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Support for the Existence of Lean Mass Hyper-Responders

Support for the Existence of Lean Mass Hyper-RespondersShareFollow us 261.1k

Quick Summary tl;dr

 New study shows that LDL cholesterol elevation on a low-carb diet is associated with leanness and metabolic health (low triglyceride to HDL ratio).

Those individuals with the most extreme low-carb lipid triad (LDL ≥ 200, HDL ≥80, TG ≤ 70) are termed “Lean Mass Hyper-Responders and, true to their name, they were significantly leaner than other participants.

Moderate reintroduction of carbohydrate (50 - 100 grams) on very low-carb diets markedly lowers LDL in Lean Mass Hyper-Responders.

To quote my colleague, Dr. Adrian Soto-Mota, MD PhD, “This study is intended to start a discussion, not end one.”

The final version of the Lean Mass Hyper-Responder (LMHR) paper was just released!

I’m pleased to report that, even in the early days since the initial release of the unedited accepted manuscript (on November 30, 2021), this paper has stimulated vigorous discussion, risen to the top of its journal for all time reads, and is among the top 15 trending papers across all American Society of Nutrition associated journals for the year 2021. So, what’s all the fuss about? This blog is intended to get you up to speed so you can be part of the discussion and follow this exciting line of biomedical research as the conversation continues to heat up.

Support for the Existence of Lean Mass Hyper-Responders

Lean Mass Hyper Responders, a History

Let’s start at the beginning. In 2017, a software engineer, Dave Feldman, made a curious observation: the people who adopted carbohydrate restricted diets who typically exhibited the most pronounced increases of LDL cholesterol (so-called “bad cholesterol”) were often very lean and/or athletic.

But the elevations in LDL exhibited by these lean persons on low-carb diets had two peculiar features that set it apart from other forms of high LDL:

Support for the Existence of Lean Mass Hyper-Responders

Extreme LDL Increases

First, the LDL increases were much larger than those typically associated with living an unhealthy lifestyle. When most doctors think about high LDL related to being unhealthy and eating a poor diet, they think about levels in the high 100s. But lean people on carbohydrate restricted diets were anecdotally observing LDL levels of 200, 300, 400, and even 500 mg/dL or more.

In fact, some LMHRs exhibit LDL levels as high as persons with homozygous familial hypercholesterolemia, a rare and devastating genetic condition (1 in 1,000,000) that likewise associates with very early heart disease.

Very High HDL and Very Low Triglycerides

Second, when lean people do see increases in LDL on a carbohydrate restricted diets, they tend to be accompanied by high HDL (so-called "good cholesterol") and low triglycerides (TG), fat in the blood. This pattern of high HDL and low TG is exactly opposite the profile of “atherogenic dyslipidemia,” which is defined by low HDL and high TG, and is, at present, the predominant risk factor for cardiovascular disease ( Libby, 2021).

Simply put, when lean people on low-carbohydrate diets saw increases in LDL they were quite often in the context of otherwise excellent metabolic health markers. Therefore, Dave created a set of three cut points that combine to define what would become the LMHR phenotype:

  • LDL cholesterol ≥ 200 mg/dL
  • HDL cholesterol ≥ 80 mg/dL
  • TG cholesterol ≤ 70 mg/dL

Now for a couple comments on the definition of LMHR. First, why these cut points? Well, in addition to approximating threshold levels Dave Feldman was empirically observing in the world around him for lean athletic people who went low-carb, these triad of cut-points were chosen for just how extreme they are.

To meet someone with LDL ≥ 200 is rare. To meet someone with HDL ≥ 80 is rare, and to meet someone with TG ≤ 70 is rare. Thus, the probability of meeting someone who meets all the cut points by chance is highly unlikely. Otherwise put, if someone presents with this triad, it seems reasonable to hypothesize that the markers are associated with each other.

Other important point is that LMHR are only defined by this triad, and NOT by any measure of leanness. This is confusing because “lean” is in the name of the phenotype, but that’s only because the triad — at least in Dave’s point of view in 2017 – tended to occur in people who were lean and/or athletic. In other words, the name LMHR is the hypothesis — that this triad presents in lean people who go low-carb.

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Study Suggests That LMHR Exist

Being Leaner & Having Lower TG/HDL Predicts Larger LDL Increases on a Low-Carb Diet

It was a long time coming, but we finally put that hypothesis to the test in a scientific study.

In this new study, published in Current Developments in Nutrition, we collected survey data from people who were low-carb, who were not on statins, and who had lipid data from before they started their low-carb diet as well as recent lipid data from on their low-carb diet.

Then, rather than massaging the numbers to conform to our hypothesis, we engaged in a “hypothesis-naïve exploratory analysis” in which we took all the data we had on respondents — including age, sex, BMI, and current and pre-low carb LDL, HDL, and TG levels — and asked a computer to tell us which factors were most strongly and reliably associated with increases in LDL after starting a low-carb diet.

The results were clear. No matter how we approached the question (be it multivariate linear regressions or hypothesis-naïve computer-generated decision trees [Supplemental Figure 3]) we found that having lower BMI and a lower TG/HDL ratio associated with larger increases in LDL.

Hypothesis-naïve exploratory analysis finds that having lower BMI and a lower TG/HDL ratio associates with larger increases in LDL on a low-carbohydrate diet.

The relationship can be clearly seen in the bar graph below. The further you go to the left, the lower the BMI. The further you go to the back, the lower the pre-diet TG/HDL ratio. And the height of the bar is the median increase in LDL.

