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 number 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
An often 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 Cardiovascular 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 of 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 in 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 in 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 important 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.
52 thoughts on “10 Pitfalls of Using LDL Cholesterol to Assess Risk”
Hi Doc! Thanks for this interesting post. So it seems that a lowered LDL-P is a good thing, along side a higher HDL, lower triglycerides, and low dense LDL. Can you possibly advise us of your thoughts regarding the best diet and health-generating lifestyle strategies for us to focus on to achieve this without taking statins or other drugs (assuming no prior history of CVD or atherosclerosis)?
Hilary. This is not an easy task. It may depend on the individual. If you are dealing with obesity or the metabolic syndrome I’m generally in favor of carbohydrate restriction.
Here are some general tips:
Avoid refined and added sugars
Avoid sweets and sugared beverages
Eat vegetables every day, preferably few times a day
Eat fruit (in moderation though if you’re trying to restrict carbs)
Avoid refined foods in general
Cook your own food and choose your ingredients wisely
Avoid trans fats
Eat red meat, animal and dairy fats in moderation (unless you´re restricting carbs)
Eat fish at least a couple of times a week, preferably fat fish rich in omega-3
Choose whole grains instead of refined grains (you will want to restrict grains though if you’re avoiding carbs)
I’m in favor of a Mediterranean style diet when it comes to preventing cardiovascular disease
Regular exercise is top of my list 🙂
I suggest you add “Avoid omega-6 vegetable oils” to your tips list. Quote from page 191 of “The Modern Nutritional Diseases: and How to Prevent Them” by Fred and Alice Ottoboni.
“BIOCHEMICAL LESSON: The significant point is that good health depends on regulating the D5D enzyme. High insulin levels due to dietary sugar and starch and high dietary omega-6 to omega-3 ratios, stimulate the D5D enzyme, and move the biochemical set point from normal toward inflammation. On the other hand, control of dietary sugar and starch, reduction of LA in the diet, and a daily supplement of fish oil to provide EPA will inhibit the D5D enzyme so that the appropriate amounts of both proinflammatory and anti-inflammatory eicosanoids are produced. Keep in mind that all of the eicosanoids, both the so-called good and bad, are important. The body is designed to use eicosanoids with opposing effects to control vital functions. In a state of optimum health, the good and the bad eicosanoids balance one another.”
As noted in the above excerpt, it is important to balance the omega-3/6 ratio. However, trying to achieve balance by boosting omega-3 intake alone, as most experts recommend, is problematic due to oxidative stress. The body has only limited capacity to control the action of omega-3s and 6s so it makes sense to optimize consumption of both. This means that combined omega-3/6 intake should be limited to no more than one to two percent of total calories. Prior to the industrial revolution, when heart disease was almost non-existent, intake of omega-6 was low. Excerpt from “Dietary fat quality and coronary heart disease prevention: a unified theory based on evolutionary, historical, global, and modern perspectives”:
“Traditional Mediterranean, rural Japanese, and other populations with very low CHD risk have uniformly low LA (lenoleic acid – the major omega-6 fatty acid in vegetable oils) intakes. Two US prospective cohort studies have reported inverse associations between LA intake and CHD risk. However, because LA intake was uniformly high, severalfold higher than evolutionary intakes and those of modern groups with very low CHD rates, these studies provide little insight into optimal LA intakes. Moreover, both studies relied on food frequency questionnaires, which have well-known limitations and may not be able to disentangle the effects of LA and n-3 ALA. Controlled trials in which high-LA oils replaced TFA- and SFA-rich fats have shown conflicting results, despite the fact that LA was accompanied by large amounts of medium- and long-chain n-3 PUFAs. A single small trial testing the specific effects of LA without n-3 PUFAs found increased CHD risk. The only long-term trial that reduced n-6 LA intake to resemble a traditional Mediterranean diet (but still higher than preindustrial LA intake) reduced CHD events and mortality by 70%. Although this does not prove that LA intake has adverse consequences, it clearly indicates that high LA intake is not necessary for profound CHD risk reduction.” https://www.ncbi.nlm.nih.gov/pubmed/19627662
Due to the confusion about which fats do what in the body, it has taken many decades to sort things out. Fortunately, now that scientists have the tools that enable them to chart biochemical reactions with considerable precision, we now know, biochemically speaking, what causes chronic inflammation. Sadly, the anti-saturated fat crowd continues to ignore the scientific evidence from biochemical research on inflammatory pathways. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3027152/ Consequently, this sort of dietary advice is common:
“Limit your intake of saturated fats by cutting back on red meat and full-fat dairy foods. Try replacing red meat with beans, nuts, poultry, and fish whenever possible, and switching from whole milk and other full-fat dairy foods to lower fat versions, or just eating smaller amounts of full-fat dairy products, such as cheese. Don’t replace red meat with refined carbohydrates (white bread, white rice, potatoes, and the like).
In place of butter, use liquid vegetable oils rich in polyunsaturated and monounsaturated fats, in cooking and at the table. Olive oil, canola oil, sunflower oil, safflower oil, corn oil, peanut oil, and the like are great sources of healthy fat.”
Hi Doc, great!! Thanks so much!! I really appreciate your time in responding so succinctly, and also for your knowledge and consideration of such a wide range of evidence. I am in good health and follow most of your principles already and am not overweight. This does take willpower and commitment in a world full of temptation!! However I do have some digestive and absorption issues. I read widely about general wellness, nutrition and supplementation and biochemistry (lately discovering methylation and gene activation) and I find it all fascinating even though it is difficult to determine what might be real and what might be spin, conjecture or ideology. I know the benefits and limitations of the levels of evidence and evidence-based medicine. Thanks so much for your contribution. I am really enjoying and learning a lot from your blog and the many comments as well.
