- If you know little to nothing about cholesterol->
- If you’re wanting to learn more about why cholesterol could be higher, particularly on a low carb diet->
- You can watch Dave’s recent presentation for Stanford University on the Lipid Energy Model.
- You can also check out the Lipid Energy Model poster here
- You can also check out or Frequently Asked Questions (FAQ) here
- If you’re looking to better understand the risk associated with high cholesterol on a low carb diet->
- If you’d like to understand possible benefits of cholesterol and the immune system, you can read Siobhan’s overview article on the topic here or watch her presentation here
- If you’d like to learn more about lipoprotein(a), you can watch Siobhan’s presentation on it here
- Lastly — you can always just ask us anything our Questions Page. (Just be aware our site does not constitute medical advice and we always recommend consulting with your doctor.)
I had a great chat with Dr. Bret Scher, Medical Director of Diet Doctor, on the newly launched Lean Mass Hyper-responder study.
3:06 Welcome, Dave Feldman
4:06 A rise in cholesterol for people on keto
12:05 Dave’s pushback in his research
20:14 Thoughts on the recent Women’s Health Study paper
29:39 Exciting news about Dave’s upcoming research
37:10 The concern about the data from a one-year study
43:26 What Dave hopes to achieve with the study
47:48 Switching saturated to mono-unsaturated fat in lowering LDL?
53:33 About Dave’s other work: Own Your Labs
1:03:49 Blood glucose and insulin on hypo and hyper caloric intake of low carb
1:08:40 Where to find Dave Feldman
The Citizen Science Foundation is proud to announce the launch of the Lean Mass Hyper-responder study, effective immediately.
This research will be conducted in partnership with the Lundquist Institute for Biomedical Innovation at Harbor-UCLA.
For official details, eligibility criteria, and how to join, please visit:
One of the challenges in this IRB process is that we don’t have a lot of latitude to give regular updates on it as it unfolds. Under most normal circumstances, aspects of the protocol draft and review, legal and liability considerations, and even the stages of approval are kept quiet until formal announcement and start of the study.
With that said, I’m quite confident we’re on the last step of this process. There are quite a few things on our long checklist with the IRB, and right now we’re on the last one. Hopefully we’ll have some news very soon.
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)
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:
- LDL cholesterol of 200 mg/dL or higher
- HDL cholesterol of 80 mg/dL or higher
- Triglycerides of 70 mg/dL or lower.
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.
Note from Dave – this post is actually a complete “unroll” of my Nov 2019 twitter thread. We’ve linked it many, many times and thus Siobhan rightfully pointed out I should just place it in CC as its own post. As always — and with emphasis — this is not medical advice.