The ketogenic diet has gained popularity as a weight loss solution, but its effectiveness and suitability vary greatly. World-renowned lipid expert Dr. Thomas Dayspring provides insights into ketogenic diets and personalized approaches to managing cholesterol, particularly LDL-C, in an interview with Gene Food founder John O’Connor.
Why the Ketogenic Diet is Popular
The ketogenic diet is marketed as a one-size-fits-all weight loss solution for western populations facing never-before-seen rates of obesity. Under normal circumstances, the human body burns carbs and sugar as fuel. We break down the bread, rice, and oats we eat and convert it into glucose to power all of our activities. The brain loves glucose and so do babies in the womb. Glucose is the universal fuel source for all our cells. However, in today’s fast food, standard American diet world, many of us get too much glucose, and when we eat more glucose than the body can store or burn, we convert it into fat.
Potential Pitfalls of the Ketogenic Diet
While enthusiasm surrounds low-carb diets and weight loss, several potential issues can arise:
1. Inability to Achieve Ketosis
The primary goal of a ketogenic diet is to produce elevated levels of ketones in the blood. The late Dr. Veech at Harvard was one of the pioneers of ketone research. His life’s work focused on the protective effect of ketones. However, not everyone can achieve nutritional ketosis genetically. Instead, when these individuals go on high saturated fat diets, they see large upticks in cardiovascular risk markers like triglycerides, small dense LDL, and total cholesterol. Further, these people can’t get their millimolar counts to the threshold needed to achieve the protective effects of a ketogenic diet.
Actionable Step: Routinely measure blood ketones to confirm you are in a state of ketosis. If you aren’t achieving a level of at least 0.6 mmol/L, it’s time to consider a different diet.
Read also: Health After Weight Loss
2. Sky-High Cholesterol
Elevated low-density lipoprotein (LDL), the bad cholesterol, is a major cause of heart disease. LDL causes the build-up of fatty deposits within your arteries, reducing or blocking the flow of blood and oxygen your heart needs. Diets high in saturated fat will increase LDL-C in almost everyone. the trick here is to determine what your biomarkers look like before and after going on a high fat diet.
There are a number of low carb forums that encourage members to stay on low carb and ketogenic diets despite very high LDL-C and total cholesterol. This advice goes against medical consensus and could be dangerous for your health over the long term. If you’re on the fence, the European Atherosclerosis Society issued a position paper in 2020 detailing how and why LDL causes heart disease.
A study published in 2019 in the Journal Atherosclerosis is instructive. Called the Retterstol study, researchers in Norway took 33 healthy young adults and placed them on a high fat, ketogenic style diet. Maybe you’re one of the lucky ones who fall closer to the 5% increase some subjects in the Retterstol study experienced. However, if your doctor expresses concern about high cholesterol, it’s best to respect medical advice rather than assuming partisans on the internet have figured out something the Cleveland Clinic and Mayo Clinic missed.
3. Disrupted Digestion
The ketogenic diet will alter your gut microbiome. But will it do so favorably or unfavorably?
The first study, published at UC San Francisco showed positive results for the microbiomes of obese men on keto vs. the state of their microbiome on a standard American diet. Although this was a controlled feeding trial in a metabolic ward, it was also a very small sample size of just 17 individuals. The participants in the UC San Francisco study saw the greatest increase in certain Bifidobacterium species on the ketogenic diet - but here’s the rub: the microbiome benefits on a ketogenic diet were reliant on the subjects achieving a state of ketosis, as opposed to blindly following a high fat diet. Further, it’s not entirely surprising to me that switching from a standard American diet full of sugars, processed foods, and low quality meat to a diet that presumably included some avocado, butter, nuts and seeds and the like would make for a better microbiome.
Read also: DeLauer Diet for Wellness
The next study I want to highlight saw the opposite result. This study was published in the Journal Gut which is an official journal of the British Society of Gastroenterology. In a study of 217 healthy participants aged 18-35 and placed on a ketogenic diet, researchers saw a major proliferation of “bad” gut bacteria on keto when compared to lower fat diets. The findings from the Journal Gut indicate that, at least for some people, ketogenic style diets will have a negative impact on the state of their microbiome.
