The major cholesterol-carrying lipoprotein in plasma and is the causal agent for many forms of coronary artery disease.
The main predisposing factor of the atherosclerotic process in the arterial wall.
Low density lipoproteins increase progressively from infancy, where they are less than 40 mg/dL at birth.
In the US approximately 7% of adults have severe hypercholesterolemia, defined as having untreated LDL cholesterol levels of 190 mg/dL or higher.
Familiar hypercholesterolemia mutation is present in about 1.7% patients with severe hypercholesterolemia.
Estimated by the Friedewald equation rather than by ultracentrifuge: estimates LDL-C as (total cholesterol)-HDL-C (high-density lipoprotein cholesterol -(triglycerides/5) in mg/dL.
Reduction of low-density lipoprotein cholesterol is the cornerstone of cardiovascular risk reduction.
Progressive increases in LDL cholesterol during adolescence and early childhood contribute to early lesion formation.
Epidemiological studies indicate the number of years of exposure to elevated serum LDL-C levels is predictive of cardiovascular disease risk.
Approximately 40% of people with coronary heart disease have total cholesterol level of less than 200 mg/dL and conversely, many people with a moderate elevation is LDL cholesterol level never have a clinical cardiovascular event.
Epidemiological studies reveal a dose dependent association between low density lipoprotein cholesterol and cardiovascular risk.
The magnitude of the cardiovascular event reduction is proportional to the degree to which LDL cholesterol is lower.
Genetic polymorphisms resulting in lifelong exposure to low LDL-C levels are associated with a reduction in coronary heart disease risk it is proportional to the magnitude of the LDL-C lowering.
Endothelial dysfunction leads to lipid accumulation, followed by low-grade inflammation and progressive lesion formation.
The atherosclerotic risk conferred by a large number of small LDL particles is much higher than the risk conferred by a smaller number of large, cholesterol-enriched particles.
Lipoprotein lipase is a critical enzyme in TG metabolism and a target for TG lowering therapies such as fibrates.
Genetic mutations that decrease lipoprotein lipase activity and increase TG levels are associated with increased coronary heart disease risk.
In a study of 200,000 peoples lipid profiles studying how the time since last meal affected levels found: HDL and total cholesterol values varied less than 2% with different durations of fasting, triglycerides values varied by 20%, and LDL, had a variation of about 10% (Sidhu D, Naugler C).
Approximately 20% of men and 18% of women in the U.S. have an LDL above 160 mg/dL and age adjusted prevalence of LDL cholesterol above 130 mg/dL estimated to be 46% with higher prevalence among men.
The absolute risk reduction or net benefit achieved by an individual patient with lipid lowering therapies is dependent on baseline cardiovascular risk.
Family and twin studies suggest that 40-80% of the population variation in levels are attributable to genetic factors.
One third of adults have elevated LDL levels.
The use of both statin and non-syatin drugs such as ezetimibe, bile acid sequestrants and PCSK-9 inhibitors act by up regulating the LDL-C receptors and are associated with decreased rates of major coronary events.
Bile acid sequestrants offer a viable alternative with additional LDL-C lowering in patients on statins, particularly with a metabolic syndrome.
LDL-C variability in the general population is likely to be polygenic and also affected by environmental factors.
LDL-C levels should be used as the primary target to initiate and titrate lipid lowering therapy.
Causes endothelial cell injury predisposing the artery wall to inflammation that promotes the development of atherosclerotic plaque.
It is suggested that every 10% increase in the prevalence of treatment among adults with high LDL-C could prevent approximately 8000 deaths per year in those below the age of 80 years (Farley TA et al).
All five single gene disorders that cause elevated LDL levels associated with premature coronary atherosclerosis.
Low levels increase the risk of lower respiratory tract infection.
Rare forms of hypercholesterolemia, including familial hypercholesterolemia due to mutations in the LDL receptor gene and familial defective apoliprotein B-100 due to mutations in the apolipoprotein B.
Statins of the most effective agents for reducing LDL-C levels.
High intensity statins such as atorvastatin 80mg and rosuvastatin 40 mg are expected to reduce LDL-C cholesterol by approximately 50% regardless of baseline levels.
Ezetimibe when added to statins typically reduces LDL-C level by an additional 20-25%.
Statins inhibited LDL cholesterol biosynthesis to a greater extent than they lower apolipoprotein B levels.
Statins induce atherosclerotic plaque regression when LDL-C levels are lowered to less than one hundred milligrams per deciliter.
The magnitude of the long-term clinical benefit and risk reduction with statin therapy is directly proportional to the absolute reductions in LDL-C levels.
Guidelines It is recommend lowering LDL-cholesterol to less than 100 mg/dL in persons with established cardiovascular disease and to less than 70 mg per dL, or by more than 50% or more, in those at highest risk.
It is recommended to start statin therapy on individuals age 20-40 years with LDL-C greater than 160 mg/dL, or a family history of premature atherosclerosis or who have a high lifetime estimated cardiovascular disease risk.
Goal in primary prevention is a LDL-C target level of <70 mg/dl.
Modest lifelong reductions in LDL-C confer reductions in cardiovascular risk even the presence of other risk factors, such as diabetes and hypertension.
Among individuals 20-40 years it I’starting therapy in those with LDL-C greater than 160 mg a deciliter and a family history of premature atherosclerosis will have a high lifetime estimated cardiovascular disease risk.
