HIGH CHOLESTEROL IN LOW-CARB OR KETO?

A few days ago, a very important study came out regarding people whose LDL cholesterol is raised a lot by following a low-carb or ketogenic diet. I thought it might be useful to write this in-depth study because I know that many people struggle: with cholesterol at those levels, the treating doctor pushes to take statins. Unfortunately, very few doctors in Italy know about the LMHR phenotype, so it is very normal for them to react that way. In this in-depth study, in addition to reporting the results of the study, there is also general information on LMHR and the lipid energy model. It also reports all the references to the studies, so you can forward it to your doctor. Important: send the digital format, if it is printed out there will be no links to the studies.

IMPORTANT: the information in this document is not medical advice. An Italian physician who is informed about these issues is the cardiologist Nicholas Triglione, if you know of other cardiologists who are familiar with the LMHR phenotype please let me know.

We also talked about LMHR in this live with Dr. Stefania Cazzavillan and in this live With Dr. Tabarroni.

Se sei un LMHR ti consiglio anche di vedere questo video puoi attivare i sottotitoli in italiano

FOREWORD

In 2015 Dave Feldman began the ketogenic diet and after a short time his cholesterol increased greatly to 368 mg/dL. Since he is a software engineer, he starts taking many tests and monitoring his values. He finds that he is not the only one whose cholesterol has skyrocketed by following a ketogenic or low-carb diet, and in 2017 he publishes on his blog a article where the LMHR Lean Mass Hyper Responder phenotype is described for the first time.

WHO ARE THE LMHR?

People who are defined as LMHRs are those who have seen their cholesterol levels rise considerably after starting a ketogenic or low-carb diet:

LDL greater than or equal to 200 mg/dL
HDL greater than or equal to 80 mg/dL
Triglycerides less than or equal to 70 mg/dL

IMPORTANT: Before starting a low-carb or ketogenic diet these people had normal cholesterol levels.

With this type of lipid profile, the triglyceride : HDL ratio will be less than 1. When this index is less than 1.8, there is considered to be no cardiovascular risk. Bibliographic references. here.

Usually thin: men body fat less than or equal to 20%, women less than or equal to 23%. Usually they are exercised, often a lot. These two conditions, though, occur often, are not necessary to be defined as LMHR.

But why does LDL rise so high in these people? According to Dave, the explanation is the "lipid energy model."

LIPID ENERGY MODEL

In the lipid energy model, low carbohydrate intake results in the use of fats as the cells' main fuel. Glucose can circulate in the bloodstream smoothly, while fats cannot, because fats in the blood are like oil in water, they do not mix well. So the body carries fats in the blood on little boats called lipoproteins. These fats are actually called triglycerides: three molecules of fatty acids held together by a molecule of glycerol. The lipoprotein that carries the triglycerides to the cells is called VLDL (Very Low Density Lipoprotein). Once it has delivered its load of fatty acids the VLDL changes its name, becoming an LDL (Low Density Lipoprotein).

Therefore, when we reduce carbohydrates in our diet, our cells will absorb more triglycerides from the bloodstream to use as fuel. That's why when we eat a low-carb diet, usually triglycerides decrease. I say usually because if we eat low-carb, but take in an excess of calories over our requirements, this will be converted into triglycerides and we will still have a lot of them in our bloodstream.

Important: During a ketogenic, ketones are a secondary energy source; fatty acids still remain the primary source.

So summing up:

1) Cells need energy.
2) In a low-carbohydrate diet, the main fuel for producing energy is triglycerides.
3) VLDL carry triglycerides to the cells and after delivering them, they turn into LDL.

So LDL increases because it is the transport medium of the main fuel used by cells: triglycerides. To be precise, the transport medium is VLDL, which once delivered triglycerides become LDL.

For a more detailed and scientific description I recommend reading this article.

OREO COOKIE EXPERIMENT

I think it is also important in this context to mention the very interesting experiment By Nick Norwitz, PhD, also LMHR. Nick started the ketogenic diet to send his ulcerative colitis into remission (he succeeded). At the time of starting this experiment Nick had been on ketogenic for 1520 days. Before starting ketogenic Nick's LDL was 95 mg/dL and then rose steeply to 545 mg/dL.

