Skip to main content
SpringerLink
Log in

Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at “Extreme” ASCVD Risk

  • Macrovascular Complications in Diabetes (VR Aroda and A Getaneh, Section Editors)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

To review randomized interventional clinical and imaging trials that support lower targeted atherogenic lipoprotein cholesterol goals in “extreme” and “very high” atherosclerotic cardiovascular disease (ASCVD) risk settings. Major atherosclerotic cardiovascular event (MACE) prevention among the highest risk patients with ASCVD requires aggressive management of global risks, including lowering of the fundamental atherogenic apolipoprotein B-associated lipoprotein cholesterol particles [i.e., triglyceride-rich lipoprotein remnant cholesterol, low-density lipoprotein cholesterol (LDL-C), and lipoprotein(a)]. LDL-C has been the long-time focus of imaging studies and randomized clinical trials (RCTs). The 2004 adult treatment panel (ATP-III) update recognized that the long-standing targeted LDL-C goal of < 100 mg/dL potentially fostered substantial undertreatment of the very highest coronary heart disease (CHD) risk individuals and was lowered to < 70 mg/dL as an “optional” goal for “very high” 10-year CHD [CHD death + myocardial infarction (MI)] risk exceeding 20%. This evidence-based guideline change was supported by the observed benefits demonstrated in the high-risk primary and secondary prevention populations in the Heart Protection Study (HPS), the acute coronary syndrome (ACS) population in the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 trial (PROVE-IT), and the secondary prevention population in the Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) intravascular ultrasound (IVUS) study. Subsequent national and international guidelines maintained a targeted LDL-C goal < 70 mg/dL, or a threshold for management of > 70 mg/dL for patients with CHD, CHD risk equivalency, or ASCVD.

Recent Findings

Subgroup or meta-analyses of several RCTs, IVUS imaging studies, and the ACS population in IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) supported the evidence-based 2017 American Association Clinical Endocrinologist (AACE) guideline change establishing a targeted LDL-C goal < 55 mg/dL, non-HDL-C < 80 mg/dl, and apolipoprotein B (apo B) < 70 mg/dL for patients at “Extreme” ASCVD risk, i.e., 10-year 3-point-MACE-composite (CV death, non-fatal MI, or ischemic stroke) risk exceeding 30%. Moreover, with no recognized lower-limit-associated intolerance or safety issues, even more intensive lowering of atherogenic cholesterol levels is supported by the following evidence base: (1) analysis of eight high-intensity statin-based prospective secondary prevention IVUS atheroma volume regression trials; (2) a distribution analysis of on-treatment, ezetimibe and background-statin, of the very low LDL-C levels reached and CVD event risk in the IMPROVE-IT ACS population; (3) the secondary prevention Global Assessment of Pl\aque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) on background-statin; and (4) the secondary prevention population of Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER). By example, in FOURIER, the population on background-statin at a baseline median 92 mg/dL achieved median LDL-C level of 30 mg/dL and non-HDL-C to < 65 mg/dl, and apo B to < 50 mg/dL, and subgroup and post hoc analyses all demonstrated additional ASCVD event reduction benefits as LDL-C was further reduced.

Summary

The level of ASCVD risk determines the degree, urgency, and persistence in global risk management, including fundamental atherogenic lipoprotein cholesterol particle lowering. “Extreme” risk patients may require extremely low targeted LDL-C, non-HDL-C and apo B goals; such efforts, implied by more recent interventional trials and analyses, are aimed at maximal atheroma plaque regression, stabilization, and MACE event reduction with the aspiration of improved quality lifespan.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

ACC:

American College of Cardiology

ACS:

Acute coronary syndrome

AHA:

American Heart Association

apo B:

Apolipoprotein B

ARR:

Absolute risk reduction

ASCVD:

Atherosclerotic cardiovascular disease

ATP-III:

Adult treatment panel

CAD:

Coronary artery disease

CHD:

Coronary heart disease

CVD:

Cardiovascular disease

HR:

Hazard ratio

LDL-C:

Low-density lipoprotein cholesterol

MI:

Myocardial infarction

MACE:

Major adverse cardiovascular events

NCEP-ATP:

National Cholesterol Education Program Adult Treatment Panel III

NNT:

Number needed to treat

Non-HDL-C:

Non-high density lipoprotein cholesterol

RRR:

Relative risk reduction

TG:

Triglyceride

FOURIER:

Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk

GLAGOV:

Global Assessment of Plaque Regression with a PCSK9Antibody as Measured by Intravascular Ultrasound

HPS:

Heart Protection Study

IMPROVE-IT:

IMProved Reduction of Outcomes: Vytorin Efficacy International Trial

JUPITER:

Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin

ODYSSEY:

Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab

PROVE-IT:

Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22) Trial

REVERSAL:

REVERSal of atherosclerosis with Aggressive lipid Lowering trial

TNT:

Treating to New Targets

VOYAGER:

An IndiVidual Patient Meta-Analysis Of Statin TherapY in At-Risk Groups: Effects of Rosuvastatin, Atorvastatin and Simvastatin

RCTs:

Randomized Clinical Trials

IVUS:

Coronary Intravascular Ultrasound

LDL-C:

Low Density Lipoprotein Cholesterol

PAV:

Percent Atheroma Volume

References

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

  1. •• Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, 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(32):2459–72. https://doi.org/10.1093/eurheartj/ehx144. This is an exquisitely concise review article of the atherogenic lipoprotein cholesterol principle evidence; it presents the case and satisfied criteria for LDL causality appraising evidence from genetic, epidemiologic, and clinical intervention studies.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Klarin D, Zhu QM, Emdin CA, Chaffin M, Horner S, McMillan BJ, et al. Genetic analysis in UK Biobank links insulin resistance and transendothelial migration pathways to coronary artery disease. Nat Genet. 2017;49(9):1392–7. https://doi.org/10.1038/ng.3914.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Paththinige CS, Sirisena ND, Dissanayake V. Genetic determinants of inherited susceptibility to hypercholesterolemia - a comprehensive literature review. Lipids Health Dis. 2017;16(1):103. https://doi.org/10.1186/s12944-017-0488-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ramasamy I. Update on the molecular biology of dyslipidemias. Clin Chim Acta. 2016;454:143–85. https://doi.org/10.1016/j.cca.2015.10.033.

    Article  CAS  PubMed  Google Scholar 

  5. Khera AV, Emdin CA, Drake I, Natarajan P, Bick AG, Cook NR, et al. Genetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. 2016;375(24):2349–58. https://doi.org/10.1056/NEJMoa1605086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Steinberg D. The cholesterol controversy is over: why did it take so long? Circulation. 1989;80(4):1070–8.

    Article  CAS  PubMed  Google Scholar 

  7. Steinberg D, Witzum JL. Lipoprotein and atherogenesis: current concepts. JAMA. 1990;264:3047–52.

    Article  CAS  PubMed  Google Scholar 

  8. Steinberg D. An interpretive history of the cholesterol controversy: part I. J Lipid Res. 2004;45:1583–93.

    Article  CAS  PubMed  Google Scholar 

  9. Robinson JG, Williams KJ, Gidding S, Borén J, Tabas I, Fisher EA, et al. Eradicating the burden of atherosclerotic cardiovascular disease by lowering apolipoprotein B lipoproteins earlier in life. J Am Heart Assoc. 2018;7(20):e009778. https://doi.org/10.1161/JAHA.118.009778.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Sniderman AD. Applying apoB to the diagnosis and therapy of the atherogenic dyslipoproteinemias: a clinical diagnostic algorithm. Curr Opin Lipidol. 2004;15:433–8. https://doi.org/10.1097/01.mol.0000137220.39031.3b.

    Article  CAS  PubMed  Google Scholar 

  11. Sniderman A, Shapiro S, Marpole D, Skinner B, Teng B, Kwiterovich PO Jr. Association of coronary atherosclerosis with hyperapobetalipoproteinemia [increased protein but normal cholesterol levels in human plasma low density (β) lipoproteins]. Proc Natl Acad Sci. 1980;77(1):604–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hodis HN, Mack WJ. Triglyceride-rich lipoproteins and the progression of coronary artery disease. Curr Opin Lipidol. 1995;6:209–14.

    Article  CAS  PubMed  Google Scholar 

  13. Alaupovic P, Mack WJ, Knight-Gibson C, Hodis HN. The role of triglyceride-rich lipoprotein families in the progression of atherosclerotic lesions as determined by sequential coronary angiography from a controlled clinical trial. Arterioscler Thromb Vasc Biol. 1997;17:715–22.

