Will GLP-1 Drugs Replace Diets Forever?

David: 
There’s a lot of interesting overlaps between a low-carb diet and these new drugs, which are not commonly understood, but it raises the possibility that these drugs could be used synergistically, or you have a dietary approach by which you can transition off the drug and maintain some of the long-term effects.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

GLP-1 medications are all the rage, improving weight loss, metabolic health, potentially addressing brain-based disorders, the heart, the liver, kidney, all these potential impacts. So our GLP-1 medications going to replace the need for dietary interventions. Will we now be curing all these diseases with medications and have to worry a lot less about lifestyle?

There’s certainly that potential and that may not be a good thing. So I’m joined by Dr. David Ludwig and Gary Taubes to discuss this in greater detail with both sort of a mechanistic side of things, how the drug should interplay with medications, maybe more responsible use, and so you can walk away knowing more about the medications, where they’re beneficial, where there maybe are some shortfallings and why diet and lifestyle still matter, but maybe not the diet and lifestyle we’ve been talked about. 

Dr. David Ludwig, is a MD PhD. He’s a clinician. He’s a researcher who works at Harvard and Boston Children’s Hospital and has written the book Always Hungry and is really focused on the carbohydrate insulin model as a means to addressing our obesity crisis.

Gary Taubes is an investigated journalist with multiple books, including Good Calories, Bad Calories; The Case Against Sugar; Why We Get Fat; The Case for Keto and others, and together they come to provide a very good perspective about these medications, and how to responsibly use them to potentially work with lifestyle to, hopefully, prevent and solve this obesity and metabolic health crisis.

Many of the interventions we discussed can have potentially dangerous effects of done without proper supervision. Consult your healthcare provider before changing your lifestyle or medications. In addition, it’s important to note that people may respond differently to ketosis and there isn’t one recognized universal risk.

Thank you both for joining me again, another discussion that’ll be quite interesting, I’m sure. But, David, I want to start with you about these GLP-1s and the role in improving metabolic health and weight loss. You’ve been practicing for a couple decades and seeing this rise of metabolic dysfunction and this rise of obesity, this obesity crisis.

So I’d imagine anything that improves that or can address that in one way has to be a good thing. But set the stage for us, set the stage about your thoughts about these GLP-1s, what they are, where they came from, and how we can use them. 

David: 
Okay, that’s a big question.

Bret: 
That’s a lot of questions.

David: 
Big question. Let’s dive right in. Obesity has been treated by drugs for more than a century. And up until 15 years ago or so, all of these drugs which entered the market with great promise ultimately left the market due to lack of long-term efficacy or life-threatening complications from amphetamine that was used in the 1950s through. 

Then in the end of the 20th century, which turned out to have, which was effective, but turned out to have sometimes, very serious heart valve complications. The new GLP-1 receptor agonists, that’s the formal name, do represent a revolution in the drug approach to obesity treatment.

They work far more effectively and, although they certainly have side effects and some rare serious concerns, their overall safety profile is much better. So what are these drugs? they’re in a class of, called the incretins. Incretins are hormones that are made in the gut, and they have effects on insulin secretion and other pathways in the body.

So the word incretin comes from an observation that’s almost a century old, whereby, it was noticed that the insulin response to carbohydrate when consumed the normal way by mouth was much greater than if you gave the same amount of carbohydrate or glucose by vein. So if you ate 50 grams of sugar versus took an equivalent amount to raise your blood sugar as much by intravenous root, you’d make much more insulin.

And so scientists, 50 years ago, postulated that there was some set of factors in the gut incretins that explained that incremental difference in insulin response. And sure enough, in the last three or four decades, these incretins were discovered, and there are two main ones. One is GLP-1, glucagon alike, protein one, which is the basis of these new exciting drugs. And there’s a second incretin called GIP. And GIP is also made in the gut. It’s actually the main incretin, it’s the hormone that explains most of that increase of insulin response.

And the two together are being used in the latest generation of these incretin agonists we can go into. 

Bret: 
Yeah. So, that sets the stage for what these drugs are and where they came from. But now the question is, are they going to revolutionize the obesity epidemic and success in weight loss as they’re being advertised?

And will this be a long-term solution? Gary, you’ve been spending decades figuring out why do we gain weight, why do we become metabolically healthy? So from your perspective, are the GLP-1s an answer? 

