Optimizing Dyslipidemia Management for the Prevention of Cardiovascular Disease: a Focus on Risk Assessment and Therapeutic Options
Primary prevention of incident atherosclerotic cardiovascular disease (ASCVD) as well as decreasing the risk of future events in those with established atherosclerosis is critical from a public health perspective. Management of dyslipidemias constitutes a key target in decreasing the risk of developing ASCVD events. While there have been great strides in the treatment of dyslipidemia over the last three decades, there are important recent developments and ongoing research that will expand the available therapeutic options and enable further cardiovascular risk reduction.
Purpose of Review
The purpose of this paper is to review new developments relating to the primary prevention and management of ASCVD with a specific focus on optimizing the treatment of dyslipidemias.
In the realm of ASCVD risk prediction, mounting evidence over the last decade has demonstrated that coronary artery calcium testing is superior to any serum biomarker in the prediction of future ASCVD events and in discriminating future cardiovascular risk. As such, it has been incorporated into the most recent ACC/AHA primary prevention guideline to help guide management decisions in select patients. In terms of the management of dyslipidemias, PCSK9 inhibitors lower LDL-C by 50–70% and provide an additional 15% reduction in key cardiovascular events in high-risk patients with known ASCVD, as demonstrated in the ODYSSEY and FOURIER trials. Cholesteryl ester transfer protein (CETP) inhibitors, which significantly increase HDL-C levels, demonstrated mixed results in large clinical trials and have helped reframe HDL-C as a risk marker rather than a modifiable risk factor. In regard to the management of triglycerides, the REDUCE-IT trial demonstrated a nearly 5% absolute reduction in key cardiovascular events with a highly purified fish-oil derivative named icosapent ethyl in high-risk patients already on statin therapy. Finally, in regard to lipoprotein(a)—which is a strong risk factor for ASCVD—there are exciting developments in the therapeutic pipeline which reduce circulating lipoprotein(a) levels by nearly 90%.
The management of dyslipidemias continues to be an exciting field with several ongoing cardiovascular outcomes trials, improvement in risk prediction models, and new therapeutic agents in the pipeline that will further mitigate residual cardiovascular risk in both primary and secondary prevention patients.
KeywordsDyslipidemia ASCVD Cardiovascular disease prevention Emerging therapies Lipoprotein(a) LDL-C Hypertriglyceridemia
Compliance with Ethical Standards
Conflict of Interest
Adam Berman declares that he has no conflict of interest.
Ron Blankstein reports grants from Astellas Inc. and Amgen Inc.
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.GBD 2017 Causes of Death Collaborators. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1736–88.Google Scholar
- 2.Murphy SL, Xu J, Kochanek KD, Arias E. Mortality in the United States, 2017. NCHS Data Brief. 2018(328):1–8.Google Scholar
- 4.Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2018;0(0):CIR0000000000000625.Google Scholar
- 6.Lloyd-Jones DM, Hong Y, Labarthe D, Mozaffarian D, Appel LJ, Van Horn L, et al. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association’s strategic impact goal through 2020 and beyond. Circulation. 2010;121(4):586–613.PubMedGoogle Scholar
- 9.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. J Am Coll Cardiol. 2014;63(25 Pt B):2935–59.PubMedGoogle Scholar
- 10.Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease. Circulation. 2019;0(0):CIR0000000000000678.Google Scholar
- 12.Lloyd-Jones DM, Braun LT, Ndumele CE, Smith SC Jr, Sperling LS, Virani SS, et al. Use of risk assessment tools to guide decision-making in the primary prevention of atherosclerotic cardiovascular disease. Circulation. 2018;0(0):CIR0000000000000638.Google Scholar
- 14.DeFilippis AP, Young R, McEvoy JW, Michos ED, Sandfort V, Kronmal RA, et al. Risk score overestimation: the impact of individual cardiovascular risk factors and preventive therapies on the performance of the American Heart Association-American College of Cardiology-Atherosclerotic Cardiovascular Disease risk score in a modern multi-ethnic cohort. Eur Heart J. 2017;38(8):598–608.PubMedGoogle Scholar
- 16.•• Nasir K, Bittencourt MS, Blaha MJ, Blankstein R, Agatson AS, Rivera JJ, et al. Implications of coronary artery calcium testing among statin candidates according to American College of Cardiology/American Heart Association cholesterol management guidelines: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2015;66(15):1657–68 This important analysis underscores the utility of coronary artery calcium testing in accurately classifying ASCVD risk.PubMedGoogle Scholar
- 17.Hong JC, Blankstein R, Shaw LJ, Padula WV, Arrieta A, Fialkow JA, et al. Implications of coronary artery calcium testing for treatment decisions among statin candidates according to the ACC/AHA cholesterol management guidelines: a cost-effectiveness analysis. JACC Cardiovasc Imaging. 2017;10(8):938–52.PubMedGoogle Scholar
- 19.Roberts ET, Horne A, Martin SS, Blaha MJ, Blankstein R, Budoff MJ, et al. Cost-effectiveness of coronary artery calcium testing for coronary heart and cardiovascular disease risk prediction to guide statin allocation: the Multi-Ethnic Study of Atherosclerosis (MESA). PLoS One. 2015;10(3):e0116377.PubMedPubMedCentralGoogle Scholar
