The goal of treatment in FH is to reduce the risk of atherosclerotic heart disease. All patients with FH, whether heterozygous or homozygous, should undergo a comprehensive program of lifestyle modification. This has three primary objectives: dietary changes, exercise and behavioral therapy [
13]. Dietary changes include reduction in saturated fats, transfats, and cholesterol. Referrals should be made to a nutritionist and smoking cessation encouraged. Risk factors such as hypertension, diabetes, and smoking should be addressed. Although these measures are of benefit, they are unlikely to lower the LDL-C levels sufficiently and direct intervention is invariably needed to reduce the levels.
Treatment for HeFH
To date, no randomized controlled trials have been conducted assessing the benefit of lipid-modification treatment on CHD events among patients with HeFH. As such, much of the pharmacotherapy currently used is based on an extrapolation of data among non-FH patients or from a few observational studies conducted principally using hydroxymethylglutaryl co-enyzme A (HMG CoA) reductase inhibitors (statins) in patients with FH [
20,
21]. Statins remain the only class of lipid-lowering therapy to reduce total and coronary mortality post-myocardial infarction. It is widely accepted that maximal potent statin dose should be initiated as first-line therapy in adults post-diagnosis of HeFH [
5]. If started prophylactically in early adulthood, statin use has been shown to lower the risk of CHD by up to 80 % [
20]. NICE recommends a target of 50 % reduction in LDL-C concentration [
22]. In accordance with the European Society of Cardiology, the EAS has outlined new LDL targets [
5]:
-
children <3.5 mmol/L (<135 mg/dL);
-
adults <2.5 mmol/L (<100 mg/dL);
-
adults with CHD or diabetes <1.8 mmol/L (<70 mg/dL).
Although the 2013 American College of Cardiology/American Heart Association Guidelines do not recommend a target LDL level, high-intensity statin therapy is recommended in asymptomatic arteriosclerotic CV disease (ASCVD) with LDL-C levels greater than 190 mg/dL where tolerated [
23]. Due to its net benefit in terms of reduction in ASCVD risk versus potential adverse effects, statin therapy is recommended for those at increased risk.
Despite maximal dose statin therapy, LDL-C levels may yet remain elevated. The addition of ezetimibe (a cholesterol absorption inhibitor) to statins or as monotherapy reduces CVD events with NICE and EAS both recommending its co-administration, which may help reduce LDL-C levels by 60 to 70 % in total [
18,
21]. Results from the recent Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT; ClinicalTrials.gov #NCT00202878) presented at the American Heart Association 2014 Scientific Sessions have demonstrated modest benefit with combined use of ezetimibe and simvastatin in stable patients post-acute coronary syndrome (ACS) [
72]. Significant reduction in the primary end point—a composite of CV death, major coronary events, and stroke—by 6.4 % compared to monotherapy with statins was noted (
P = 0.016). The absolute risk reduction was 2 %. Ezetimibe may also be used as monotherapy in patients unable to tolerate statins.
Bile acid sequestrants, such as cholestyramine, colestipol, or colesevelam, may be added as a third agent in very high-risk patients with CHD, type 2 diabetes, or LDL-C levels greater than 1.8 mmol/L (>70 mg/dL) [
18]. Colesevelam is preferred due to its lower gastrointestinal side effect profile than cholestyramine and colestipol, both of which are also associated with poor patient compliance and significant multi-drug interactions [
24].
Despite a lack of evidence of the clinical benefit of niacin co-administration, high-dose therapy has until recently been recommended, especially in the USA and Canada where its use had doubled [
23,
25,
26]. Its availability in Europe has started to decline due to two recently published neutral CVD outcome studies. The AIM-HIGH (ClinicalTrials.gov #NCT00120289) study was prematurely stopped at 3 years due to a lack of clinical benefit of niacin therapy when compared to placebo in patients with established CV disease who were already being treated with statins and ezetimibe [
27]. One of the criticisms of the study was that it was not powered to determine a difference in CV events. The recent randomized, placebo-controlled HPS2-THRIVE (ClinicalTrials.gov #NCT00461630) trial attempted to address this by recruiting 25,673 patients with atherosclerotic vascular disease and also found no benefit of the addition of niacin therapy to statin-based LDL-C-lowering therapy on major vascular events [
28]. Quite worryingly, serious adverse effects were noted involving the gastrointestinal, musculoskeletal, and cutaneous systems. In a subgroup analysis, there was a trend toward improved outcomes in patients with a high baseline LDL (≥58 mg/dL). Routine administration of niacin should be curtailed, although it may still have a role in very select statin-intolerant patients at high risk of CV events who are unable to reduce LDL-C levels optimally despite multiple therapies. This decision should ultimately be made by specialized clinicians with expertise in dyslipidemia.
