BIG NEWS: The Lean Mass Hyper-Responder 1 Year Data Just Dropped!

Data from a brand-new study published by our research team just dropped—and the results rub up against one of the biggest beliefs in modern cardiology.

FINALLY! The Lean Mass Hyper-Responder (LMHR) 1 Year Data Just Dropped!

For those of who who have been living under a rock and need to catch up: we followed 100 LMHR and near- LMHR persons on ketogenic diets, having mean BMI 22.5 kg/m² and sky-high cholesterol (mean LDL-C = 254 mg/dl) with high resolution coronary CT angiography. We followed them to see whether, and to what degree, plaque accumulated in the arteries of these individuals with extremely high LDL-C.

I won’t make you wait for the high-level points:

• Most participants showed no or minimal progression of coronary plaque

• Neither ApoB nor LDL exposure predicted plaque progression

This letter will give you some more high-level points and direct you to more information.

Necessary Background

Colleagues and I have spent the last several years studying what happens to cholesterol levels in people who adopt very low-carbohydrate ketogenic diets:

• Most don’t see increases in cholesterol.

• Many even see decreases.

However, some see their LDL cholesterol (LDL-C) levels rise so high that most doctors think it’s “inconceivable.”

These individuals are called ‘lean mass hyper-responders’ (LMHR) because they are, as a population, generally lean and healthy.

In fact, our prior meta-analysis of 41 human randomized controlled trials showed that the leaner a person is, the higher their LDL-C tends to rise on a low-carbohydrate diet trials.

This study also showed that having a BMI < 25 kg/m² was >5X as powerful as being in the top quartile of saturated fat intake for predicting LDL-C change.

So, this is certainly far more interesting than a ‘blame-the-butter’ story …

The data presented in this new publication build upon a prior publication where we compared the baseline plaque scores of this population with a matched population and found, strikingly, that even after having LDL-C levels between 200 - 600 mg/dl for almost 5 years, the LMHR folk did NOT exhibit any greater total plaque score compared to a matched control group of persons with much lower LDL-C.

But in this study, we report on prospective data—i.e., when we follow these individuals, does plaque accumulate in their arteries? And, if so: What predicts accumulation?

Results

The vast majority of participants exhibited no or minimal progression of coronary artery disease.

Six participants showed decreases in total plaque scores over one year.

Median change in percent atheroma volume (PAV)—a measure of how much of the coronary artery surface is covered in plaque—was 0.8%. This reflects a level of progression that is expected with aging and is comparable to that observed in other cohorts.

So, to be crystal clear, if you asked the question, “Are lean mass hyper-responders completely protected against heart disease?” the answer is “no, of course not.”

BUT, we MUST then ask:

What predicts progression of plaque?

Is it LDL-C or the associated biomarker ApoB?

NO! - Neither LDL-C nor ApoB were associated with plaque changes.

By contrast, baseline coronary artery calcium (CAC) score was positively associated with a change in plaque.

I cannot over emphasize how important this is: While some people did see plaque advance, what predicted this advancement had nothing to do with cholesterol but rather whether they had plaque at baseline.

What Does this Mean?

This finding will ruffle some feathers, maybe even the whole bird. But these are the data. Now I want to delve into what this means in a nuanced and responsible manner:

While both LDL-C and ApoB are independent risk factors for atherosclerosis, the absolute risk associated with elevated LDL-C and ApoB is CONTEXT-DEPENDENT, including the etiology (cause) of the elevations in these biomarkers, LDL-C and ApoB as well as interactions with other risk markers, like insulin resistance.

Thus, these data are consistent with the observation that high LDL-C and ApoB among a metabolically healthy population have different cardiovascular risk implications than high LDL-C among those with metabolic dysfunction.

It is worth emphasizing that the population at hand here—LMHR and near-LMHR individuals on a ketogenic diet—is distinct from any previously studied population in several ways:

• Elevations in LDL-C and ApoB are dynamic and result from a metabolic response to carbohydrate restriction, rather than as a function of a genetic defect. These people aren’t born with high LDL, it’s a response to carbohydrate restriction having to do with energy flux through the body.

• These participants are of normal-health weight (BMI <25 kg/m²) and metabolically healthy rather than living with obesity, pre-diabetes or type 2 diabetes or other insulin resistance disorders.

• The high LDL-C and ApoB in this phenotype emerge as part of a lipid triad, also inclusive of high HDL-C and low triglycerides, representing a metabolic signature of a distinct physiological state.

These points are worth emphasizing because unique populations require independent study to properly characterize the risk associated with their metabolic profiles.

Furthermore, this is the first and only population in which LDL-C is independently elevated without any clear underlying congenital genetic cause and outside the content of any other notable metabolic dysfunction.

Therefore, the LMHR population constitutes a unique and important natural experiment for evaluating the lipid heart hypothesis in an unprecedented manner.

These data are consistent with the notion that elevated ApoB, even at extreme levels, does not drive atherosclerosis in a dose-dependent manner in this population of metabolically healthy individuals with carbohydrate-restriction-induced elevations in LDL-C and ApoB.

How To Learn More…

• Read the paper! https://www.jacc.org/doi/10.1016/j.jacadv.2025.101686

• If you’re able, please share that link in an original X post (Twitter post) or as a quote RT to THIS tweet with your thoughts. It helps the algorithm massively.

• Be the first to know the latest about our upcoming movie, THE CHOLESTEROL CODE, by signing up for the newsletter and notifications at cholesterolcodemovie.com.

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Special Thanks

Science is a team sport. In fact, it’s only been through the tremendous collective efforts of multiple teams, including Dave and Adrian, the generosity and support of Baszucki Group and Metabolic Mind, and – of course – the team at UCLA and the Lundquist institute overseen by the principal investigator of this study and cardiac imaging expert, Professor Matthew Budoff, that this pivotal project was completed. But this is not the end! It’s actually the 11th paper in a long series of investigations that’s only getting warmed up. That said, I do think these data and this paper will be a catalyst for change!

Amendment & Clarifications (Day 4 post-publication)

I first want to thank everyone for the tremendous interest in these data. My colleagues and I have been drowning in the deluge of emails, direct messages, replies/comments/questions, phone calls, and media solicitations (in a good way!)

Following on those correspondences, we want to clarify several points:

• Lean Mass Hyper-Responders exhibited a heterogenous risk profile. As stated, most did not exhibit rapid plaque progression, as the conventional viewpoint would hold.

• A minority exhibited faster progression (>1% PAV change over 1 year); however, neither ApoB nor LDL cholesterol exposure explain this change. We will have more details on this in another publication that’s currently under review.

• Across-study comparisons are challenging because they are sensitive to differences in imaging (CCTA) acquisition and technology. We used a particularly sensitive – novel – AI-powered system (Cleerly).

• Some have suggested we didn’t report the primary outcome. We did. It’s in Figure 1 of the paper, It is highlighted by size, color, and within confidence bands, and each participant’s individual non-calcified plaque volume change is shown for transparency.

These clarifications are all consistent with the points we’ve made so far. The ‘story’ has not changed. For more details and nuance, please feel encouraged to read co-first author Professor Adrian Soto-Mota’s Q&A threads: 1, 2, 3. MUCH more to come, and thank you again!

Personal Thoughts…