Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated Low-Density Lipoprotein Cholesterol (LDL-C) levels in these patients are usually in the range 500 to 1200 mg/dL. Moreover, these patients
exhibit a scarce responsiveness or even non responsiveness to oral lipid lowering agents. Patients with heterozygous familial hypercholesterolemia (HetFH) tend to have untreated LDL-C levels of 250-500 mg/dL. Many of these patients are responsive to 3-hydroxy-3-methylglutaryl-coenzyme A (HMGCoA-reductase)
inhibitors (statins) and/or other specific drugs. Unfortunately, a significant subset of these patients (5-10%) have a severe and/or refractory form of HetFH and after current maximal oral therapy, they remain significantly far from treatment goals (The National Cholesterol Education
Program (NCEP) ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL - prior Coronary Heart Disease (CHD) or CHD equivalent - or ≥ 250 mg/dL (no prior CHD or CHD risk-equivalent). The only current therapy option for these patients is Low Density Lipoprotein-apheresis
(LDL_a). While LDL_a is very effective in reducing LDL-C, many patients do not receive this extracorporeal therapy because of costs and limited availability of LDL_a centers. Recently, new potent lipid-lowering drugs have been developed and are currently under investigation. Proprotein convertase
subtilisin/kexin type 9 (PCSK9) plays a critical role controlling the levels of LDL-C. Studies have demonstrated that PCSK9 acts mainly by enhancing degradation of the Low-Density Lipoprotein receptor (LDLR) protein in the liver. Inactivation of PCSK9 in mice reduces plasma cholesterol levels.
Since the loss of a functional PCSK9 in human is not associated with apparent deleterious effects, this protease is becoming an attractive target for lowering plasma LDL-C levels either alone or in combination with statins. Mipomersen, an apolipoprotein B (ApoB) synthesis inhibitor, for lowering
of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HoFH who are already receiving lipid-lowering drugs, including high-dose statins. Lomitapide is a potent inhibitor of microsomal triglyceride transfer protein and is highly efficacious in reducing LDL-C
and triglycerides (TG). Lomitapide is currently being developed for patients with HoFH at doses up to 60 mg/d. These new powerful lipid-lowering drugs might be possibly superior than available hypolipidemic agents. Their mechanisms of action, effectiveness, safety, and indication in severe,
genetically determined dyslipidemias, are reviewed.
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