Apolipoprotein B (apoB), the protein component of low-density lipoprotein (LDL), may be a target for therapy to reduce the risk of cardiovascular events, as it appears to have better predictive value for events than does LDL cholesterol.
Apolipoprotein B (apoB), the protein component of low-density lipoprotein (LDL), may be a target for therapy to reduce the risk of cardiovascular events, as it appears to have better predictive value for events than does LDL cholesterol. A review of the effect of current therapies on apoB and drugs in the pipeline that affect this lipoprotein was provided by Michael Davidson, MD.
Current approaches to lowering apoB are the same as those used to modify other lipids-statins, fibrates, niacin, cholesterol absorption inhibitors, stanols, and omega-3 fatty acids-and each does so to differing degrees. LDL cholesterol and LDL particles are affected differently by most, if not all, therapeutic interventions, says Dr. Davidson.
Statins, ezetimibe, and estrogen replacement reduce LDL cholesterol more so than the number of LDL particles, whereas fibrates, niacin, glitazones, and omega-3 fatty acids have preferential effects on the number of LDL particles. For example, pioglitazone is associated with a 16% increase in LDL cholesterol but a 4% decrease in LDL particles. Rosiglitazone increases LDL cholesterol to a larger extent than the number of LDL particles.
"ApoB-100 is an ideal target for an antisense drug," says Dr. Davidson, clinical professor and director of preventive cardiology at the University of Chicago. ApoB-100 is essential for the synthesis and transport of very-low-density lipoprotein (VLDL) cholesterol and LDL cholesterol. The ideal apoB-100 inhibitor should offer a complementary mechanism to statins for additive effects when the two are coadministered.
The antisense drug mipomersen is currently in phase 3 clinical trials. Mipomersen predictably lowers apoB and LDL cholesterol as monotherapy and as add-on therapy to statins but may be limited by an elevation in liver enzymes and bilirubin and the occurrence of skin reactions with its use.
Microsomal triglyceride transfer protein (MTP) inhibition may be another option for apoB lowering, as MTP is involved in VLDL assembly, says Dr. Davidson. Inhibition of MTP will limit secretion of cholesterol and triglycerides from the intestine and liver. Past attempts, however, have been associated with hepatic steatosis, liver enzyme elevations, and severe nausea at high doses, "so the idea is to use a lower dose of MTP inhibitors to affect modest reductions in apoB levels that can be safe and well tolerated," he says. One of those compounds is implitapide; as monotherapy, implitapide lowers levels of apoB by up to 24% after 12 weeks of therapy.
Thyroid mimetics, proprotein convertase subtilisin/kexin type 9 (PCSK9)/apoB antisense agents, and cholesteryl ester transfer protein inhibitors (dalcetrapib) represent other potential approaches to reducing cardiovascular risk via apoB reduction.