    Article  CAS  PubMed  Google Scholar 

  14. Grundy SM. Hypertriglyceridemia, atherogenic dyslipidemia, and the metabolic syndrome. Am J Cardiol. 1998;81:18B–25B.

    Article  CAS  PubMed  Google Scholar 

  15. Krauss RM. Atherogenicity of triglyceride-rich lipoproteins. Am J Cardiol. 1998;81:13B–7B.

    Article  CAS  PubMed  Google Scholar 

  16. Assmann G, Schulte H, Funke H, von Eckardstein A. The emergence of triglycerides as a significant independent risk factor in coronary artery disease. Eur Heart J. 1998;19(suppl M):M8–M14.

    PubMed  Google Scholar 

  17. Austin MA, Hokanson JE, Edwards KL. Hypertriglyceridemia as a cardiovascular risk factor. Am J Cardiol. 1998;81:7B–12B.

    Article  CAS  PubMed  Google Scholar 

  18. Sacks FM, Alaupovic P, Moye LA, Cole TG, Sussex B, Stampfer MJ, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 2000;102:1886–92.

    Article  CAS  PubMed  Google Scholar 

  19. Rosenson RS, Davidson MH, Hirsh BJ, Kathiresan S, Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease. J Am Coll Cardiol. 2014;64(23):2525–40. https://doi.org/10.1016/j.jacc.2014.09.042.

    Article  CAS  PubMed  Google Scholar 

  20. National Cholesterol Education Program Expert Panel on Detection E, Treatment of High Blood Cholesterol in A. Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143–421.

    Article  Google Scholar 

  21. Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F, Watts GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31(23):2844–53. https://doi.org/10.1093/eurheartj/ehq386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res. 2016;57(11):1953–75. https://doi.org/10.1194/jlr.R071233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tsimikas S, Brilakis ES, Miller ER, McConnell JP, Lennon RJ, Kornman KS, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med. 2005;353(1):46–57. https://doi.org/10.1056/NEJMoa043175.

    Article  CAS  PubMed  Google Scholar 

  24. Kiechl S, Willeit J, Mayr M, Viehweider B, Oberhollenzer M, Kronenberg F, et al. Oxidized phospholipids, lipoprotein(a), lipoprotein-associated phospholipase A2 activity, and 10-year cardiovascular outcomes: prospective results from the Bruneck study. Arterioscler Thromb Vasc Biol. 2007;27(8):1788–95. https://doi.org/10.1161/ATVBAHA.107.145805.

    Article  CAS  PubMed  Google Scholar 

  25. Tselepis AD. Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role. J Biomed Res. 2016;31. https://doi.org/10.7555/JBR.31.20160009.

  26. Sniderman AD. Differential response of cholesterol and particle measures of atherogenic lipoproteins to LDL lowering therapy: implications for clinical practice. J Clin Lipidol. 2008;2:36–42. https://doi.org/10.1016/j.jacl.2007.12.006.

    Article  PubMed  Google Scholar 

  27. Sniderman AD, Williams K, Contois JH, Monroe HM, McQueen MJ, de Graaf J, et al. A meta-analysis of low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B as markers of cardiovascular risk. Circ Cardiovasc Qual Outcomes. 2011;4:337–45. https://doi.org/10.1161/CIRCOUTCOMES.110.959247.

    Article  PubMed  Google Scholar 

  28. Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–39. https://doi.org/10.1161/01.CIR.0000133317.49796.0E.

    Article  PubMed  Google Scholar 

  29. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495–502. https://doi.org/10.1056/NEJMoa040583.

    Article  CAS  PubMed  Google Scholar 

  30. •• Cannon CP, Blazing MA, Giugliano RP, McCagg A, White JA, Theroux P, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372(25):2387–97. https://doi.org/10.1056/NEJMoa1410489. The ground-breaking landmark IMPROVE-IT trial demonstrated that ezetimibe, a non-statin, against the background of statin therapy, was able to significantly lower atherogenic lipoprotein cholesterol biomarkers, LDL-C, non-HDL-C, and Apo B, to <55 mg/dL, <80 mg/dL and <70 mg/dL, respectively) and significantly reduce clinical ASCVD events, further validating the atherogenic lipoprotein cholesterol principle.

