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.
- The paper is open-access and a PDF can be downloaded from this link: doi.org/10.1093/cdn/nzab144
- A 24-minute talk covering the results of the paper can be found by clicking here
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:
- 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.
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)
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
Your wording of the conclusion is going to continue to be problematic. Suggest more specificity in your wording. E.g. “greater LDLc elevation on a CRD tends to occur in those who appear to be highly insulin sensitive (as indicated by TRG/HDL ratio)”
We do not have data on insulin sensitivity. Thus, the above posed statement would be overreaching the data. “Low cardiometabolic risk” is an accurate statement as “cardiometabolic risk” refers to the TG and HDLc components of metabolic syndrome, not LDcL. The statement is appropriate the the data we collected.
However, we agreed with the constructive comment from another individual that there would be no harm in the addition of the word “otherwise” to provide further clarification. The conclusion of the abstract will now read: greater LDLc elevation on a CRD tends to occur in those with otherwise low cardiometabolic risk.”
[“cardiometabolic risk” refers to the TG and HDLc components of metabolic syndrome]. This is an incorrect statement, on my understanding (but happy for you to show me any literature where this is stated). On the contrary TG and HDL are two cardiometabolic risk factors. But there are other cardiometabolic risk factors such as blood pressure, fasting blood glucose and waist circumference. If you have not measured these and have no data on them, I do not think you can just take the risk factors that you did measure and make a claim about cardiometabolic risk based solely on them. That’s not how a risk assessment works! You can’t just measure 1 or 2 risk factors and conclude low risk! Just the same as if you had only measured blood pressure, and fasting glucose and no other risk factors, I don’t think it would be justified to state “Cardiometabolic risk refers to the blood pressure and fasting glucose components of metabolic syndrome”, or report a context of low cardiometabolic risk just based on that subgroup having normal blood pressure.
Thank you for the added input, Philippa. We’ve been doing a number of meetings lately where we’re discussing finalizing aspects of the paper — I’ll be sure to bring this point forward for consideration.
You are right, you don’t have data on insulin sensitivity…I was just trying to propose something that would be less of an overreach than what you currently had! Really, your conclusion should simply be “greater LDLc elevation on a CRD tends to occur in those with a lower BMI and lower TG/HDL ratio.” and leave it at that.
Just out of curiosity..thats a lot of ‘potentially unreliable data’….were these mostly people literally making typos in their data entry, or did you have a bunch of people putting in values in mmol/l or any other trends?
We were quite strict with respect to excluding data in order to minimize bias given the dataset with which we were working. The criteria can be revealed in publicly available R-code linked in the paper. Yes, there were cases of questionable units and entry values that were excluded. To be clear, our exclusion rules were largely automated and set a priori such that we couldn’t intentionally or unintentionally recluse data that we didn’t like.
Fair enough and good to have a priori rules set
Over what period of time did the addition of some sweet potato cause the reduction in LDL – is this a quick fix you can take just before a blood panel, or something to implement over weeks or months?
Have you seen Dave’s white bread experiment? If not, search it and let me know your thoughts. I hypothesize that in most cases the reversal of the phenotype is quite quick, given the 2-4 day half-life of LDL. That said, one can not exclude further modifications that may occur over longer periods of time mediated by microbiome changes, epigenetics, or other factors.
Is there a differentiation between ‘fit’… ie endurance/strength and percentage body fat?
Are there people fitting criteria who are not lean?
First off, nice play on words. As to your question, “fit” is a vague term. In it’s broadest definition, it seemly means that an organism is well-suited to its environment. In that sense, a walrus is far more fit than a lion in the context of Arctic. Colloquially, fit is used to refer to “in good shape” or “sporty” and/or able to perform athletically. As you can see that doesn’t leave much to latch on to in the way of operationalization. Lean, by contrast and at least as I understand it, refers to someone with relatively low body fat and low-normal BMI. The catch is that there are people with higher BMI who still have low-body fat. They have high-lean mass, but are they lean? Take Dwayne Johnson as an example. His BMI is 34.3. He is obese. I wouldn’t call him lean, but he has a lot of lean mass and little body fat. Would he be LMHR if he went low-carb? I’m not sure. It’s still not clear wether BMI or body fat is more tightly linked to the phenotype, as we did not have body fat data for this paper. We hope to assess that question in future. Sorry for the ramble answer.
