This week, headlines lit up across the ketogenic community with the long-awaited release of a study titled “Plaque Begets Plaque, ApoB Does Not.” The gist? Despite high LDL and high ApoB levels, participants did not show increased plaque buildup.
Why does this matter? Because it challenges conventional wisdom, particularly findings from Mendelian randomization studies, which suggest ApoB is a central causal driver of atherosclerosis. But as this paper reveals, the full story is more nuanced.
In 2025, nutrition science faces a big challenge: it’s hard to isolate variables. Control groups often become unreliable the moment participants change their diet or lifestyle after enrollment. That’s what makes this study so valuable. The participants had been on a strict ketogenic diet for an average of 4.5 years, and they were metabolically healthy with persistently elevated LDL and ApoB—offering a rare, deep insight into markers which we often associate as bad.
Rethinking Fat and Heart Disease
Fat has been vilified for decades, often unfairly. This is likely due to the confounding factors that come along with heart disease, like inflammation, insulin resistance, and oxidative stress. When I assess heart health, I don’t stop at cholesterol. I look at the entire picture:
- Genetic markers
- Lipid patterns
- Inflammatory markers
- Insulin sensitivity
- Sympathetic dominance (via the DUTCH test)
- Estrogen levels on DUTCH (for nitric oxide production)
- Stress and cortisol patterns
- Sleep
Even with all of that, nutrition and lifestyle are always the first levers I adjust. To blame one macronutrient, like saturated fat, for a complex disease like atherosclerosis? That’s a reductionist view that no longer holds up.
Who Are Lean Mass Hyper-Responders?
For those unfamiliar, Lean Mass Hyper-Responders (LMHRs) are a small but growing subgroup of people who experience dramatically elevated LDL-C often above 200 mg/dL, when adopting a ketogenic diet. Early theories suggested that the increase was due to greater demand for cholesterol transport, possibly to fuel brain metabolism or support high fat oxidation.
Because this demographic is so unique and rare it’s been difficult to study them in depth. But thanks to trials like KETO-CTA, we’re finally seeing some data-driven insights emerge. Additionally, we can use this data and keep it into account with individuals who have hypercholesteremia.
What I loved about this study, is its strict inclusion criteria. LMHR are usually metabolically fit individuals which show higher levels of LDL, and Triglycerides. The individuals on this study were:
On a ketogenic diet, for over 24 months
LDL-C less than 160mg/dL before starting a ketogenic diet
LDL-C above 190mg/dL on a ketogenic diet
HDL-C above 60mg/dL
Triglycerides less than 80mg/dL
HbA1C less than 6.0
Fasting Glucose-less than 110mg/dL
C-Reactive Protein-less than 2mg/L
The participants were ruled out if they had diabetes, hypothyroidism, or kidney/liver dysfunction. Hence, the inclusion criteria for this study included metabolically healthy individuals with extremely high LDL-C, but driven by diet not genetics. Most individuals had a very low plaque burden despite the high biomarkers.
The study showed that there was no association with higher LDL levels, ApoB levels or saturated fat composition. So quite the contradiction as what the world expected. Now, given this study isn’t the first, I think we are seeing a shift in the way we are looking at managing lipid health. As always, I would say that more research is needed however I did like that there wasn’t much sex differences in this study as both men and women were included. There were a few participants who showed a reduction in plaque over the year, and perhaps they could have been female, given the role estrogen plays in heart health.
What this study ultimately highlights is that context matters. It’s not just about LDL on a lab slip, it’s about what else is happening in the body. Are you inflamed? Insulin resistant? Stressed? Or are you metabolically well, active, and eating nutrient-dense, anti-inflammatory foods? How’s your gut microbiome, how’s your sleep?
We’re entering a time where personalized nutrition and nuanced interpretation are more important than ever. Studies like this challenge us to pause before labelling something “bad” simply because it doesn’t fit into outdated models. Cholesterol may play a role but it’s not the villain it’s been made out to be, especially not in the absence of metabolic dysfunction.
As a practitioner, my goal is to look at each individual’s unique biochemical picture and not just check boxes based on population averages. And if this study tells us anything, it’s that we’re heading in the right direction by asking better questions and looking deeper.
I’ll be watching closely as more data emerges on lean mass hyper-responders, lipid metabolism, and how context truly shapes cardiovascular risk. But for now, I think this study gives us all permission to step back and rethink what “high cholesterol” really means in a world where metabolic health is the real root of the issue.