LOW-DENSITY LIPOPROTEIN CHOLESTEROL (LDL-C) & CARDIOVASCULAR DISEASE (CVD)

LDL-C: A critical connection to CVD

Each year 580,000 people in the US experience an MI and 210,000 experience a recurrent attack.1 On average an American has an MI every 40 seconds.1

The estimated annual incidence of stroke in the US is 795,000 with 185,000 of these being recurrent attacks.1 On average someone in the U.S. has a stroke every 40 seconds.1

While CV events often seem to arise spontaneously, they are the result of a complex process that occurs over an extended period of time. Atherosclerosis is a multidimensional process caused by the cumulation of cholesterol-rich lipoproteins in atherosclerotic plaques that occlude blood flow thereby increasing the risk for CV events.11,12

LDL-C accumulation causes atherosclerosis and is a key modifiable factor for the development of CVD3,4

The pathophysiology of atherosclerosis is characterized by the accumulation and retention of cholesterol-rich lipoproteins in the arterial wall, endothelial dysfunction and a subsequent inflammatory response that results in the formation of atherosclerotic plaques.11,12 The subendothelial retention of cholesterol-rich low-density lipoproteins (LDLs) and other apolipoprotein B-containing lipoproteins, particularly at sites of disturbed blood flow such as branch points, represents the key initiating step in the atherosclerotic process (Figure 1).3, 11, 12, 13, 14

Cholesterol-rich LDLs can normally diffuse through the arterial intima.3 At low LDL-C concentrations, typical of newborns (LDL-C ~20–40 mg/dL), the probability of LDL-C particle retention in the arterial wall is low.3 However, as the concentration of LDL-C rises, the probability of retention and the risk for the development of atherosclerosis increases in a dose-dependent manner.3

The accumulation and subsequent oxidation of LDLs trigger a chronic maladaptive inflammatory response by activated endothelial cells, smooth muscle cells and infiltrating macrophages ultimately leading to the development of atherosclerotic plaques (Figure 1).11, 13, 15

While the clinical manifestations of atherosclerosis such as MI and stroke occurs suddenly, the underlying lesions that lead to CV events develop over decades.13,16 Epidemiological studies have shown that prolonged hyperlipidemia increases the risk for CV events.17

Figure 1: Atherosclerosis begins early in life and develops over decades12, 13, 16, 18

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Elevated lipids account for the largest proportion of the risk for CV events3,4

CVD is a chronic, progressive disorder attributed to the complex interplay of many genetic and environmental factors including hyperlipidemia, diabetes, smoking and hypertension.19 Nine modifiable risk factors account for 90% and 94% of the population attributable risk for MI in men and women respectively (Figure 2).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.3,4,20

Figure 2: Lipids are one of the most critical modifiable CV risk factors4

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The risk for CV events is related to cumulative exposure and magnitude of LDL-C levels17,21,22

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.23

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.3,17,21

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 (Figure 3).24,25,26 Meta-analyses of 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 .6 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.6,24 The effect of reductions in CV risk is independent of baseline LDL-C levels and of the mechanism by which LDL-C is lowered.24,25,26,27

Data from 170,000 participants in major lipid-lowering secondary prevention 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.3,24

Figure 3: Meta-analysis of major lipid secondary prevention trials demonstrates linear correlation between LDL-C lowering and risk of CV events24,28

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