I mean for this post to serve as a transparent and prospective article of scientific intent, not a contract or final document. I will express the aim, describe the design, pose my hypothesis and provide considerations.

Overview:

Aim: To assess the impact of Oreo supplementation versus statin therapy on LDL-C levels in a lean-mass hyper-responder (LMHR) as an n = 1 crossover trial.

Design: The protocol is based on a two-arm crossover design. The participant (me) will assume a baseline ketogenic diet for 2 weeks prior to baseline lipid testing. Next, I will consume the baseline diet supplemented with 12 Oreo cookies per day for 2 weeks, along with exogenous ketone supplementation dosed in order to maintain ketosis throughout the protocol (rationale below). Lipid tests will be collected weekly. After a washout period, sufficient to return to baseline weight, I will be treated with 20 mg rosuvastatin for 6 weeks.

Hypothesis: If the LMHR phenotype emerges in the context of carbohydrate restriction and tends to reverse with carbohydrate reintroduction, supplementation with Oreos may have a similar (or stronger) effect than statin therapy in lowering LDL-C.

Disclaimer This is NOT a health intervention. Please do NOT try this at home.

More details and thoughts:

We’ve observed repeatedly that the lean mass hyper-responder (LMHR) phenotype is induced by carbohydrate restriction and can be reversed by carbohydrate reintroduction. (For interesting background, see Table 4 of the first LMHR paper; and for historic context, see Dave Feldman’s white bread experiment).

Another – and the conventional – option for lowering LDL-C/ApoB levels is pharmacotherapy, with statins being first-line standard of care.

So, an obvious and important clinical question arises: Which is more effective at lowering LDL-C/ApoB in LMHR carbs or statins? Of course, results will vary by individual, and dose matters.

Nevertheless, I desire to run a randomized crossover trial with LMHR trying to assess that very question. Resource scarcity (time and, more so, money $) make that project infeasible at this time – but that doesn’t mean I can’t pilot the concept on myself… with flare!

Disclaimer – AGAIN – for emphasis: DO NOT try this at home! This will be a scientific demonstration and is not meant to serve as any form of health advice. You can see I’m really trying to hammer home this point, so please take it seriously.

I will perform a rigorously controlled n = 1 crossover comparing Oreo supplementation to statin therapy for lowering LDL-C in an LMHR (myself). The design at present will be as follows:

• I will follow a standardized baseline ketogenic diet for 2 weeks as a run-in phase, followed by a baseline lipid panel.

• I will then begin Oreo supplementation for 2 weeks, during which time I will add 12 cookies / day to my diet, which amounts to ~100 g carbs and 640 kCal from Oreos.

Of note, this will be a dietary addition, i.e. baseline diet will remain the same. I deem this design decision preferable over controlling for calories as addition of Oreos would require reductions in fat or protein. If the Oreo addition (without other dietary subtraction) does indeed lower my LDL-C, then saturated fat intake cannot be the driver of the LDL-C.

I have also decided to remain in ketosis throughout the Oreo phase via supplementation with pure D-BHB exogenous ketone. The rationale here is to change as few metabolic variables as possible: remaining in ketosis through all phases will isolate increased Oreo (carbs) intake as a variable versus increasing carbs and knocking myself out of ketosis.

Why? There has been speculation the state of ketosis reduces LDL receptor expression to drive up LDL-C [for more see 1:21:52 in the below-linked YouTube]. I think it’s more likely the carbs are repleting liver glycogen, reducing the trigger for VLDL synthesis and export (and subsequent turnover) via the Lipid Energy Model. Remaining in ketosis with Oreos will better test the former versus the latter.

To be as rigorous as possible, I’ll aim to dose the exogenous D-BHB four times daily, targeting levels of ~1.2 – 2.0 mM, similar levels to my baseline diet for the study.

• Lipid tests will be collected weekly, while 12 – 16 hours water fasted.

• After the Oreo phase, I will undergo a washout. The time for this isn’t set but will be determined by how long it takes me to reduce my weight to baseline (prior to Oreo arm) and stabilize for at least 1 week. To compare apples to apples, I want to start the Oreo and statin arms at a similar body composition and LDL-C level, and my body fat will very likely influence my LDL-C.

• The statin arm will last 6 weeks. Yes, this arm will be longer than the Oreo arm. While I think 2 weeks will be enough of the Oreo effect (and, honestly, Oreo hyperphagy for more than a half a month sounds impractical and/or too unpleasant and/or unsafe for me), 6 weeks is considered a “fair” medication trial for statins given the medications half-life and time to reach steady state. I’ve consulted a cardiologist and a lipidologist on this matter. Rosuvastatin will be dosed at 20 mg.

For more, I appeared on PlantChompers (episode released 8/15/23: https://youtu.be/4KYsa7zG9TE) to discuss LMHR and this crossover experiment.

Concluding comment: Why Oreos?

I chose Oreos for this study because they are near universally recognized and accepted junk food. I could have used cereal, banana, pasta or Coke. Any carb should work. But the Oreos provide “flare” and – yes – I want attention on this one. I don’t want attention for my own sake, but in order to gather interest and financial resources for a larger study that will have implications on mechanism and clinical management of LMHR. Speaking candidly, it’s a challenge to draw attention to this topic. Demonstrations like this – if (or because!) they are apparently crazy – will do the trick. And, depending on what the data show, we might be challenged with the uncomfortable question: If Oreo hyperphagy lowers LDL-C in this context, is it a desirable outcome compared to no intervention at all? I like uncomfortable questions… of the right sort…

On this day last year, May 20th, 2022, we published the Lipid Energy Model in Metabolites.

