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The article entitled “Oreo Cookie Treatment Lowers LDL Cholesterol More Than High-Intensity Statin therapy in a Lean Mass Hyper-Responder on a Ketogenic Diet: A Curious Crossover Experiment”, authored by Dr. Nicholas G. Norwitz and Dr. William C. Cromwell, was published in Metabolites (ISSN: 2218-1989) and has been discussed in various media outlets. Dr. Nicholas G. Norwitz has written the following science appetizer based on his latest research:

“You have high cholesterol”. These are four words many doctors are familiar with administering and of which many patients know the sting. But what happens when a patient’s cholesterol levels are not just high, but “into space” HIGH—so high, in fact, that many doctors, upon seeing such numbers, probably think either (i) this must be a lab error or (ii) this patient should probably go coffin shopping. I am joking, of course, but with a purpose: to highlight the stomach-turning fear that accompanies levels of LDL, “bad”, cholesterol (LDL-C) that arise in some patients we now call “Lean Mass Hyper-Responders” (LMHRs).

What are LMHRs? What causes this phenotype? Can it be reversed? If so, how?

What if I told you the answer to the last two questions were “Yes!” and…“Oreo cookies.” And no, this is not a joke.

But let us back up and return to the first two questions:

What are LMHRs?

LMHRs are people who, upon adopting a ketogenic diet which is low in carbohydrates and high in fat, see their LDL-C skyrocket, along with high HDL cholesterol (HDL-C) and low triglyceride levels. This triad defines LMHRs. Simply put, LMHRs are individuals who exhibit high LDL-C, high HDL-C and low triglycerides on a low-carbohydrate or ketogenic diet.

Although there is no “leanness” criterion, they are typically lean, active and metabolically healthy.

In fact, in a recent meta-analysis of 41 randomized controlled trials, researchers found that, as a group, only those studies of low-carbohydrate diets in lean individuals (BMI <25 kg/m2) exhibited LDL-C increases, whereas there were no such increases in individuals with overweight or obesity, and in patients with class II obesity, LDL-C actually dropped. There was also an inverse association between LDL-C and BMI in low-carbohydrate diets, and the effect of being lean as a “risk factor” for high LDL-C dominated over the effects of saturated fat intake.

Now, what causes the phenotype?

The Lipid Energy Model can explain the LMHR phenotype. Briefly, in lean insulin-sensitive people on low-carbohydrate diets, there is a large shift from carb burning to fat burning as liver glycogen stores drop. Free fatty acids are repackaged into triglyceride and exported from the liver abord VLDL particles. In peripheral muscle and fat tissue, these VLDL particles are “turned over” rapidly by lipoprotein lipase (LPL), depleting the VLDL spheres of their triglyceride core. In so doing, the VLDL shrinks into LDL, which has a longer residence time, and the rim of the VLDL is shed and picked up by HDL particles. This results in the high LDL-C, high HDL-C and low triglyceride triad that defines LMHRs.

Based on this understanding, a hypothesis arises: one should be able to reverse the LMHR phenotype, and lower LDL-C, by re-adding carbs to the diet of an LMHR who is otherwise eating a very low-carb diet.

Based on prior studies and prior clinical observations, the first author of the present study (me: Nicholas G. Norwitz, a Ph.D. scientist, MD student and LMHR himself) attempted to test that hypothesis in a bold fashion and by choosing a “provocative” carb: Oreo cookies.

In a recent small (n = 1) crossover trial, I ate 12 Oreo cookies per day for 16 days and then, after a washout period of 3 months, was treated with 20 mg rosuvastatin for 6 weeks as a comparator.

The Oreo cookie supplementation lowered my LDL-C from 384 mg/dl to 111 mg/dl, a stunning 71% drop in 16 days. By comparison, the most high-dose statin therapy lowered my LDL-C over 6 weeks by 32.5%.

Thus, in an LMHR with astronomically high LDL-C, “bad cholesterol,” Oreo cookie supplementation was two times as effective at lowering LDL-C compared with high-dose statin therapy.

SHOCKING! However, this is consistent with prior data and the prediction of the Lipid Energy Model.

So, the next question is, why would I conduct such an odd experiment? The answer is simple: to raise awareness. This experiment was a form of “legit bait,” as it were, a dramatic metabolic demonstration meant to turn heads and get communities asking questions about LMHRs and the Lipid Energy Model.

While I may be biased, I do think the study of LMHRs and the Lipid Energy Model has a tremendous amount to teach us about human metabolism and physiology. Understanding these phenomena could lead to breakthroughs in science and medicine. But to make those advances, we need engagement, collaboration and resources. The first step to acquiring those is awareness.

Now you know. Are you curious to learn more?

If you are, here are some places to start:

• Full (8 min) video abstract: https://youtu.be/L1mMnnyJrgk?si=rDAlXIr6sfy4dJ3r;
• Break-down of our recent meta-analysis of RCTs: https://youtu.be/FcUUqGJBXFM?si=WmdSqzoF1ZcKxk5U;
• Explanation of the Lipid Energy Model: https://www.youtube.com/watch?v=AkzxESsTJyM.

Also, follow along on Twitter: @nicknorwitz @lipoprotein @realDaveFeldman

Flagship tweet: https://x.com/nicknorwitz/status/1749426902274580911?s=20