Gary: 
There’s certainly an answer for some people. You can’t stop an epidemic by treating it after it happens. And you can prevent a disease from occurring with a therapy that’s aimed at treating the symptoms of the disease.

You have to go a step further upstream to figure out what’s causing the disease on one level. The drugs are expensive. When you look at real world data versus clinical trials, there’s clearly an issue with people staying on the drugs for some reason.

Just saw a study circulating the other day suggesting that in real world circumstances, only 25%, roughly maybe a quarter of the patients, stay on the drugs for a year. And that it certainly at a thousand dollars a month, which is roughly what they cost in the United States, they’re prohibitively expensive for many people.

So it’s likely to be a therapy that benefits the upper social classes and not the lower where obesity is very prevalent. There are these issues like this, I have a particularly, I’m prone to anxiety, so I worry about long-term use of these drugs because they’re very powerful drugs.

You could think of them, I mean that we tend to think of them, as appetite inhibition drugs. So they make you eat less, but they functionally change the shape of your body. The weight loss and change in lean tissue. So these are very powerful drugs and we have really no idea what happens past about three years in terms of long-term chronic effects and what’ll happen when people get off these drugs.

But they will not solve the obesity crisis. So the epidemic, they simply can’t do that. We’re not going to put the nation on. But we once people used to, I think, they joked that they would put statins in the drinking water to prevent heart disease. We never got that far so I doubt we’ll get to the GLP-1 drugs in the drinking water.

Bret: 
Yeah. But it’s not going to stop some people from talking about it, that’s for sure. Yeah, David, go ahead. 

David: 
Yeah, statins used to be very expensive drugs and now there are generic statins are very cheap and probably the majority, I don’t have the statistics, but the majority of adults in the United States, certainly beyond age 40 or 50, are probably on a statin and a blood pressure medicine and other drugs to address what a root cause that might be related to the metabolic syndrome.

Now is that conceptually wrong? I think if it’s working, if it’s reducing the risks caused by our lifestyle, our diet that’s leading to this constellation of metabolic stress, which we can talk more about if the drugs are working well, why not? That’s a legitimate option.

Of course, we all want to know, can we avoid the problem in the first place through what seems like a sensible approach, a non-pharmacological approach, understanding how food affects our hormones can prevent insulin resistance, and inflammation, and perhaps the need for the drugs in the first place and the side effects that result from them. 

Bret: 
Yeah, and that’s a great point, preventing versus treating as you both have alluded to, but I want to circle back to what you said, Gary, that there is a study showing that maybe only 25% of people stay on the drugs at a year.

I think I’ve seen values between 25 and 50, but it clearly is not a hundred percent. I guess a question for both of you, if we give someone these medications for a year, they lose 12% of their body weight and then they stop the medication. Have we done them any good? Have we done them any benefit long term?

Gary: 
I mean if it’s, I’m not sure this is a appropriate metaphor, but I’m going to run with it anyway because I was thinking about it when David was talking. But let’s say we had a drug that would cure lung cancer and so you didn’t have to actually quit smoking cigarettes. You could continue to smoke. I’m an ex-smoker.

I still miss cigarettes 29 years after I quit. If I could continue to smoke and then just take a drug to prevent drug cancer, would that be better than not smoking? And the difference between this metaphor and the obesity metaphor and GLP-1s is in lung cancer, we know that cigarettes cause lung cancer.

That’s the established beyond reasonable doubt. So we know that there is an option to taking the drug, which is not smoking, and that will dramatically lower your risk of lung cancer and obesity science. We don’t have the equivalent knowledge of what’s causing the obesity epidemic so we can’t say it’s the drug or this dietary approach.

We all happen to think that there’s one dietary approach that’s ideal because we also believe in a sort of conceptual framework that says that insulin is the driver of the obesity epidemic. So you minimize insulin levels and you do that by minimizing carbohydrate consumption, but that’s not widely accepted.

We’re a minority in the community and because we’re a minority in the community, arguing that there is a better dietary approach to replace the benefits of these drugs is a minority position. 

David: 
Let me play devil’s advocate for a moment here before we go into 

Gary: 
I was playing devil’s advocate.

David: 
I’ll be the, let me play angel’s advocate to your devil. Then, first off, there are all sorts of drugs that stop working when we stop taking them. I don’t think anybody would argue that somebody whose blood pressure was 180 over 90 should not control it with drugs, at least as a first step.