Support for the Existence of Lean Mass Hyper-Responders

Picking Out the LMHR

After establishing that those who are leaner with lower TG/HDL ratios exhibited larger increases in LDL with carbohydrate restriction, it made sense to try to separate the true LMHR (those who met all three cut-points) from the larger cohort and see how different they really were…

Of the 548 participants that met the inclusion criteria, 100 were bona fide LMHR (which is a lot, considering many people don’t believe LMHR exist). And, true to their name, they were Lean!

The average BMI of a LMHR was 22.0, as compared to 24.6 for the rest of the low-carb sample in this study (between group p = 1.2 x 10-10). Furthermore, LMHR exhibited higher LDL, higher HDL, and lower TG, with mean values of 320, 99, and 47 mg/dL respectively.

And, importantly, LMHR did not differ in terms of their pre-diet LDL when compared to the non-LMHR population. In fact, median pre-diet LDL was 135 mg/dL in non-LMHR and 133 mg/dL in LMHR. No difference!

In the Lean Mass Hyper-Responders (LMHR) paper, the average LDL, HDL, and TG of LMHR were 320, 99, and 47 mg/dL on low-carb, respectively. This was despite normal pre-diet LDL levels.

A LMHR Case Report Shows the Phenotype is Reversible

Now, you’ve probably sensed a lot of enthusiasm from me, but don’t mistake intellectual excitement about a fascinating observation for a suggestion that high LDL levels in LMHR are benign.

Setting my own hypotheses aside, we do not yet know if the risk associated with high LDL is any different in the context of LMHR as compared to any other context. And most experts would agree that high LDL is dangerous, regardless of cause.

This very question — is high LDL harmful in LMHR? — is currently being assessed in a prospective study (data from which are expected to drop in 2023). And I will be vocal about the data when they emerge, whatever they say.

Nevertheless, for the time being, many or most LMHR patients and their doctors are concerned about their high LDL. That said, many of those same people find a low-carb way of life to be tremendously beneficial for their various metabolic disorders. This begs the question, can you “fix” the LDL problem (perceived or true) through lifestyle? The answer, yes — at least partially.

As part of this study, we also wrote up a case series of five patients who were LMHR or near-LMHR. These patients all exhibited extraordinary increases in LDL upon starting a ketogenic diet. And, importantly, all were tested for genetic mutations associated with high LDL and all tested negative, supporting the notion that being a LMHR is not a genetic condition but a metabolic phenomenon.

One patient saw his LDL increase from 116 to 665 mg/dL (no surprise, he was the leanest).

All of the patients refused, or were intolerant of, statins and instead opted to reintroduce a moderate amount of carbohydrate, ~50 – 100 grams, in order to transition from a very low-carb ketogenic diet to a diet that was still low-carb (<130 grams net carbs per day).

Impressively, all participants saw their LDL drop by at least 100 mg/dL, with larger drops occurring on those with high levels. The patient who saw his LDL increase to 665 mg/dL exhibited a 480 mg/dL drop in LDL by doing nothing more than adding about a small, sweet potato’s worth of carbs per day.

Stop and think about that for a second. In this context, a sweet potato per day could drop LDL by almost 500 mg/dL!

Support for the Existence of Lean Mass Hyper-Responders

Future Directions

This is only step one, putting the LMHR phenomenon on the map. This paper suggests that LMHR are real and, if I do say so myself, really interesting!

In my opinion, no true student of health and/or medicine can observe this phenomenon and not be intrigued.

But what this paper does not do is explain the “how.” It likewise can’t evaluate the risk. Those are the subjects of upcoming projects.

  • We are working on formulating an official “Lipid Energy Model” manuscript, explaining the potential mechanisms at work behind the findings of this paper.
  • We are compiling some preliminary patient data as case series to provide clinical vignettes of this LMHR phenotype.
  • And, a LMHR responder study also recently launched out of ULCA, courtesy of Dave’s efforts, that will track plaque progression in the coronary arteries of 100 LMHRs.

This paper was just the first domino...

Additional Notes

  • This paper describes a phenomenon. It does not explain the mechanism nor comment on risk.

  • Saturated fat intake was not measured; however, it seems highly unlikely variations in saturated fat intake can explain the findings as this would assume that, across the study sample of 548 people, lean people and those with good metabolic health preferentially and reliably consumed more saturated fat.

  • The phenomenon is likely metabolic, not genetic. This is supported by at least three lines of evidence in this study:

    • LMHR have normal pre-low carb LDL levels. In fact, in the study, pre-diet LDL levels were the same between LMHR and non-LMHR.
    • It’s been anecdotally observed that LMHR who gain weight exhibit drops in LDL, despite no change in their genetics.
    • Most importantly, genetic testing in the five patients in the case series were negative. Genetic testing performed on other subjects not reported in this study have also been negative.
    • This does not rule out a polygenetic contribution or gene-environment interaction.

If you found this blog interesting and/or you think this line of research is important, my team and I would appreciate if you go directly to the paper, download it, and try to give it a read. Downloads really help the article metrics and will help to further amplify the discussion around this important phenomenon.

For a list of selected podcasts, videos, and media releases that cover this paper, please see the links below (Updated January 28, 2022):

Podcasts:

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Other Media:

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Dr. Nicholas Norwitz
PhD in Ketogenics and Metabolism, Oxford University

Nicholas Notwitz

Dr. Nicholas Norwitz is a new shining star in nutrition science. This 25-year-old Ivy League Valedictorian obtained his PhD at Oxford University in just two years and is now pursing his MD at Harvard Medical School. His research expertise is ketosis and brain aging; however, he has published scientific papers on topics ranging from neuroscience to heart disease to gastrointestinal health to genetics to bone health to diabetes.

You can find Nick on Twitter at @nicknorwitz.

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