Thanks Hilary. Appreciate your interest in my blog and hope you continue visiting.
where’s the controversy? LDL/TC is hardly alone, the predictive effect of nearly every single biomarker is confounded at later stages of life. Blood-pressure, BM, etc all show J-shaped curve in regards to total mortality. My own grandmother recently died to lung-cancer, the cancer wasn’t diagnosed until she was admitted to acute ward few days prior to her death. She was nearly anorectic the last ten years with very low cholesterol and blood-pressure (and obviously BMI). If only your scope would include even a tiny bit of global epidemiology, you’d see there’s not really much controversy out there. Elderly people in Okinawa have traditionally been very lean even in their old days with cumulative, over-life exposure to very low levels of cholesterol (no BMI nor cholesterol confusion here).
1) See the meta-analysis of 123 studies; just recently published
The Age-Specific Quantitative Effects of Metabolic Risk Factors on Cardiovascular Diseases and Diabetes: A Pooled Analysis
2) Effect of cholesterol on mortality and quality of life up to a 46-year follow-up.
“A strong and graded relation was found between the cholesterol level and total mortality, with the men with a cholesterol level ≤4 mmol/L (154 mg/dl) having the lowest mortality. In all, the men with the lowest cholesterol gained the most life years. However, no association was found with the cholesterol level in 2000 (when 16% were using statins) and subsequent mortality. The lowest (≤4 mmol/L) cholesterol value in midlife also predicted a higher score in the physical functioning scale of RAND-36 in old age. In conclusion, a low total cholesterol value in midlife predicts both better survival and better physical functioning in old age”.
3) Explaining the obesity paradox: cardiovascular risk, weight change, and mortality during long-term follow-up in men. Eur Heart J (2009) 30 (14): 1720-1727
You can obviously insist on the “beyond LDL lowering effects” of statins, but I see this rather futile. If statins would work with some other unknown mechanism besides lipid lowering, then how do you explain the fact that people with inherited polymorphism that lower LDL via the statin targeted HMG-CoA gene cumulatively over life enjoy 55% reduced risk for CHD per each mmol/l lower LDL compared to norm (Ference et al 2012), this same applies to all 9 polymorphism studied so far, with no sign of heterogeneity, lowering LDL seems to beneficial independently of the mechanism used.
An aggravate analysis of pre-statin lipid lowering lowering trials showed a benefit as well. This included surgical trials that lower LDL, hormone therapies, bile-acid sequestrants, etc. The benefits that come with LDL lowering via statins are most likely strongly tied to LDL lowering by itself, just sayin’. And of course, we’ll have soon evidence with PCSKY-9 inhibitors that lower LDL with very different mechanism compared to HMG-CoA reductase inhibitors (statins).
Meta-analysis of 108 randomized controlled trials with 300,000 subjects and with a mean follow-up of only three years establishing that lowering LDL significantly reduces both coronary heart disease and all-cause mortality independent of changes to HDL cholesterol and triglycerides, and non-lipid effects of specific interventions.
Richard. You cite some studies indicating an association between total cholesterol and mortality. I cited other studies that don’t support such an association. Then you ask: “Where’s the controversy?” Of course there is no controversy if you only look at the data that support your opinion.
You refer to The Helsinki Businessmen Study. These were all men with relatively high cholesterol numbers. In fact, very few had total cholesterol lower than 155 mg/dL (4.0 mmol/l). By not including individuals with low cholesterol levels you will of course miss the J-shape of the curve. If the study had included individuals with lower cholesterol levels, which are known to have increased mortality, the correlation might have disappeared.
I don’ understand why you cite the “Obesity Paradox study”. It barely touches on cholesterol. Interestingly, in that paper Strandberg and coworkers mention in their discussion the relationship between cholesterol and dementia when they say” Findings from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study showed that the relationship between cholesterol and dementia is bidirectional: both high cholesterol earlier and low cholesterol in late life were associated with dementia”. Richard, you must admit that this adds to the controversy; or are you still only looking in one direction?
Please keep in mind that the main focus of my article was to highlight some important issues that have to be kept in mind when using LDL-C for risk assessment. I was not saying that LDL-C is useless. However, clinicians and people in general should know the limitations of using this measure to assess risk and guide therapy.
there’s controversy once you pay attention to quality of the study. You enunciate that science is a some sort of show of hands or a democracy where every study has an equal value. I already mentioned the shortcomings of the Norwegian study. The Helsinki study is superior in every meaningful way, huge 46-year follow-up, quality control of the data, exclusion of people on statins and chronic disease. Nothing even close to this was achieved in the Norwegian paper, which was basically just a show of number crunching.
What do you mean, there were no people with low-cholesterol in the study of Helsinki men? There were plenty of people who had low cholesterol in the mid-life. I referred to obesity paradox to indicate that nearly every biomarker show J-curve in regards to total mortality. I also referred to meta-analysis of 123 which demonstrated that BMI looses its predictive power in people reaching their 60s, this does not indicate that low BMI is not beneficial on old people, it implies that chronic disease makes people loose weight.
Again you see controversy in places where it does not exist. Strandberg demonstrated that the worst prognosis was for men that were obese in their midlife, but suddenly started loosing weight at later stages of life. Do you think these people started loosing weight and got dementia because they suddenly adhered to cholesterol lowering Ornish program or is there possible something else going on?
The association of low cholesterol at mid-life and decreased risk for dementia is most likely causal, whereas the link between low cholesterol at later stages of life and dementia is most likely not causal. Very simple.
Richard. This is a quote from the Heslinki study publication where the authors discuss the limitations of their study: “Only one measured baseline serum cholesterol value was available, and the proportion of men with very low cholesterol levels (≤4 mmol/L, 154 mg/dl) at baseline was quite small (n = 22), because high cholesterol values were very common in Finland in the 1960s.” So, indeeed very few had low cholesterol levels.