    Article  CAS  PubMed  Google Scholar 

  31. •• Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664. The ground-breaking landmark FOURIER trial demonstrated that a PCSK9 inhibitor, evolocumab, a non-statin, against the background of statin therapy, in otherwise stable patients with established ASCVD, i.e. very high risk and extreme risk was able to significantly lower atherogenic lipoprotein cholesterol biomarkers, LDL-C, non-HDL-C, and Apo B, to very low levels, <30 mg/dL, <65 mg/dL and <50 mg/dL, respectively) and significantly reduce clinical ASCVD events.

    Article  CAS  PubMed  Google Scholar 

  32. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomized placebo-controlled trial. Lancet. 2002;360:7–22. https://doi.org/10.1016/S0140-6736(02)09327-3.

    Article  Google Scholar 

  33. Wiviott SD, Cannon CP, Morrow DA, Ray KK, Pfeffer MA, Braunwald E, et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with intensive statin therapy: a PROVE IT-TIMI 22 substudy. J Am Coll Cardiol. 2005;46:1411–6. https://doi.org/10.1016/j.jacc.2005.04.064.

    Article  CAS  PubMed  Google Scholar 

  34. LaRosa JC, Grundy SM, Kastelein JJ, Kostis JB, Greten H, for the Treating to New Targets (TNT) Steering Committee and Investigators. Safety and efficacy of atorvastatin-induced very low-density lipoprotein cholesterol levels in patients with coronary heart disease (a post hoc analysis of the TNT to new targets [TNT] study). Am J Cardiol. 2007;100:747–52. https://doi.org/10.1016/j.amjcard.2007.03.102.

    Article  CAS  PubMed  Google Scholar 

  35. Leeper NJ, Ardehali R, de Goma EM, Heidenreich PA. Statin use in patients with extremely low low-density lipoprotein levels is associated with improved survival. Circulation. 2007;116:613–8. https://doi.org/10.1161/CIRCULATIONAHA.107.694117.

    Article  CAS  PubMed  Google Scholar 

  36. Hsia J, MacFayden J, Monyak J, Ridker P. Cardiovascular risk reduction and adverse events among subjects attaining LDL-C <50 mg/dL with rosuvastatin: the JUPITER trial. JACC. 2011;57:1666–75. https://doi.org/10.1016/j.jacc.2010.09.082.

    Article  CAS  PubMed  Google Scholar 

  37. Giugliano RP, Wiviott SD, Blazing MA, De Ferrari GM, Park JG, Murphy SA, et al. Long-term safety and efficacy of achieving very low levels of low-density lipoprotein cholesterol: a prespecified analysis of the IMPROVE-IT trial. JAMA Cardiol. 2017;2(5):547–55. https://doi.org/10.1001/jamacardio.2017.0083.

    Article  PubMed  PubMed Central  Google Scholar 

  38. •• Giugliano RP, Pedersen TR, Park JG, De Ferrari GM, Gaciong ZA, Ceska R, 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. https://doi.org/10.1016/S0140-6736(17)32290-0. This prespecified subgroup analysis of FOURIER demonstrated a highly significant monotonic relationship between low LDL-C concentrations and lower risk of the primary and secondary efficacy composite endpoints extending from an LDL-C of 100 mg/dL to 7 mg/Dl, and no safety concerns.

    Article  CAS  Google Scholar 

  39. Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa JC, Nestel PJ, et al. Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis. JAMA. 2012;307:1302–9. https://doi.org/10.1001/jama.2012.366.

    Article  CAS  PubMed  Google Scholar 

  40. Boekholdt SM, Hovingh GK, Mora S, Arsenault BJ, Amarenco P, Pedersen TR, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials. JACC. 2014;64(5):485–94. https://doi.org/10.1016/j.jacc.2014.02.615.

    Article  CAS  PubMed  Google Scholar 

  41. •• Nicholls SJ, Puri R, Anderson TJ, Ballantyne CM, Cho L, Kastelein JJP, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–84. https://doi.org/10.1001/jama.2016.16951. The GLAGOV intravascular ultrasound (IVUS) trial demonstrated that a PCSK9 inhibitor, evolocumab, a non-statin, against the background of statin therapy, was able to significantly lower atherogenic lipoprotein cholesterol biomarkers, LDL-C, non-HDL-C, and Apo B, to <37 mg/dL, <58 mg/dL and <43 mg/dL, respectively, and significantly induce regression reduce plaque volume, a post-hoc LOESS plot (figure 4) that showed a linear relationship between achieved LDL-C level and PAV progression for LDL-C levels ranging from 110 mg/dL to as low as 20mg/dL.