I am 3 months into Keto Carnivore and over a year into Keto. On Monday I had blood work. Cholesterol of 303, LDL of 213, HDL of 78 and Trig of 58, BMI 21.4. I thought they must have swapped my sample with someone else. 69 years of active lifestyle and 4 to 5 days week in the gym, I was to put it mildly, shocked. My wife, through Dr Berry’s site found this site and I have been following this with great interest. Thank you for your work and some clarity on this issue.
Thanks for sharing Tom. You reaction is understandable. Dave and I both had similar reactions. For me, I saw an initial increase in LDL from 95 to 321, with my HDL jumping to ~110. My TG run around 40. I was shocked and, coming from a medical family (four doctorates between my two parents) we were all confused and concerned. I never would have guessed that lab value would eventually inspire a scientific interest that connected me to a software engineer, revolutionized my professional network, and redirected my career interests. Life is unpredictable.
This happened to me (& I refused the statin). My LDL came down to something more like normal when I started taking thyroid (my TSH was high & my T3 borderline low, but I had antibodies to thyroid).
It’s been probably over a decade since the cholesterol stuff started & I’m still alive anyway. 🙂
FWIW, I wasn’t fat when I started low carb, but I did lose weight & am now at the lower end of normal (bmi of 18.5 & I do exercise regularly). On the last test, HDL 110, LDL 15o & TG 48.
Thanks for sharing Beth. Based on the thyroid panels I’ve seen from LMHR (including myself) most don’t have hypothyroidism either clinically or by biomarkers (in particular TSH, although free T3 is also interesting). That’s an entirely different conversation that I’d like to have with a few specific people and a research topic on which I’d like more data.
Humans becoming fat-burning beings from high carb fat storage persons.
We ought to help every person figure out how to be able to get rid of the extra inflammatory fat.
#removingbarrierstohealing
Agreed. Let’s remove the barriers and give people a complete array of options. I like that you used the word “help” because I think it’s important to emphasize that this is someone each persons has to figure out on their own. It’s a teach a man to fish situation. It’s about education and self-exploration.
I’ll make the other point here that I made on twitter, because I also think it was misunderstood, from listening in to the clubhouse discussion. I know that you did not collect ethnicity data and my point has nothing to do with that. My point is that you are claiming to have observed a context of ‘low cardiometabolic risk’ based essentially on the observed TG/HDL ratio. However this ratio is known to not well represent cardiometabolic risk in people of black African descent. Your paper should include this fact as a limitation, in my opinion. https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC5582986/
There are almost certainly factors modifying the phenotype, including polymorphisms roughly linked to geographic ancestry. As an initial observational study describing: the inverse relationship between BMI and LDLc change + the inverse relationships between TG/HDLc and LDLc change + classifying the LMHR phenomenon, it was not within the realm of this paper to generate different thresholds based on genes or ancestry/ethnicity/race (with the latter two not technically having a biological basis) or sex. The LMHR study will have genetic data, and in future we hope that research will be able to link the lipid triad to underlaying lipid dynamics and that different thresholds can be determined in a more personalized manner. Again, once the final manuscript is online, we invite you to compose a letter to the editor.
Unfortunately, your reply has not addressed the point I made, which was entirely to do with your interpretation of the implication of the low TG/HDL ratio. If you are observing X, which you then claim to mean Y, but X is known to not mean Y in a large section of the population, it would be good practice to discuss this fact in your discussion, IMHO.
Did you test the pattern of LDL particles?
Hi Dave, just new here and Im very interested and would greatly appreciate it if you could give me some tips or biohacks to raise my HDL (55) and lower my Trigs (115)….Im on a quasi keto lifestyle considering that one day a week I have no restriction in to what I eat. Thanks for the feedback.
I definitely saw this phenomena with myself. Decrease in TG, rise in HDL and LDL. My LDL is not high enough for the study though. Thanks for pursuing and making this a reality!
Fascinating
To be completely honest, I am here just because I am freaking out and looking for evidence that I am not going to have a heart attack and drop dead any second now. (Reading this site is helping.)
I am a lean and athletic 40-year-old female (rock climber/runner/cyclist/mountaineer) with a BMI of 19. I was recently diagnosed with T1 diabetes, and subsequently stopped being vegetarian (after 20 years) AND started the Bernstein protocol (30g of carbs per day). My ever-evolving (and recently crazy) lipid profiles (and other figures):
My CRP followed a similar pattern 0.2mg/L – 0.4mg/L – 0.2mg/L. Ketones were 0.48 mmol/L at diagnosis (Oct.) and 0.3mmol/L in the last labs (Nov.).