It is believed prolonged exposure to lower LDL-C beginning early in life is associated with a greater reduction in the risk of cardiovascular disease then lowering LDL-C beginning later in life.
The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) primary prevention guidelines among adults aged 35-85 years could prevent 20,000 myocardial infarctions and 10,000 deaths from coronary artery disease per year (Pletcher MJ et al).
Small dense LDL with increased levels of Apo B are more atherogenic than larger more buoyant LDL even if the LS+DL-C levels is in the normal range.
Small dense LDL with increased levels of Apo B is associated with insulin resistance and increase glucose levels.
Aggressive treatment to lower levels associated with reduction in rates of cardiovascular events.
Low density lipoprotein cholesterol levels may not adequately evaluate cardiovascular risk when other apolipoprotein B containing atherogenic particles predominate-in cases such as diabetes, metabolic syndrome, or coronary heart disease.
Each low density lipoprotein, intermediate density lipoprotein, or very low density lipoprotein particle has a single Apo B molecule.
Proprotein convertase subtitllisin/kexin type 9 (PCSK9) has an important role mediating and binding of LDL trafficking of LDL receptors.
Proprotein convertase subtitllisin/kexin type 9 (PCSK9) Is a serine protease and is produced predominately in the liver, and is secreted into the plasma and plays a major role in regulating levels of LDL cholesterol by binding to hepatic LDL receptors and promoting their degradation.
PCSK9 inhibitors significantly reduce LDL-cholesterol levels.
The proprotein convertase subtilisin/kexin type 9 map reduce LDL-C levels by approximately 60%.
Proprotein convertase subtilisin-Kexin type 9 inhibitors evolocumab and alirocumab reduces low density lipoprotein cholesterol levels by approximately 60%.
Evolocumab plus standard therapy reduced the LDL cholesterol levels by 61% from the median of 120 mg/dL to 48 mg/L compared with standard therapy during approximately one year of therapy(Sabatine MS et al).
In the above study Evolocumab reduced cardiovascular events after one year of therapy.
The amount of cholesterol in each LDL particle is heterogeneous and can vary in individuals.
The National Health and Nutrition Examination Survey (NHANES) data 2005 through 2008 demonstrated: the prevalence of high LDL-C increases with age 11.4%, 41.2% and 58.2% for age groups 20-39, 40-64 and 65 years or greater, respectively(MMWR).
In the above study the prevalence of high LDL-C did not change significantly from 1999-2002( 34,5%) to 2005-2008(33.3%).
Highest doses of statins offers limited additional lowering of LDL cholesterol at the expense of increased side effects.
The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends lowering of the LDL-C to 100 mg/deciliter for individuals at moderately high risk of coronary artery disease with two or more major coronary artery disease risk factors and a 10-20% 10 year coronary artery disease risk.
Up to 40% of individuals who develop coronary artery disease have LDL-C levels that are lower than the previous goal of less than 130 mg/dL.
Thyroid hormone lowers the level of serum LDL cholesterol.
Thyroid hormone analogue eprotirone utilized in a randomized, placebo controlled, double blind trial in patients with hypercholesterolemia on statins was associated with decreases in serum LDL levels and similar reductions in serm apoliprotein B, triglycerides and Lp(a) lipoprotein (Ladenson PW).
The National Health and Nutrition Examination Survey (NHANES) data 2005 through 2008 demonstrated: high LDL-C can be managed successfully wave lifestyle changes, medications or combination of these efforts.
The National Health and Nutrition Examination Survey (NHANES) data 2005 through 2008 demonstrated: Lifestyle modifications with low-fat and high fiber diets and increase physical activity and weight control can decrease LDL-C levels by up to 20 to 30%.
Meta-analysis of 14 clinical trials with statins indicated that such drugs can reduce the five-year incidence of major coronary events, coronary revascularization and stroke by each 20% for each millimole per liter (about 39 mg per deciliter) reduction in LDL-C (Baigent C et al).
After an ischemic stroke with evidence of atherosclerosis, patient to head to target LDL cholesterol level of less than 70 mg/dL had a lower risk of subsequent cardiovascular events in those who had a target range of 90 mg-110 milligrams per deciliter.
A phase 2 study in statin intolerant patients subcutaneous monoclonal antibody to PCSK9 significantly reduced LDL cholesterol levels (GAUSS Randomized trial).
Among patients with primary hypercholesterolemia and mixed dyslipidemia, evolocumab, a fully human monoclonal antibody to PCSK9 added to high intensity statin therapy results in additional LDL-C lowering (LAPLACE-2 Randomized Trial).
The addition of bile acid sequestrants, niacin, or ezetimibe to statins adds an additional 10-20% reduction in LDL cholesterol.
Of 29 randomly controlled studies of cholesterol reduction reported: only two of 29 studies reported a mortality benefit, while nearly 2/3 reported no cardiovascular benefit at all.(DuBroff R).
In a Cochrane meta-analysis of 18 randomized controlled studies of statins for acute coronary syndrome there was no benefit reported in 14,303 patients (Vale N).
For patients 75 years of age or older randomized controlled studies for statin therapy is not strong.
There is limited evidence supporting primary prevention in adults older than 75 years, and no evidence supporting a low density lipoprotein cholesterol cut off greater than 70 mg/dL as a treatment threshold in this group.
The supplements fish oil, garlic, cinnamon, turmeric, plant sterols and red yeast rice do not improve LDL cholesterol levels,