To say this was a milestone in my unlikely journey into research would be an understatement. The Lipid Energy Model (LEM) started as a simple idea around why I suspected my LDL cholesterol (LDL-C) would rise substantially on a low carb, ketogenic diet. I kept doing self experiments (N=1) and writing about it here, back when this was just a simple blog.

Over half a decade later, we have a rapidly evolving, published model that proposes core concepts surrounding this phenomenon and likewise makes bold, testable predictions. If you haven’t yet, I strongly recommend giving it a read. But if you’re pressed for time, I also put in quite a bit of work on its video abstract here (below).

Dream Team of Authors

A big game changer that made this all possible was our slate of coauthors who each had uniquely valuable contributions, Adrian Soto-Mota, Bob Kaplan, David S. Ludwig, and Matthew Budoff. I was incredibly humbled to have the great Anatol Kontush co-senior authoring it with me given his prior work was foundational to LEM. But I want to give an extra large shoutout to my good friend and LEM collaborator, Nick Norwitz. I’m certain we wouldn’t have gotten as far as we have without his considerable talent and drive.

Overall Reception

The paper has performed surprisingly well in spite of its specific niche.

Our overall Altmetric score is currently a whopping 339. (Over 20 alone is exceptional)

The paper also performed “higher than 99% of its contemporaries” in all four categories: All Research Outputs, Outputs from Metabolites, Outputs of a Similar Age, and Outputs of a Similar Age from Metabolites.

Challenges to the LEM?

Both Nick and I were quite certain our inboxes would be filled with challenges to the LEM once it had gotten published. However, to date the publisher hasn’t received a single Letter to the Editor. Moreover, we’ve actively corresponded with many senior lipidologists and cardiologists seeking critical feedback wherever possible.

The only challenge generally proposed via social media was the suggestion the LMHR phenotype can be mostly explained by the consumption of saturated fat. However, we’ve now published on this phenomenon extensively in papers prior to, and following, the LEM publication. Nick even wrote an extensive guest post on the topic here. (We also have some very powerful data on this topic dropping very soon.)

Coming LMHR Studies on Risk

Naturally, there is a degree of skepticism about whether this phenomenon is both physiological and poses minimal risk, underlining the significance of our direct investigation via the LMHR Study conducted at Lundquist at UCLA. We are pleased to share that participant recruitment concluded in February, followed by a brief presentation of an initial overview at Low Carb Denver. The findings thus far have been quite compelling, and we anticipate publishing them soon.

Moreover, these initial data have sparked further discussion for a companion study that we’re currently working on. I should have more updates on this in coming posts here and at CitizenScienceFoundation.org.

We’re beyond excited to announce the Lean Mass Hyper-Responder has completed enrollment. Needless to say, this has been a long awaited milestone.

We’ve updated the recruitment page at CSF to let everyone know we are no longer taking participants for the study.

Again, each of our 100 participants will make a total of two trips to the Lundquist Institute. The first will provide the baseline scan, then they will return a year later for their second scan. Once all participants have completed both scans, we’ll move ahead with the final analysis.

We’re still in the process of completing our funding for this study as travel costs have proven more challenging in the current economic environment. Again, thanks to everyone for all their support!

Hello everyone!

You may have noticed we’ve been posting less frequently here at CholesterolCode.com (CC). This isn’t for lack of interesting things to share and update you on – it’s because Siobhan and I are now fully entrenched in both formal research through the CitizenScienceFoundation.org and expanding our blood testing service, OwnYourLabs.com.

A Quick Recap

Here’s a brief rundown of everything Dave been doing over the last year:

• Four papers published on the Lipid Energy Model and the Lean Mass Hyper-Responder phenotype, including one first authored
• Produced video abstracts on two of these papers (here and here)
• Four presentations and eleven interviews
• And, of course, extensive ongoing work with the LMHR Study out of UCLA

Here’s a brief rundown of everything Siobhan been doing over the last year:

• One paper published (but stay tuned for updates…)
• First report of preliminary data on the Voices of Lipedema Project via The Lipedema Project
• Much time spent researching lipedema pathophysiology resulting in the KetoFest 2022 presentation recapping the current working model of how and why lipedema may develop
• Other presentations on lipedema including one on possible mechanisms behind the efficacy of Ketogenic diets for management
• Additional work as the research specialist for The Lipedema Project including as-of-yet announced research projects, continued work on The Voices of Lipedema Project, helping to coordinate two events per year for the lipedema community (via Lipedema Simplified), and other related side projects such as co-writing an article on lipedema for Keto-Mojo

The Developments We Hoped For

We’ve long used CC as a means to stay close to the community and help promote the research we would like to see happen. But each of these circumstances have changed –– in a good way.

Before, the community was small and it was uncertain how prevalent things like the LMHR phenotype were. Now, as of this writing, the LMHR Facebook group and its sister CholesterolCode Facebook group boast over 9,000 members each(!), and it’s very active in knowledge sharing.

Also, we previously wrote emails and visited NLA conferences in the hopes we could get researchers to help advance this science. Now we’re working directly with researchers on the endeavors we dreamed of, both in the publication of papers and running studies directly.

To put it simply, we’ve replaced our responsibilities in pitching these projects with actually doing them.

What’s Next for CC?

We’re going to continue to be an information hub for our research, such as hosting an active published papers page.

• We’ll also continue to post major announcements here.
• However, we don’t have the bandwidth we once did for actively responding to all comments. Thus, we’re going to be retiring the Questions Page, and will not be actively responding to comments on CC.
• More of the key questions folks are looking for will be answered in our current and ongoing published research, such as the LMHR study. For other questions, consider reaching out to us on social media via Twitter (@realDaveFeldman, @siobhan_huggins), or tagging us in the Facebook groups.

Again, we can’t thank everyone enough for their continued support at getting our research where it’s at — there’s so much more to come!