The Study That MIGHT Change Lipidology

Last weekend, UCLA cardiologist Dr. Matthew Budoff presented preliminary baseline data at the World Congress on Insulin Resistance, Diabetes, and Cardiovascular Disease that could theoretically, potentially, eventually, help turn the fields of lipidology and cardiology on their heads. 

The first of its kind prospective (ie. forward-looking) study directly assesses arterial plaque and calcification in a population of individuals with extremely high LDL-C resulting from a very low carbohydrate diet (Why this happens HERE). This population, while not entirely uncommon, is largely unstudied and may offer a number of clues to the true nature of lipid behavior and cardiovascular disease. 

Why is this? Because these individuals have very, very high LDL-C - an average of 272 mg/dl. Remember, conventional medical guidance considers an LDL-C above 100 mg/dl to be "high" while average is something around 120 mg/dl. 272 mg/dl is way past the 99th percentile and is more than 40% higher than the American Heart Association's threshold for automatic, no-questions-asked high-intensity statin therapy. Factor in the subject's average age of 56 years and they should, in theory, seem like a no-brainer for lipid-lowering therapy. 

These people should be at extreme risk for cardiovascular disease, should they not? Well, yes...if the traditional paradigm is correct. But the lipid-heart hypothesis is not nearly the settled science the AHA, pharmaceutical companies, and the medical establishment would have you believe. Instead, there are I believe two principle theories by which atherosclerotic cardiovascular disease may develop: 

•  Theory 1 is that LDL-C and LDL particles themselves are the direct, primary, and uniquely necessary elements of atherosclerotic disease. Elevated levels of LDL particles and LDL-C increase your risk for such disease by increasing the chance that, over time, more and more of these particles will become trapped in the wall of the blood vessel and ultimately lead to the development of plaque, arterial occlusion, etc. This is the common theory advanced by the medical industry. 

• Theory 2 is that LDL particles damaged as a result of oxidative stress or hyperglycemia are the target of immune cells whose function is to trap the damaged particles for recycling and removal. When poor metabolic efficiency, hyperglycemia, and increased oxidative stress lead to an excessive number of damaged LDL particles, this process occurs at a greatly increased rate. The development of plaque, arterial occlusion, etc. is fundamentally an inability of the body to remove and recycle these damaged particles as quickly as they accumulate. I've written many thousands of words about why I favor this theory. 

Now the subjects in this study are excellent candidates to test these theories because they not only have very high LDL-C, but also good metabolic health (HDL = 90, Triglycerides = 64, BP = 117/76, A1C = 5.4%). This means the key sentence in Theory 2 ("poor metabolic efficiency, hyperglycemia, and increased oxidative stress...") is of limited relevance and allows a unique opportunity to compare the two theories. If Theory 1 is correct, these individuals should rapidly develop cardiovascular disease. If Theory 2 is correct, they should not.

So far we only have preliminary, baseline date, which you can watch be presented HERE, but which I'll summarize briefly:

CAC and plaque scores for low-carb and control groups

• The researchers assessed two direct measures of atherosclerotic disease - coronary artery calcification and a "total plaque score" (calculated via CT angiography). These were measured in both the low-carbohydrate group and a control group matched for age, metabolic health, etc. The only major difference between the two groups was LDL-C, which was more than twice as high in the low-carb group. 

• The researchers will assess both of these metrics again in another year to assess any disease progression in each group

• The majority of subjects in each group had coronary artery calcification scores (CACs) of 0, indicating no calcification (CACs of significantly at-risk individuals commonly range from 100-400 or higher).

• Total Plaque Score is calculated from 0 to 45 (0-3 at each of 15 different potential plaque sites). In the low-carb group, the median subject had a TPS of 0 with an interquartile range (the middle 50%) of 0-2. No subject had a TPS greater than 12. The control group had a median TPS of 1 with an interquartile range of 0-4. The difference between the two groups was not statistically significant. 

• There was no difference in CAC or TPS between the low-carb, high LDL-C group and the control group.

• There was no relationship in either group between LDL-C levels and measured plaque.

Now, it should be noted that CACs and TPSs of 0 are not particularly remarkable. In fact a little more than half of 56 year olds have a CAC of 0 (you can play around on this NLHBI site if you'd like to see). Its normal and healthy to be free of coronary calcification. But what makes this study so potentially fascinating is that these subjects aren't considered "healthy" in a traditional sense. Years of extremely high LDL-C should predict the impending doom of atherosclerosis, but so far at least this group shows little and often no disease progression whatsoever. In fact, their cardiovascular disease state is indistinguishable from matched subjects with good metabolic health and no elevated LDL-C. 

We'll have to wait until 2024 for follow-up results, in which actual plaque progression in each group will be compared. But if two groups with similar metabolic health yet vastly different LDL-C levels continue to demonstrate identical disease states (or the lack thereof), it would lend significant credence to the notion that metabolic health and other associated factors, rather than LDL Cholesterol, drive chronic cardiovascular disease. Ideally, this would help launch a number of other studies to further challenge common assumptions and explore underappreciated aspects of lipidology and cardiovascular disease. Will that be the case? TBD...