Your statement is interesting: “The association of low cholesterol at mid-life and decreased risk for dementia is most likely causal, whereas the link between low cholesterol at later stages of life and dementia is most likely not causal. Very simple.” However, I wonder if this is a scientifically based conclusion or an opinionated one.
Doc for sorting this out. There are limits with the Helsinki study, but the conclusions should be easy for us to accept. Those with famial hypobetalipoprotenemia usually have their life-long LDLs around 10-40mg/dl and live around 15 years more than their peers.
The conclusion I made in regards to dementia, is a result of a careful line of thought. Do you suggest that low cholesterol levels cause dementia? I suggest that low cholesterol levels protect from dementia and other form of vascular disease. What about your optimal cholesterol levels indicated by your favorite studies; should we ask Okinawa islanders to elevate their LDL by eating eggs and promise them lower risk of mortality?
You can find all sorts of funny associations with cholesterol, BMI and blood pressure. Huge Korean cohort was published with over 800 000 participants. They found an association with low cholesterol and hemorrhagic stroke, when they looked more carefully the association persisted only with those who had low cholesterol together with high blood pressure; the found evidence that this peculiar cocktail was confined to binge drinkers, and that the low cholesterol was essentially a marker of liver damaging effects of alcohol.
Now, a new study that makes use of powerful databases of genetic information has found that raising HDL levels may not make any difference to heart disease risk. People who inherit genes that give them naturally higher HDL levels throughout life have no less heart disease than those who inherit genes that give them slightly lower levels. If HDL were protective, those with genes causing higher levels should have had less heart disease.
Researchers not associated with the study, published online Wednesday in The Lancet, found the results compelling and disturbing. Companies are actively developing and testing drugs that raise HDL, although three recent studies of such treatments have failed. And patients with low HDL levels are often told to try to raise them by exercising or dieting or even by taking niacin, which raised HDL but failed to lower heart disease risk in a recent clinical trial.
“I’d say the HDL hypothesis is on the ropes right now,” said Dr. James A. de Lemos, a professor at the University of Texas Southwestern Medical Center, who was not involved in the study.
Dr. Michael Lauer, director of the division of cardiovascular sciences at the National Heart, Lung and Blood Institute, agreed.
“The current study tells us that when it comes to HDL we should seriously consider going back to the drawing board, in this case meaning back to the laboratory,” said Dr. Lauer, who also was not connected to the research. “We need to encourage basic laboratory scientists to figure out where HDL fits in the puzzle — just what exactly is it a marker for.”
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
How low should cholesterol go?
The primary and secondary prevention and atherosclerosis regression studies below in aggregate suggest that for optimal effects, LDL cholesterol should be lowered well below 100 mg/dl, to levels around 70 mg/dl.
IS THERE AN ASYMPTOTIC LIMIT FOR LDL AT WHICH CARDIOVASCULAR EVENT RATES APPROXIMATE ZERO?
The LDL level at which cardiovascular event rate may approach ZERO is estimated to be ~ 60 mg/dl for primary prevention (no previous clinical coronary disease), and 30 mg/dl for secondary prevention (previous clinical coronary disease).
Familial hypobetalipoproteinemia: LDL cholesterol 30-40 mg/dl, associated with longevity, and life expectancy 15 years longer than their birth cohort. Atherosclerotic coronary and cerebrovascular disease almost never occurs in this common inherited disorder.
Threshold for progression of atherosclerosis estimated to be approximately 70 mg/dl
REVERSAL STUDY: 654 cases with symptomatic coronary disease and baseline stenosis ≥ 20%, randomized to Lipitor 80 mg or Pravachol 40 mg. Coronary atherosclerosis (by IVUS) halted in Lipitor group where 48% reduction in LDL led to mean LDL on treatment of 79 mg/dl. Pravachol group had 28% decline in LDL to a mean of 110 mg/dl. There was a 0.4% regression of atheroma volume in the Lipitor group vs 2.7% mean progression in the Pravachol group over 18 months. High specificity CRP was reduced by 36% in the Lipitor group vs 5% decrease in the Pravachol group.
ASAP STUDY: Lipitor 80 mg vs Zocor 40 mg, 325 cases with familial hypercholesterolemia. Carotid intimal-medial thickness (IMT) regressed 0.031 mm over 2 years in the Lipitor group vs 0.036 mm progression in Zocor group.
ARBITER STUDY: Lipitor 80 mg vs 40 mg Pravachol, 161 cases with baseline LDL = 150 mg/dl. Lipitor reduced LDL by 50% to 76 mg/dl vs 110 mg/dl on Pravachol. Carotid IMT regressed 0.038 mm in Lipitor group vs mean progression of 0.026 mm in Pravachol group.
HEART PROTECTION STUDY: 3500 cases with LDL <100 mg/dl before treatment, with mean LDL of 97 mg/dl reduced to 65 mg/dl on Zocor 40 mg. This was associated with 25% reduction in CHD events.
PROVE-IT-TIMI: 4162 acute coronary symptom cases with pre-treatment total cholesterol ≤ 200 mg/dl to Lipitor 80 mg or Pravachol 40 mg. On Lipitor, 51% fall in LDL to 62 mg/dl, vs 95 mg/dl (22%) decrease on Pravachol. After 2 years, 16% reduction in adverse CHD events, 28% reduction in CHD death in Lipitor group. In a retrospective analysis, there were lower clinical coronary heart disease events in patients who achieved LDLC <60 or <40 mg/dl compared with those in the 80-100 mg/dl range. LDL <60 or < 40, well below current guidelines, were not associated with adverse safety outcomes. Hence, do not reduce statin dose if LDL levels fall below the 70 mg/dl goal.
