A Clinical Guide to Combination Lipid-Lowering Therapy

  • Cori Russell
  • Samip Sheth
  • Douglas Jacoby
Nonstatin Drugs (E. deGoma, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nonstatin Drugs


Purpose of Review

We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction.

Recent Findings

Medical societies, including the American College of Cardiology (ACC), National Lipid Association (NLA), and American Association of Clinical Endocrinologists (AACE), have released guidelines to address the appropriate use of non-statin therapies. The guidelines incorporated new evidence, including the IMPROVE-IT and FOURIER clinical trials, which demonstrate that the combination of statin therapy with other non-statin agents such as ezetimibe and PCSK9 inhibitors has a significant clinical benefit. Increasing evidence that aggressive low-density lipoprotein cholesterol (LDL-C) lowering leads to lower cardiovascular disease risk supports the need for continued exploration of the role of combination lipid-lowering therapies.


A review of guidelines and clinical trials evaluating non-statin agents illuminates the growing base of evidence and expert opinion supporting the use of combination lipid-lowering therapies. While the majority of clinical trial data utilizes dyslipidemia monotherapy, especially statins, combination therapies represent an opportunity for individualized, patient-centered approach to LDL-C lowering and atherosclerotic cardiovascular disease (ASCVD) risk reduction. The overview provides a perspective on lipid management intended for clinicians who seek additional information and guidance on the use of combination therapies.


Clinical practice guidelines Atherosclerotic cardiovascular disease (ASCVD) Dyslipidemia PCSK9 inhibitors Non-statins Cardiovascular disease prevention Ezetimibe Low-density lipoprotein cholesterol (LDL-C) LDL-C targets 


Compliance with Ethical Standards

Conflict of Interest

Cori Russell, Samip Sheth, and Douglas Jacoby declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Stone NJ, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–45.CrossRefPubMedGoogle Scholar
  2. 2.
    Investigators, A.-H, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.CrossRefGoogle Scholar
  3. 3.
    Group, A.S, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1563–74.CrossRefGoogle Scholar
  4. 4.
    Keech A, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366(9500):1849–61.CrossRefPubMedGoogle Scholar
  5. 5.
    • Jacobson TA, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—executive summary. J Clin Lipidol. 2014;8(5):473–88. This document provides recommendations for the use of non-statin agents for reduction of LDL-C and ASCVD as well as introduces new LDL-C targets. CrossRefPubMedGoogle Scholar
  6. 6.
    •• Cannon CP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–97. IMPROVE-IT was the first trial to demonstrate incremental ASCVD risk reduction with combination therapy. CrossRefPubMedGoogle Scholar
  7. 7.
    Robinson JG, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–99.CrossRefPubMedGoogle Scholar
  8. 8.
    Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–9.CrossRefPubMedGoogle Scholar
  9. 9.
    •• Writing C, et al. 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016;68(1):92–125. This document provides a clinical algorithm for the use of non-statin agents in combination with statins for further LDL-C and ASCVD risk reduction. CrossRefGoogle Scholar
  10. 10.
    • Jellinger PS, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1–87. These guidelines created a new category of ‘extreme risk’ for ASCVD and suggested a lower LDL-C goal of < 55 mg/dL. CrossRefPubMedGoogle Scholar
  11. 11.
    Sabatine MS, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22.CrossRefPubMedGoogle Scholar
  12. 12.
    Giugliano RP, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377(7):633–43.CrossRefPubMedGoogle Scholar
  13. 13.
    • Lloyd-Jones DM, et al. 2017 focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2017;70(14):1785–822. This document provides an update to the 2016 ACC Expert Consensus Pathway taking into account the results of the FOURIER trial and provides further support for the use of PCSK9 inhibitors in combination therapy. CrossRefPubMedGoogle Scholar
  14. 14.
    Goldberg AC, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5(3 Suppl):S1–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129(9):1022–32.CrossRefPubMedGoogle Scholar
  16. 16.
    Karalis, D.V., B; Ahedor, L; and Liu, L., Use of lipid-lowering medications and the likelihood of achieving optimal LDL-cholesterol goals in coronary artery disease patients. Cholesterol, 2012. 2012: p. Article ID 861924.Google Scholar
  17. 17.
    Lin I, et al. Patterns of statin use in a real-world population of patients at high cardiovascular risk. J Manag Care Spec Pharm. 2016;22(6):685–98.CrossRefPubMedGoogle Scholar
  18. 18.
    Morrone D, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis. 2012;223(2):251–61.CrossRefPubMedGoogle Scholar
  19. 19.
    Gudzune KA, Monroe AK, Sharma R, Ranasinghe PD, Chelladurai Y, Robinson KA. Effectiveness of combination therapy with statin and another lipid-modifying agent compared with intensified statin monotherapy: a systematic review. Ann Intern Med. 2014;160(7):468–76.CrossRefPubMedGoogle Scholar
  20. 20.
    Farnier M. Update on the clinical utility of fenofibrate in mixed dyslipidemias: mechanisms of action and rational prescribing. Vasc Health Risk Manag. 2008;4(5):991–1000.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bays H, Rhyne J, Abby S, Lai YL, Jones M. Lipid-lowering effects of colesevelam HCl in combination with ezetimibe. Curr Med Res Opin. 2006;22(11):2191–200.CrossRefPubMedGoogle Scholar
  22. 22.
    The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA. 1984;251(3):365–74.CrossRefGoogle Scholar
  23. 23.
    • Adhyaru BB, Jacobson TA. Role of non-statins, LDL-C thresholds, and special population considerations: a look at the updated 2016 ACC Consensus Committee Recommendations. Curr Atheroscler Rep. 2017;19(6):29. This article reviews the role of non-statin agents in combination with statins for LDL-C and ASCVD risk reduction after the publication of the 2016 ACC Expert Consensus Pathway and the 2015NLA Recommendations. CrossRefPubMedGoogle Scholar
  24. 24.
    Siscovick DS, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017;135(15):e867–e884.CrossRefPubMedGoogle Scholar
  25. 25.
    Maggioni AP, Franzosi MG, Fresco C, Turazza F, Tognoni G. GISSI trials in acute myocardial infarction. Rationale, design, and results. Chest. 1990;97(4 Suppl):146S–50S.PubMedGoogle Scholar
  26. 26.
    Barter P, Ginsberg HN. Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Am J Cardiol. 2008;102(8):1040–5.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cardiovascular Division, Department of MedicineUniversity of Pennsylvania Health SystemPhiladelphiaUSA
  2. 2.Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Penn Presbyterian Medical CenterPhiladelphiaUSA

Personalised recommendations