Guest Post: Making of a LMHR?

Note from Dave: Mark Lightell is actually a frequent commenter at the LMHR Facebook group, but he is notably an advocate for reduction of LDL cholesterol and ApoB, and a firm believer in the Lipid Heart Hypothesis. However, he’s also interested in our work and saw a clear opportunity to make a contribution with this experiment. I think you’ll find this guest post on his experiment very interesting. Also, see Nick’s companion analysis for this experiment, and our added note at the end.

Vegan Diet vs Keto/Carnivore Diet – My Attempt to Create a LMHR

The LMHR phenotype paper by Nick Norwitz, Dave Feldman, and colleagues suggests that LMHRs, rather than being a genetic anomaly, may be a reproducible metabolic phenomenon.  If this is true, it should be possible to recreate this LMHR lipid profile in most people who are metabolically healthy (low TG/HDL ratio) and lean, and in whom dietary energy is derived primarily from fat with minimal carbohydrate intake. Due to LDL particles having a half-life of 3 days, I further expect the LMHR phenotype could be seen over the course of 2 weeks.

My Hypothesis

In people who are lean, metabolically healthy (exhibiting a low TG/HDL-C ratio), and with lower BMI, adherence to a very low carb ketogenic diet will produce a LMHR lipid profile within a timespan of 2 weeks.

I fit these criteria, with the added benefit of having a high energy demand due to my daily exercise (50+ miles of running per week).  According to the Lipid Energy Model, proposed to mechanistically explain the phenotype, this should amplify the effect due to my body requiring a greater volume of lipoproteins (LDL) to traffic triglycerides for energy.  I’ve never done a low carb diet, but given that I should be the ideal candidate for this effect, I decided to give it my best shot.

Dec 2020 – 15k

General Health and Physical Fitness

I’m a 29 year old endurance athlete, 5′ 9″ with lifelong weight around 130-135 lbs.  I’m in good health with no known medical conditions. I take no medications or supplements.  My most recent race (January 2022) was a 10k in 40:11 (~6:28 min/mile pace).

Experiment Design

  • Step 1: Reduce LDL-C as low as possible with a carb-based Vegan diet.
  • Step 2: Immediately switch to a 2 week Keto-carnivore diet to maximally increase LDL-C.
  • 3 weekly lab draws as follows: March 3 (Vegan), March 10 (Keto), March 17 (Keto).
  • Lab draws will be ~14 hours water fasted.
  • All food weighed via food scale.
  • Maintain aerobic training (50+ miles per week).

In case you’re pressed for time, here’s the summary:

Over the two week experiment my LDL-C increased over 2-fold, albeit not quite to the LMHR LDL-C threshold of 200.  Specifically, my LDL-C increased from 68 to 139, which suggests to me that it is very much possible to induce the LMHR metabolic phenomenon, but that 2 weeks is not a sufficient time frame. I suspect 3-4 weeks would have shown LDL-C of 200 or more.

Main Lab Results

Lab changes greater than 20% are shaded gray

Sample Meals & Daily Routine

Weight

The Start

I wanted to begin the experiment by establishing a low baseline LDL-C. After the conclusion of my December 2021 Vegetarian experiment (where I brought LDL-C down to 64) I was enjoying the freedom of “no diet,” eating frequently at restaurants.  I’ve always been weight stable so it wasn’t that I had gained weight, but rather that it was extremely likely my LDL-C was far above the 64 I got in December.

So starting February 5, 2022 I began the work to reduce my LDL-C.  I went back to my proven Vegetarian diet, but was tempted with ideas to achieve an even lower LDL-C than last time, so I changed it to a Vegan diet.  I removed animal products, got dietary cholesterol down to 0mg, reduced saturated fat as much as possible, while maximizing PUFA intake via walnuts, and increasing fiber.

Week 1 – Vegan Foods

  • Walnuts, Wheat bread, Soymilk, Cheerios, Campbell’s Vegetable Soup, Blueberries, Diet Coke

At the time, I thought the PUFA-to-saturated fat ratio was key to getting my LDL-C even lower, ideally to 50s. I had promising results going from a 3:1 to a 6:1 PUFA-to-saturated fat ratio during my December 2021 Vegetarian experiment, so naturally I thought increasing the ratio to 9:1 would produce an even greater effect.

Week 1 – Vegan Routine

  • Two meals a day
  • Wake up at 11am
  • Breakfast of ~2800 calories. Finish breakfast by ~1pm
  • Go to work at 2pm
  • Lunch at 7pm, just Diet Coke or water
  • Get off work at 11pm
  • Run after work at ~11:30pm
  • After run, Dinner at ~1am, ~400 calories

I found this diet easily tolerable and enjoyable, even if fairly restrictive and mundane.  I ended up running 52 miles this week, with total carbs averaging 418g/day.

