For Medical Professionals (Part I): Hyper-responders and the Lipid Triad

In recent months, there has been a growing focus in Lipidology on the phenomenon of high cholesterol levels for those going on a low carb diet. In particular, there have been recent case series published in the Journal of Clinical Lipidology discussing this specifically. This increased interest is certainly welcome, and we definitely advocate for expanding research on this important topic as it has been a central focus of our work for over five years.

It should first be emphasized neither myself (Dave Feldman) nor my colleague, Siobhan Huggins, are medical professionals and this doesn’t constitute medical advice. Moreover, we frequently make this distinction to those following our work. That said, while much of our research isn’t in a formal setting, we have accumulated a great deal of data and analyses that we’ve found helpful to ourselves and others. And, we’ll soon be partnering with doctors Spencer Nadolsky and Tommy Wood on a coming clinical study that will be testing these high levels of cholesterol and its association development of atherosclerosis. (More on this below)

Hyper-responders

The term “hyper-responder” has been used within the low carb community for several years, and it generally refers to those who see a substantial increase in their total and LDL cholesterol levels after adopting a low carb, high fat diet. We believe the term was first used by Dr. Thomas Dayspring in relation to this dietary outcome (originally discussed in an article on LecturePad.org, but this site is longer available).

The Low Carb Lipid Triad

We believe there is a particular lipid profile of enormous interest that goes beyond simply higher LDL cholesterol (LDL-C) seen in hyper-responders. It’s the combination of high HDL cholesterol (HDL-C) and low triglycerides (TG) alongside it. This is actually much more common in those having adopted a low carb diet who appear in excellent metabolic health. And we believe it’s an extremely important clue in helping to explain why LDL-C is higher in these individuals. We’ll go into this in further detail in the next part of this series.

Studies on those with this “triad” of high LDL-C, high HDL-C, and low TG are limited. But of those studies we’ve found, this profile associates with a low risk of cardiovascular disease overall, though slightly more than its counterpart triad with low LDL-C.

In this Framingham Offspring study, we highlight the odds ratio of those both with LDL-C ≥ 100 and 130 under the “High HDL-C” column (≥ 40 males, ≥ 50 females), and triglycerides < 100. (Colored markings and overlay mine)

In this observational cohort study of 2906 men aged 53 to 74 years free of IHD at baseline, we see this relationship as well. (Colored markings mine)

Thus, while these studies are not explicitly on those consuming a low carb diet, that may give us the most insight we can for the time being on what the risk level may be with this particular lipid profile.

Conversely, low HDL and high triglycerides are well established in the literature as key components to Atherogenic Dyslipidemia and Metabolic Syndrome overall. These profiles are strongly associated with Coronary Artery Disease and all-cause mortality.

Lean Mass Hyper-responders

The phenotype “Lean Mass Hyper-responder” (LMHRs) is a subset of these hyper-responders, and are characterized as having an extraordinarily pronounced lipid triad. These were first defined myself in an article on Cholesterol Code in July of 2017.

There are exactly three criteria for LMHRs:

  1. LDL cholesterol of 200 mg/dL or higher
  2. HDL cholesterol of 80 mg/dL or higher
  3. Triglycerides of 70 mg/dL or lower.
Figure 1 Individual lipid measures for high-carbohydrate (n=10) and low-carbohydrate (n=10) ultra-endurance athletes. Bars represent mean±1SD. HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol. TC, total cholesterol; TG, triglyceride. *P< 0.05; **P < 0.01; ***P < 0.001.

Much of the reason this phenotype was referred to as “Lean Mass” is that many who presented with this pattern were often very lean and/or fit while on a very low carb diet. But this term was strictly observational. We have since observed a few outliers that have been slightly overweight, but none as of yet that have been obese.

While counterintuitive, generally the highest levels of total and LDL cholesterol in the low carb community are found almost exclusively in LMHRs. Where it is often observed marginally higher cholesterol is found in those with poor health, LMHRs often presents with very low risk markers across the board, such as low blood pressure, waist-to-hip ratio, inflammatory markers, and HOMA-IR to name a few.

There has been speculation of a genetic component that might result in these substantially higher levels, such as a polygenetic FH or ApoE4. But shared data among this community has continued to show a wide genetic variability with no predominant genetic variants yet identified. Moreover, existing studies from Volek and Phinney on low carb athletes show a near ubiquity in this pattern as well. (At right, see Figure 1 from the study)

A Possible Model to Help Explain

We believe higher total and LDL cholesterol levels in those going on a low carb diet can be in part explained by greater synthesis, secretion, and turnover of triglyceride-rich VLDL, thus leading to a higher resulting quantity of LDL particles, particularly with LMHRs. This “Lipid Energy Model” is being developed by our team and we hope to have it published in the future. For a brief overview, you can visit our Lipid Energy Model poster, or watch my presentation to Stanford.