4. Persistent Fatigue
While anecdotal stories can’t be relied on for scientific consensus, there are well designed studies which have identified fatigue and muscle weakness as common side effects of ketogenic diets. As it turns out, the anecdotal accounts of fatigue on keto are backed up by studies. For example, this study which appeared in the peer reviewed Journal Nutrients, looked at the athletic performance of 17 healthy women on a low carbohydrate ketogenic diet with no restrictions on calories. The bottom line is this: if you have tried a ketogenic diet and are tired all the time, you’re not alone.
5. Unsustainable Weight Loss
New science from some of our best medical journals is teaching us that keto weight loss strategies are hard to maintain, and many amount to nothing more than a crash diet. Everyone will lose weight when they starve themselves, but can they keep the weight off? A 2020 study from the peer reviewed Journal BMC Nutrition, which evaluated 114 people struggling with their weight, found that those placed on a ketogenic diet lost more weight in the first 24 weeks when compared to a DNA diet, however, over 18 months the DNA diet group had lost on average 19 more pounds than the keto group! The BMC study teaches us that, yes, DNA diets work, but also that one size fits all prescriptions for ketogenic diets don’t. The idea that we can simply say - “oh, yes, you are a human therefore you will benefit from a ketogenic diet” is simply false.
Actionable Step: Use an app like Cronometer to track calories.
Individual Variability and Genetic Predisposition
Not everyone is well suited to a ketogenic diet; for some, a high-fat diet will increase the risk for heart disease. Lost in all the enthusiasm about low carb diets and weight loss, is the actual goal of a ketogenic diet, which is to produce elevated levels of ketones in the blood. Here is where the rubber meets the road and personalized nutrition enters the fray: not everyone can achieve nutritional ketosis genetically.
Read also: Weight Loss Transformation: Latricia Thomas
Thomas Dayspring on Atherosclerosis and Cardiovascular Risk
Thomas Dayspring is a world-renowned expert in clinical lipidology. In an interview, Dr. Dayspring explores the foundations of atherosclerosis and why atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death worldwide for both men and women. He examines how the disease develops from a pathological perspective and discusses key risk factors, including often-overlooked contributors such as insulin resistance and chronic kidney disease.
He breaks down the complexities of cholesterol and lipoproteins-including LDL, VLDL, IDL, and HDL-with an in-depth discussion on the critical role of apolipoprotein B (apoB) in the development of atherosclerosis. “It takes decades for this plaque to finally get to a point where it’s noticeable on some diagnostic image. Certainly, it would take even longer for symptoms to occur, and everything.
The 2013 ACC/AHA Guideline: A Critical Perspective
Dr. Dayspring offers a critical perspective on the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. He notes that the guideline aimed to simplify risk assessment and treatment but may have oversimplified the approach by relying heavily on Level 1 evidence from large, randomized, double-blinded trials. This, he argues, led to the elimination of valuable knowledge about atherothrombosis risk assessment, diagnosis, and aggressive treatment.
The Importance of ApoB and Particle Counts
Dr. Dayspring emphasizes the importance of measuring apolipoprotein B (apoB) and LDL particle (LDL-P) counts for a more accurate assessment of cardiovascular risk. Atherosclerosis is a lipoprotein-mediated disease, and counting the number of lipoproteins that can penetrate the artery wall provides valuable information beyond traditional cholesterol measurements.
- ApoB: The protein that enwraps LDL and VLDL. Measuring apoB is a way of counting how many LDL-Ps are in your blood.
- LDL-P count: The number of LDL particles in your blood.
He explains that LDL-P size often correlates with LDL-P count, but in many cases, it doesn’t. So, apoB or LDL-P counts are better tests.
Apolipoprotein A1 (apoA1) is the protein that enwraps HDL. The one thing the new guideline got right is it told you not to follow HDL-C, because whatever you do to HDL-C with any therapy will have zero correlation with the patient’s outcome. If you measure apoA1, it’s sort of a way of counting how many HDL particles (HDL-Ps) you have, which can be very different than the mass of cholesterol they are carrying, which is assayed by HDL-C tests. So, apolipoprotein tests are basically ways of counting particle numbers, and cholesterol is just how much cholesterol is in those particles. They often correlate, but in many cases, they don’t, so most people who want to do serious risk assessment prefer to count particles in addition to measuring cholesterol content.If a patient has very few apoBs and a lot of apoA1s, then that correlates pretty well with low risk. And, of course, if the ratio is high - meaning way too many LDLs and too few HDLs — then that’s associated with high risk.