    Article  CAS  PubMed  Google Scholar 

  42. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, et al. Effect of intensive compared with moderate lipid lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071–80. https://doi.org/10.1001/jama.291.9.1071.

    Article  CAS  PubMed  Google Scholar 

  43. Puri R, Nissen SE, Shao M, Uno K, Kataoka Y, Kapadia SR, et al. Impact of baseline lipoprotein and C-reactive protein levels on coronary atheroma regression following high-intensity statin therapy. Am J Cardiol. 2014;114:1465–72. https://doi.org/10.1016/j.amjcard.2014.08.009.

    Article  CAS  PubMed  Google Scholar 

  44. Smith SC Jr, Allen J, Blair SN, Bonow RO, Brass LM, Fonarow GC, et al. AHA/ACC Guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 Update: Endorsed by the National Heart, Lung, and Blood Institute. Circulation. 2006;113:2363–72. https://doi.org/10.1161/CIRCULATIONAHA.106.174516.

    Article  PubMed  Google Scholar 

  45. Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV, Stein JH, et al. Lipoprotein management in patients with cardiometabolic risk: consensus conference report from the American Diabetes Association and the American College of Cardiology Foundation. J Am Coll Cardiol. 2008;51:1513–24. https://doi.org/10.1016/j.jacc.2008.02.034.

    Article  Google Scholar 

  46. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, et al. ESC/EAS Guidelines for the management of dyslipidaemias: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:1769–818. https://doi.org/10.1093/eurheartj/ehr158.

    Article  Google Scholar 

  47. Jellinger PS, Smith DA, Mehta AE, Ganda O, Handelsman Y, Rodbard HW, et al. American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis. Endocr Pract. 2012;18(Suppl 1):1–78.

    Article  PubMed  Google Scholar 

  48. Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GB, McPherson R, et al. 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol. 2013;29:151–67. https://doi.org/10.1016/j.cjca.2012.11.032.

    Article  PubMed  Google Scholar 

  49. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. American Association of Clinical Endocrinologists Comprehensive Diabetes Management Algorithm 2013 consensus statement. Endocr Pract. 2013;19(Suppl 2):1–48.

    Article  Google Scholar 

  50. Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel. An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia, full report. J Clin Lipidol. 2014;8:29–60. https://doi.org/10.1016/j.jacl.2013.12.005.

    Article  Google Scholar 

  51. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1-executive summary. J Clin Lipidol. 2014;8:473–88.

    Article  PubMed  Google Scholar 

  52. Jacobson TA, Ito MK, Maki KC, Orringer CE, Bays HE, Jones PH, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1 – full report. J Clin Lipidol. 2015;9:129–69. https://doi.org/10.1016/j.jacl.2015.02.003.

    Article  PubMed  Google Scholar 

  53. Catapano AL, Graham I, De Backer G, Wiklund O, Chapman MJ, Drexel H, et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Atherosclerosis. 2016;253:281–344. https://doi.org/10.1016/j.atherosclerosis.2016.08.018.

    Article  CAS  PubMed  Google Scholar 

  54. Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, 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. https://doi.org/10.1016/j.jacc.2016.03.519.

    Article  PubMed  Google Scholar 

  55. •• Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, et al. 2017 AACE/ACE Guidelines American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease. Endocr Pract. 2017;23(Supplement 2):1–87. https://doi.org/10.4158/EP171764.APPGL. The 2017 AACE/ACE dyslipidemia guideline introduced the concept of partitioning the very high ASCVD risk category in recognition of the more ominous multi-morbidities described by the ‘extreme’ risk category defined generally in epidemiology and randomized clinical trials 10-year 3-point MACE exceeding 30% and based on the results of the IMPROVE-IT trial, that demonstrated additional benefits beyond guidelines at that time justified lowered targeted atherogenic cholesterol markers, LDL-C, non-HDL-C, and Apo B goals <55 mg/dL, <80 mg/dL and <70 mg/dL, respectively.

    Article  PubMed  Google Scholar 

  56. 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. J Am Coll Cardiol. 2014;63:2889–934. https://doi.org/10.1016/j.jacc.2013.11.002.

    Article  PubMed  Google Scholar 

  57. Karlson BW, Nicholls SJ, Lundman P, Palmer MK, Barter PJ. Achievement of 2011 European low-density lipoprotein cholesterol (LDL-C) goals of either <70 mg/dL or 50 percent reduction in high-risk patients: results from VOYAGER. Atherosclerosis. 2013;228:265–9. https://doi.org/10.1016/j.atherosclerosis.2013.02.027.

