on CV outcomes has not yet been determined.
Lomitapide is associated with elevated levels of aminotransferase due to its mechanism of action, which most likely represents high liver fat and poor gastrointestinal tolerability [63,64]. The most prominent reason for inhibiting dosage increment of lomitapide in clinical trials, is the gastrointestinal side effects [63]. However, it has been reported that the incidence and severity of gastrointestinal side effects diminish with time. Therefore, lomitapide treatment requires proper patient education and counselling, in addition to close monitoring of liver function.

iii. Mipomersen
Mipomersen, an antisense oligonucleotide capable of binding to ApoB-100 messenger RNA (mRNA), hence resulting in selective degradation of the mRNA molecules, is preferentially transferred to the liver after subcutaneous injection. This results in inhibition of ApoB protein translation, leading to diminished synthesis of atherogenic lipids and lipoproteins, including LDL-C and Lp(a) [65]. Mipomersen, clinically indicated for LDL-C lowering in HoFH patients, is a supplementary therapy to LLT and diet. Albeit officially approved by the US Food and Drug Administration (FDA), mipomersen is still not registered with the European Medicines Agency (EMA). The most frequent adverse effect reported in patients on mipomersen therapy is injection site reactions [66]. The key safety issues of mipomersen is associated with liver toxicity. In addition, mipomersen has also be reported to contribute to the development of liver steatosis. Mipomersen-treated patients have demonstrated greater liver fat from baseline, compared to placebo. [65]. Long-term mipomersen therapy in terms of efficacy and safety are currently being investigated in patients with statin intolerance and serious HeFH.

iv. Inclisiran
Inclisiran, an experimental drug for LLT, is a chemically engineered double-stranded small interference ribonucleic acid (RNA) conjugated with triantennary N-acetylgalactosamine (GalNAc) to promote uptake by hepatocytes. In the hepatocytes, the antisense strand is integrated into the ribonucleic acid (RNA)-induced silencing complex (RISC) and guides the catalytic breakdown of mRNA for PCSK9, hence, preventing the translation of the protein PCSK9. The decreased intrahepatic PCSK9 increases the recycling and expression of LDLR on the hepatocyte cell surface, increases LDL-C absorption and reduces circulating LDL-C levels [67]. Inclisiran tends to have more benefits over PCSK9-directed monoclonal antibodies, including its infrequent administration (2 injections/year vs. 12-26 PCSK9i injections/year) and the fact that anti-PCSK9 monoclonal antibodies is a challenge at plasma level. Inclisiran, on the other hand, acts to mitigate LDL-C and PCSK9 levels at the intracellular level of hepatocytes [68].
Recently, a post-hoc review of inclisiran from the Phase III, ORION-10, and ORION-11 trials revealed an average 54.1 percent decline in LDL-C levels after 17 months treatment compared to placebo. The data also supported reassuring safety profile and efficacy data of inclisiran, with 99 percent of inclisirantreated patients exhibiting LDL-C reduction (placeboadjusted) of around 30 percent [69]. Inclisiran is currently under review by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of primary hyperlipidaemia (including HeFH) in adults who have elevated LDL-C while being on a maximally tolerated dose of statin therapy [70].

CONCLUSION
This review highlights the overall management, and most optimal treatment combinations in HeFH and HoFH in adults and children, newer lipid lowering medications including PCSK9i, MTP inhibitor, ASO to mRNA of ApoB100 and PCSK9. Screening high-risk individuals, or cascade family screening, is the most cost-effective way of identifying FH cases and initiating adequate statin therapy alone or in combination with other LLT. In the case of severe FH, where plasma LDL-C levels remain high despite maximally-tolerated statin and ezetimibe treatment, PCSK9i should be considered.

Conflict of Interest
Hapizah Nawawi is an Amgen Advisory Board Member on Evolocumab for treatment of FH, while Noor Alicezah Mohd Kasim and Chua Yung An declared no conflict of interest with regards to this article preparation.

Authors' Contribution
Noor Alicezah Mohd Kasim and Hapizah Nawawi are clinicians who have managed the FH patients and prepared the manuscript. Hapizah Nawawi is the Principal Investigator who is the recipient of the research grants, initiated and conceived the study, and coordinated the overall patient management and research projects. Chua Yung-An is a post-doctoral researcher who have assisted in managing the patients' data and preparing the manuscript.