Blood levels of low-density lipoprotein cholesterol (LDL-C), commonly termed the “bad cholesterol” are widely used to assess the risk of future heart disease.
A traditional lipid panel measures total cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C). These numbers are then used to calculate LDL-C which has been found to be strongly correlated with the risk of cardiovascular disease (CVD).
For the past 25 years, LDL-C has been the primary lipid parameter for risk stratification and goal-directed therapy. Lifestyle measures to lower LDL-C are generally recommended, and statins (cholesterol-lowering drugs) are used by millions of healthy people worldwide in order lower LDL-C numbers. Nonetheless, relying on LDL-C may be misleading.
Many individuals with high LDL-C have an excellent prognosis and low risk of CVD, while many with normal or low LDL-C may be at high risk. Furthermore, low levels of total cholesterol and LDL-C are often associated with an increased risk of death. Therefore, it is important to understand the pitfalls of LDL-C measurements in clinical practice. Indeed, scientific evidence suggests that the role of LDL-C as a risk factor may be overestimated.
1. LDL-C Is a Calculated Variable
LDL-C is a measure of the amount of cholesterol carried within low-density lipoprotein particles. However, LDL-C is a calculated number. LDL-C is usually not measured directly in blood. To be able to calculate LDL-C we need to know the total concentration of cholesterol in blood, triglyceride (TG) concentration and HDL-cholesterol (the “good cholesterol”). By using the Friedewald formula we can get an estimate of LDL-C.
Here is how LDL-C is calculated:
If mg/dl is your unit, like in the United States the formula looks like this:
LDL-C = [Total cholesterol] – [HDL-cholesterol] – [TG]/5
If mmol/l is your unit like in Australia, Canada and Europe the formula looks like this:
LDL-C= [Total cholesterol] – [HDL-cholesterol] – [TG]/2.2
The formula relies on the assumption that the ratio of triglyceride to cholesterol is constant, which is not always the case. Therefore, LDL-C calculations may have limitations when blood triglyceride levels are either high or low. For example, the Friedewald equation cannot be used if TG levels are above 400 mg/dL (4.52 mmol/L).
2. The Association Between LDL-C and Mortality is Controversial
The relationship between measurements of total cholesterol and mortality was addressed in the Framingham Study. Under age 50, cholesterol levels were directly related to 30-year overall mortality and mortality from CVD. After age 50 there was no increased overall mortality with either high or low serum cholesterol levels. It was proposed that after age 50 the association of mortality with cholesterol values is confounded by people whose cholesterol levels are falling, perhaps due to diseases predisposing to death.
Serum cholesterol is generally considered a strong predictor of coronary heart disease and all-cause mortality in middle-aged populations. Data from the MRFIT trial showed increased overall mortality among men in the top 10-15% cholesterol levels. Among the other 85 percent, the difference in mortality was very small when those with high and low levels were compared, although mortality seemed to increase in a linear fashion with elevated LDL-C levels.
However, those with the lowest cholesterol levels had an increased mortality. The J-shaped curve is typical when describing the association between cholesterol levels and overall mortality. When it comes to total mortality, some data indicate that optimal levels of serum cholesterol may be between 210 and 230 mg/dl (5.4 and 5.9 mmol/l).
A large Italian study published 2005 showed that the risk of total mortality in women and fatal heart failure in both sexes decreased with higher LDL-C. Nonetheless, higher LDL-C levels were associated with an increased risk of heart attack (myocardial infarction).
The association between blood cholesterol and mortality was also studied among middle-aged and elderly individuals in the Honolulu Heart Program. The study results indicate that lower cholesterol levels are associated with increased mortality.
The authors concluded that their results lent support to previous findings that low serum cholesterol imparts a poor outlook when compared with higher concentrations of cholesterol in elderly people. Their data also suggested that those individuals with a low serum cholesterol maintained over a 20-year period had the worst outlook for all-cause mortality
A Norwegian study found an inverse relationship between cholesterol levels and mortality among women, for whom (according to the authors) moderately elevated cholesterol (by current standards) may prove to be not only harmless but even beneficial.
Thus, although high LDL-C may be associated with increased risk of heart disease, low levels are associated with increased risk of death. Among elderly individuals there appears to be an inverse relationship between cholesterol levels and mortality, indicating that high cholesterol levels are protective or reflect better health. Furthermore, the relationship between cholesterol levels and disease may be different for men and women.