    Article  CAS  PubMed  Google Scholar 

  58. Wong ND, Young D, Zhao Y, Nguyen H, Caballes J, Khan I, et al. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011-2012. J Clin Lipidol. 2016;10(5):1109–18. https://doi.org/10.1016/j.jacl.2016.06.011.

    Article  PubMed  Google Scholar 

  59. Cannon CP, Khan I, Klimchak AC, Reynolds MR, Sanchez RJ, Sasiela WJ. Simulation of lipid-lowering therapy intensification in a population with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2(9):959–66. https://doi.org/10.1001/jamacardio.2017.2289.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Kataoka Y, St John J, Wolski K, Uno K, Puri R, Tuzcu EM, et al. Atheroma progression in hyporesponders to statin therapy. Arterioscler Thromb Vasc Biol. 2015;35(4):990–5. https://doi.org/10.1161/ATVBAHA.114.304477.

    Article  CAS  PubMed  Google Scholar 

  61. O’Keefe JH Jr, Cordain L, Harris WH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43:2142–6.

    Article  PubMed  Google Scholar 

  62. Martin SS, Blumenthal RS, Miller M. LDL cholesterol: the lower the better. Med Clin N Am. 2012;96:13–26. https://doi.org/10.1016/j.mcna.2012.01.009.

    Article  CAS  PubMed  Google Scholar 

  63. Giugliano RP, Cannon CP, Blazing MA, Nicolau JC, Corbalán R, Špinar J, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018;137(15):1571–82. https://doi.org/10.1161/CIRCULATIONAHA.117.030950.

    Article  CAS  PubMed  Google Scholar 

  64. Murphy SA, Cannon CP, Blazing MA, Giugliano RP, White JA, Lokhnygina Y, et al. Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: the IMPROVE-IT trial. J Am Coll Cardiol. 2016;67:353–61. https://doi.org/10.1016/j.jacc.2015.10.077.

    Article  CAS  PubMed  Google Scholar 

  65. Eisen A, Cannon CP, Blazing MA, Bohula EA, Park JG, Murphy SA, et al. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur Heart J. 2016;37(48):3576–84. https://doi.org/10.1093/eurheartj/ehw377.

    Article  CAS  PubMed  Google Scholar 

  66. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, et al. Efficacy and safety of evolucumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9. https://doi.org/10.1056/NEJMoa1500858.

    Article  CAS  PubMed  Google Scholar 

  67. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99. https://doi.org/10.1056/NEJMoa1501031.

    Article  CAS  PubMed  Google Scholar 

  68. • Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab to control. Circulation. 2016;134:1931–43. https://doi.org/10.1161/CIRCULATIONAHA.116.024604. Pooled analyses of the PCSK9 mAb, alirocumab, in its ODYSSEY Phase 3 Trials clearly demonstrated the practicability of reducing atherogenic cholesterol markers to very low levels, i.e. LDL-C, 25 mg/dL; ApoB, 40 mg/dL; and non-HDL-C, 50 mg/dL.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. American Diabetes Association. Cardiovascular Disease and Risk Management. Sec. 8. In Standards of Medical Care in Diabetes 2016. Diabetes Care. 2016;39(Suppl. 1):S60–71. https://doi.org/10.2337/dc16-S011.

    Article  Google Scholar 

  70. Garber AJ, Abrahamson MJ, Barzilay JI, Blonde L, Bloomgarden ZT, Bush MA, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2017 executive summary. Endocr Pract. 2017;23(2):207–38. https://doi.org/10.4158/EP161682.CS.

    Article  PubMed  Google Scholar 

  71. D'Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–53. https://doi.org/10.1161/CIRCULATIONAHA.107.699579.

    Article  PubMed  Google Scholar 

  72. Goff DC Jr, Lloyd-Jones DM, Bennett G, Coady S, D’Agostino RB Sr, Gibbons R, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S49–73. https://doi.org/10.1161/01.cir.0000437741.48606.98.

    Article  PubMed  Google Scholar 

  73. Sabatine MS, Leiter LA, Wiviott SD, Giugliano RP, Deedwania P, De Ferrari GM, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017 Dec;5(12):941–50. https://doi.org/10.1016/S2213-8587(17)30313-3.

