title: Non-statin Treatments for Managing LDL Cholesterol and Their Outcomes.
abstract: OBJECTIVE
  Over the past 3 decades reducing LDL-C has proven to be the most reliable and easily achievable modifiable risk factor to decrease the rate of cardiovascular morbidity and mortality. Statins are effective, but problems with their side effects, adherence, or LDL-C efficacy in some patient groups remain. Most currently available alternative lipid-modifying therapies have limited efficacy or tolerability, and additional effective pharmacologic modalities to reduce LDL-C are needed.
  
  
  METHODS
  Recent literature on new and evolving LDL-C-lowering modalities in preclinical and clinical development was reviewed.
  
  
  RESULTS
  Several new therapies targeting LDL-C are in development. Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), a recently elucidated key regulator of plasma LDL-C, is the most promising and effective, with a number of approaches aimed at this target. The most advanced are monoclonal antibodies, which have demonstrated LDL-C reductions of ~60%, whether given alone or added to statins. Other PCSK9-targeted therapies in clinical development include adnectins and gene silencing techniques. Preclinical approaches involve vaccines, whereas a search remains for small molecule inhibitors. Other new pharmacologic approaches in Phase III clinical trials include a refocusing of cholesterol ester transfer protein inhibitors from primarily agents to increase HDL-C to their off-target effect on LDL-C and adenosine triphosphate citrate lyase inhibition. In earlier clinical development is new delivery of nicotinic acid-containing compounds. Additional agents are being developed as orphan indications expressly for patients with homozygous familial hypercholesterolemia, including peroxisome proliferator activated receptor-δ agonists, angiopoietin-like protein 3 inhibitors, and gene therapy.
  
  
  CONCLUSIONS
  Monoclonal antibodies that inhibit PCSK9 were shown to be very effective reducers of LDL-C and well tolerated despite subcutaneous administration, and no significant safety issues have yet emerged during large Phase II and III trials. They have the potential to substantially impact further the risk of cardiovascular disease. A number of additional new, but less effective, oral LDL-C-lowering agents are also in various stages of development, including some which are targeted only to patients with homozygous familial hypercholesterolemia.
authors.affiliation: Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio.
authors.forename: Traci
authors.initials: T
authors.lastname: Turner
authors.affiliation: Metabolic & Atherosclerosis Research Center, Cincinnati, Ohio. Electronic address: esteinmrl@aol.com.
authors.forename: Evan A
authors.initials: EA
authors.lastname: Stein
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood*; D002986:Clinical Trials as Topic; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000188:drug therapy
chemical_list: D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors
keywords: CETP inhibitors; Familial hypercholesterolemia; LDL cholesterol; PCSK9 inhibitors