3. Lifestyle Measures that Lower LDL-C Have Not Been Shown to Cut Risk
The largest controlled intervention trial on diet and heart disease to date, the Women’s Health Initiative randomly assigned more than 48 thousand women, 50 – 79 years old, to a low-fat intervention or a comparison group.
Saturated fat intake was lower in the intervention group as was dietary polyunsaturated fat. Dietary carbohydrates were higher in the intervention group.
LDL-C was significantly lowered in the intervention group compared to the comparison group. Nonetheless, after six years of follow-up, there were no differences between the groups in the incidence of coronary heart disease and stroke.
The MRFIT trial evaluated 12,866 high-risk middle-aged men who were randomly assigned either to a special intervention program consisting of stepped-care treatment for high blood pressure, counseling for cigarette smoking, and dietary advice for lowering blood cholesterol levels or to their usual sources of health care in the community. LDL-C was significantly lowered in the special intervention group compared to the “usual care” group. However, during a follow-up of seven years, there was no significant difference in total death rates between the groups and no differences in the number of deaths from heart disease.
The results of these two large trials strongly indicate that lifestyle measures aimed at lowering LDL-C do not improve survival or reduce mortality from CVD. Therefore, one has to wonder why such lifestyle measures are generally recommended by public health authorities.
4. LDL-C Can Underestimate Risk in People With the Metabolic Syndrome
An epidemic of obesity and metabolic syndrome has evolved in many countries over the past few decades, mostly due to changes in diet and lifestyle. Approximately one-third of U.S. adults currently suffer from metabolic syndrome.
Individuals with metabolic syndrome, overweight or obesity often have a lipid profile with elevated triglyceride-rich remnant lipoproteins, characteristic of insulin resistance.
These lipoproteins include very-low-density lipoproteins (VLDL) and their remnants, intermediate-density lipoproteins, and chylomicron remnant particles.
This lipid profile is much better accounted for by measuring non–HDL Cholesterol than LDL-C. Indeed, relying on LDL-C to assess risk in these individuals may be misleading and could underestimate risk. Furthermore, recommendations or treatment aimed at lowering LDL-C may not be the best therapeutic option under these circumstances. Measures aimed at reducing insulin resistance, lowering triglycerides and elevating HDL cholesterol could be more important.
5. LDL-C Does Not Reflect the Concentration of Atherogenic Particles
It is important to emphasize, that it is lipoprotein that interacts with the arterial wall and starts the cascade of events that leads to atherosclerosis. Cholesterol is only one of many components of lipoproteins. Therefore, measurements of total cholesterol are only indirect measurements of the lipoproteins that transport the bulk of cholesterol. Indeed, measurements of the number of LDL-particles (LDL-P) seem more predictive of risk than the measurements of the cholesterol mass within these particles, reflected by LDL-C.
Due to the fact that LDL-C has traditionally been used for so many years to reflect the amount of LDL particles, LDL-C and LDL have become almost synonymous. This is quite misleading because the cholesterol content of LDL particles varies greatly. Thus, LDL-C is a surrogate measure that only provides an estimate of LDL levels. Studies indicate that the risk for atherosclerosis is more related to the number or concentration of LDL-particles than the total amount of cholesterol within these particles.
6. LDL-C Does Not Reflect LDL Particle Size
It has been known for a couple of decades that the size of LDL particles may influence the risk of atherosclerosis. Studies suggest that small, dense LDL doesn’t travel alone, it typically comes along with low HDL-C and high triglycerides. This pattern has been called “lipoprotein pattern B”. Its opposite is “lipoprotein pattern A” where LDL particles are large, HDL-C often high and triglycerides low.
Interestingly, studies have shown that diets rich in saturated fat seem to increase LDL-particle size. Therefore, in theory, such diets could improve the lipid profile of individuals with small, dense LDL particles which is often associated with the metabolic syndrome. However, public health guidelines generally recommend avoidance of saturated fats as the may elevate LDL-C.
7. A Large Proportion of Patients with Coronary Artery Disease Don’t Have Elevated LDL-C
A much cited study published in 2009 reported lipid measurements among 232.000 patients with coronary artery disease admitted to hospitals in the U.S. between 2000 and 2006. Almost half of these individuals had LDL-C levels less than 100 mg/dl (2.6 mmol/l) which is relatively low. However, almost 55 percent of these patients had very low levels of HDL-C (less than 40 mg/dl or 1.0 mmol/l).