    Article  CAS  PubMed  Google Scholar 

  74. Sabatine MS, De Ferrari GM, Giugliano RP, Huber K, Lewis BS, Ferreira J, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation. 2018;138(8):756–66. https://doi.org/10.1161/CIRCULATIONAHA.118.034309.

    Article  CAS  PubMed  Google Scholar 

  75. Bonaca MP, Nault P, Giugliano RP, Keech AC, Pineda AL, Kanevsky E, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation. 2018;137(4):338–50. https://doi.org/10.1161/CIRCULATIONAHA.117.032235.

    Article  CAS  PubMed  Google Scholar 

  76. Charytan DM, Sabatine MS, Pedersen TR, Im K, Park JG, Pineda AL, et al. FOURIER steering committee and investigators efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial. J Am Coll Cardiol. 2019;73(23):2961–70. https://doi.org/10.1016/j.jacc.2019.03.513.

    Article  CAS  PubMed  Google Scholar 

  77. Hwang YC, Ahn HY, Lee WJ, Park CY, Park SW. An equation to estimate the concentration of serum apolipoprotein B. PLoS One. 2012;7(12):e51607. https://doi.org/10.1371/journal.pone.0051607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Masana L, Girona J, Ibarretxe D, Rodríguez-Calvo R, Rosales R, Vallvé JC, et al. Clinical and pathophysiological evidence supporting the safety of extremely low LDL levels-The zero-LDL hypothesis. J Clin Lipidol. 2018;12(2):292–299.e3. https://doi.org/10.1016/j.jacl.2017.12.018.

    Article  PubMed  Google Scholar 

  79. Jones PH, Bays HE, Chaudhari U, Pordy R, Lorenzato C, Miller K, et al. Safety of alirocumab (a PCSK9 monoclonal antibody) from 14 randomized trials. Am J Cardiol. 2016;118:1805–11. https://doi.org/10.1016/j.amjcard.2016.08.072.

    Article  CAS  PubMed  Google Scholar 

  80. Ray KK, Ginsberg HN, Davidson MH, Pordy R, Bessac L, Minini P, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab to control. Circulation. 2016;134:1931–43. https://doi.org/10.1161/CIRCULATIONAHA.116.024604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. •• Schwartz GG, Steg PG, Szarek M, Bhatt DL, Bittner VA, Diaz R, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–107. https://doi.org/10.1056/NEJMoa1801174. Landmark clinical trial demonstrating the effect of PCSK9 inhibitor, alirocumab, as add-on to background statin therapy in patient with ACS. After median 2.8 years-follow-up, LDL-C levels were 53.3 mg/dL in the alirocumab group and 101.4 mg/dL in the control-placebo group; an absolute reduction of 54.7%, and there were significant reduction in 5-point MACE by 24%, that translated to an absolute risk reduction (ARR) of 3.4%; CHD death by 28% (ARR 0.9 percent); CV death by 31% (ARR 1.3 percent) and all-cause death by 28% (ARR 1.7 percent). Components of non-fatal MI, fatal & non-fatal stroke, any CVD event, any CHD event, major CHD event, and all-cause death, were significantly reduced by 14%, 27%, 13%, 12%, 12% and 15%, respectively. ODYSSEY Outcomes was not designed or prespecified to evaluate a targeted LDL-C goal at the lowest level, but rather a dose-up and dose-down titration algorithm was utilized to achieve a narrow, limited treat-to-target LDL-C to 25–50 mg/dL goal range, permitting as low as 15 mg/dL, on the lowest alirocumab dose.

    Article  CAS  PubMed  Google Scholar 

  82. Steg PG, Szarek M, Bhatt DL, Bittner VA, Brégeault MF, Dalby AJ, et al. Effect of alirocumab on mortality after acute coronary syndromes. Circulation. 2019;140(2):103–12. https://doi.org/10.1161/CIRCULATIONAHA.118.038840.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ray KK, Colhoun HM, Szarek M, Baccara-Dinet M, Bhatt DL, Bittner VA, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(8):618–28. https://doi.org/10.1016/S2213-8587(19)30158-5.

    Article  CAS  PubMed  Google Scholar 

  84. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018. https://doi.org/10.1016/j.jacc.2018.11.003.

    Article  PubMed  Google Scholar 

  85. Steinberg D. Earlier intervention in the management of hypercholesterolemia: what are we waiting for? J Am Coll Cardiol. 2010;56(8):627–9.

