Elevated Lipids Account for the Largest Proportion of the Risk for CV Events1,2

CVD is a chronic, progressive disorder attributed to the complex interplay of many genetic and environmental factors including hyperlipidemia, diabetes, smoking, and hypertension.3 Nine modifiable risk factors account for 90% and 94% of the population-attributable risk for MI in men and women, respectively.2,4

Elevated lipids are an independent risk factor for the development of CVD and one of the most critical modifiable CV risk factors accounting for the largest proportion of the risk, independent of gender, ethnic group, and geographic region.1,2,6

Lipids Are One of the Most Critical Modifiable CV Risk Factors2


INTERHEART: nine modifiable factors account for 90% of first-MI risk worldwide; n = 15,152 patients and 14,820 controls in 52 countries.

*Proportional increase in population disease that would occur if exposure to a risk factor was reduced to an alternative ideal exposure scenario (eg, no tobacco use). Adjusted for all risk factors.

CV, cardiovascular; MI, myocardial infarction.

  • LDL-C levels are one of the strongest modifiable risk factors independently associated with the development of CVD. CVD risk increases with rising number of risk factors and advancing age.5-7

The Risk for CV Events Is Related to Cumulative Exposure and Magnitude of LDL-C Levels8-10

The linear relationship between LDL-C levels and the prevalence and extent of atherosclerosis in the absence of other risk factors highlights the pivotal role of LDL-C in the early development and progression of CVD.7

Randomized clinical trials of different LDL-lowering agents have consistently demonstrated a causal relationship between the absolute magnitude and duration of exposure to LDL-C levels and the risk of incident atherosclerotic CVD events.1,8,9

Many years of studies with LDL-C-lowering therapies have demonstrated reductions in CV risk are proportional to absolute reductions in LDL levels, with the benefit accumulating over time.11-13 Meta-analyses of statin studies evaluating the effects of lipid-lowering treatments on CV outcome demonstrated a 22% reduction in the risk for major CV events per 39 mg/dL.14 In addition, the Cholesterol Treatment Trialists' Collaboration (CTTC) meta-analyses showed a significant 12% reduction in the incidence of major vascular events during the first year after lipid-lowering treatment initiation and reductions of about a quarter during each subsequent year.11,14 The effect of reductions in CV risk is independent of baseline LDL-C levels and of the mechanism by which LDL-C is lowered.11-13,15

  • Data from 170,000 participants in major lipid-lowering secondary prevention statin trials with a median follow-up of 5 years have consistently demonstrated a dose-dependent, log-linear association between the absolute magnitude of exposure to LDL-C and risk of CVD.1,11

Meta-analysis of Major Lipid Secondary Prevention Statin Trials Demonstrates Linear Correlation Between LDL-C Lowering and Risk of CV Events11,16


CTTC meta-analysis of major lipid secondary prevention statin trials conducted in 2010: median follow-up ~ 5 years, N = 169,138.

CTTC, Cholesterol Treatment Trialists’ Collaboration; CV, cardiovascular; LDL-C, low-density lipoprotein cholesterol.

  1. 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(32):2459-2472. doi:10.1093/eurheartj/ehx144.
  2. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364(9438):937-952. doi:10.1016/S0140-6736(04)17018-9.
  3. Jellinger PS, Handelsman Y, Rosenblit PD, 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. doi:10.4158/ EP171764.APPGL.
  4. Bhatt DL, Eagle KA, Ohman EM, et al. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA. 2010;304(12):1350-1357. doi:10.1001/jama.2010.1322.
  5. Hong YM. Atherosclerotic cardiovascular disease beginning in childhood. Korean Circ J. 2010;40(1):1-9. doi:10.4070/kcj.2010.40.1.1.
  6. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. Circulation. 2019;139(25):e1046-e1081. doi:10.1161/CIR.0000000000000624.
  7. Fernández-Friera L, Fuster V, López-Melgar B, et al. Normal LDL-cholesterol levels are associated with subclinical atherosclerosis in the absence of risk factors. J Am Coll Cardiol. 2017;70(24):2979-2991. doi:10.1016/j.jacc.2017.10.024.
  8. Navar-Boggan AM, Peterson ED, D’Agostino RB, Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease. Circulation. 2015;131(5):451-458. doi:10.1161/CIRCULATIONAHA.114.012477.
  9. Ference BA, Yoo W, Alesh I, 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):2631-2639. doi:10.1016/j.jacc.2012.09.017.
  10. Rocha VZ and Santos RD. Cholesterol and inflammation: the lesser the better in atherothrombosis. Eur J Prev Cardiol. 2018;25(9):944-947. doi:10.1177/2047487318772936.
  11. Cholesterol Treatment Trialists’ (CTT) Collaboration, Baigent C, Blackwell L, et al. 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):1670-1681. doi:10.1016/ S0140-6736(10)61350-5.
  12. Soran H, Dent R, Durrington P. Evidence-based goals in LDL-C reduction. Clin Res Cardiol. 2017;106(4):237-248. doi:10.1007/ s00392-016-1069-7.
  13. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267-1278. doi:10.1016/S0140-6736(05)67394-1.
  14. Sampson UK, Fazio S, Linton MF. Residual cardiovascular risk despite optimal LDL cholesterol reduction with statins: the evidence, etiology, and therapeutic challenges. Curr Atheroscler Rep. 2012;14(1):1-10. doi:10.1007/s11883-011-0219-7.
  15. Sabatine MS, Wiviott SD, Im KA, Murphy SA, Giugliano RP. Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels: a meta-analysis. JAMA Cardiol. 2018;3(9):823-828. doi:10.1001/jamacardio.2018.2258.
  16. Raymond C, Cho L, Rocco M, Hazen SL. New guidelines for reduction of blood cholesterol: was it worth the wait? Cleve Clin J Med. 2014;81(1):11-19. doi:10.3949/ccjm.81a.13161.

