Setting the Record Straight on NATURE-CT and Ketogenic Diets

Bret: 
This is Metabolic Mind Bitesize. I’m Dr. Bret Scher. A new study was just published about coronary plaque progression. Now, does it tell us anything about plaque while eating a keto diet? No, it doesn’t. So, why are some people on social media drawing that comparison? Let’s get into that because it’s important.

So first, the study is called NATURE-CT, and it gives us something pretty valuable. It’s a look at how coronary plaque progresses naturally over five years in relatively low-risk adults, who are not taking lipid-lowering therapy. But the way some people are using this study online kind of concerns me. And as a cardiologist, I think it’s important to separate what this data actually shows from what some of the conclusions that are being drawn from it.

So, those two things are very different, and let me start with the study itself. There were 205 adults with a mean age of 55, no prior cardiovascular events, heart attacks, strokes, et cetera, no lipid-lowering therapy, and critically, all with a baseline coronary artery calcium score under 100. So, remember that part.

So, they’re relatively low-risk individuals by conventional standards, and they had a plaque analysis by CT angiogram at baseline. And again, approximately five years later. And the findings are clinically important. Total plaque volume roughly doubled over the five-year period with non-calcified plaque volume increasing on average about five cubic millimeters per year.

And even low attenuation plaque, which is the most dangerous plaque and most strongly associated with heart attacks, that also increased. It was present in only 9% at baseline and went up to 23% of the participants at follow-up. All that data is meaningful because we don’t have a lot of published information on the natural trajectory of plaque in lower risk untreated adults. And that’s key, untreated.

Most plaque studies are conducted in higher risk populations or in people already getting lipid-lowering treatment. So, NATURE-CT kind of fills that gap. But one interesting note worth pointing out is although they claimed they were healthy, they might not be. So, 25% had high blood pressure, and the average triglyceride to HDL ratio was suboptimal at 2.3.

But we don’t have any other metabolic health data like, fasting insulin, resistance scores, et cetera. So, that’s important because metabolic health isn’t simply the absence of diabetes. It goes much deeper than that. So, maybe this population was even a little bit sicker than we thought at baseline.

And the other observation from this study that deserves more attention is the LDL. The mean baseline LDL in this cohort was 111 milligrams per deciliter, and that’s pretty good LDL, what used to certainly be considered normal. And plaque still progressed substantially over five years with an average LDL of 111.

So, some would say, that proves we need LDL to be lower, which it doesn’t prove that. But that’s a conclusion some people would make. I would say maybe that should prompt us to look beyond LDL as the primary or the sole driver of coronary disease progression, and with metabolic health kind of being the most obvious one for me, especially since this data set didn’t account for that.

Okay, but now let’s address directly what’s happening in online discussions around this study and keto. So, some people are comparing NATURE-CT to the Keto-CTA study, and claiming that since plaque progressed faster in the KETO-CTA study, it thereby proves that ketogenic diets are dangerous for heart health.

But hold on a second. That’s for me, that’s a little outlandish because there’s a critical flaw with that claim. The KETO-CTA manuscript was retracted. It was retracted at the author’s request because there was unblinded and inaccurate plaque analysis. So, there is no peer-reviewed published CTA study, and making a scientific comparison to the retracted inaccurate data is not a valid scientific argument.

It’s not a comparison at all. Now, of course, there are additional KETO-CTA data being analyzed using QAngio and HeartFlow plaque methodology, and it’s available as a pre-print and will hopefully be published and peer reviewed in the future. And it’s difficult to comment on pre-prints. So, once it’s published, I’ll engage with it fully, whatever it shows, and discuss it.

But even when that data is published, even still, we still can’t compare it as a whole to the NATURE-CT cohort because it’s only valid if we restrict the KETO-CTA group to the participants with a calcium score under 100. This matters because higher baseline plaque burden independently predicts faster plaque progression.

So, you can’t compare someone in the KETO-CTA trial with a baseline calcium score of 200 to someone in the NATURE-CT study with a calcium score of 100. You just can’t do that. Because when you compare populations with meaningfully different baseline calcium scores, you’re not making an apples to apples comparison.

You’re introducing confounding variables that could explain any observed difference in progression rates entirely on its own. And look, the scientific question that motivated the KETO-CTA study is legitimate, right? And it deserves a rigorous answer. Does dramatically elevated LDL in lean mass hyper-responders on a ketogenic diet, people who are otherwise metabolically healthy, does that correlate with accelerated plaque progression?

That’s a question worth investigating carefully. But even when the KETO-CTA study is eventually published in a peer-reviewed journal, it cannot and should not be extrapolated to ketogenic therapy broadly. The KETO-CTA specifically enrolled lean mass hyper-responders, and that’s a specific phenotype that does not represent the much larger population of people using ketogenic therapy for metabolic health reasons.

And remember, there’s no one single keto diet. Approaches that are vegan and vegetarian, Mediterranean-inspired, animal based, they can all produce therapeutic ketosis when done correctly. So they’re all, quote-unquote, keto diets. They have different nutritional profiles, different food sources, and potentially, different health implications, right?

So, we can’t consider them as one. So, treating a finding from one specific ketogenic phenotype as a statement about all forms of ketogenic therapy is not scientifically defensible. Plus, take this further, someone using ketogenic therapy to reverse type 2 diabetes, reverse insulin resistance, and meaningfully improve their cardiometabolic profile, that represents a population that, in my opinion, would probably see significant reductions in their cardiac risk and maybe even reductions in their plaque.

Certainly worth studying. So, treating lean mass hyper-responders and all of ketogenic therapy as equivalent and applying the same risk framework to both is simply misguided. All right, so let me rewind and let’s be precise about what the current evidence actually shows. NATURE-CT, that study tells us that plaque progresses in metabolically undefined, I’d call them, otherwise low risk, untreated adults over five years, even at modest LDL levels.

Okay, that’s valuable and important data, but it says nothing about ketogenic diets. There are no published peer-reviewed data demonstrating that ketogenic therapy is dangerous for coronary arteries. Citing that as an established finding is not scientifically supportable right now with the evidence that exists.

The KETO-CTA analysis, when published, will add important data about a specific phenotype that genuinely deserves more rigorous study, but it will not tell us about ketogenic therapy or a ketogenic dietary approach, in general. So, I would say if you want to learn more about ketogenic therapy and metabolic health, including its implication for mental health and brain function, I think metabolicmind.org is a great place to start.

I may be a little biased of course, but still, check it out. And if this video was helpful, please like and subscribe, and please leave us a comment as we always love to hear your perspective. 

So, thank you for watching. I’m Dr. Bret Scher. We’ll see you here next time at Metabolic Mind, a non-profit initiative of Baszucki Group.