Because if they stopped taking the drug in a few years, their blood sugar, their blood pressure would, return to the baseline, but there’s more than that. We know from the recent cardiovascular outcomes trials that these new generation weight loss drugs don’t just produce cosmetic benefit.

They’re reducing a remarkable range of complications from heart attacks, strokes. Every time we look at a new body system, it seems like there’s some benefit. The liver, the kidney, the latest question is whether that will also apply to the brain Alzheimer’s so I don’t think that this is a reason not to take them, but it does ask us to consider why these drugs could have such broad effects and that.

Leads us to, if you’re willing to follow me, Gary, a discussion about basic mechanisms and where we can find common ground with diet or even use diet to reduce or prevent the need for drugs in the first place. 

Bret: 
In basic mechanisms and also, not only mechanisms of how the drug works, but the mechanism of how it provides all these beneficial effects from kidneys to heart, to brain, to liver, et cetera.

And I would say that the line connecting the dots is metabolic health that’s the mechanism. And I’d imagine you would all agree, but let’s drill down on that. Yeah. A little bit, please. 

David: 
So because of the term incretin, a shocking number of people who really, experts in the field, assume that these drugs raise insulin levels because that’s what incretin do in the test tube for most people.

These drugs immediately decrease insulin, and reduce insulin acutely and chronically, basically from the first dose. GLP-1, which is the heart of these new drugs, does something else that is critically important to understanding this, which is it slows gastric emptying.

It delays the transition of food from the stomach into the intestines. The overall effect is to lower insulin. And, and again, that happens after the first dose. It’s chronic. And in addition to that, these drugs have a whole range of effects that look very much like a low-carb diet. So they lower the surge of blood sugar after the meal because of the delayed gastric emptying.

They lower insulin, they seem to raise sensitivity to leptin, which is a critical hormone that signals the brain. They do a bunch of other hormonal things that again look just like a low-carb diet. Now these drugs also act in the brain, and that has led people to assume that the main action is directly on suppressing appetite, like letting us feel less hungry, but clearly the peripheral mechanisms, that delayed gaster are important.

And lastly, I would say that just because something acts in the brain, as Gary has made this point too, doesn’t mean that it’s acting directly on appetite.

The brain controls metabolism just as it controls appetite. This is something that Claude Bernard, the famous physiologist, showed with the experiments on dogs in the 1860s or so, that when that the brain affects how the liver is metabolizing glucose, it affects how fat cells are innervated.

In fact, it affects virtually every metabolic path in the body. In summary, there’s a lot of interesting overlaps between a low-carb diet and these new drugs, which are, is not commonly understood, but it raises the possibility that these drugs could be used synergistically or you have a dietary approach by which you can transition off the drug and maintain some of the long-term effects. 

Bret: 
And that’s a danger maybe if you’re looking for the one mechanism.

How does this work? What’s the one mechanism? You eat less, case closed. And some people might say the same about a ketogenic diet. You eat less, case closed. But as you pointed out, no, there are all these other hormonal, and hormonal effects rooted in insulin. So Gary, when we talk about mechanisms and we talk and how David relates it to low-carb diets, how do you see that fitting into the picture to say, yes, they’re basically another version of low-carb diets, or is there or more to it?

Gary: 
As soon as we say they’re just another version of low-carb diets, it sounds like we’re going to make everything that beneficial. Just another version of low-carb diets, even though it might be, so let’s just start with the biological mechanisms to begin with. And as David pointed out, we’ve known for 150 years since he’s the pioneering research of this brilliant French physiologist named Claude Bernard, that the brain controls what’s called intermediate metabolism as well as behavior, and that its effects on intermediate metabolism, which is everything that happens after you eat a food and before you excrete it.

Everything in the periphery that you influence intermediate metabolism, influence, hunger and appetite as a response. So the gist of it is you have a lot of evidence with these drugs and from clinical trials that they in effect change what’s called fuel partitioning.
One of the mechanisms might be the slowing of, gastric emptying, but there are probably other direct mechanisms on the liver and the pancreas and the fat cells and the hormones that are responding not just insulin, but glucagon itself, and that if you change fat partitioning to decrease fat storage in effect. Increase fatty acid oxidation in the liver, you’ll get an inhibition of appetite as a result.

