Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia.

1022 L ow-density lipoproteins (LDLs) are a proven causal risk factor for the development of atherosclerotic cardiovascu-lar disease. Plasma levels of LDL cholesterol (LDL-C) and its major protein, apolipoprotein B (apoB), are positively associated with incident cardiovascular events. 1 Individuals with genetic conditions of extremely high LDL-C develop premature cardiovascular disease; conversely, those with genetically low LDL-C are protected from cardiovascular disease. Interventions that reduce LDL-C, including statins and bile acid sequestrants, are proven to reduce cardiovascular risk. 2 Indeed, therapy to reduce LDL-C is a cornerstone of the treatment and primary prevention of atherosclerotic cardiovascular disease. Despite the commercial availability of 3 major classes of LDL-lowering drugs (statins, bile acid sequestrants, and a cholesterol absorption inhibitor), a substantial unmet need has remained with regard to LDL-lowering treatment. Some patients are intolerant of statins because of myalgias. Others have genetic conditions that substantially elevate their LDL-C and make it challenging to achieve desirable LDL-C levels even with combination therapy. Perhaps the single best example of a genetic condition in which patients frequently fail to achieve acceptable LDL-C levels despite aggressive therapy is famil-ial hypercholesterolemia (FH). 3,4 This condition, classically caused by loss-of-function mutations in the LDL receptor, 5 is associated with substantially elevated LDL-C and premature atherosclerotic cardiovascular disease. Patients with heterozy-gous FH typically have untreated LDL-C levels in the range of 200 to 400 mg/dL, and many cannot achieve desirable LDL-C levels on available combination therapy. Patients with 2 mutant LDL receptor alleles have homozygous FH (hoFH) with LDL-C levels usually >400 mg/dL and cannot achieve desirable LDL-C levels on available therapy. There are other causes of autosomal-dominant hypercholesterolemia 4 resulting from mutations in the receptor-binding region of apoB (the ligand for the LDL receptor) and gain-of-function mutations in PCSK9 (a protein that targets the LDL receptor for degradation), and these patients can resemble patients with heterozygous FH in their clinical presentation and difficulty in achieving adequate LDL-C control. LDL-C levels are regulated by the rate of LDL production and the rate of LDL catabolism (Figure 1A). The liver synthesizes and secretes very-low-density lipoproteins (VLDLs), which are lipolyzed in the plasma compartment and eventually converted to LDL. Thus, the hepatic production of VLDL is a major determinant of plasma levels of LDL-C. LDL is catabolized largely by the liver via the LDL receptor, and this process plays a key role in determining plasma LDL-C levels. Importantly, the 3 major …