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.
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.
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.
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.
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:
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 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.
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!
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…
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):
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.
The contributors to CholesterolCode are not doctors, and cannot give medical advice. The information contained on CholesterolCode is for general information purposes only and is not intended to replace a professional diagnosis, nor is it intended to treat, cure, or prevent any medical conditions. You are encouraged to confirm any information obtained from this website with additional sources, and review all information regarding any medical condition or treatment with your physician. Always consult with your doctor before making any changes to medication, diet, or lifestyle.