The study is a reminder that low LDL-C according to current definitions does not prevent coronary artery disease. Although some scientists claim that further lowering is needed, this has still not been proven.
The current evidence, therefore, indicates that when it comes to lipids and cardiovascular prevention, relying on LDL-C is an oversimplification and will not solve any problems in the long run. Many other factors have to be taken into account. Overemphasizing the role of LDL-C in order to increase the use of statin drugs is misleading and has to stop.
8. Statin Drugs May Work Through Other Mechanisms than Lowering LDL-C
The Jupiter trial suggested that treatment with statins (cholesterol lowering drugs) may have beneficial effects among people with relatively low levels of LDL-C. The individuals who participated in this trial all had elevated levels of hs-CRP which is a marker of inflammation.
The study raises the question whether cholesterol lowering is only a byproduct, and whether the efficacy of statins is mediated through other mechanisms, such as reducing inflammation.
Statins are potent inhibitors of cholesterol biosynthesis. They are effective in secondary prevention of individuals with CVD. However, the overall benefits observed with statins appear to be greater than what might be expected from changes in lipid levels alone, suggesting effects beyond cholesterol lowering.
Indeed, recent studies indicate that some of the cholesterol-independent or “pleiotropic” effects of statins involve improving endothelial function, enhancing the stability of atherosclerotic plaques, decreasing oxidative stress and inflammation, and inhibiting blood clotting mechanisms.
9. Modern Risk Calculators Don’t Rely on LDL-C when Assessing Cardiovascuar Risk
The new cardiovascular risk calculator provided by the American Heart Association (AHA) and The American College of Cardiology (ACC) does not rely on LDL-C when assessing the risk for CVD. The only lipid parameters the calculator uses when assessing risk are total cholesterol and HDL cholesterol.
However, the new AHA and ACC guidelines still believe that LDL-C is an important marker of risk. The guidelines recommend that all individuals with LDL-C above 190 mg/dL (4.9 mmol/L) should receive treatment with statin drugs.
10. It’s Unlikely that LDL-C Is Always Bad and Never Good
Low-density lipoprotein plays an important biologic role. It’s a carrier of different lipid molecules that are essential for many cells and tissues of the body, among these, are cholesterol and triglycerides.
Cholesterol plays an important role for cell membranes and it’s essential for the production of many hormones in our body. However, we don’t have to get cholesterol from the food we eat because the body is able to produce it. Cholesterol is mainly produced by liver cells.
The fact that cholesterol is an important substance for our body does not necessarily imply that it can’t be afflicted with atherosclerosis and heart disease.
In animal models, atherosclerosis does not occur in the absence of greatly elevated blood cholesterol.
Heart attacks have been shown to be uncommon in humans with very low LDL-C due to a sequence variation in the PCSK9 gene.
In cell cultures, according to Nobel prize winners Brown and Goldstein, cellular needs for cholesterol can be met with an LDL-C level of 25 mg/dl (0.65 mmol/L) which is very low.
Human newborns have an LDL-C in the range of 40-50 mg/dl (1.1-1.3 mmol/L). Healthy adult levels are 3-4 times higher.
The normal LDL cholesterol range is 50 to 70 mg/dl (1.3-1.5 mmol/L) for native hunter-gatherers, free-living primates, and other wild mammals, all of whom do not develop atherosclerosis.
Randomized trial data suggest atherosclerosis progression and coronary heart disease events are minimized when LDL-C is lowered to <70 mg/dl (1.8 mmol/L). No major safety concerns have surfaced in studies that lowered LDL-C to the range of 50 to 70 mg/dl.
So, there is a lot of evidence suggesting that lowering LDL-C may be helpful and will not cause harm. However, we can’t ignore the fact the low-density lipoprotein, and the lipid molecules it carries play an important role for bodily function. Therefore, although lowering LDL-C may reduce the risk of heart disease, it may, in theory, have harmful effects, many of which may not yet be fully understood.
We know that statins have side effects, among them are muscle disorders, increased risk of diabetes and negative effects on cognitive function. This is not surprising because these drugs affect a biologic pathway that does play a role for cells and tissues in our body. It would be naive to believe that such mechanisms can be blocked by chemicals without causing any harm.