I think it is important to make a point: the conditioning that saturated fats are bad for you is really die hard, in fact some doctors and researchers suggest that LMHRs limit saturated fats, assuming that they may be the cause of the increased cholesterol. So Nick in the study specifies that his LDL was at 545 mg/dL as "Was particularly thin and, incidentally, Was following a ketogenic diet low in saturated fat". He makes this statement to show that in his case limiting saturated fat did not lower LDL cholesterol.

The experiment consisted of two separate interventions: in the first intervention Nick took 12 Oreo cookies for 16 days divided into two daily meals. This amount provided him with 100 g more carbohydrate per day. "Oreo cookies were chosen as a canonical example of "unhealthy food" and as a demonstration that, for reducing LDL cholesterol in the LMHR phenotype, the quality of carbohydrates is not as relevant as their mere presence."

Nick is a very strict person and to eliminate possible confounding factors from decided to maintain the same level of ketosis even while taking Oreo cookies. This was made possible by taking exogenous ketones.

After the phase with Oreos, Nick followed a 3-month "cleanse" period, following a ketogenic diet that allowed him to return to his starting weight and similar cholesterol levels. This is very important, as it ensures that the starting conditions of the two interventions are similar and there is no residual effect of the diet with Oreos.

After this cleansing period Nick began the second intervention: he took for 6 weeks 20 mg of Rosuvastatin daily (chosen after consultation with the subject's primary care physician and a cardiologist) deemed sufficient to allow LDL-C levels to reach a stable state.

Results (I quote the text of the study)

"The subject's baseline BMI was 20.8 kg/m² with LDL cholesterol at 384 mg/dL. Supplementation with Oreo, reduced LDL to 111 mg/dL, a reduction of 71%, bringing LDL back within the 'normal' baseline range. The subject's weight increased by 1.5 kg during the Oreo phase. BMI returned to baseline (20.8 kg/m²) after ad libitum consumption of a ketogenic diet during the cleansing period.

Treatment with 20 mg per day of rosuvastatin reduced the subject's LDL from 421 mg/dL to 284 mg/dL, equal to a reduction of 32%. Therefore, LDL reduction with statins was less than half that achieved with Oreos, despite the 6-week intervention with statins versus 16 days with Oreos. The only notable side effects of statin treatment were myalgias, with a slight increase in creatine kinase."

This experiment seems to prove the validity of the lipid energy model:

• When we eat carbohydrates, we will have glucose in the blood, and the cells will use that as their main fuel.
• When we eat few carbohydrates, there will be little glucose in the blood, and cells will use triglycerides as their main fuel leading to an increase in circulating LDL needed to deliver triglycerides to cells (to be precise, LDL is generated after VLDL has delivered triglycerides).

If your cholesterol has risen as a result of reducing the carbohydrates in your diet, you might try increasing them for a few weeks and see if your cholesterol also drops. Nick took 100 g of extra carbohydrates for 16 days, divided into two meals. As a reminder, 100 g of pasta contains about 70 g of carbohydrates. It is not necessary to use low-quality carbohydrates such as Oreos.

IMPORTANT: A study done on only one person cannot be considered reliable. Because that person may be particularly sensitive to the intervention tested. Certainly it is interesting. It seems that following the study several LMHR people tried increasing carbohydrates and got similar results. However, they remain isolated cases; it would take a study with an adequate number of participants. Hopefully they will organize it soon.

IS IT DANGEROUS TO HAVE HIGH LDL IN LMHR?

In December 2023, Professor Matthew Budoff, a UCLA professor of medicine and researcher, has presented The preliminary results of a study on LMHRs. I find it important to emphasize that the research led by Professor Budoff is dedicated to improving procedures that can help physicians identify early patients at high risk for cardiac events and progression of atherosclerosis.

Lo the study was published at the end of August 2024, and the results were warmly welcomed by the entire international low-carb world as very positive.

80 LMHRs were compared with 80 people with "normal" LDL levels, and plaque, stenosis and coronary calcium levels in the two groups were compared.