TNT: 10,001 cases with stable coronary heart disease, all started on Lipitor 10 mg, and after run in period, half to 80 mg, half remained on 10 mg. LDL remained at 101 mg/dl in the case on 10 mg, and fell to 77 mg/dl on the Lipitor 80 mg. The reduction in CHD events 22% (p<.01), 27% reduction in stroke (p<.01).
Why does the Dean Ornish extreme low fat diet so effectively reduce all cholesterol levels? Well the initial substrate from which cholesterol is synthesized is acylCoA (acetoCoA, acetylacetyl CoA) which is derived from fatty acid breakdown (oxidation). So eliminating fat from the diet will drastically reduce endogenous cholesterol synthesis and all cellular cholesterol levels will lessen. As cellular cholesterol synthesis reduces, less is effluxed via ABC family transporters into HDL particles: HDL-C will lessen. Also in people significantly restricting fat intake, the liver will have less cholesterol (less chylomicron delivery of fat, less production, less being brought back to the liver in HDLs: the results is when the liver makes VLDLs and IDLs, they carry a lot less cholesterol (less VLDL-C, less IDL-C and this will ultimately result in less LDL-C. Of course Ornish showed that by drastically reducing TC levels (as well as LDL-C) via fat restriction angiographic improvement occurs in persons with CHD. It mattered little that because of reduced cellular cholesterol, HDLs were no longer being fully lipidated (thus reducing HDL-C).
Thanks for the comment Charles. I often reject such lengthy “copy/pasting comments”. People usually don´t read them, unless it´s summarized into a clear message. Did you have a specific message you wanted to bring forward? I would prefer that, rather than such a pile of information.
it seems to me that you are not willing to accept the LDL theory because it does not cope well with your predetermined idea’s of multi-faceted nature of CHD. That’s the feeling I get. Although, I’d like hear your take on this. However, you must at least acknowledge that the truth can be very simple, this is one possibility, after all.
If you look at the Norwegian study in a bit more detailed manner, you’d understand that the authors did not exercise any kind of quality control over their data, no exclusion of people on statins or other chronic disease (accompanied by weight-loss and plummeting cholesterol levels). It’s well known that cholesterol levels go down very rapidly on elderly people in Western cultures. See Figure 2 in this classic paper for diet-heart by Jeremiah Stamler (1978) presented before AHA meeting. It’s not too difficult to understand why no one, apart from few bloggers, are not really taken by that silly Norwegian paper.
“I have great respect for such people who explore “the baroque beauty of biology” in its infinite perplexities. But I must admit to greater admiration for the distinguished clinician or scientist who sees the whole picture, not just its complex parts, and who realizes the importance of simple ideas and even of “simple research” on those ideas. For example, the terrible biologic complexity of metaplasia and carcinoma in the bronchi would, of course, largely disappear with one simple (?) public health measure – cessation of cigarette smoking”.
It has been observed that the long-term feeding of cholesterol and saturated fat has resulted in heart attacks, sudden death, development of gangrene, softening on the bones and numerous other serious complications in nonhuman primates. For example, it has been shown that when diets rich in cholesterol and saturated fat are fed to monkeys of the genus Macaca, including the rhesus monkey and the crab-eating macaque, they experience heart attacks at approximately the same rate as high-risk populations living in developed nations. Armstrong and colleagues induced severe atherosclerosis in rhesus monkeys by feeding a diet with 40% of calories from egg yolks for 17 months. The egg yolks were then removed from the monkeys diet and replaced with a cholesterol-free diet with either 40% of calories from corn oil or low-fat chow with 77% calories from sugar for three years, resulting in a reduction of serum cholesterol to <140 mg/dl and a marked regression of atherosclerosis.
I think, it's rather straight forward that high-caloric, high-fat, highly mutagenic cholesterol elevating animal foods are behind coronary disease. This idea can be demonstrated rather easily. It seems that for some reason, you are not really willing to embrace this idea despite all the data. Well, at least I want to demonstrate that this "mainstream" view can be demonstrated rather easily, despite what you hear online.
Thanks Charles Grashow, a great pile good info you just put up.
Again Richard: The main focus of my article was to highlight some important issues that have to be kept in mind when using LDL-C for risk assessment. I was not saying that LDL-C is useless. However, clinicians and people in general should know the limitations of using this measure to assess risk and guide therapy.
You´re right. I believe there is more to atherosclerosis and coronary heart disease than cholesterol.
It seems that whatever I write you jump up in defense of the cholesterol hypothesis. I was not rejecting it with this particular post. You can’t go on like this 🙁
Egad, there’s so much wrong with what you’re saying it’s hard to know where to being. For one, we’re not monkeys. Thus, a study with monkeys pretty much has little relevance to humans. Two, if it were “easy” to determine that “mutagenic cholesterol elevating animal foods” (which are what, by the way?) are “behind” coronary disease, then there wouldn’t be literally hundreds of studies that disagree with this notion. See, for instance, this one:
Now, that’s a meta-analysis, but there are many others (including Mrfit, as one of the “risk factors” was fat intake, and the Women’s Health Initiative, both of which found no relationship between fat/saturated fat intake and stroke, heart disease, cancer, etc.).
There’s definitely a controversy.
Nicely balanced piece. Thanks Dr. Sigurdsson. Such open-mindedness on this topic, by a practicing Cardiologist is encouraging.
Shame that any talk of “cholesterol” inevitably seems to lead to an outpouring of verbal diarrhoea from vegan trolls — perhaps I can recommend a good herbicide? 😛
Great that you emphasised the key differences between LDL and LDL-C. It seems that too many try to “dumb it down” so as to obscure the reality of the situation — makes me suspicious of their motivation; when there is so much financial gain at stake, in the marketing of drugs which specifically lower LDL-C (as calculated).