So it’s quite likely on one level, there’s at least the possibility on one level that the primary effect of these drugs is not to just inhibit appetite. And that appetite inhibition might even be an indirect effect of what they’re doing below the neck and the body. And if all that’s true, you end up with thinking that suggests that this also can be accomplished by removing carbohydrates from the diet. 

David: 
Let me give you, let me give an example of this med metabolism appetite interaction. Clearly people are less hungry and they are eating less. So let’s not, let’s be very clear, we’re not saying that these drugs do not make people eat less. They do, they reduce the hunger, cravings and a lot of the addictive like behavior around that. But again, that doesn’t mean that they’re acting specifically on brain centers, to turn off the hunger. This is where the critical question is, what are the mechanisms? So let’s think about insulin. Let’s think about insulin again.

If you take, and this has again been known for 80 years or so, if you take an animal or a human with diabetes and inject a lot of insulin, that insulin is not, for the most part, getting into the brain. It’s acting peripherally to cause to very rapidly suppress the amount of calories in the blood. It does that by turning off lipolysis, so it shuts down the release of calories from fat.

It shuts down the release of glucose from the liver. It drives those fuels into storage. Nothing to do with how insulin’s acting in the brain, but by understanding what the origins are of these effects, we can look to see how to use these drugs in the most sophisticated way together with diet. And it’s, again, lastly, it’s not to say that a low-carb diet is the same as these drugs.

Clearly not. But there are shared mechanisms, and once you have shared mechanisms, it opens up a whole new world of possibilities rather than just saying diet versus drug, and we can find a way of perhaps using the two together to reduce the drug amount, reduce the costs, increase the effectiveness and of course minimize the side effects.

Bret: 
Yeah. And I think that’s key, right? Diet and drugs to reduce the cost to side effects and have equal effect or diet instead of drugs as a preventive rather than reactive strategy. As you were talking about Gary. 

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Now, back to the video. 

It seems like if we look into the future, these drugs are going to evolve. Right now they’re looking at oral versions that have equal effects, and they’re going to be looking at different dose formulations, different combinations. They’re even looking to combine GLP-1s with drugs that will help maintain skeletal muscle because we know you lose so much skeletal muscle, so they’re going to evolve and the, focus seems to be.

Drugs will solve the problem. Let’s find an alternative to diet because diet doesn’t work. Drugs will solve the problem. It really seems like that’s the framework, but when you bring up these shared mechanisms, it really does narrow the focus on saying, look, drugs, diet can do the same thing, so why don’t we compare them?

So this is a huge question without an answer, but Gary, you’ve been yelling into the void about low-carb diets, about the beneficial, the benefits of low-carb diets, which are starting to catch on, but now it seems like with these drugs will the focus on diet just disappear completely?

Do you think that’s a risk for the future? 

Gary: 
I think it’s hard to tell. First of all, yes, I do think it’s a risk. I was always used to joke with my friends that as soon as we have an effective obesity drug, we’re done. Nobody’s going to care. You actually saw this happen in the history of gout research.

Gout was also epidemic in American. Gout rates were rising dramatically. In the 1960s, researchers came up with this drug, allopurinol, that was a cheap, inexpensive way to treat gout and basically the NIH shut down research on gout funding, funding on research to study the etiology of gout

because it no longer seemed necessary because we had a drug. So arguing about the cause of obesity or the best dietary therapy for obesity now seems very 20th century. I think one thing we’re living through now because we read the news and the news is by definition about what’s new and what’s new is these drugs.

In certain socioeconomic classes, which happen to include journalists to some extent, a lot of people are on these drugs, maybe not even because they’re obese, but because they’re heavier than they want to be. And the drugs allow them to be as thin as they lean as they’d like to be. So the drugs are news to write about the fact that people will either have to get off the drugs under some circumstances or will want to get off the drugs under some circumstances, or will not be able to afford the drugs at all. And what is the best dietary therapy either with the drugs instead of the drugs or after the drugs, is to step right into this, controversy, debate that we’ve been having for,

I’m reading the research literature so I could say with safety that we’ve been having it for at least 125 years, and that’s an old story. And it’s not a story that the journalists, whether they’re working for the newspapers or social media or even the medical journals that have articles, it’s not a story they really care about anymore or understand.

