Determinants of Achieved LDL Cholesterol and “Non-HDL” Cholesterol in the Management of Dyslipidemias
Purpose of Review
The advent of combination therapy to provide LDL lowering beyond that achieved with statins necessitates the development of greater understanding of how drugs work together, what changes occur in key lipoprotein fractions, and what residual risk remains.
Clinical trials of agents that, when added to statins, generate profound LDL lowering have been successful in reducing further the risk of cardiovascular disease. LDL cholesterol can be now decreased to unprecedented levels, so the focus of attention then shifts to other apolipoprotein B-containing, atherogenic lipoprotein classes such as lipoprotein(a) and remnants of the metabolism of triglyceride-rich particles. “Non-HDL cholesterol” is used increasingly (especially if measured in the non-fasting state) as a more comprehensive index of risk.
Metabolic studies reveal how current drugs act in combination to achieve profound lipid lowering. However, care is needed in interpreting achieved LDLc and non-HDLc levels in the emerging treatment paradigm.
KeywordsLipoproteins CVD prevention Clinical trials Statin Ezetimibe PCSK9 inhibitors
Compliance with Ethical Standards
Conflict of Interest
Chris J. Packard reports grants/honoraria from the following pharmaceutical companies: Merck, Sharp & Dohme, Pfizer, Amgen, Sanofi, Regeneron, and Daiichi-Sankyo.
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.Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, 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:S1–45.CrossRefPubMedGoogle Scholar
- 3.•• Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017;38:2459–72. A seminal overview that brings together evidence from multiple fields of investigation to support the causal role of LDL in atherogenesis. This is a very useful resource to counteract the claims of those who question the benefits of focusing on lipoproteins as targets for therapy. CrossRefPubMedPubMedCentralGoogle Scholar
- 5.• Vitali C, Khetarpal SA, Rader DJ. HDL cholesterol metabolism and the risk of CHD: new insights from human genetics. Curr Cardiol Rep. 2017;19:132. This article offers an excellent overview of where we are in understanding HDL and its relationship to cardiovascular disease. CrossRefPubMedGoogle Scholar
- 9.•• Sabatine MS, Giugliano RP, Keech AC, FOURIER Steering Committee and Investigators, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22. The landmark first outcome trial of a PCSK9 inhibitor showing incremental risk reduction when evolocumab is added to statin therapy. LDLc levels on combination therapy were the lowest yet seen in an outcome trial. CrossRefPubMedGoogle Scholar
- 10.•• Ference BA, Cannon CP, Landmesser U, et al. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J. 2017; https://doi.org/10.1093/eurheartj/ehx450. This analysis shows the importance of treatment duration in assessing the observed risk reduction. The headline relative risk reduction in short trials (e.g., 2 years follow-up) does not reveal the full effect.
- 14.Joshi PH, Khokhar AA, Massaro JM, Lipoprotein Investigators Collaborative (LIC) Study Group, et al. Remnant lipoprotein cholesterol and incident coronary heart disease: the Jackson Heart and Framingham Offspring Cohort Studies. J Am Heart Assoc. 2016;5:e002765. https://doi.org/10.1161/JAHA.115.002765.CrossRefPubMedPubMedCentralGoogle Scholar
- 17.• Saleheen D, Haycock PC, Zhao W, et al. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a Mendelian randomisation analysis. Lancet Diabetes Endocrinol. 2017;5:524–33. A comprehensive examination of the relationship of Lp(a) and its characteristic protein apo(a) to risk of CHD. Both apo(a) size and Lp(a) concentration are important. CrossRefPubMedPubMedCentralGoogle Scholar
- 19.•• Watts G, Chan D, Dent R, Somaratne R, Wasserman S, Scott R, et al. Factorial effects of evolocumab and atorvastatin on lipoprotein metabolism. Circulation. 2016;135:338–51. Elegant study of the mechanism of action of a PCSK9 inhibitor when given as monotherapy or combined with statin. CrossRefPubMedGoogle Scholar
- 20.•• Reyes-Soffer G, Pavlyha M, Ngai C, et al. Effects of PCSK9 inhibition with alirocumab on lipoprotein secretion and production in healthy humans. Circulation. 2016;135:352–62. A contemporaneous, equally elegant study of the mechanism of action of a PCSK9 inhibitor in man using stable isotope tracers. CrossRefPubMedGoogle Scholar
- 21.•• Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57:1086–96. As well as an excellent overview of the clinical trial findings on Lp(a) lowering, this paper investigates potential mechanisms of action of these powerful new agents. CrossRefPubMedPubMedCentralGoogle Scholar
- 36.• Lawler PR, Akinkuolie AO, Harada P, Glynn RJ, Chasman DI, Ridker PM, et al. Residual risk of atherosclerotic cardiovascular events in relation to reductions in very-low-density lipoproteins. J Am Heart Assoc. 2017;6:e007402. https://doi.org/10.1161/JAHA.117.007402. An important investigation into lipoprotein-associated residual risk when LDLc is reduced to low levels. CrossRefPubMedPubMedCentralGoogle Scholar