Also good to note that 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.”. I had noticed the same apparent oversight in the WHO’s Clinical Criteria for Metabolic Syndrome: which specifically mentions Triglycerides and HDL-C but fails to mention LDL-C at all…
Thanks for the comment Frank.
You´re right. LDL-C is not included when defining the metabolic syndrome. Only triglycerides and HDL-C are This indeed reflects the fact that LDL-C is not the main issue in this situation. As pointed out in my paper, today one third of U.S adults suffer from the metabolic syndrome. One more reason to stop overemphasizing LDL-C 🙂
BTW, thanks for sharing this link; very useful, great material.
Lipoprotein Management in Patients With Cardiometabolic Risk
Consensus statement from the American Diabetes Association and the American College of Cardiology Foundation
“The dramatic success of cholesterol-lowering therapy might suggest that low cholesterol levels would be all that is required to prevent the development of atherosclerotic disease or halt or reverse established disease. This might be true if plasma cholesterol concentration could be reduced to very low levels long before the usual time of development of clinical disease”
“Experimental studies directly support the central role of LDL in atherogenesis. Current concepts suggest that higher plasma levels of LDL lead to increased transport into the intima, where LDL becomes bound to proteoglycans, greatly prolonging its residence time. This makes LDL susceptible to a variety of modifications, including oxidation, enzymatic modification, nonenzymatic glycation, aggregation, and immune complex formation. All of these lead to enhanced macrophage uptake, foam cell formation, and initiation of the cascade of events resulting in progression of the atherosclerotic lesion”.
Based on the curvilinear relationship between LDL cholesterol and CHD in the general population, from a public health standpoint it has been suggested that LDL cholesterol values 100 mg/dl.
If you don’t mind, Doc, I thank for your patience and open-mindedness, and share this link with you, hopefully you’ll find it useful. It’s your colleague from NYC:
“For years after my training, I applied evidence-based medicine, recommended a “healthier” lifestyle, which typically included a Mediterranean-style diet, and watched as my patients’ diseases often progressed. I became frustrated. There had to be something more”.
I then learned the major differences between carnivores and herbivores, and humans clearly come down on the herbivore side. The teeth of carnivores are sharp and those of herbivores, more flat; the intestinal tract of carnivores is short (about 3 times body length), whereas that of herbivores is long (about 12 times body length); carnivores cool their bodies by panting, herbivores, who can also pant, do so mainly by sweating (carnivores cannot sweat); carnivores lap their fluids, herbivores sip them; carnivores make their own vitamin C, herbivores obtain that vitamin only from their diet.
Brown and Goldstein in the early 1980s identified the low-density lipoprotein (LDL) cholesterol receptor and showed that only 1 in 500 individuals had deficient numbers of LDL receptors, demonstrating that atherosclerosis was rarely a genetic problem (6). When I was in medical school I was taught that atherosclerosis was a degenerative disease, the price of residing on planet earth, but that is not the case. We people are the degenerates, not the disease! We get atherosclerosis by eating too much cholesterol and saturated fat. It is our fault, not our parents’ fault. Atherosclerosis is very rare in populations with LDL cholesterol levels <70 mg/dL for a lifetime. We need to prevent and arrest atherosclerosis and not be satisfied with simply trying to decrease its risk, which is what the guidelines are about. We need to think about atherosclerosis like the pediatricians think of measles, mumps, whooping cough, and polio. Let's prevent it. We don't have to have it.
Of the various atherosclerotic risk factors, which one is an absolute prerequisite for development of atherosclerosis?
The answer is hypercholesterolemia. What level of total cholesterol and specifically LDL cholesterol is required for atherosclerotic plaques to develop? Symptomatic and fatal atherosclerosis is extremely uncommon in societies where serum total cholesterol levels are <150 mg/dL and serum LDL cholesterol levels are <100 mg/dL (8). If the LDL cholesterol level is <100— and possibly it needs to be 150 mg/dL and the LDL cholesterol is >100 mg/dL, the other risk factors clearly accelerate atherosclerosis.
What evidence connects atherosclerosis to cholesterol?
The connection between cholesterol and atherosclerosis is strong (9, 10):
Atherosclerotic plaques similar to those in humans can be produced in nonhuman herbivores by feeding them large quantities of cholesterol and/or saturated fat. It is not possible to produce atherosclerotic plaques experimentally in carnivores.
Cholesterol is found within atherosclerotic plaques.
In societies where the serum total cholesterol is 150 mg/dL, the frequency of symptomatic and fatal atherosclerosis increases as the level above 150 increases.
The higher the serum total cholesterol level, and specifically the higher the serum LDL cholesterol, the greater the frequency of symptomatic atherosclerosis, the greater the frequency of fatal atherosclerosis, and the greater the quantity of plaque at necropsy.
In placebo-controlled, double-blind, lipid-lowering studies of adults without symptomatic atherosclerosis, the group with lowered serum LDL cholesterol developed fewer symptomatic and fatal atherosclerotic events compared with controls.
In placebo-controlled, double-blind, lipid-lowering studies of adults with previous symptomatic atherosclerosis, the group with lowered LDL cholesterol levels after the event had fewer subsequent atherosclerotic events than did the group that did not lower their cholesterol levels (controls).
LDL receptors were discovered in the liver by Brown and Goldstein, and the absence or decreased numbers of LDL receptors in patients with quite elevated serum cholesterol levels indicates a genetic defect in an occasional patient (3–5).