So what we get are the drugs and it’s left to those of us who believe that there is a dietary cause to obesity that is not just eating too much. Specific macronutrients in the diet are left making this argument and maybe yelling into the void a little louder than we did before, that this is important because there are circumstances in which people will have to get off these drugs. You know what worries me if I hear of a person, an individual my age, going on the drug because they want to lose 20 or 40 or even 50 pounds. I don’t really worry about them that much, but if I had an 18-year-old who was burdened with obesity and you could see that the drug would be a great benefit to them and to their lives.

But nonetheless, they’re going to, if it’s a woman, she might she’ll probably want to get pregnant as she gets older. And to have children under those circumstances, she’s likely to want to get off the medication. And we may, the insurance might stop covering it. The finances might change and it, I think it would be natural for anyone who was on the drug for a year or two to want to experiment with not being on the drug.

Whether or not they have, if they have side effects, they’ll certainly want to experiment with a life without, they’ll think, okay, now I’ve got this problem solved, and if I have it solved, then how should I eat? Post drug to maximize the solution and effect there. Is there a solution? Do I have to be on this drug?

And again, there we have clinical trials where people on the drug got off and then were randomized to continue drug therapy or sort of healthy lifestyle dietary therapy. Conventional wisdom on diet and it doesn’t, they regain the weight. The question is if they went for a little less conventional wisdom on diet, and the San Francisco startup, Virta Health, is published data on this. Would they find an efficacy as great as being on the drug by a dietary therapy that they’re happy to live with? 

Bret: 
I’m shocked that study, that specific study you referenced, that showing that you can transition off of the GLP-1s to a low-carb diet and maintain the weight loss.

I’m shocked that didn’t get, i’m shocked and I’m not shocked that it didn’t get more attention because it doesn’t fit the narrative people are trying to tell for sure. 

Gary: 
But the issue with that is Virta also gives an extraordinary amount of coaching, and you have the access to all the Virta, telemedicine, and medical coaching through, so the assumption, and they’re not randomized controlled trials.

They’re not randomized. So the assumption could do this with any diet that cuts calories and makes you eat less that pick your explanation for why these drugs work. And yeah, if it was randomized to different diets, then you could have possibly said, no, this only works for carb restriction.

It doesn’t work for calorie restriction. 

David: 
And so that’s a testable hypothesis and there’s a very simple study. To examine it, the context here is that all of these drugs are used on the background of a weight loss diet that’s primitive. If you look at the methods section for all of these new drug studies, they recommend typically a 500 calorie deficit diet.

And you meet with a nutritionist a few times and they maybe give you some materials, we know we’ve known for decades that kind of low intensity, non-specific advice doesn’t work for people in the real world. Calorie restriction. tends to make people hungry because you’re depriving the body of something that it’s wanting.

And so how long are people supposed to maintain this discrepancy? Restricting calories with increasing hunger? There are ways of doing this more with a more sophisticated study. One, that I’d like to get done, uses something called a Latin Square design, a two by two Latin Square design.

So you have four groups. You take the drug versus placebo, and then you take, say a low-carb versus a high-carb diet. And so everybody gets all, both combinations. So you get people who are on the drug and low-carb, the drug and high-carb placebo and low-carb, placebo and high-carb. And it’s a very powerful design and it lets you ask some very important questions critically.

Is there synergy between any of these combinations? If we find it, that’s going to be really interesting, both to understand mechanisms. The drug companies should be very interested in the results because it could make their drug work better and then the diet folks should be interested too. It gives us something to transition to as an alternative to a lifetime of these medicines.

This study that I just described is randomized controlled. It would cost 20 to $40 million to do definitively, but that’s a bargained basement compared to a single phase three drug trial, which can easily cost over a hundred billion dollars. And we have dozens and dozens of these phase three drug trials.

Yeah, so interestingly, it’s really time that this gets done. 

Bret: 
Yeah, I agree. It sounds like a study that should get done. But, I want to push back on, you said the drug should be interested in this, but there’s that one group, the placebo low-carb group, if that was shown to be as effective or better than the drug companies are sunk.

So is that one potential enough to scare the drug companies away so they’ll never fund this type of study? 

