Cholesterol: The Standard Measure Of Blood LDL Cholesterol Is Inaccurate

For the last 5 decades, most medical and nutrition scientists have focused on low-density lipoprotein (LDL) cholesterol (“bad cholesterol”) as a primary cause of coronary heart disease. While cholesterol lowering therapy has become the standard of care for some individuals with well-defined heart disease risk, this focus on cholesterol in general – and LDL cholesterol in particular – remains very controversial.

Unfortunately the standard measure of blood LDL cholesterol is inaccurate, and when the various components of the blood LDL are measured they represent only a fraction of the lipid (fatty acids) and other biomarkers of heart disease risk.

A turning point in understanding the limitations of LDL and heart disease came with the publication of the Lyon Diet Heart Study. This randomized trial pitted a standard low fat diet against a Mediterranean diet for people with a prior heart attack. There was no difference in LDL cholesterol changes between the Mediterranean and low fat diet groups. The standard calculated LDL value did not seem to matter that much indicating that some very important drivers of coronary disease risk were going unmeasured.

In the recently published 1-year results from the IUH/Virta diabetes reversal study, they reported a small but significant rise in the average blood LDL cholesterol level in patients on a well-formulated ketogenic diet (WFKD). At the same time, however, they noted major reductions in a number of coronary disease risk factors including weight, blood pressure, and HbA1c.

The pattern of how these other risk factors change is independent of the changes in LDL.

In Figure 1, (please see the original post) the number of patients whose LDL went up was somewhat greater than the number whose LDL went down.

In the Figure 2, the 14 other risk factors with improved risk far outweigh those indicating a negative response. The heart disease risk factors indicate that a WFKD is much healthier than one might conclude by focusing on the single LDL risk factor.

Novel results from the IUH Diabetes Reversal Study:

Figure 2

Blog - July 26 actual numbers for each of the risk factors -3.png

Here is a table (figure 2) with the actual numbers for each of the risk factors shown in figure 1, plus HbA1c and weight. For each factor, there is a change between baseline and 1-year as a percent, the P-value indicating the chance this change might occur at random (i.e., the smaller the better), and then arrows up or down indicating how this change might influence overall heart disease and mortality risk.

These results are interesting for two reasons. First, none of the short term studies of ketogenic diets given to patients with type 2 diabetes lasting a few week to a few months have sustained these benefits without weight regain and/or rising HbA1c values after 1 year.

Second, no prior prospective outpatient low carbohydrate diet study has documented anything near this degree (0.6 mM at 10 weeks and 0.3 to 0.4 mM at one year) of sustained nutritional ketosis in such a large group past the first few months of treatment.

Note that only the arrow for calculated LDL cholesterol points up, whereas all of the other 16 point down. Also note that of these 16, only two have associated P-values that are non-significant or borderline. All of the others indicate a chance of random error of less than 1-in-ten-thousand. This means in turn is that these observations of reduced risk are statistically very strong.

This sustained nutritional ketosis may be a pivotal factor in risk reductions. The resultant beta-hydroxybutyrate (BOHB) is now understood to be a potent epigenetic signal controlling the body’s defenses against oxidative stress, inflammation, and insulin resistance.

What Blood Lipids Actually Do:

We have known for a long time that blood levels of both cholesterol and saturated fat tend to be independent of how much of these nutrients we eat.

But a completely different set of factors come into play when we eat less energy than we burn, which forces the body to dip into its energy stores and thus mobilize body fat. Similarly, when we restrict dietary carbohydrates, either body fat or dietary fat has to become the body’s principle source of energy. This is most profound in the keto-adapted state, where circulating lipids and blood ketones (made from fat in the liver) together provide 75-85% of the body’s energy. Lipoproteins play a critical role in the transport of lipid in the bloodstream, so changes in delivery needs in turn will impact lipoprotein lab results.

In response to the state of nutritional ketosis, humans can more than double their rates of fat oxidation (i.e., use for fuel) at rest and during exercise. So when you combine a doubling of fat intake with a doubling of fat use, clearly a lot more fat has to pass through the bloodstream.