New Attention by the National Lipid Association

Recently, the Journal of Clinical Lipidology has published case series on this phenomenon, Keto diets, not for everyone and Extreme elevations of low-density lipoprotein cholesterol with very low carbohydrate, high fat diets. These data include some patients with concerning outcomes, such as the case of hypertriglyceridemia (high TG, rather than low) and xanthoma development.

To be sure, we’re not aware of any in the series published that meet the criteria of Lean Mass Hyper-responders, but this term is mentioned prominently in these articles and may result in some confusion that the phenotype can apply to everyone observing increased LDL cholesterol from diet without regard to HDL and triglycerides. Again, this phenotype is defined by all three all three cut points (per above), not LDL-C alone. Moreover, we would likewise agree that low HDL-C and high TG (characteristic of Atherogenic Dyslipidemia) is a concerning profile whether one has high or low LDL-C.

As our site was mentioned in the initial case series, we submitted a Letter to the Editor for our response. However, our letter was rejected. We’ve since published it as an Open Letter to the Editor which you can read here. We’ll continue to seek productive engagement with the National Lipid Association as we appreciate their exceptional ability to help move this research forward.

To speak plainly, if you’re a Lipidologist reading this now and you’ve been instinctively skeptical of our work, it’s entirely understandable given the high saturation of poorly researched advice given to patients found on the internet. Winning trust for our unique circumstances may take time for many in this important field, but we’ll continue to do our best in accomplishing it. Please be aware we’re always interested in discussing this crucial topic with professionals, sharing our community data, and helping in any way we can to further advance research in this important (and in our opinion, understudied) phenomenon.

Our Coming Clinical Trial on LMHRs

A year and a half ago we founded a fully qualified 501(c)(3) public charity, the Citizen Science Foundation. It was started in large part because we wanted to raise money for clinical trials to take this important data to the next level. And I’m pleased to say we’ve successfully crowdfunded a study that is now in IRB. This study will enroll 100 Lean Mass Hyper-responders and capture high resolution CT angiograms on each, both at the beginning and end of the trial one year later. With these comparison scans, we’ll have strong data on progression of plaque volume to better understand the true risk level for this phenotype.

We’ll have much more to share on this coming study once we’ve reached approval from the IRB.

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Ellie
Ellie
6 months ago

Dave and Siobhan,
I am so excited to follow your study on LMHR individuals and their risk of atherosclerosis! I am considered to be a LMHR based my my past NMR lipid tests. I can use as much info as possible to try to explain my situation to my cardiologist. Will your study include the investigation of small LDL particles? I seem to have an above normal amount, yet I follow a low-carb Keto diet. Hmm I am in the process of researching why I have a high number of small particle LDL and how to improve that. Thank you so much for all the help and information that you have provided us!
-Ellie

Ellie
Ellie
6 months ago
Reply to  Dave

Hi Dave,
I so do appreciate your response! On my last NMR my LDL-P was 2735, and my small LDL-P was 672. Is it correct to divide the LDL-P by the small LDL-P to obtain the percentage of the total LDL particle count? If so, mine would be 4.07%, which doesn’t look quite as horrible as I initially thought….. I look forward to following all the data/analysis your study will provide us. Thank you so much for all that you do for us. Sorry that you became a human-pin-cushion, but we are very grateful for your work!

  • Ellie
Siobhan Huggins
Admin
Siobhan Huggins (@siobhanh)
5 months ago
Reply to  Ellie

Hi Ellie –
Yes, you can divide one by the other to determine the percentage. But, to get the percentage out of the total, you divide 672 by 2735, which would be 0.247 or about 25% which is within the range Dave described that has been observed.

Ellie
Ellie
5 months ago

😀 thanks for your help!!!

Daniel Cordeiro
Daniel Cordeiro (@danielscseta)
6 months ago

“Again, this phenotype is defined by all three all three cut points (per above), not LDL-C alone.” This phrase should be in all caps, bolded, and in red.

Carol van def Harten
Carol van def Harten
6 months ago

Have you considered looking at the rs5082 variant of the Apo A ll gene? These individuals seem to hyper absorb dietary saturated fat.

TINA
5 months ago

OK

Paul Melzer
Paul Melzer
6 months ago

Thanks for the update!

Hilda Thielen
Hilda Thielen
6 months ago

Great post!!!!!