So March 3, 2022 arrives and I have labs drawn.

Results: Week 1 – Vegan

  • HDL: 80 
  • Trig: 48 
  • LDL: 68

Pft, 68??  Where’s my 50?  I found this result disappointing, as I really thought my “improvements” would beat my last result of 64 from December 2021 to give me my lowest LDL-C yet. From this result I’ve concluded that the PUFA-to-saturated fat ratio is not as powerful as I thought for reducing LDL-C.  While LDL-C did not behave as I predicted, it was not the goal of this experiment (just an “along the way” project).

It was time for the Keto/Carnivore arm of the experiment.  

I tried Dave Feldman’s baseline diet of Colby jack cheese, beef franks, and hard boiled eggs but found the diet intolerable after 2 days, primarily due to the hard boiled eggs.  So I switched to uncured bacon, Colby jack cheese, and diet coke for the remaining 5 days.

Week 2 – Keto/Carnivore Foods

  • Day 1 & 2: Colby Jack Cheese, Beef Franks, Hard boiled eggs, Diet Coke
  • Day 3 – 7: Uncured Bacon, Colby Jack Cheese, Diet Coke

Week 2 –  Keto/Carnivore Routine

  • 3 Meals a Day
  • Wake up at 11am
  • Breakfast of ~2000 calories. Finish breakfast by ~1pm
  • Go to work at 2pm
  • Lunch at 7pm, ~800 calories
  • Get off work at 11pm
  • Run after work at ~11:30pm
  • After run, Dinner at ~1am, ~600 calories

The switch to bacon had a promising start but eventually became difficult to tolerate, which is to be expected after consuming 12 packs of bacon in 5 days.  I managed to stick with it until the first Keto lab draw.  I ended up running 74 miles this week, with total carbs averaging 5g/day.

So March 10, 2022 arrives and I have labs drawn.

Results: Week 2 – Keto/Carnivore

  • HDL: 84
  • Trig: 51
  • LDL: 90  

LDL-C increased by 32% in 7 days.

Not quite what I expected.  I was hopeful for something in the 130s range, so I found this a bit disappointing.

At this point I was quite sick of bacon and Colby Jack cheese, so I adopted a slightly more flexible Keto/Carnivore diet while maintaining the supreme directive of minimal carbohydrates.  

Week 3 – Keto/Carnivore Foods

  • Grilled Chicken, Scrambled Eggs, Butter, Pork Sausage, Pepper Jack Cheese, Mozzarella, Cream Cheese, Pepperoni, Heavy Whipping Cream, Diet Coke

Week 3 – Keto/Carnivore Routine

  • 3 Meals a Day
  • Wake up at 11am
  • Breakfast of ~2200 calories. Finish breakfast by ~1pm
  • Go to work at 2pm
  • Lunch at 7pm, ~800 calories
  • Get off work at 11pm
  • Run after work at ~11:30pm
  • After run, Dinner at ~1am, ~400 calories

I ended up running 52 miles this week, with total carbs averaging 12g/day. 

Finally March 17, 2022 arrives and I have labs drawn.

Results: Week 3 – Keto/Carnivore

  • HDL: 85
  • Trig: 44
  • LDL: 139  

LDL-C increased an additional 54% in 7 days. (104% increase over 2 weeks.)

Better, but at the start of this I fully believed it was going to be a slam dunk of an experiment with LDL 200+.  Instead, what I feared most ended up happening: A middling result that effectively demands a longer experiment.  What would have happened in just one more week?  I was this close to finding out, but wow was this diet difficult and absolutely unenjoyable.  Maximal carb elimination made the diet so restrictive to the point that I could not continue it past 2 weeks.  I had so much drive and motivation at the start, but that was largely sapped from me on this diet.  Food became a chore that gave me no enjoyment, I was not hungry most of the time, and generally did not feel great.  It was made worse by the fact that, given my activity levels, I needed to consume ~3400+ calories per day of food that I did not care for just to maintain my weight. 

All that to say: Yes I had a miserable time, and yes I fell short of my goal to create LMHR lipids at will, but I’m still glad I did it.  Now hopefully someone else can take the torch and try for 3-4 weeks to see what would have happened. 

Why did you do this experiment in the first place?

I find lipids and biomarkers pretty fascinating.  Especially the nature of LDL and its function in the body.  I know it’s a controversial topic, so to clarify my position I will say that I’m convinced of LDL/apoB being causal in cardiovascular disease.  My main interest is the quantification of that risk.  

