New targets and emerging therapies for reducing LDL cholesterol

PURPOSE OF REVIEW: Effective therapies for lowering LDL-cholesterol reduce the incidence of cardiovascular disease and provide associated decreases in morbidity and mortality. Progress in our understanding of metabolism and innovations in drug design have jointly identified promising new drug targets and alternative approaches to old targets. This review focuses on the mechanism, safety and efficacy of emerging LDL-cholesterol lowering therapies. RECENT FINDINGS: Decreasing apolipoprotein B expression or preventing the formation of a stable lipoprotein structure by inhibiting microsomal triglyceride transfer protein attenuates the secretion of atherogenic lipoproteins containing apolipoprotein B into the plasma. Increases in LDL receptor-mediated cholesterol clearance occur when hepatic cholesterol stores are reduced secondary to inhibition of squalene synthase or LDL receptor degradation is disrupted by reduced activity of proprotein convertase subtilisin kexin type 9. Each of these developing therapies demonstrably reduces LDL-cholesterol levels. SUMMARY: The emergence of modalities that act in series and in parallel with available agents may allow more effective LDL-cholesterol lowering in those patients intolerant of current therapy, and may permit decremental reductions in LDL-cholesterol for those unable to achieve aggressive LDL-cholesterol goals using existing agents.