New clinical perspectives of hypolipidemic drug therapy in severe hypercholesterolemia

Patients with homozygous familial hypercholesterolemia (HoFH) represent the most severe patients within the spectrum of dyslipidemias. Untreated LDL-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 nonresponsiveness 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 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 (NCEP ATPIII guidelines). This would be defined as LDL-C levels of ≥ 190 mg/dL (prior CAD or CAD equivalent) or ≥ 250 mg/dL (no prior CAD or CAD risk-equivalent). The only current therapy option for these patients is Low Density Lipoproteins-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 LDL 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 synthesis inhibitor, for lowering of LDL-C showed to be an effective therapy to reduce LDL-C concentrations in patients with HozFH 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. Lomitapide is currently being developed for patients with HozFH 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.