Charles. I appreciate your comments, but I can´t continue to accept this type of lengthy copy/pasting comments. You even include the reference numbers from the articles you’re copying. Please 🙁
I don’t understand your comment. I attach the link to the whole article and paste in the necessary portions.
Your statement – ” I often reject such lengthy “copy/pasting comments”. People usually don´t read them, unless it´s summarized into a clear message. Did you have a specific message you wanted to bring forward? I would prefer that, rather than such a pile of information.”
Are you saying that your readers are lazy? Are piles of information that much of a burden for them to read?
Okay – here’s my “clear message” – I believe that the preponderance of evidence supports the idea that TC<150 and LDL-C<80 is necessary to prevent and reverse arterial plaque. I (and Dr Roberts) believe that it doesn't really matter whether it's done thru diet, drug therapy or a combination of both.
Dr William C Roberts is a cardiac surgeon AND a cardiac pathologist who has performed autopsies on over 15,000 human hearts so I would think that his opinions would carry some weight.
I currently take 10mgs Atorvastatin/day BUT I still eat grass fed/finished ground beef, full fat raw goat milk, full fat goat milk yogurt/kefir, 1 duck egg yolk/day and I also eat nuts, seeds, fruits, veggies, etc.
I modified my diet by eliminating coconut mil/oil and reducing the number of eggs consumed.
Blood test results – 10/18/13
Vitamin D3 – 46
That’s great Charles. This lipid profile should be associated with a very low risk of cardiovascular disease.
Bill Roberts is the editor in chief of American Journal of Cardiology; he is in his 80s, seems to be great health, still groin’ strong and working full-days. He spoke recently at McDougall Program and seems to fully in the plant-based bandwagon.
Doc needs to read his landmark review:
The Cause of Atherosclerosis
Every single top-notch atherosclerotic expert I’ve communicated seems to believe we need to keep LDL as low as possible, and get it down to the floor very quickly. I recently talked about this with young PhD student in vascular chemistry. “It’s the cholesterol stupid”. Many of the top-snotch expert seems to very positive to low-fat plant-based diets as well (William Roberts, William Castelli, John LaRosa, etc). I tried to communicate this info to Doc so that he could pass this info to Iceland, but nothing seems to work!
Richard. Dr. Roberts starts his lanmark review you cited with these words: “Most physicians, I believe, consider atherosclerosis to be a multifactorial disease, and the greater the number of atherosclerotic risks factors present, the greater the chance of having an atherosclerotic event. I am in the minority in believing atherosclerosis to be a unifactorial disease, the result of abnormal serum or plasma cholesterol levels.”
Dr. Roberts obviously considers himself to belong to the minority of experts that don’t believe that atherosclerosis is a multifactorial disease. So, according to him, the Doc’s there with the majority.
By the way, Icelanders are very well aware of the cholesterol hypothesis. Don’t waste your time worrying about that 🙂
What are your thoughts on Dr William Davis (Wheat Belly)? In his book Track Your Plaque he lays out this
Track Your Plaque Program Details – Attain the Following Targets:
a) Reduction of LDL to 60 mg/dl (LDL should be measured directly, not calculated)
b) Reduction of triglycerides to 60 mg/dl.
c) Raising HDL to 60 mg/dl.
d) Correction of hidden causes of plaque on Lipoprotein profile such as total number of small LDL particles, IDL, and Lp(a).
e) Achieving normal blood pressure (<130/80) Even a small elevation of blood pressure in diseased
arteries can cause increased mortality. Diseased arteries are fragile and plaque rupture can occur easily.
f) Achieving normal blood sugar (≤100 mg/dl). Diabetes is a high risk factor for heart disease.
g) Reduction of C-reactive protein to <1 mg/l
Charles. I haven’t read Wheat Belly. I’ve given it a try a couple of times but somehow the book didn’t appeal to me. I’m planning on giving it another go.
I’m a bit skeptical about serial CAT scans to assess coronary calcium score. I don’t know of any scientific studies favoring such an approach. The targets are interesting. However, probably very difficult to reduce LDL-C to 60 mg/dl and at the same time elevate HDL-C to 60 mg/dl. A lipid profile where HDL-C is higher than LDL-C is difficult to attain.
I realize this post is a bit old however I just recently found it :)…Doc, I’m just curious if you could elaborate on the reasons for skepticism on CAT scan/coronary calcium score. Many thanks, great blog!!!
Hi DN. I think what I meant to say was that I’m sceptical about using CCS as a screening tool for everybody. However, I think it can be very helpful as an additional tool when needed.
Dr Roberts also says
” If dyslipidemia is present, then systemic hypertension, diabetes mellitus, cigarette smoking, inactivity, and excessive body weight increase the likelihood of an atherosclerotic event, but none of them in and of themselves is required for severe atherosclerosis to occur. In contrast, atherosclerosis does not occur if dyslipidemia is not present, irrespective of the blood pressure level, blood glucose level, the degree of obesity, the degree of activity, or the number of cigarettes smoked daily.
I thought the ‘humans as herbivores hypothesis’ was pretty neatly debunked by the relative belly sizes of primates versus humans. If we were indeed built to eat only vegetable matter then we would have a much larger gut designed to break down all of that woodsy material. We also need the nutrients that animals provide. Though I do have much respect for anyone who chooses to eschew meat for moral reasons.
Dr. Axel – thanks for pointing out that the new primary prevention risk calculator is using a better tool to predict risk: non-HDL-C instead of LDL-C. However, the new calculator recommends that more than twice as many should take statins based on a new lower 10 year risk threshold: >7.5% vs >20%, yuk! On what basis has the threshold been lowered? Look more like speculation!
