title: Nonstatin therapies for management of dyslipidemia: a review.
abstract: OBJECTIVE
  Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Recently published cholesterol treatment guidelines emphasize the use of statins as the preferred treatment strategy for both primary and secondary prevention of CVD. However, the optimal treatment strategy for patients who cannot tolerate statin therapy or those who need additional lipid-lowering therapy is unclear in light of recent evidence that demonstrates a lack of improved cardiovascular outcomes with combination therapy. The purpose of this review is to summarize and interpret evidence that evaluates nonstatin drug classes in reducing cardiovascular outcomes, to provide recommendations for use of nonstatin therapies in clinical practice, and to review emerging nonstatin therapies for management of dyslipidemia.
  
  
  METHODS
  Relevant articles were identified through searches of PubMed, International Pharmaceutical Abstracts, and the Cochrane Database of Systematic Reviews by using the terms niacin, omega-3 fatty acids (FAs), clofibrate, fibrate, fenofibrate, fenofibric acid, gemfibrozil, cholestyramine, colestipol, colesevelam, ezetimibe, proprotein convertase subtilisin/kexin 9 (PCSK9), cholesteryl ester transfer protein (CETP), and cardiovascular outcomes. Only English language, human clinical trials, meta-analyses, and systematic reviews were included. Additional references were identified from citations of published articles.
  
  
  RESULTS
  Niacin may reduce cardiovascular events as monotherapy; however, recent trials in combination with statins have failed to show a benefit. Trials with omega-3 FAs have failed to demonstrate significant reductions in cardiovascular outcomes. Fibrates may improve cardiovascular outcomes as monotherapy; however, trials in combination with statins have failed to show a benefit, except in those with elevated triglycerides (>200 mg/dL) or low HDL-C (<40 mg/dL). There is a lack of data that evaluates bile acid sequestrant in combination with statin therapy on reducing cardiovascular events. Ezetimibe-statin combination therapy can reduce cardiovascular outcomes in those with chronic kidney disease and following vascular surgery or acute coronary syndrome. Long-term effects of emerging nonstatin therapies (CETP and PCSK9 inhibitors) are currently being evaluated in ongoing Phase III trials.
  
  
  CONCLUSIONS
  Nonstatin therapies have a limited role in reducing cardiovascular events in those maintained on guideline-directed statin therapy. In certain clinical situations, such as patients who are unable to tolerate statin therapy or recommended intensities of statin therapy, those with persistent severe elevations in triglycerides, or patients with high cardiovascular risk, some nonstatin therapies may be useful in reducing cardiovascular events. Future research is needed to evaluate the role of nonstatin therapies in those who are unable to tolerate guideline-directed statin doses.
authors.affiliation: College of Pharmacy, Department of Pharmacotherapy & Translational Research, University of Florida, Gainesville, Florida. Electronic address: ksando@cop.ufl.edu.
authors.forename: Karen R
authors.initials: KR
authors.lastname: Sando
authors.affiliation: College of Pharmacy, Department of Pharmacotherapy & Translational Research, University of Florida, Gainesville, Florida.
authors.forename: Michelle
authors.initials: M
authors.lastname: Knight
mesh_terms: D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D002318:Cardiovascular Diseases / Q000517:prevention & control*; D053480:Cholesterol Ester Transfer Proteins / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000097:blood; D002994:Clofibrate / Q000627:therapeutic use; D019468:Disease Management; D050171:Dyslipidemias / Q000188:drug therapy*; D000069438:Ezetimibe / Q000627:therapeutic use; D015525:Fatty Acids, Omega-3 / Q000627:therapeutic use; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D009525:Niacin / Q000627:therapeutic use; D043484:Proprotein Convertases / Q000378:metabolism / Q000627:therapeutic use; D012307:Risk Factors; D029701:Saccharomyces cerevisiae Proteins / Q000627:therapeutic use; D014280:Triglycerides / Q000097:blood; D014481:United States
chemical_list: D000924:Anticholesteremic Agents; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D015525:Fatty Acids, Omega-3; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D029701:Saccharomyces cerevisiae Proteins; D014280:Triglycerides; D009525:Niacin; D043484:Proprotein Convertases; C058751:KEX2 protein, S cerevisiae; D000069438:Ezetimibe; D002994:Clofibrate
keywords: bile acid sequestrant; ezetimibe; fenofibrate; niacin; non-statin therapy; omega-3 fatty acid