All else seems to be fine, but I am an emergency room nurse, hence my training makes it impossible for me to not freak out about these numbers. Needless to say, I am freaking out. My endocrinologist, at one of the largest uni/research hospitals in Canada (MUHC), will be doing some follow-up and more detailed lipid tests.
Could I be one of these weird LMHRs?
Hi Aleksa,
We’re not doctors and can’t give medical advice so can only comment with our thoughts in case they may be of interest.
It does indeed look like you fit the profile of a Lean Mass Hyper-responder e.g. someone who is typically lean, active, and powered by fat (e.g. on a low carb/ketogenic diet). You may be interested in the Lean Mass Hyper-responder facebook group as there are many there with similar profiles who explore the latest research regarding it, their experience, their perspective, and how they’ve approached having the profile (e.g. taking steps to move away from the profile and how they did so, sticking with it but getting additional testing to keep an eye on things, etc). Additionally, you may find the recent Lean Mass Hyper-responder paper of interest as well.
We can’t say whether this profile is of concern or not (as, again, we’re not doctors and can’t give medical advice), but we can offer some resources to explore different perspectives on the topic. For example there’s this presentation from Dave looking at high LDL in the context of high HDL and low triglycerides from a cautiously optimistic perspective, plus this post from Dr. Nadolsky looking at the same topic from a cautiously pessimistic perspective.
Thoughts?
Hi Julie,
We’re not doctors and can’t give medical advice so can only comment with our thoughts in case they may be of interest.
It looks like you fit the profile of a Lean Mass Hyper-responder e.g. someone who is typically lean, active, and powered by fat (e.g. on a low carb/ketogenic diet). You may be interested in the Lean Mass Hyper-responder facebook group as there are many there with similar profiles who explore the latest research regarding it, their experience, their perspective, and how they’ve approached having the profile (e.g. taking steps to move away from the profile and how they did so, sticking with it but getting additional testing to keep an eye on things, etc). Additionally, you may find the recent Lean Mass Hyper-responder paper of interest as well.
We can’t say whether this profile is of concern or not (as, again, we’re not doctors and can’t give medical advice), but we can offer some resources to explore different perspectives on the topic. For example there’s this presentation from Dave looking at high LDL in the context of high HDL and low triglycerides from a cautiously optimistic perspective, plus this post from Dr. Nadolsky looking at the same topic from a cautiously pessimistic perspective.
For those who decide they are not comfortable with it for the longterm, or would just like to confirm it is dietarily induced, the most consistently effective method (presuming it is dietarily induced) that we’ve seen demonstrated by people thus far is to decrease fat and proportionally increase carbs (e.g. isocaloric carb swapping), which is discussed here.
Thank you for your response, I appreciate the fact you cannot give medical advice. I’ve recently joined the Facebook group and hope to find out more information on this subject. Many thanks, Julie from Liverpool UK xxx
Anyone know what is the effect, if any, on HDL/TG/HbA1c of reintroducing carbs in an effort to reduce LDL as to LMHRs? Did not see this in the most recent paper on LMHR phenotype or in the 2 videos on YouTube. Thanks.
Hi Joseph – it may depend on the LMHR in question, what type of carbs they’ve added, etc but it would be a good question for those in the Lean Mass Hyper-responder facebook group – especially for those who’ve shifted away from the profile for a longer period (e.g. a few months) and have updated bloodwork.
LMHR here with life-long affliction from highly intense lactose intolerance. Started OMAD with alternate day fasting and low carb around March 2020 (start of pandemic shutdown). Recently discovered that this lactose intolerance has disappeared (!!!!!!). Cannot explain it (change in microbiome?), but it is demonstrably true. Can digest dairy without any problem for first time in my life. One example is merely anecdotal, but thought it worth posting in case other LMHRs have had this or a similar change in dietary problems.
Very interesting, Joseph! It might be of interest to others to post this in the LMHR facebook group where it may be more visible to others in case they’ve experienced similar. I haven’t heard of lactose intolerance, specifically, easing up/going into remission as far as I recall but I’ve heard other things like seasonal/pet allergies and sometimes other allergies/intolerances improving or apparently going away in passing from some who have gone on diets that have improved their metabolic health (I usually hear about this in terms of low carb/keto/carnivore, possibly just because those are who I’m generally exposed to). It is not always and not in everyone but I have heard people comment on it occasionally.
If this is more than coincidence and ends up being a pattern that is spotted, it would definitely be interesting if more rigorous study could take place in the future to see what the mechanism might be. 🙂
Congrats regardless!