Goals for ApoB
Every goal of therapy depends on the risk of the patient, so you’re going to have a stricter apoB goal if you’re treating a patient who’s already survived a heart attack, as opposed to a young person whose risk lies in the future. If we take the average person, we like to get lipid and lipoprotein concentrations below what’s called the 20th-percentile cut point, which for apoB would be 80 mg/dL, for LDL-P count would be 1,000 nmol/L, for LDL-C would be 100 mg/dL, and for non-HDL-C would be 115 mg/dL. Their LDL-C looks really good, but if you count the number of atherogenic particles, they’re still high risk. And so, what I believe is you have to measure both, because in some cases, normal LDL-C is accompanied by the high particle counts, and that’s residual risk.
Remnant Particles
A remnant is sort of a shadow of its former self. The liver secretes VLDLs, which are triglyceride-rich particles that bring the fatty acids to the muscles or fat cells. Think about this: a VLDL carries 80-90% triglycerides and only 10-20% cholesterol, but as it shrinks and loses the triglyceride, you still have a rather large apoB containing a particle full of cholesterol, like a very big LDL-P. Now, you would hope the liver would clear that remnant very quickly as is supposed to happen. But if it didn’t - and there are reasons why it might not — then that cholesterol-enriched VLDL, now called the remnant, could crash your artery wall, and particle for particle, it carries more cholesterol than an LDL.
Remnants contribute to atherogenesis, so we don’t like to see them floating around. Most believe if we had therapeutic measures - and we do with lifestyle changes and various drugs — we could eliminate remnants in addition to LDL-Ps, which would likely be beneficial.
Dayspring's Ideal Guideline
If you could write your own guideline for the measurement of lipids and reduction of cardiovascular (CV) risk, what would it be? Would you lump stroke, coronary artery disease (CAD), and peripheral vascular disease together and say lowering cholesterol would reduce all of those risks?
First of all, I believe history is very important. Premature heart disease in a first-degree relative of either gender would be important to know, as well as smoking status. I would do a physical examination quickly to look for xanthomas or something bizarre that would immediately identify a genetic lipid disorder. Of course, I would check blood pressure and pulses, and if I don’t feel pulses in the feet, then the patient has peripheral vascular disease, which also tells me they are at very high risk for CAD and extracranial arterial disease. But let’s presume there’s no family history, all pulses are great, and I don’t see any xanthomas. Then, my only prayer of doing a risk assessment is looking at various biomarkers.
There’s emerging evidence that total HDL-P count more than apoA1 level is incredibly desirable, and that low total HDL-P counts are quite a bad risk factor and a better predictor than any HDL-C measurement. So, those are 2 things I want right off the bat. The most atherogenic lipoprotein known to afflict humans is called lipoprotein(a) [Lp(a)], which is an LDL-P that’s carrying a potentially pathogenic protein on its surface. This is way more common than familial hypercholesterolemia (FH), as it’s estimated a third of the American public have a high-risk Lp(a). It’s a genetic test that’s only needed once in a patient’s lifetime, but patients either have it or they don’t. I need that on the chart somewhere, because if they have that, then I’m worried about them even if everything else comes back clean.
Lipoprotein(a) [Lp(a)]
The most atherogenic lipoprotein known to afflict humans is called lipoprotein(a) [Lp(a)], which is an LDL-P that’s carrying a potentially pathogenic protein on its surface. This is way more common than familial hypercholesterolemia (FH), as it’s estimated a third of the American public have a high-risk Lp(a). It’s a genetic test that’s only needed once in a patient’s lifetime, but patients either have it or they don’t. I need that on the chart somewhere, because if they have that, then I’m worried about them even if everything else comes back clean.