If LDL/apoB is the only risk factor, what is the risk for someone like me? An athlete with high HDL, low triglycerides, and low body fat, but on an “anything goes” diet of restaurant food my LDL-C will rest at around ~130.  How much risk do I have between 68 and 130?  I don’t think anyone has an answer to that, other than the basic binary answer of “yes it’s more atherogenic”.  I think it matters if we’re talking months to a year vs years to a decade+ in life expectancy.  Some people may be willing to make that trade of not having to limit their food choices for a lifetime if the cost is “minimal” with regard to elevated LDL/apoB.

That’s why I find Dave Feldman’s research into this topic interesting, because he is essentially exploring a niche where increases in LDL may not be a pathological response, but rather a benign adaptive one.  While I would like for that to be the case, I’m also aware that the preponderance of evidence we currently have is stacked against that idea, but that doesn’t mean it’s not an idea worth exploring.  If it did end up being true, it would be a fascinating discovery if only because literally, “how does that work?”.  And for those of us in good health with high HDL and low triglycerides, where elevated LDL/apoB is our only risk factor, we would no longer have to limit food choices to keep this marker within range.  

In summary, I think there is something interesting happening here with this massive increase in LDL, and this was my attempt at adding my piece to the puzzle. 

Miscellaneous Results

hsCRP – Increased to 1.45 on Keto/Carnivore, compared to my baseline in the 0.17-0.39 range. I think it’s interesting how my hsCRP perfectly matches how unwell I felt without carbs.

Platelets – Arguably the most unusual result. Platelets were below ref range (common for me) in Week 1 – Vegan and Week 2 – Keto. Only Week 3 – Keto showed normal platelets.

HDL-P – Increased to the 35.9umol/L on Week 3 – Keto/Carnivore, which is the highest it’s ever been. I’m usually quite low in HDL-P, even when I’ve had 92 HDL-C.

Bilirubin – Decreased linearly with the duration of the keto diet.  Bilirubin went from my normal of 3.2 down to 1.7 by Week 3 – Keto, which is the lowest I’ve ever seen it.

Resting HR – The Keto/Carnivore diet resulted in a higher resting HR.  At first I thought it was because I went from 50 to 70 miles in one week, but my HR was at its highest after reducing my mileage down to 50 in the final week of the experiment, so this is clearly an effect from diet and not training load.

Insulin – This behaved as expected.  Insulin was already low on a carb-based diet, and went even lower on a Keto diet.

Comprehensive Nutrition and Health Metrics Chart

Supporting Data

LabCorp Reports

NMR LipoProfile Reports

Body Fat % and Weight Scale (Eufy Smart Scale P1)

Resting HR (Garmin Forerunner 245)

Note from Nick: I want to begin my concluding remark by repeating two quotes from Mark: (i) “I find lipids and biomarkers pretty fascinating,” and (ii) “If LDL/apoB is the only risk factor, what is the risk for someone like me?” These quotes represent questions I and other LMHR ask themselves every day. Notably, the fact that Mark’s personal hypothesis leans towards isolated high LDL-C being sufficient to drive atherosclerosis (and, thus, less in line so with some in the LMHR community) does not preclude him from sharing a genuinely scientific interest in the LMHR phenomenon, nor should it. This n=1 experience is a testament to how those with different hypotheses can share scientific curiosity and collaborate in genuine attempts at pursuing scientific truth. For more thoughts, read my commentary here.

Our Paper on Low Carb, LDL Cholesterol, and the LMHR Phenotype is Now Finalized

Note from Dave: this guest post from Nick Norwitz discusses our #LMHRpaper, which as of today, is now finalized. 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

Help Us Raise $46,000 for the LMHR Study

Hello everyone and Happy New Year!

We’ve been quite proud of how well we’ve set up efficient budgeting with our research partners for this important study. Lundquist and our bloodwork providers are providing strong discounts along with Keto Mojo and GB HealthWatch completely contributing their products and services.

Unfortunately, there’s one area of cost we don’t have much control over: travel and lodging.

Rising Costs for Travel, Participants

At the time we were building our projected expenses, it seemed likely we could negotiate packages between plane, car service, and hotel coming in around $250 combined per person, per trip. And to be fair, that was pretty realistic in December 2020 when travel industries were struggling, which was when we published this video.

However, the IRB process didn’t happen in short time as we’d hoped. We weren’t fully approved until August of 2021 when I announced the study launch. Unsurprisingly, as travel across the nation has resumed in those nine months, prices for all these travel services have increased, which is where we are now.