Genetically Induced Low LDL-C Levels and Implications for Cardiovascular Risk

Consistent with data from clinical trials, Mendelian randomization studies have demonstrated that variants in over 50 genes associated with lower LDL-C levels, including variants in HMG-CoA reductase, NPC1L1, and the LDLR, confer a lower risk for coronary heart disease (CHD).1 The effect of each variant on the risk for CHD is proportional to the magnitude of absolute change in LDL-C and all variants have the same effect on CHD risk per unit reduction in LDL-C levels, again indicating that the reduction in the risk for CHD is independent of the mechanism by which LDL-C is lowered.1

Genetic Studies and Pharmacologically Lowered LDL-C Show Causality With Reduced Risk for CHD1


CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol.

  • Reducing plasma LDL-C levels with a statin leads to dose-dependent reduction in the risk of major ASCVD events that is proportional to the absolute magnitude of the reduction in achieved LDL-C.1

Familial Hypercholesterolemia

Studies in patients with inherited disorders of lipid metabolism provided the first evidence of a causal relationship between cholesterol and coronary heart disease.2 Familial hypercholesterolemia (FH) is an autosomal co-dominant disorder caused by mutations that affect LDL-C clearance.

FH is most often caused by:1,3

Heterozygous FH affects between 1 in 200 and 250 patients and is characterized by marked hyperlipidemia (LDL-C levels typically > 190 mg/dL ) and premature development of atherosclerosis and coronary artery disease.4,5



  • In patients with FH, the risk of CV events and the extent of underlying atherosclerosis is proportional to the absolute magnitude and duration of exposure to elevated LDL-C levels.1

Commonly used assessment tools, such as the US Framingham Risk Score, are therefore not appropriate in these patients as they do not account for lifelong exposure to hyperlipidemia.1 FH is often not diagnosed until after the occurrence of a major coronary event and is undertreated, with fewer than 1 in 20 (ie, only 5%) patients achieving the recommended LDL-C levels.4,5 Patients with homozygous FH (HoFH), present with a much more severe phenotype compared to patients with heterozygous FH (HeFH), with untreated LDL-C levels that can exceed 500 mg/dL at birth and almost universal development of advanced CVD before the age of 10 years old.1,7 Genetic and biochemical studies in patients with FH led to several landmark discoveries in the field, including the role of the LDLR in LDL-C clearance, the discovery of LDLR endocytosis and recycling, and the description of feedback loops regulating cholesterol biosynthesis and LDLR number.7

  1. 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(32):2459-2472. doi:10.1093/eurheartj/ehx144.
  2. Goldstein JL, Brown MS. A century of cholesterol and coronaries: from plaques to genes to statins. Cell. 2015;161(1):161-172. doi:10.1016/ j.cell.2015.01.036.
  3. Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res. 2008;49(7):1595-1599. doi:10.1194/jlr.cx00001-jlr200.
  4. Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol Clin. 2015;33(2):169-179. doi:10.1016/j.ccl.2015.01.001.
  5. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34(45):3478-3490a. doi:10.1093/eurheartj/eht273.
  6. Sharifi M, Rakhit RD, Humphries SE, Nair D. Cardiovascular risk stratification in familial hypercholesterolaemia. Heart. 2016;102(13):1003-1008. doi:10.1136/heartjnl-2015-308845.
  7. Goldstein JL, Brown MS. History of discovery: the LDL receptor. Arterioscler Thromb Vasc Biol. 2009;29(4):431-438. doi:10.1161/ ATVBAHA.108.179564.