If you’re measuring Lp(a) mass, considerable risk is typically above 30 mg/dL. If you’re doing it in molar concentration, it’s 75. There’s a new test called Lp(a) particle counts, and if it’s above 75, that’s considerable risk. So, there are different ways of assaying Lp(a) and you have to become familiar with the various ones out there, as each has different levels.
The treatment right now is to blow away LDL-P count and apoB level, and maintain blood pressure control, smoking control, and healthy diets. No drug has data showing if it lowers Lp(a), patients will have less heart attacks. In fact, we were stunned last year when a big trial with niacin - which does lower Lp(a) — reduced Lp(a) but didn’t reduce one heart attack. However, the Justification for the Use of Statins in Primary Prevention (JUPITER) trial said even though statins do not lower Lp(a), they significantly reduce clinical events in primary prevention settings in patients with high Lp(a).
Inflammatory Biomarkers
There are many biomarkers a lipidologist like myself uses to fully ascertain risk, but what you’ve got to do is count particles, perform some rudimentary inflammatory tests, and measure Lp(a) in addition to the historical and physical exam findings. For the inflammatory markers I previously mentioned, there are plenty of trials showing no matter what type of lipoprotein abnormality you have or don’t have, they give you more CV risk information in a given patient. If 2 people came to see me with identical apoB or LDL-P counts, I would worry a little bit more about the one who has concomitant inflammatory elevations, as opposed to somebody who doesn’t. In my belief, the better a risk assessment I do, the better I know what intensity of treatment is necessary. And depending on what’s abnormal, I can customize the treatment.
Say a patient is at great risk for an impending event and maybe we better check out if he or she has soft plaque. Is it possible to decipher that? No, but an elevation of inflammatory biomarkers would certainly suggest there is unstable plaque present. So, again, you’d look at particle counts and other treatable risk factors like blood pressure, smoking, and insulin resistance, in which case a low-carb diet or even metformin would help. You’d also assess platelet function and tell the patient to take an aspirin, or if they’re aspirin-resistant, perhaps a more potent platelet inhibitor. You could run a thyroid function on everybody who’s got a lipid abnormality. You might also look at other types of factors that might contribute to atherogenesis or unstable plaque, such as very high homocysteine levels, low vitamin D, and Lp(a).
Pharmaceutical Interventions and Lifestyle
In Episode #253, Dr Thomas Dayspring joins me to round out our three-part masterclass on blood lipids and atherosclerotic heart disease. In Episode #251, we covered what blood lipids are and what happens when things go wrong within the lipid transportation system, and in Episode #252 we looked towards how to test and understand your blood lipids as an individual. “If there was widespread improvement in nutrition and lifestyle there would certainly be a lot less [of] many chronic diseases, including atherosclerotic heart disease. In this episode, Part Three of the lipid series, we discuss interventions to lower risk of atherosclerotic cardiovascular disease (ASCVD). Both Dr Dayspring and I believe in a lifestyle-first approach to lipid optimisation. As discussed in previous episodes with the likes of Dr Gil Carvalho and Dr David Jenkins, there is no doubt that nutrition is the most powerful lifestyle tool we have to dramatically lower ApoB. In other cases, where people have a genetic predisposition to higher ApoB, or cannot sustain dietary changes, pharmacotherapy is required to optimise lipid levels and achieve low risk of ASCVD. This conversation is designed to help you better understand the treatment options available if you do require a pharmaceutical approach.
Given Dr Dayspring’s expertise in both research and practice, this episode focuses almost exclusively on the available pharmaceutical drugs to lower ApoB, an elevation of which is essential for developing atherosclerosis. We cover the history of treatment options for ASCVD, tracking the drugs that have been available over time and the main treatment options available now. Are we becoming a drug-dependent society? Is Bempedoic acid a good statin alternative? Do statins increase the risk of diabetes? In cases where someone already has existing ASCVD and ApoB target levels are much lower, it is much more likely that pharmacotherapy will be required to restore physiologic levels (the level we are born with) of ApoB.
With this in mind, my personal philosophy on lipid optimisation is to not look at this as an either/or scenario. The rationale for this is two-fold. One, the dietary changes required to improve ApoB will also benefit other risk factors for chronic disease.