In clinically diagnosed HoFH, the occurrence of the first major cardiovascular events is localized in the adolescence, although a significant phenotypic variability exists in subjects with HoFH in terms of cardiovascular disease and clinical outcomes, mainly due to eventual residual activity of LDLR, the therapeutic treatments, and the time of therapy initiation [12, 13]. As example, markers of atherosclerosis were significantly correlated with age at which lipid-lowering therapies started in a group of HoFH patients [12]. Thus, current guidelines recommend to lower LDL-C as early as possible, based on the evidence that the severity of atherosclerosis and cardiovascular disease correlates with the cumulative burden of high levels of LDL-C and that early lipid lowering may reduce this burden and delay the onset of cardiovascular events [8, 12, 14]. Lifestyle interventions including a low-saturated fat, low cholesterol diet, physical activity, and not smoking are strongly encouraged, but aggressive lipid-lowering treatments are essential to lower LDL-C levels drastically. Statins are the first-line therapy for lowering LDL-C levels [10, 15] and may be effective in some HoFH patients, but the presence of functional LDLR is required for such effect; thus, statins may be effective in HeFH, or in receptor-defective HoFH at the maximal dose tolerated [8, 10], and in children statins should be only those that have been proved to be relatively safe [10, 16, 17]. However, HoFH patients rarely reach the LDL-C level target, as statins in HoFH trigger an LDL-C reduction of about 20 %, which is significantly lower compared with reductions observed in other types of hypercholesterolemic patients (40–60 %) [18]. This observation points out to the need to treat HoFH patients with combined lipid-lowering therapies, using drugs with different mechanisms of action that may guarantee a higher reduction of LDL-C levels. Ezetimibe, which reduces cholesterol absorption, and LDL apheresis, which removes LDL particles from the circulation, are usually associated with statin therapy in the management of HoFH patients, resulting in an impressive LDL-C reduction [8, 19]. Other drugs may be added to the therapy, such as fibrates for HoFH subjects with high triglyceride levels [10].

Accordingly with current guidelines, recommended LDL-C goals for both HeFH and HoFH patients are <100 mg/dL (<2.5 mmol/L) for adults, <135 mg/dL (<3.5 mmol/L) for children, and <70 mg/dL (<1.8 mmol/L) for adults with coronary heart disease or diabetes (Table 8.1) [10].

Several studies have established the efficacy of statin therapy in reducing either cardiovascular or all-cause mortality in homozygous familial hypercholesterolemia, even in LDLR-negative patients. High doses of simvastatin (80 or 160 mg/day) were found to significantly reduce LDL-C levels in HoFH patients (Table 8.2), even if receptor negative: at 80 mg/day there was a 25 % LDL-C reduction, and at 160 mg/day it reached 31 %, while the lower dose (40 mg/day) was less effective in reducing LDL-C levels (−13.8 %) [20]. As expected, simvastatin significantly reduced VLDL-C, total cholesterol, apoB, and TG levels (Table 8.2) [20].

As the main mechanism by which statins act is through the inhibition of endogenous cholesterol biosynthesis, with subsequent upregulation of LDLR to enhance LDL clearance, it was expected that only receptor-defective HoFH would respond to statin therapy; on the contrary, also receptor-negative subjects showed significant decreases of LDL-C levels with high-dose statin [20, 21], suggesting that alternative mechanisms of action of statins may explain this finding. Statins, by inhibiting cholesterol biosynthesis in the liver, may limit cholesterol availability for apoB-containing lipoprotein formation, including VLDL, that are the major source of circulating LDL, and LDL itself; this mechanism is likely to play a relevant role in statin-induced LDL lowering in subjects that are receptor negative. On the contrary, in receptor-defective subjects, which may produce some functional receptors, both mechanisms may play a role. In addition, subjects exhibiting the same LDLR mutations have different LDL-C levels and respond in a heterogeneous way to the same therapy, suggesting the involvement of other mechanisms.

These findings have been confirmed by other studies: high doses of atorvastatin (40 and 80 mg/day) lowered LDL-C levels by 17 and 28 %, respectively, with similar reductions in receptor-negative subjects (14 and 28 %, respectively) [22]. Atorvastatin 40 and 80 mg significantly reduced total cholesterol and TG levels (Table 8.2) [22]. However, no additional reductions were observed by further increasing atorvastatin doses [22], suggesting a plateau effect. This is a relevant finding, yet observed in subjects with HeFH [23], suggesting a limit to the LDL-C-lowering properties of statins in FH and that drugs with a different mechanism of action should be added to statin therapy aiming at achieving LDL-C targets.