    Article  PubMed  Google Scholar 

  86. Kones R. Primary prevention of coronary heart disease: integration of new data, evolving views, revised goals, and role of rosuvastatin in management. A comprehensive survey. Drug Des Devel Ther. 2011;5:325–80. https://doi.org/10.2147/DDDT.S14934.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Robinson JG. Starting primary prevention earlier with statins. Am J Cardiol. 2014;114(9):1437–42. https://doi.org/10.1016/j.amjcard.2014.07.076.

    Article  PubMed  Google Scholar 

  88. Robinson JG, Gidding SS. Curing atherosclerosis should be the next major cardiovascular prevention goal. J Am Coll Cardiol. 2014;63(25 Pt A):2779–85. https://doi.org/10.1016/j.jacc.2014.04.009.

    Article  PubMed  Google Scholar 

  89. Domanski MJ, Fuster V, Diaz-Mitoma F, Grundy S, Lloyd-Jones D, Mamdani M, et al. Next steps in primary prevention of coronary heart disease: rationale for and design of the ECAD trial. J Am Coll Cardiol. 2015;66(16):1828–36. https://doi.org/10.1016/j.jacc.2015.08.857.

    Article  PubMed  Google Scholar 

  90. Jepsen AM, Langsted A, Varbo A, Bang LE, Kamstrup PR, Nordestgaard BG. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease. Clin Chem. 2016;62(4):593–604. https://doi.org/10.1373/clinchem.2015.253757.

    Article  CAS  PubMed  Google Scholar 

  91. Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis. Atherosclerosis. 2015;242(1):357–66. https://doi.org/10.1016/j.atherosclerosis.2015.07.035.

    Article  CAS  PubMed  Google Scholar 

  92. Bhatt DL, Steg PG, Miller M, Brinton EA, Jacobson TA, Ketchum SB, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22. https://doi.org/10.1056/NEJMoa1812792.

    Article  CAS  PubMed  Google Scholar 

  93. Tsimikas S. Lipoprotein(a): novel target and emergence of novel therapies to lower cardiovascular disease risk. Curr Opin Endocrinol Diabetes Obes. 2016;23(2):157–64. https://doi.org/10.1097/MED.000000000000023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM, Nielsen SF, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3(7):619–27. https://doi.org/10.1001/jamacardio.2018.1470.

    Article  PubMed  PubMed Central  Google Scholar 

  95. Rosenblit PD. Extreme atherosclerotic cardiovascular disease (ASCVD) risk recognition. Curr Diab Rep. 2019;19(8):61. https://doi.org/10.1007/s11892-019-1178-6.

    Article  PubMed  Google Scholar 

  96. Bohula EA, Morrow DA, Pedersen TR, Kanevsky E, Murphy SA, Giugliano RP, Sever PS, Keech AC, Sabatine MS. Atherothrombotic Risk Stratification and Magnitude of Benefit of Evolocumab in FOURIER. Circulation. 2017;136:A20183.

Download references

Acknowledgments

The author would like to thank Dr. Vanita R. Aroda for critical review, feedback, and edits of earlier and current drafts of this review.

Author information

Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes, & Metabolism, University California, Irvine (UCI), School of Medicine, Irvine, CA, 92697, USA

    Paul D. Rosenblit

  2. Diabetes Out-Patient Clinic, UCI Medical Center, Orange, CA, 92868, USA

    Paul D. Rosenblit

  3. Diabetes/Lipid Management & Research Center, 18821 Delaware St., Suite 202, Huntington Beach, CA, 92648, USA

    Paul D. Rosenblit

Authors
  1. Paul D. Rosenblit
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Paul D. Rosenblit.

Ethics declarations

Conflict of Interest

Paul D. Rosenblit received clinical trial research site funding from Amgen, Dexcom, GlaxoSmithKline, Ionis, Lilly, Mylan, and Novo Nordisk; speaker faculty honoraria from Akcea, Amgen, and Merck; and advisory board honoraria from Akcea, Esperion, and Novo Nordisk.

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.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Macrovascular Complications in Diabetes

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rosenblit, P.D. Lowering Targeted Atherogenic Lipoprotein Cholesterol Goals for Patients at “Extreme” ASCVD Risk. Curr Diab Rep 19, 146 (2019). https://doi.org/10.1007/s11892-019-1246-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11892-019-1246-y

Keywords

Search

Navigation