Future Lipid-Altering Therapeutic Options Targeting Residual Cardiovascular Risk
- 622 Downloads
Low-density lipoproteins (LDL) play a causal role in the development of atherosclerosis, and reduction of LDL cholesterol with a statin is a cornerstone in prevention of cardiovascular disease. However, it remains an unmet need to reduce the residual risk on maximally tolerated statin alone or in combination with other drugs such as ezetimibe. Among the new LDL-lowering therapies, PCSK9 inhibitors appear the most promising class. Genetic studies suggest that triglyceride-rich lipoproteins are associated with cardiovascular risk and several promising triglyceride-lowering therapies are at various stages of development. At the opposite end, high-density lipoprotein (HDL) cholesterol seems to not be causally associated with cardiovascular risk, and thus far, trials designed to reduce cardiovascular risk by mainly raising HDL cholesterol levels have been disappointing. Nevertheless, new drugs targeting HDL are still in development. This review describes the new drugs reducing LDL, apolipoprotein(a), and triglyceride-rich lipoproteins, and the strategies to modulate HDL metabolism.
KeywordsLDL cholesterol Triglyceride-rich lipoproteins HDL metabolism PCSK9 inhibitors Cardiovascular risk Antisense oligonucleotide
Compliance with Ethical Standards
Conflict of Interest
Dr. Farnier reports having received grants, consulting fees, and/or honoraria, and delivering lectures for Abbott/Mylan, Amgen, AstraZeneca, Eli Lilly, Genzyme, Kowa, Merck and Co, Pfizer, Roche, Sanofi/Regeneron, and Servier.
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
- 4.The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–701.CrossRefGoogle Scholar
- 5.Stone NJ, Robinson J, Lichtenstein AH, 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
- 18.Hedrick JA. Targeting PCSK9 for the treatment of hypercholesterolemia. Curr Opin Invest Drugs. 2009;10:938–46.Google Scholar
- 20.Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–8.CrossRefPubMedGoogle Scholar
- 21.Fitzgerald K, Simon A, White S, et al. ALN-PCSsc, an RNAi investigational agent that inhibits PCSK9 synthesis with the potential for effective bi-annual dosing. Presented at AHA scientific session 2015.Google Scholar
- 25.Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging, study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115:1212–21.CrossRefPubMedGoogle Scholar
- 26.Kastelein JJP, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled phase 2 study. Eur Heart J. 2016; Jan 12: online.Google Scholar
- 27.••Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78-week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolemia. Eur Heart J. 2015;36:2996–3003. Studies evaluating efficacy of alirocumab in two large cohorts of heterozygous FH.PubMedPubMedCentralGoogle Scholar
- 29.••Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B); a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385:341–50. Study showing a significant effect of evolocumab for homozygous FH with residual LDL receptor activity.CrossRefPubMedGoogle Scholar
- 30.••Robinson JG, Farnier M, Krempf M, et al. For the ODYSSEY LONG TERM Investigators. Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events. New Engl J Med. 2015;372:1489–99. Important phase III trial evaluating long term efficacy and safety of alirocumab, with a post-hoc analysis suggesting a cardiovascular benefit.Google Scholar
- 31.Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169:906–15.CrossRefPubMedGoogle Scholar
- 32.Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186–94.CrossRefPubMedPubMedCentralGoogle Scholar
- 41.••Sabatine MS, Giugliano RP, Wiviott SD, for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9. Important phase III trial suggesting a cardiovascular benefit after one year of evolocumab treatment.CrossRefPubMedGoogle Scholar
- 44.Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial. Am Heart J. 2016;173:94–101.Google Scholar
- 46.SPIRE-1: The evaluation of Bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects. www.clinicaltrials.gov, NCT 01975376, accessed on February 2016.
- 47.SPIRE-2: The evaluation of Bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects. www.clinicaltrials.gov, NCT 01975389, accessed on February 2016.
- 48.EBBINGHAUS: Evaluating PCSK9 Binding antiBody Influence oN cognitive HeAlth in High cardiovascular Risk Subjects. www.clinicaltrials.gov, NCT02207634, accessed on February 2016.
- 53.Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:998–1006.CrossRefPubMedGoogle Scholar
- 55.Cuchel M, Meagher EA, du Toit Theron H, for the phase 3 HoFH Lomitapide Study Investigators, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. 2013;381:40–6.CrossRefPubMedGoogle Scholar
- 56.Stefanutti C, Blom DJ, Averna MR, for the phase 3 HoFH Lomitapide Study Investigators, et al. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia – A post-hoc analysis of a Phase 3, single-arm, open-label trial. Atherosclerosis. 2015;240:408–14.CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Gutierrez MJ, Rosenberg NL, MacDougall DE, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014;34:676–83.CrossRefPubMedGoogle Scholar
- 58.Ballantyne CM, Davidson MH, MacDougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia. Results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154–62.CrossRefPubMedGoogle Scholar
- 73.REDUCE-IT: A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin. www.clinicaltrials.gov, NCT 01492361, accessed on February 2016.
- 74.STRENGTH: Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia. www.clinicaltrials.gov, NCT 02104817, accessed on February 2016.
- 83.Kingwell BA, Chapman MJ, Kontush A, et al. HDL-targeted therapies: progress, failures and future. Nat Rev. 2014;13:445–64.Google Scholar
- 88.REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification. www.clinicaltrials.gov, NCT 01252953, accessed on February 2016.
- 91.Hovingh GK, Smits LP, Stefanutti C, et al. The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: the Modifying Orphan Disease Evaluation (MODE) study. Am Heart J. 2015;169:736–42.e1.CrossRefPubMedGoogle Scholar
- 97.Van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein(a). J Lipid Res. 2015 Dec 4.Google Scholar