Mark
Mark
6 months ago

Hi Both,
Thanks so much for this study it’s really fascinating. I’m 59 and have had high cholesterol all of my life and have also been slightly overweight by around 12 pounds. 3 months ago I changed to LCHF diet and feel amazing. I am right down to optimal weight and exercise for about an hour 6 days per week. My lipids are typical of a hyper responder but I also had a very high ALT liver enzyme come back on my last liver test which I am really concerned about. I wondered if anyone else in the community has experienced this? I’ve been told that liver enzymes are often high with regular exercisers. I’ve also read that high amounts of protein intake may causes it. Other than that I am stumped as to why it is elevated. I intermittent fast 18/6 every day and don’t drink alcohol. Any advice would be hugely appreciated
Thanks
Mark

Siobhan Huggins
Admin
Siobhan Huggins (@siobhanh)
5 months ago
Reply to  Mark

Hi Mark,
We’re not doctors and can’t give medical advice so can only offer our thoughts in case they may be of interest. Just wanted to add on what Dave said.
Just anecdotally, I have seen this pop up a couple times with regards to exercise and elevated liver enzymes. Additionally this study investigated the scenario and did indeed find that ALT and AST could be elevated by exercise for several days afterwards, but GGT (another liver enzyme) was not elevated in the same situation. However, if it were me, I wouldn’t want to assume it was the exercise without first verifying and would likely want to work with my healthcare team to help clarify.

Efa Mortty
Efa Mortty
6 months ago

Hi all I am a Lean mass hyper responder total cholesterol 10.recently had a CAC score test. Result ZERO

Siobhan Huggins
Admin
Siobhan Huggins (@siobhanh)
5 months ago
Reply to  Efa Mortty

Thanks for sharing your results Efa! Anecdotes from both sides have definitely been shared, but hopefully the Lean Mass Hyper-responder study will further help start to clarify this profile and what it may mean for cardiovascular health, so people can make more informed decisions.

Sara Tirner
Sara Tirner
4 months ago

Just curious, in the planned LMHR study, will you attempt to have even representation between the sexes? Will you also differentiate between different age groups?

Siobhan Huggins
Admin
Siobhan Huggins (@siobhanh)
4 months ago
Reply to  Sara Tirner

Hi Sara – further information on the study will be shared as soon as it can, but for the time being all that can be shared has been posted to the Citizen Science Foundation website. Any updates, including updates on details that can be shared, will be posted there as well as soon as it is appropriate to do so. 🙂

Cheryl
4 months ago

Thank you so much for your excellent work. I really need it. I believe I am LMHR (TC=377, LDL=277, HDL=91, TG=41, HbA1C=4.8, BP low). My blood was taken after fasting for 18 hours. I am 59, female, and thin (5’4”, 108 lbs). I resistance train most days with cardio every 3 days and have been keto for 4 months. I look and feel better than I have in years. Only problem is osteoporosis (I wish keto could cure that.) My PCP nearly had her own heart attack when she saw my numbers. She begged me to see a cardiologist who specializes in lipids. That person is recommending statins or PCSK9 inhibitors. I’m taking the notes I’ve taken from your lectures to my meeting with her. Wish me luck. I won’t take those meds, but I sure hope I can at least get her to listen. I understand the requirements of standards of care, but it seems ludicrous (and malpractice) to give a healthy woman meds without even knowing my LDL particle size. Crimo, all she has to do is look at me. I wonder if she’ll “see”?

Colin
Colin
11 days ago

I have regularly had my levels tested over the last few years:

Note: I’m in the UK so I receive my results in mmol/L I’ve converted these to mg/dL using https://www.omnicalculator.com/health/cholesterol-units so might not be totally accurate

Jul 2019
Total: 6.69 mmol/L – 258.7 mg/dL
LDL: 4.60 mmol/L – 177.88 mg/dL
HDL: 1.46 mmol/L – 56.46 mg/dL
Tri: 1.39 mmol/L – 123.12 mg/dL

Oct 2020
Total: 6.40 mmol/L – 247.49 mg/dL
LDL: 4.40 mmol/L – 170.15 mg/dL
HDL: 1.50 mmol/L – 58 mg/dL
Tri: 1.10 mmol/L – 97.43 mg/dL

I am 52 male, my diet/weight over the last few years has been pretty consistent, lots of carbs, BMI of around 25 (height 179cm 84kg) and body fat % of around 15-18% (body fat based on using a Withings scale which could be a wee bit off). I exercise 2-3 times a week with brisk walks of 2.5 miles and hikes of between 1-3 hours.

In Sep 2021 I started a Keto diet and 18/6 IF regime of eating between 12pm and 6pm daily, and have maintained a <20g Carb intake for over 60 days now.

My weight is down to 77.5kg, BMI 24 and my scales reckon my body fat is now 12%.

I had my bloods taken 2 days ago (at 8:30am so a good 14 hours of fasting), usually it takes over a week for the results to come back but 1 day ago I received a call from a (panic sounding pharmacist) to give me the results below

Nov 2021
Total: 9.60 mmol/L – 371.23 mg/dL
LDL: 7.50 mmol/L – 290.02 mg/dL
HDL: 1.60 mmol/L – 61.87 mg/dL
Tri: 1.10 mmol/L – 97.43 mg/dL

So looking at this article I don’t seem to fit into the phenotype but thought I’d pass on my results. My LDL has “shot way up”.

I am planning to make an appointment with a local lipid clinic to help guide on if I should continue with my current diet.

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