Similar results were obtained in a comparative study of atorvastatin and rosuvastatin that showed similar mean reductions with these two drugs at 80 mg/day (18 and 19 %, respectively) (Table 8.2) [24], suggesting the need of additional cholesterol-lowering treatments.

Although statins did not decrease LDL-C levels at the recommended target, these reductions of LDL-C levels might be beneficial for HoFH patients, possibly translating in a reduced risk of early onset of major cardiovascular events, especially if therapy is started early [8]. This effect was reported by a study that evaluated the impact of advances in lipid-lowering therapies (mainly statins) on cardiovascular disease morbidity and mortality in a large HoFH population: despite a mean reduction of LDL-C levels of 26 %, patients treated with lipid-lowering drugs showed a significant reduction of mortality and an increased age at which the first major adverse cardiovascular event occurred [14]. These findings suggested that, although LDL-C levels remained elevated, lipid-lowering therapy with statins is associated with a better prognosis for HoFH, with delayed cardiovascular events and prolonged survival. Nevertheless, despite the use of high-potency statins at high doses, only a small proportion of HoFH patients reach the recommended LDL-C target [10, 18]; in addition, some subjects may exhibit intolerance to statins, leading to therapy discontinuation. All these observations suggest the need of new therapeutic options to decrease LDL-C levels in these patients. Lomitapide and mipomersen were recently developed for the treatment of HoFH patients.

The microsomal triglyceride transfer protein (MTP) is a lipid transfer protein that plays an essential role in the assembly and secretion of apolipoprotein-B-containing lipoproteins, including very low-density lipoprotein (VLDL) and chylomicrons (Fig. 8.2) [25]. It is localized in the endoplasmic reticulum (ER) of hepatocytes and enterocytes and acts by transferring neutral lipids (triglycerides and cholesteryl esters) from the ER membrane to the nascent apoB [25]. The key role of MTP has been identified in subjects carrying mutations of the gene encoding for MTP (MTTP), which exhibit inadequate formation of VLDL and chylomicrons and increased apoB degradation; this condition ultimately results in the significant reduction of circulating VLDL and the deriving LDL [26]. Thus, it was hypothesized that MTP inhibition could represent a possible therapeutic strategy to reduce LDL-C levels in subjects with familial hypercholesterolemia. In contrast to other lipid-lowering therapies, MTP inhibition affects the production of apoB-containing lipoproteins in both the liver and intestine, thus preventing both hepatic VLDL and intestinal chylomicron secretion and resulting in significant reduction of both cholesterol and TG plasma levels. Preclinical studies performed in animal models of HoFH supported this hypothesis, showing that MTP inhibition normalized the levels of atherogenic lipoproteins by greatly reducing the secretion rate of VLDL in WHHL rabbits [27, 28] and in Ldlr ^−/− mice [29].

Lomitapide is a MTP inhibitor that binds to MTP and inhibits MTP-mediated synthesis of VLDL and chylomicrons and, as a result, significantly reduces LDL-C levels (Fig. 8.2). Lomitapide was first tested in six patients with homozygous familial hypercholesterolemia [30]. The patients were 18–40 years old, and two of them had known clinically relevant cardiovascular disease; five patients were found to be negative for the LDLR, while one was LDLR defective [30]. The patients received lomitapide at 4 different daily doses (0.03, 0.1, 0.3 and 1.0 mg/kg body weight), each for 4 weeks. The mean LDL-C level was reduced by 24.7 % after 0.3 mg/kg for 4 weeks and by 50.9 % from the baseline level after 1.0 mg/kg for 4 weeks (Table 8.3) [30]; similarly, total cholesterol was reduced by 29.8 and 58.4 % from the baseline level, respectively (Table 8.3) [30]. Both TG and apoB were significantly reduced (TG: −34.1 and −65.2 %, and apoB: −14.7 and −55.6 %, respectively) (Table 8.3) [30]. Overall, the drug was well tolerated; the most serious adverse events were elevations in liver aminotransferase levels and hepatic fat accumulation [30]. This study showed that treating patients with HoFH with lomitapide is highly effective in reducing LDL-C levels; the accumulation of fat in the liver, however, requires further investigations for the evaluation of adverse effects during long-term treatment with lomitapide.