Important to note that:

• the LMHR had mean LDL cholesterol of 272 mg/dL, while people in the group with "normal" LDL had mean LDL of 123 mg/dL.
• LMHRs had such high LDL cholesterol for an average of 4.7 years. Some had it much higher, the maximum value in study participants being 591 mg/dL
• Before starting a low-carb or ketogenic regimen, LMHR subjects had cholesterol at normal levels

I would like to mention that the study was funded by the Citizen Science Foundation founded by Dave Feldman. My idea to one day have a Live Better Foundation that funds research studies stems from here. Things only change when there are people willing to invest time and resources to make them change. Anyone can donate to the Live Better Foundation.

CAUTION: If you have high LDL as a result of a low-carb or ketogenic diet you may be taking the most predictive test for cardiovascular risk, the calcium score. It is a test that can be done almost only privately, but you need a doctor's prescription (often it can be provided by the doctor working in the testing center). The full name of the exam is: CT scan without contrast medium for coronary calcium score calculation. It is not an expensive exam, it costs less than 200 € usually. If they ask you for much higher figures, it means that they have not well understood that the examination you want to do, unfortunately it is still not well known. Specify well that it is a CT scan without contrast medium. We have discussed this examination extensively in the live With cardiologist Nicola Triglione. I report to anyone interested in learning more about cardiovascular prevention that on Dr. Triglione's website find a masterclass dedicated.

 Last important thought: the calcium score examination shows the current status of calcium in the coronary arteries, but that calcium may have been there for some time. This is explained very well by Dr. Paul Mason at minute 42:15 of this interview. "A high calcium score may be due to past damage. In this situation it may be useful to repeat the examination every 2 to 3 years, because it is very important to detect whether or not it increases. Ideally we want to have a lower increase of 5% annually, actually better if zero. I have had several patients who through proper lifestyle have completely stopped the progression of calcification.”

In English videos on Youtube you can turn on automatic subtitle translation, in this tutorial I explain how to do it.

Finally, I report that in the section insights on our website you will find written Italian translations of three very important presentations by Dr. Paul Mason:

Why your doctor thinks cholesterol is bad for you (a must read)
The truth about high cholesterol (somewhat technical but most interesting, explains oxidized LDL issue)
The real history of statins (very very interesting)

They can be downloaded as PDFs and printed.

Very well, the time has finally come to read Professor Budoff's important article. The exact words of the study are given from here on. The study in English can be found here.

INCREASED LDL CHOLESTEROL INDUCED BY CARBOHYDRATE RESTRICTION AND ATHEROSCLEROSIS: THE KETO TRIAL

BACKGROUND: In ketogenic and low-carbohydrate diets, increases in LDL cholesterol may occur. Lean, metabolically healthy individuals with a low ratio of triglycerides to HDL cholesterol seem particularly susceptible and give rise to a new phenotype called "Lean Mass Hyper-Responder" (LMHR).

GOAL: The aim of the study is to assess coronary plaque burden in LMHR and near-LMHR individuals with LDL ≥ 190 mg/dL compared with indivuduals with lower LDL from the Miami Heart Study (MiHeart).

METHOD: 80 individuals with LDL-C ≥ 190 mg/dL, HDL cholesterol ≥ 60 mg/dL, and triglyceride levels ≤ 80 mg/dL (parameters induced by a low-carbohydrate diet) and without familial hypercholesterolemia were included. These individuals were matched 1:1 with subjects from the Miami Heart Study. Coronary artery calcium and coronary computed tomographic angiography (CCTA) were used to compare plaque between groups and correlate LDL level with plaque level.

RESULTS: The mean age was 55.5 years, with a mean LDL cholesterol of 272 mg/dL (highest was 591 mg/dL) and a mean of 4.7 years on ketogenic diet. No significant difference was found in the presence of coronary plaque in the LMHR group compared with MiHeart controls (mean LDL 123 mg/dL). No correlation was also found between LDL level and coronary plaque.

CONCLUSIONS: Coronary plaque in metabolically healthy individuals with LDL ≥ 190 mg/dL induced by carbohydrate restriction through a ketogenic diet followed for an average of 4.7 years is not greater than in a group with a lower mean LDL of 149 mg/dL. No association emerges between LDL and plaque in either group.

Changes in LDL cholesterol in ketogenic diet studies

Wide variations in LDL cholesterol occur in studies of the ketogenic diet: it can either decrease or increase. Subjects with normal body mass index (<25 kg/m²) are the most likely to show an increase in LDL cholesterol following carbohydrate restriction.