I agree Jeff. I don’t really know why they chose 7.5%. It’s almost like an arbitrary decision. Interestingly, age counts very strongly as a risk factor. So if you feed the calculator with very healthy numbers, average blood pressure and no other risk factors, all men will reach 7.5% risk at age 58 and all women at age 70. So according to the guidelines, all healthy men 58 years and older, and all women 70 years and older should be offered statins, nonwithstanding
other risk factors.
Dr Axel; I exchanged emails today with Dr. Donald M Lloyd-Jones the principle who worked on the CV risk calculator. Based on primary prevention trials, they pushed the primary prevention treatment threshold down as low as possible to 7.5% while keeping diabetes risk as low as possible. With an even lower threshold like 5% the diabetes risk went up. This is explained in the guidelines section 4.6, but it was not obvious to me. https://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437738.63853.7a/ At least the panel believes that a 1-2% absolute risk reduction is enough to warrant such prolific use of statins for primary prevention.
Thanks Jeff. That’s very interesting. I still believe that 1-2% absolute risk reduction is very low considering treatment with potential side effects. If you look at it from a different angle (assuming your risk of cardiovascular event is 8% over ten years), the likelihood of not having a cardiovascular event in the next ten years will be 92% if you don´t take statins, but 93-94% if you take statins. That´s not a huge difference.
Many are questioning the role of statins for primary prevention!
Getting More People on Statins
William Clifford Roberts, MD Editor in Chief Baylor Heart & Vascular Institute Baylor University Medical Center Dallas, Texas
“But what serum cholesterol numbers are necessary to prevent atherosclerotic plaques from forming. The evidence is substantial that if over decades the serum total cholesterol is <150 mg/dl, the LDL cholesterol <100mg/dl, and the high-density lipoprotein (HDL) cholesterol 〉20 mg/dl, the chances of forming atherosclerotic plaques are slim. (I realize that many readers will be shocked by the mention of an HDL-cholesterol of only 〉20 mg/dl. But this number is only when the total cholesterol is <150 mg/dl and the LDL-cholesterol is <100 mg/dl . If the total cholesterol is 200 mg/dl and the HDL-cholesterol is only 21
mg/dl an atherosclerotic event is likely.) Because about 45% of adults in the Western World die from cardiovascular diseases, these numbers need to be the goals of all adults, not just adults with atherosclerotic events and/or diabetes mellitus, and now lipid-lowering agents, which can achieve these goals in most
patients, are available. Thus, lower the bar for those eligible for statin therapy!
The American Association of Clinical Endocrinologists decided not to promote these new guidelines by AHH/ACC. National Lipid Association withdrew their support already at the initial stage.
It seems that every single lipid expert knows that lower the LDL, the better and quicker the better.
Anyways, pay attention to the new report by AHA/ACC, they set the upper limit for SFA at 5-7%.
So, in short we should ignore these new guidelines by AHH/ACC because the “National Lipid Association withdrew their support already”
BUT simultaneously, we should pay attention to these new guidelines by AHH/ACC because they set an upper limit for SFA?
Not to mention that humans — who apparently are herbivores (I can’t help but wonder what my ice-age European ancestors would have to say about that) — are all suffering from an acute shortage of statins!
Every single lipid expert…? Every, single one… ALL of them… seriously?!?
Is it any wonder that your comments lack credibility?
And who exactly is the National Lipid Association and why should we listen to them anyway?
With their next “Clinical Lipid Update”, Spring 2014 in Maui Hawaii..! Book soon for the early bird special prices!
Are they yet another self-appointed group of people with (I suspect) strong ties to the pharmaceutical industry like the NCEP – ATP III Committee?
ATP III Update 2004: Financial Disclosure of NCEP members…
Out of the eight member (self-selected) committee, there were seventy two potential financial conflicts of interest…
“Imagine if eight Supreme Court judges, ruling on any issue, had seventy two direct financial conflicts of interest to do with that issue…”
Your total cholesterol level is in the Desirable range, but your level of “bad” LDL cholesterol is borderline high. If your LDL goes higher, your total cholesterol level could become Borderline High. Consider reducing the amount of foods you eat with saturated fats and increasing physical activity. If you get more exercise, your level of “good” HDL cholesterol may increase, which could also help to keep your levels of LDL and total cholesterol in check.
Dear collegue, I agree with Your position.
The theory “lower is better” is founded on the Cholesterol Treatment Trialists’ Collaborators work  : the results of their individual-data meta-analysies suffer nevertheless for several methodological pitfalls  and the parallel “dogma” of the LDL-Cholesterol targets  is
moreover founded only on illustrious opinions with lack of any experimental evidence (=RCTs results based) regard the effectiveness of a certain “cholesterol target” about mayor cardiovascular end-points . In fact the most cited RCTs [4,5,6,7] from supporters of the “target theory” randomised drugs, not targets of LDL-CL, so that the dogma consists on a observational interpretation of experimental data .
As a matter, within the large clinical research experiences about the efficacy of statins in secondary prevention that considered non-surrogate endpoints, only two RCTs [9,10 ] achieved in the intervention arm a level of LDL-CL below the raccomanded  target of 70 mg/dl and only one
 with significant results. For example, it is hard to understand why we would at any cost obtain a 70 mg/dl LDL-CL level in a coronary disease affected person whereas the most famous RCT in secondary prevention, the 4S study , showed significant results about mortality and morbidity
end-points already at LDL-CL levels of 122 mg/dl.
These extreme levels of lowering are difficult to reach (and also dangerous for some people); in a recent audit experience in the primary care setting (107 italian general practitioniers of the Veneto district) only 15% of the patients in secondary prevention statin-based therapy reached in the year 2012 LDL-Levels below this cut-off.
The results of a recent well conducted meta-analysis show as a matter that only 50% of the efficacy of these drugs seem be based upon their LDL-CL lowering effect .