We have spent a few decades studying how the body adapts to a WFKD, and have come to recognize a pretty consistent pattern for the changes in most blood lipids, but a quite inconsistent pattern for the calculated LDL cholesterol level in particular. The consistent changes are:

  • A dramatic reduction in serum triglycerides
  • A rise in HDL cholesterol and
  • The same or lower levels of saturated fats in serum triglycerides

The one inconsistent variable in this otherwise predictable pattern of change is the calculated serum LDL cholesterol level. For some people, following a ketogenic diet makes their LDL cholesterol go down and for some it does not change. But for a fair number of people the calculated LDL cholesterol value rises, in some cases quite a lot. Thus the key question is: How important is the calculated LDL cholesterol relative to the other risk factors that have been recently characterized?

Why LDL Cholesterol is Not a Single Number:

There are two important limitations of the commonly reported serum LDL cholesterol level.

First, the usual test procedure does not actually measure LDL – it reports a calculated value based upon measurements of serum total and HDL cholesterol and triglycerides, along with a number of assumptions. And in particular, when the triglyceride value undergoes a big change, it can skew the calculated LDL value considerably.

Second, the circulating lipoprotein particles classed as LDL are actually quite diverse in size, and it is now recognized that the smaller, more dense particles (which carry proportionately less triglyceride) are the sub-fraction that is associated with vascular damage and heart disease.

In Figure 2, only the calculated LDL cholesterol value went in the ‘wrong direction.’ But in this case, it appears that this was due to a shift to a greater proportion of the larger particles because the total particle number did not change, the average particle size increased, while the small dense particle number was significantly decreased.

Inflammation as an Independent Risk Factor for Coronary Vascular Disease:

Three decades ago, a number of mainstream investigators noted that the total white blood cell count and then c-reactive protein levels appear to predict coronary disease and mortality independent of cholesterol.

The key question as to whether this was a mere association or causal. This question was resolved with the recent CANTOS Trial, which reduced coronary risk by 15% without any effect on LDL cholesterol levels.

Unfortunately a side effect of the antibody used in this study (an increase in fatal infections) cancelled out the coronary disease risk reduction, so the CANTOS Trial answered an important question but did not offer a therapeutic solution. However this does offer an interesting insight into the mystery of why the Lyon Diet Heart Study reduced coronary disease risk AND mortality. In that study, blood anti-oxidant levels increased and granulocytes (aka white blood cells) decreased, suggesting that a dietary anti-inflammatory intervention can have potent benefits absent the dangerous side-effects of anti-inflammatory drugs.

Blood Saturated Fats and CVD Risk:

The key fact to keep in mind is that while a primary source of saturated fat in the blood is de novo lipogenesis (i.e., the production of fat from excess dietary carbohydrate), there is little if any relationship between dietary saturated fat intake and blood saturated fat content. And most importantly, because the keto-adapted state doubles the body’s ability to burn saturated fat for fuel while at the same time shutting down de novo lipogenesis, blood levels of saturated fats are reduced independent of dietary saturated fat intake.

There is a review of this topic in the blog, The Sad Saga of Saturated Fat.

Getting Beyond Single Biomarkers of Cardiovascular Risk:

There is a wide range of processes that contribute to atherosclerosis and coronary artery disease risk. American College of Cardiology offers a 10-year heart disease risk predictor that includes the following inputs: age, sex, race, total cholesterol, HDL cholesterol, LDL cholesterol, systolic blood pressure, diastolic blood pressure, diabetes, smoking and medication use (statin, hypertension, aspirin).

Based upon this equation, the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score in the recent Virta study decreased -11.9% (P = 5×10-5). This is a large beneficial effect experienced by the participants in the Virta study despite the observed changes in calculated LDL values.

Continuous doctor’s care treatment including nutritional ketosis in patients with type 2 diabetes improved most biomarkers of CVD risk after the Virta one-year study. The increase in LDL-cholesterol appeared limited to the large LDL sub-fraction; whereas LDL particle size increased, total LDL-P and ApoB were unchanged, and inflammation and blood pressure decreased.

There so many different factors are associated with coronary risk we need to avoid focusing on just LDL.

This Post has been condensed from the Virta blog: Blood Lipid Changes With A Well-Formulated Ketogenic Diet In Context by Rich Wood, PhD, Amy McKenzie, PhD, Jeff Volek, PhD, RD, Stephen Phinney, MD, PhD on May 2, 2018. Please see the original for the Footnotes and Citations for the scientific studies. Here is the link

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