Elevated Lipids Account for the Largest Proportion of the Risk for CV
Events1,2
Cardiovascular disease (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
- 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-C-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-C levels, with the benefit accumulating over
time.11-13 Meta-analyses of statin studies evaluating the effects of lipid-lowering
treatments on CV outcomes demonstrated a 22% reduction in the risk for major CV events per 39 mg/dL
of LDL-C reduction.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
-
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.
-
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.
-
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.
-
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.
-
Hong YM. Atherosclerotic cardiovascular disease beginning in childhood.
Korean Circ J. 2010;40(1):1-9.
doi:10.4070/kcj.2010.40.1.1.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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.
-
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
- 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
- Loss-of-function (LOF) mutations in the LDL receptor (LDLR) gene
- LOF mutations in the apoB gene that reduce the ability of apoB-containing lipoproteins to bind
to the LDLR
- Gain-of-function (GOF) mutations in the PCSK9 gene that result in reduced levels of LDLR in the
liver.
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 pooled cohort equations, 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 ASCVD 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
-
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.
-
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.
-
Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J
Lipid Res. 2008;49(7):1595-1599.
doi:10.1194/jlr.cx00001-jlr200.
-
Bouhairie VE, Goldberg AC. Familial hypercholesterolemia. Cardiol
Clin. 2015;33(2):169-179. doi:10.1016/j.ccl.2015.01.001.
-
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.
-
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.
-
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.