- 25.Emerging Risk Factors C, Di Angelantonio E, Sarwar N, Perry P, Kaptoge S, Ray KK, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302(18):1993–2000.Google Scholar
- 26.• Trialists CT. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81 This large meta-analysis demonstrated the safety and efficacy of further LDL-C lowering, without evidence of a threshold effect. Google Scholar
- 27.Ference BA, Yoo W, Alesh I, Mahajan N, Mirowska KK, Mewada A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. 2012;60(25):2631–9.PubMedGoogle Scholar
- 31.•• 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 This wide-ranging analysis demonstrated the nearly incontrovertible causal relationship between LDL-C and ASCVD. PubMedPubMedCentralGoogle Scholar
- 34.Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279(20):1615–22.PubMedGoogle Scholar
- 36.Scandinavian Simvastatin Survival Study G. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383–9.Google Scholar
- 38.Lloyd-Jones DM, Morris PB, Ballantyne CM, Birtcher KK, Daly DD Jr, DePalma SM, 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.PubMedGoogle Scholar
- 39.Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377(9784):2181–92.PubMedPubMedCentralGoogle Scholar
- 40.• 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 The IMPROVE-IT trial demonstrated the ability of a non-statin agent to both reduce LDL-C and recurrent ASCVD events in secondary prevention. PubMedPubMedCentralGoogle Scholar
- 41.• 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 The FOURIER trial with the PCSK9 inhibitor evolocumab demonstrated the therapeutic role of these agents in secondary prevention. PubMedPubMedCentralGoogle Scholar
- 42.• 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(22):2097–107 The ODYSSEY trial with the PCSK9 inhibitor alirocumab demonstrated the therapeutic role of these agents in secondary prevention. PubMedGoogle Scholar
- 43.• Ray KK, Landmesser U, Leiter LA, Kallend D, Dufour R, Karakas M, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430–40 This large phase II trial of the siRNA molecule inclisiran demonstrated the tolerability and efficacy of this unique molecule in reducing LDL-C via the PCSK9 receptor. PubMedGoogle Scholar
- 51.Group HTC, Landray MJ, Haynes R, Hopewell JC, Parish S, Aung T, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371(3):203–12.Google Scholar
- 52.Investigators A-H, Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes-Nickens P, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365(24):2255–67.Google Scholar
- 56.Group HTRC, Bowman L, Hopewell JC, Chen F, Wallendszus K, Stevens W, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377(13):1217–27.Google Scholar
- 62.Madsen CM, Varbo A, Nordestgaard BG. Unmet need for primary prevention in individuals with hypertriglyceridaemia not eligible for statin therapy according to European Society of Cardiology/European Atherosclerosis Society guidelines: a contemporary population-based study. Eur Heart J. 2018;39(7):610–9.PubMedGoogle Scholar
- 68.Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J. 2011;32(11):1345–61.PubMedPubMedCentralGoogle Scholar
- 73.• 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(1):11–22 The REDUCE-IT trial demonstrated the added cardiovascular benefit of targeted triglyceride lowering with a highly purified fish-oil derivative named icosapent ethyl. PubMedGoogle Scholar
- 77.Emerging Risk Factors C, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302(4):412–23.Google Scholar
- 84.Berg K. A new serum type system in man—the Lp system. 1963;59(3):369–82.Google Scholar
- 85.Ballantyne CM. Clinical lipidology: a companion to Braunwald’s heart disease. Philadelphia: 2nd edition; 2015.Google Scholar
- 87.Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, et al. The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest. 1994;93(6):2758–63.PubMedPubMedCentralGoogle Scholar
- 92.Cao J, Steffen BT, Budoff M, Post WS, Thanassoulis G, Kestenbaum B, et al. Lipoprotein(a) levels are associated with subclinical calcific aortic valve disease in White and Black individuals: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2016;36(5):1003–9.PubMedPubMedCentralGoogle Scholar
- 94.Guan W, Cao J, Steffen BT, Post WS, Stein JH, Tattersall MC, et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the Multi-Ethnic Study of Atherosclerosis. Arterioscler Thromb Vasc Biol. 2015;35(4):996–1001.PubMedPubMedCentralGoogle Scholar
- 98.•• Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69(6):692–711 This comprehensive review of lipoprotein(a) and cardiovascular disease synthesizes important insights into the lipoprotein(a) and its future as a therapeutic target. PubMedGoogle Scholar
- 99.• O’Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E, Gouni-Berthold I, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019;139(12):1483–92 This analysis of the FOURIER trial demonstrated that the PCSK9 inhibitor evolocumab reduced the risk of major cardiovascular events by a greater degree in patients with an elevated Lp(a) as compared with those with Lp(a) levels below the median. This analysis supported Lp(a) as a modifiable risk factor and provides insight into which patients may benefit the most from PCSK9 inhibition. PubMedGoogle Scholar