- 38.•• Bowman L, Hopewell JC, Chen F, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. HPS3/TIMI55–REVEAL Collaborative Group. N Engl J Med. 2017;377:1217–27. This is the latest (last?) definitive outcome trial of cholesteryl ester transfer protein inhibition. It shows a moderate risk reduction that can be accounted for by the change in apoB-containing lipoproteins. CrossRefPubMedGoogle Scholar
- 40.•• Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017;318:947–56. This report of Mendelian randomization studies reveals a level of complexity in examining the risk reduction attributable to LDLc change. An important distinction is made between situations where LDLc and apoB are reduced “concordantly” or in discordance. CrossRefPubMedPubMedCentralGoogle Scholar
- 43.Ference BA, Majeed F, Penumetcha R, Flack JM, Brook RD. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 × 2 factorial Mendelian randomization study. J Am Coll Cardiol. 2015;65:1552–61.CrossRefPubMedGoogle Scholar
- 45.Landmesser U, Chapman MJ, Stock JK, Amarenco P, Belch JJF, Borén J, et al. 2017 Update of ESC/EAS Task Force on practical clinical guidance for proprotein convertase subtilisin/kexin type 9 inhibition in patients with atherosclerotic cardiovascular disease or in familial hypercholesterolaemia. Eur Heart J. 2017;39:1131–43. https://doi.org/10.1093/eurheartj/ehx549.CrossRefGoogle Scholar
- 46.Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma S, 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;70:1785–822.CrossRefPubMedGoogle Scholar
- 47.• Nordestgaard BG, Langsted A, Mora S, European Atherosclerosis Society (EAS) and the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) Joint Consensus Initiative, et al. Fasting is not routinely required for determination of a lipid profile: clinical and laboratory implications including flagging at desirable concentration cut-points—a joint consensus statement from the European Atherosclerosis Society and European Federation of Clinical Chemistry and Laboratory Medicine. Eur Heart J. 2016;37:1944–58. A joint report from experts in atherosclerosis and laboratory medicine stating that it is no longer required to have subjects fast before measuring a lipid profile. CrossRefPubMedPubMedCentralGoogle Scholar
- 48.•• Sathiyakumar V, Park J, Golozar A, Lazo M, Quispe R, Guallar E, et al. Fasting versus nonfasting and low density lipoprotein cholesterol accuracy. Circulation. 2018;137:10–9. This paper is a leading example of a number of reports highlighting the shortcomings of traditional LDLc determination using the Friedewald equation. It offers a more accurate, customized-to-the-patient, method of calculation. CrossRefPubMedGoogle Scholar
- 49.Whelton SP, Meeusen JW, Donato LJ, Jaffe AS, Saenger A, Sokoll LJ, et al. Evaluating the atherogenic burden of individuals with a Friedewald-estimated low-density lipoprotein cholesterol <70 mg/dL compared with a novel low-density lipoprotein estimation method. J Clin Lipidol. 2017;11:1065–72.CrossRefPubMedGoogle Scholar
- 51.UK National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification 2016: www.nice.org.uk/guidance/cg181 (last accessed Jan 2018).
- 56.• Giugliano RP, Wiviott SD, Blazing MA, et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: a pre-specified analysis of the IMPROVE-IT trial. JAMA Cardiol. 2017;2:547–55. Important findings regarding the safety of very low LDLc levels. No cause for concern in terms of treatment-emergent side effects was seen on ezetimibe. CrossRefPubMedPubMedCentralGoogle Scholar
- 57.• Giugliano RP, Pedersen TR, Park JG, FOURIER Investigators, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962–71. Important findings regarding the safety of very low LDLc levels. No cause for concern in terms of treatment-emergent side effects was seen on evolocumab. CrossRefPubMedGoogle Scholar
- 58.Kastelein JJ, Hovingh GK, Langslet G, Baccara-Dinet MT, Gipe DA, Chaudhari U, et al. J. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. Clin Lipidol. 2017;11:195–203.CrossRefGoogle Scholar
- 59.Thedrez A, Blom DJ, Ramin-Mangata S, Blanchard V, Croyal M, Chemello K, et al. Homozygous familial hypercholesterolemia patients with identical mutations variably express the LDLR (low-density lipoprotein receptor): implications for the efficacy of evolocumab. Arterioscler Thromb Vasc Biol. 2017; https://doi.org/10.1161/ATVBAHA.117.310217.
- 61.Ridker PM, Mora S, Rose L, on behalf of the JUPITER Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering drugs. Eur Heart J. 2016;37:1373–9.CrossRefPubMedPubMedCentralGoogle Scholar
- 63.Chasman DI, Giulianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statin-induced low-density-lipoprotein cholesterol reduction. The justification for the use of statins in prevention: an intervention trial evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012:257–64.Google Scholar
- 66.Natarajan P, Young R, Stitziel NO, Padmanabhan S, Baber U, Mehran R, et al. Polygenic risk score identifies subgroup with higher burden of atherosclerosis and greater relative benefit from statin therapy in the primary prevention setting. Circulation. 2017;135:2091–101.CrossRefPubMedPubMedCentralGoogle Scholar