The target theory favours undoubtedly the interest of Pharmaceutical Companies but needs an impartial critical appraisal.
Alessandro Battaggia, MD
 Lancet 2005 366:1267-78 and subsequents
 Lancet 2012 380:1814-17
 Circulation 2004 110:227-239 and subsequents american and european guidelines
 NEJM 2005 352:1425-35
 NEJM 2004 350:1495-504
 JAMA 2005; 294:2437-45
 EurHeartJ 199920:725-41
 Ann Intern Med.2006145:520-30
 N Engl J Med 2004350:1495-504
 JAMA 2004 15: 292:1307-16
 Lancet 1994 19;344(8934):1383-9
JAMA 2012; 307:1302-09
Good Morning! I just stumbled across your blog and love it. I really enjoy your take on the whole fat and nutrition thing. So hard these days to determine what is the best way to navigate it all. I have moved to a more low carb high fat way of eating…just because that is what makes me feel good, I am the leanest/fittest I have ever been…However since trending this way my lipid profile has changed considerable and all though I read all the blogs that assure me this is ok, I am still of the non fat generation so it kind of scares me. Would you mind offering your ideas on this… A little history:
I am 5’0″ and 117lbs. I am very active (I alternate daily between climbing a local mountain and climbing about 4K of stairs.)
I currently eat fruits, veggies, full fat dairy and lots of eggs, chicken breasts and very occasional red meat.
Before going to eating the above, I followed more of a low carb (other than daily oatmeal- so I guess not really low carb :0), low fat way of eating…and my lipid profile was:
LDL Direct Cholesterol 103 mg/dl
HDL Cholesterol. 90
Triglyceride 53 mg/dl
and a year previous this is what it was:
HDL Cholesterol. 81
Non-HDL Cholesterol Calculation 87
Chol/HDL Ratio 2.1
Triglyceride 49 mg/dl
my current lipid profile after going to my current way of eating (higher fat, eggs, fruits and veggies, limited meat):
LDL Direct Cholesterol 209 mg/dl
HDL Cholesterol. 108
Triglyceride 45 mg/dl
Non-HDL Cholesterol Calculation 218
Chol/HDL Ratio 3.0 ratio
So the possible culprits to the increase in cholesterol are:
I switched from NF yogurt to FF yogurt (daily)
Do intermittent fasting (5 / 19)
taking L-Glutamine (for sugar cravings- seems to work)
And stopped with almost all grains (used to eat oatmeal daily)
Should I be concerned with the increase in ldl and cholesterol? On a good note, HDL went up and triglycerides went down :0)
Thank you so much for your input!!!
@ Flavor Seeker
Thanks for the comment and the kind words. Elevation of total cholesterol and LDL-cholesterol together with elevation of HDL-cholesterol is quite common on a low carb high fat diet. However, not all people respond in this way. Some experts believe this is nothing to worry about, partly because Triglyceride/HDL ratio improves together with many other metabolic abnormalities (such as insulin resistance for example). However, nobody knows whether LDL-cholesterol can be ignored under these circumstances. I usually recommend my patients to lower the intake of saturated fat (like the full fat dairy products in your case) under these circumstances. This will usually lower LDL-C. People usually switch to other types of fat instead – you don’t have to increase your carbs. I don’t know if this is the right way to go but it is what I usually recommend.
thank you!! I got the remaining results that make me feel a little better but I have switched from full fat yogurt to low fat..not sure I can give up my eggs though :0) Will see if this lowers my LDL-C.
The lipid subclass tests came back showing that I have more of the type a LDL( large buoyant) then the type B (dense) LDL.
My high-sensitivity CRP (marker of inflammation blood vessels)is still low at 0.3 (normal less than 1.0) and my homocystine level came back normal.
Always find your articles stimulating Axel
Have you seen???
That’s interesting. Confirms that there is so much we don’t really know yet.
i just took my hdl test and it not good 49mg/dl. What do I need to do to raise it?
Take a look at my article on HDL cholesterol here.
Hi Dr Axel,
I just turned 40. Height 1.78m 79kg. No family history of heart disease,
At least one hour of exercise a day (mountain biking, martial arts, resistance training). In general good health. Diet is mainly low carb, high protein, and high fats (grass fed beef, grass fed butter, coconut and MCT oil)
As an army reservist, I just went for my annual standard Lipid panel test:
Total Cholesterol 7.68 296.98
HDL Cholesterol 1.79 69.21
LDL-Cholesterol 5.25 203.01
Triglycerides 1.4 124.00
Cholesterol/ HDL ratio 4.29
Diabetes Mellitus profile: (Glucose fasting)- 5.1 mmol/L
The attending doctor immediately downgraded me and excused me from physical activity due to my high LDL levels, and suggested that I consult a specialist to begin a regimen of statins.
What would you suggest I do, for further tests? I understand that folks on these low carb diets typically display elevated LDL scores.
Great post. I did want to comment on one thing. I think it would be more accurate to say the AHA calculator doesn’t rely solely on LDL-C. That said, using TC is even more questionable perhaps than using LDL-C in isolation since it adds together a score than you want to maximize (HDL) with one that should be minimized (triglycerides) with LCL-C (which may be low impact or inconsequential). It seems kind of crazy.
50 year old male; non-smoker
Family History: father had stroke due to A-Fib; mother has high blood pressure and CVD; CVD in grandparents on both sides
BP averages 125/70
Lift heavy 4 days per week; run 3 miles three times per week
5’7″ and 160lbs with a good bit of muscle
Total Cholesterol: 188
Small LDL-P: 790
LDL Size: 20.9
HDL Size: 8.7
LP-IR Score: 52
H1C always runs just under 6
Do I need a statin? If so, which one targets LDL-P?
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