Although the mechanism of action of fibric acid is not fully understood, its effect is thought to be due to β-oxidation of fatty acids in peroxisomes and mitochondria. Fibrates reduce plasma TG and cholesterol levels, while elevating HDL-C levels [
29]. Due to the increased risk of myopathy, rhabdomyolysis, and liver impairment when co-administered with statins, fibrate use should be restricted to patients with raised TG levels (>4.5 mmol/L or 170mg/dL) and low HDL levels only [
30]. A recent meta-analysis, however, showed that neither niacin nor fibrate treatment reduced all-cause mortality, CHD mortality, myocardial infarction, or stroke in patients already treated with statins [
31].
Patients with very high CV risk, whose LDL-C levels remain elevated despite combination therapies, may be candidates for weekly or bi-weekly adjunctive lipoprotein apheresis, especially if there is evidence of progression of disease. LDL-C and Lp(a) levels may be reduced by 50–75 % and, while effective, availability of this service, high costs, and the inconvenience and invasive nature of this treatment (use of peripheral veins and, occasionally, requirement of a fistula) limit its widespread use [
5,
32,
33].
Treatment for HoFH
All patients with HoFH should be initiated on lipid-lowering therapy as early as possible, with LDL-C targets the same as in HeFH [
6]. Statins remain the cornerstone of treatment with the observed benefit due to inhibition of hepatic lipoprotein synthesis, up-regulation of LDLR, or an increase in trans-intestinal cholesterol excretion [
34]. While no randomized controlled trials have been conducted looking at the end point of CV mortality in HoFH, statins in the non-FH population are known to reduce the incidence of major vascular events in primary prevention, with intensive regimens producing greater reduction than less intensive regimens [
35,
36]. In HoFH, observational studies show a dose-dependent effect on LDL-C reduction and maximum tolerable doses should generally be prescribed [
37,
38]. The degree of reduction is however less than that seen in HeFH. Although individual response may be variable, LDLR-defective patients may achieve LDL-C reduction of 25 %, while LDLR-negative patients achieve around 15 %, thus suggesting that some receptor function is needed for clinical benefit [
6,
39,
40]. Despite this, statin monotherapy does not reduce LDL-C levels sufficiently and co-administration of ezetimibe is often necessary, yielding a further 15–20 % reduction [
41].
Medical therapy with statins alone or in combination with other lipid-lowering agents such as ezetimibe, bile acid sequestrants, niacin, or probucol rarely provide an adequate solution, and the majority of patients ultimately require LDL apheresis. In the late 1970s unselective plasmapheresis was used in patients with HoFH in an attempt to control hypercholesterolemia, slow coronary atherosclerosis, and prolong survival with limited success [
42,
43]. Subsequently, work began to focus on removing LDL more selectively [
44,
45]. Due to its dramatic benefits, extracorporeal removal of LDL-C by lipoprotein apheresis is now the treatment of choice in HoFH. Despite being expensive, time-consuming, and not readily available, the substantial benefits of single treatment reducing LDL-C levels by up to 70 % have been recommended by the EAS and make it cost-effective overall [
12].
Liver transplantation was first described in 1983 and has now emerged as the most effective treatment, markedly improving LDL-C levels long term [
46,
47]. Surgery provides a liver with functional LDLRs, thereby correcting the molecular defect. It is indicated in patients who despite maximal medical therapy and apheresis fail to reduce LDL-C levels sufficiently. Although successful, it poses significant challenges including procedure-related morbidity and mortality, lack of available donors, and the need for long-term immunosuppression [
48]. Although effective, transplantation is not a realistic option for many patients. Due to the limitations of existing therapies, novel lipid-lowering agents are being developed and provide a new avenue for research for the management of FH.