BREAKING: Our Paper on Low Carb, LDL Cholesterol, and the LMHR Phenotype is Now Available

IMPORTANT UPDATE 1-28-2022: Our paper is now finalized with this guest post from Nick Norwitz now fully updated. Thanks again to the many wonderful readers who contributed their efforts in our final edit.

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.

Lean Mass Hyper-Responders (LMHRs), 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.

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:

  1. LDL cholesterol ≥ 200 mg/dL
  2. HDL cholesterol ≥ 80 mg/dL
  3. 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 athletic. In other words, the name LMHR is the hypothesis – that this triad present in lean people who go low-carb.

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 lowcarb 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.

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.

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 = 1.2×10-11). 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!

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 borderline 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!

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. And, a LMHR 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.

Media and Podcasts Around the Paper

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

Podcasts

DietDoctor #87 Best of 2021 (44 minutes)

https://www.dietdoctor.com/video/podcast/episode-87-best-of-2021

DietDoctor #86 with Bret Scher (84 minutes)

https://www.dietdoctor.com/video/podcast/episode-86-low-carb-ldl-hyper-responders

Human Performance Outliers with Zach Bitter #273 (71 minutes)

https://humanperformanceoutliers.libsyn.com/episode-273-lean-mass-hyper-responder-paper-with-nick-norwitz-dave-feldman

Low-Carb MD podcast #204 (118 minutes)

https://lowcarbmd.com/episode-204-dave-feldman-dr-nick-norwitz-and-dr-adrian-soto-mota

YouTube

Discussion Dr. Ken Berry (51 minutes)

Paper breakdown (24 minutes)

Video Abstract (of unedited version; 6 minutes)

Other Media

Original Twitter Announcement

American Society of Nutrition Top 15 Trending papers of 2021

15 Trending Nutrition Research Articles from 2021

Announcement: $20,000 Donation for Lipid Triad Analysis

BREAKING: Last night I posted a tweet (see below) curious if any data scientists would be interested in querying one of the major longitudinal datasets (such as UK Biobank) on the “Lipid Triad” (high LDL-C + high HDL-C + low triglycerides) vs All Cause Mortality.

To my great surprise, an anonymous donor has come forward who is interested in funding this analysis to publication for $20,000.

If you or anyone you know is a data scientist who would be interested in this endeavor, please reach out to me via twitter (@daveketo) or via comment below.

https://twitter.com/DaveKeto/status/1459694737493921792?s=20

Discussing the LMHR Study on the Diet Doctor Podcast

I had a great chat with Dr. Bret Scher, Medical Director of Diet Doctor, on the newly launched Lean Mass Hyper-responder study.

0:00 Introduction

3:06 Welcome, Dave Feldman

4:06 A rise in cholesterol for people on keto

12:05 Dave’s pushback in his research

20:14 Thoughts on the recent Women’s Health Study paper

29:39 Exciting news about Dave’s upcoming research

37:10 The concern about the data from a one-year study

43:26 What Dave hopes to achieve with the study

47:48 Switching saturated to mono-unsaturated fat in lowering LDL?

53:33 About Dave’s other work: Own Your Labs

1:03:49 Blood glucose and insulin on hypo and hyper caloric intake of low carb

1:08:40 Where to find Dave Feldman

THE LEAN MASS HYPER-RESPONDER STUDY LAUNCHES TODAY

The Citizen Science Foundation is proud to announce the launch of the Lean Mass Hyper-responder study, effective immediately.

This research will be conducted in partnership with the Lundquist Institute for Biomedical Innovation at Harbor-UCLA.

For official details, eligibility criteria, and how to join, please visit:

CitizenScienceFoundation.org/study

One Last Step

One of the challenges in this IRB process is that we don’t have a lot of latitude to give regular updates on it as it unfolds. Under most normal circumstances, aspects of the protocol draft and review, legal and liability considerations, and even the stages of approval are kept quiet until formal announcement and start of the study.

With that said, I’m quite confident we’re on the last step of this process. There are quite a few things on our long checklist with the IRB, and right now we’re on the last one. Hopefully we’ll have some news very soon.

Note: this is a duplicate post from our sister site, CitizenScienceFoundation.org