In 41 randomized clinical trials with daily carbohydrate intake lower than 130 g, an increase in LDL cholesterol was observed only in subjects with "normal" body mass index (<25 kg/m²). In subjects with overweight or class I obesity, LDL cholesterol did not change, while in subjects with class II obesity, LDL cholesterol decreased.

"Lean mass hyper-responder" phenotype (LMHR)

"Lean mass hyper-responders" (LMHR) are individuals who, by adopting a reduced carbohydrate diet show striking increases in LDL cholesterol ≥200 mg/dL, along with high levels of HDL cholesterol ≥80 mg/dL and low triglycerides ≤70 mg/dL. This phenotype Is defined only by this triad of lipid markers and not by any markers of "thinness", although it is typically characterized by a low or normal body mass index.

Collecting data through coronary computed tomography (CCTA) on LMHRs will provide interesting new data as they have high LDL cholesterol and Apo B, but absence of other traditional cardiovascular risk factors and absence of genetic lipid dysfunction.

Objective of the study

To provide the first evidence on the presence or absence of coronary plaque in LMHR and near-LMHR individuals, we sought to test whether individuals with this phenotype (LDL-C ≥190 mg/dL, mean 272 mg/dL, on ketogenic for an average of 4.7 years) had a different coronary plaque burden than individuals with similar characteristics belonging to the Miami Heart Study (MiHeart).

To see the standard deviations of the values refer to the the study

The LMHR subjects had been on a ketogenic diet for an average of 4.7 years. Before starting the ketogenic diet they had normal LDL cholesterol levels (122 ± 36 mg/dL) and no genetic familial hypercholesterolemia.

Remarks

Current guidelines for the prevention of atherosclerotic cardiovascular disease recommend drug therapy when LDL cholesterol is greater than or equal to 190 mg/dL, regardless of the 10-year risk level. However, data on the evolution of atherosclerotic cardiovascular disease in individuals with elevated LDL cholesterol in the absence of metabolic disease and/or familial hypercholesterolemia are limited. This has raised questions about whether prevention guidelines should also apply to those with the LMHR or near-LMHR phenotype or whether this phenotype could represent a physiological response with a potentially unique risk profile.

Although clinical caution is needed, as comprehensive data on this phenotype are still lacking, the questions are scientifically legitimate: what is the level of risk associated with increased LDL cholesterol in metabolically healthy people on a low-carbohydrate diet? And why does this response occur in these people? One of the hypotheses to explain the emergence of the LMHR phenotype is the "lipid energy model," which postulates that the triad high LDL cholesterol, high HDL cholesterol, and low triglycerides emerges in the context of relatively lean people who follow a low-carbohydrate diet.

Lipid energy model hypothesis

Typically, when a relatively lean and metabolically healthy person adopts sufficient carbohydrate restriction to deplete liver glycogen stores, free fatty acids released from adipocytes are absorbed by hepatocytes and resynthesized into very low-density lipoprotein (VLDL). Increased VLDL export from the liver, in combination with an increase in lipoprotein lipase-mediated VLDL turnover in peripheral tissues (adipocytes and myocytes), generates an increase in Apo B-lineage LDL. Lipoprotein lipase activity similarly reduces triglyceride content in these lipoproteins and increases the transfer of surface membrane components to Apo A particles, increasing HDL cholesterol; this may explain the triad of high LDL, high HDL, and low triglycerides that defines LMHR.

Conclusions

After a mean duration of 4.7 years of high LDL cholesterol (mean 272 mg/dL) induced by carbohydrate restriction, a metabolically healthy group of LMHR subjects had no greater atherosclerotic plaque burden than a group of healthy subjects with markedly lower LDL cholesterol.

Given the preponderance of previous evidence on LDL cholesterol as a risk factor for atherosclerotic disease and the lack of evidence that this is also valid in the case of LMHRs, it is believed that the study of this phenotype should be a research priority.

Elena's note in simpler words: we are not sure that what we now believe to be correct about the danger of high LDL also applies to LMHR people. The data from the present research suggest to us that a high LDL value in people metabolically healthy is not a risk factor. Carrying out further research on these people should be a priority.

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