There have been a handful of other expenses that were unanticipated. One of our bloodwork partners has required us to set up a specialized account for clinical trials that involves greater expense. Another overseas bloodwork partner needs samples shipped as frozen throughout the trip, which costs quite a bit. And we did add a $50 meal voucher per trip for participants as recommended strongly by our research partners to accommodate their stay.

All together, we believe we’ll need to raise an additional $97,000.

OwnYourLabs.com Contribution

The good news is that our other venture, OwnYourLabs.com, has been accumulating proceeds throughout 2021 to contribute directly to the Citizen Science Foundation. I’m pleased to announce this totals $51,000, thus cutting the amount we need to raise to $46,000.

(And also, props to each and every one of you who bought your labs through OwnYourLabs.com as all of them contributed directly to this study!)

How You Can Help

There are three primary ways you can show your support:

  • Contribute directly to the Citizen Science Foundation. Again, we are a fully qualified, 501(c)(3) Public Charity. Naturally, this is the easiest and most direct way to help. The contribution is generally tax deductible – please talk to your tax preparer for more details. It’s worth noting we have a 0% admin overhead, save third party services (such as credit card processing).

  • Order your private bloodwork through OwnYourLabs.com. Proceeds are continuing to accumulate for further funding directly to the CSF to support this study. Moreover, if you opt in, you can further help citizen science by volunteering your anonymized data for a discount (see site for details).

  • Share, retweet, repost – spread the word! Obviously, the more you can help us let others know about this important cause, the better. 🙂

Blasting Off Into 2022

Make no mistake, 2021 has been a watershed year for us. There have been many substantial developments both in what has been completed and what has just begun.

New Research Spotlight for Siobhan Huggins

Early in the year my colleague, Siobhan Huggins was diagnosed with Lipedema and quickly shifted focus to this and related conditions. In a very short time, she has developed a number of hypotheses that she has since presented on, with more presentations planned (including Low Carb Boca this upcoming January). She is also now communicating closely with leadership at the Lipedema Project to see where future collaboration on this important topic may be useful to the community and for seeking to increase the knowledge on Lipedema where possible. As a result, just last last week Siobhan was selected as Program Co-Director for the upcoming April Symposium, which will focus on ketogenic diets for Lymphatic and Fat Disorders.

https://twitter.com/siobhan_huggins/status/1474168501203922948

Lean Mass Hyper-responder Study Launched

After an extensive process for the protocol, we received official IRB approval and announced the study on August 27th. This study will be focusing on LMHRs and borderline LMHRs, and note it is still recruiting.

For more details and to see if you’re eligible, visit our official recruitment page to learn more.

Feel free to watch the announcement video here:

Lean Mass Hyper-responder Paper Published

Our new paper for low carb impacts on lipids and the Lean Mass Hyper-responder phenotype was published in Current Developments in Nutrition. Here’s the direct link:

https://doi.org/10.1093/cdn/nzab144

You can watch this interview from Diet Doctor where my coauthors and I discuss this paper in depth:

Lipid Energy Model Paper in Development

I know it’s been a long time coming, and you can see much of its progress through this time in our poster, my Stanford presentation, or even the super simplified, Lipid Energy Model in a nutshell (just 5 minutes). But there have still be plenty of updates to expand the model since then.

The new collaboration of Nick Norwitz, Adrian Soto-Mota, and myself have helped shaped the model for its coming submission for publication. I’m incredibly honored to be working with such extensive talent and can’t wait until we finally have our 1.0 up in the literature.

Debut of the Triad and All Cause Mortality

A recent analysis was performed with the Women’s Health Study data that concluded the highest LDLc levels correlate to the highest All Cause Mortality (ACM) where compared to low and mid ranges of likewise HDLc ≥ 50 and TG ≤ 100 levels. The process in how it came to this finding is very interesting and worth a coming post of its own which I’ll be doing in collaboration with a biostatistician.

Of special interest, the event actually helped to solve one of the largest problems in this space I’ve long struggled to tackle. For some time I’ve wanted to fashion a criteria for analyses that would be “pre-approved” as much as possible by all major voices in this debate. This would be the ideal given it would be in place before approaching the datasets we’d apply it to. But in reality, this was also likely near impossible given the wide variety of opinions across the spectrum on what the right methodology might be.

Fortunately, this current analysis and its originating criteria were widely accepted and shared by prominent voices for low LDLc (including many I’ve long discussed this with online). Its final iteration excluding standard attributes of metabolic syndrome is of special significance, and exactly what I was hoping given this helps better stratify toward metabolic health. In other words, over a short time we not only have mutual interest in looking to the triad vs ACM, but a lot of agreement on the specific parameters to use for the approach. This helps provide an important roadmap for our coming analyses.

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