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)
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.
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.
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.
This site has been uncharacteristically lacking in posts the last month and a half, mainly due to a large number developments behind the scenes. Here we’ll be providing a summary of what’s been happening:
This was in large part due to our new video and website overhaul. We’re actually quite pleased with the functional updates especially, as we wanted better searching and selecting compared to our original version.
While we’re quite ecstatic for the extraordinary increase, it has certainly required a bit more bandwidth on our part, particularly for Siobhan, who heads up operations for OYL. This now has her working significantly longer than she was before and thus we’re doing some back office reshuffling on resources to make OYL a much more central role to her responsibilities.
I’ll concede, it’s some of the most intensive collaboration and detail deliberation I’ve experienced in a long time. Quite a bit of work is being injected in getting the foundation of this study properly set forth.
Many, many rules. While I can’t discuss these things openly until the IRB is approved, I’ll just say there are a number of different expected procedures and processes in both setup and execution of the study that certainly exceeded my original expectations.
And the documents… to say we’ve had many documents to write and revise (and revise again, and again) would be an understatement. There’s just a lot of work that is required in getting this set for its launch.
All that said, I feel quite blessed to have such a strong team to work with in making this happen. Many thanks to Spencer Nadolsky, Tommy Wood, and our partner center (which we hope to announce soon).
Siobhan and Lipedema
One recent and personal development is the possibility Siobhan may be diagnosed with Lipedema. This hasn’t been a confirmed diagnosis yet, but she’ll be seeing a specialist this coming week to find out with greater certainty.
The origin of this being a possibility was actually due to her recent #EpicFast experiment. In posting pictures at the end of the experiment, many familiar with Lipedema reached out to her on the topic given her weight loss distribution was very characteristic of the condition.
Unsurprisingly, Siobhan has ramped up her research for this topic and has already begun making headway on better understanding the condition. To be sure, she starts off with several advantages given her background already in lipids, inflammation, and of course, her extensive wealth of prior bloodwork throughout her metabolic transformation. Many (like myself) are predicting bring a lot of new innovation to understanding this important and prominent disease.
Presentations, for Limited Engagement Only
I decided early in the year to keep presentations at a minimum. I had already turned down a few offers simply because I had too much on my plate with the IRB. But I went ahead and did four over the last two weekends. They all had a few subtle differences, but shared much of the same material. I’ll concede this was a bit more exhausting than I was expecting given the existing work load, but it was nice to unload some of our latest advancements for the Lipid Energy Model.
The videos won’t be posted for a while, but we’ll add them to an article here when they are.
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.