David: 
That is the downside for the drug companies, but with also with an upside. If their new drugs are very potent, now people, as Gary said, don’t stay, the majority of people don’t stay on it for a year,

although a lot of that is the finances. And finances will come down. In Europe, the drug costs a third or a fourth of what it costs in the United States, and in a few years there are going to be much less expensive alternatives. So if you believe in these drugs, if they’re getting 15 to 20% weight loss, no, I’m a long-term advocate of a low-carb diet, but I think we can be pretty confident that a low-carb diet by itself is not going to cure obesity in everybody. There are many people who are not going to want to follow it, and even if it does cause substantial weight loss, which in my clinical and research experience does much more than the conventional low fat diets and the meta-analyses are showing us.

But I think there’s, I think that if you’re a drug CEO, you say, all right, there’s a risk that some people will go off. The will not ever take the drug in favor of the diet, but you’ve also produced something that can potentially make your drug at 15% effectiveness, 15% weight loss, go up to 25 or 30%, and that should be such an attractive possibility that it brings them in. We’ll see. 

Gary: 
I fear that’s wishful thinking though, in the sense that, yeah, I have this were to get funded. I would very much doubt. 

David: 
We’re not waiting, we shouldn’t have to wait for drug companies to fund this.

This has got NIH with the new policy statements from Jay Bhattacharya about their interest in looking at root cause diseases and funding definitive reproducible clinical trials. This should be at the top of the list or for philanthropy too. 

Bret: 
I want to steer the discussion for a moment back to metabolic health and all these other health conditions that the medications have been shown to potentially be beneficial for including Alzheimer’s disease.

And there’s some talk about psychiatric conditions and fatty liver, heart disease and people are talking about cancer, right? The whole spectrum of metabolic and insulin, potentially driven conditions, but when you talk about weight loss and someone, 25% of people are on the drug at one year, they gain the weight back.

But what if you’re using that to treat Alzheimer’s and 25% are on it at one year and then the Alzheimer’s comes back or same for a mental health condition? It seems like in that setting, it truly would be inadequate if it can’t be a long-term sustainable treatment. So do you see that differently than from weight loss or how do you see that?

David: 
But Bret, if we showed that these drugs, arrested progression of Alzheimer’s, people would take them. Just like they take all sorts of other drugs with side effects. 

Gary: 
And, this is also one of the arguments with low-carb diets, right, is the idea is that they’re too hard to adhere to, but if people see benefits and want to be healthy, they will adhere to them.

The same is likely to be true for the drug. 

David: 
I agree with that. And that’s why there’s never been a single NIH sponsored multicenter, low-carb diet trials. It’s egregious that’s the case. So we certainly should be looking at neurodegenerative diseases and such with low-carb but I don’t think that there needs to be such a binary choice, and it leads us back to asking why are these drugs looking so promising across such a wide range of apparently disparate conditions from the brain, heart, liver, kidneys, and the like? And the only way I can put it together is that it relates to the metabolic syndrome, which we know can affect all of these conditions.

The metabolic syndrome is the soil out of which diabetes, heart disease, and all of these other chronic diseases grow and it’s characterized at its core by insulin resistance and hyperinsulinemia. That combination drives inflammation and it drives tissue dysfunction and organ dysfunction leading to all of these conditions.

And if these drugs act in part by lowering insulin and improving insulin resistance, if that’s the mechanism, you’re talking our language, we can do that with diet. We can at least augment that effect, if not provide a mechanism to transition off the drug once its initial benefits are achieved.

Gary: 
One of the interesting issues with low-carb ketogenic diets since Atkins in the 1960s, it affect the conventional medical community tended to think of the doctors who prescribe these as them as quacks because the doctor said look everything gets better on these diets. Blood pressure comes down and weight comes down and blood sugar comes under control and people have more energy.

And their eczema clears up and their moods get better. And it sounded like that’s what quacks promise miracle cures. In the course of doing my research for my first book, Good Calories, Bad Calories, one of the many revelations in the historical research was you had all these physicians and observers over the course of 50 years saying, look, when we add refined carbohydrates and sugars to populations, we see all these different diseases appear. So perhaps the refined sugar and grains are the cause of these diseases, and if you remove them, which you do in a ketogenic diet or a low-carb diet, then you would expect all these diseases to get better.

And now we have drugs in which people are making very similar claims and making very similar observations. But because there’s so much drug company, pharmaceutical company money in this, they’re actually doing long-term trials and seeing that all these disease states improve or risk for chronic disease goes down with these drugs.

And then the question becomes simply, as David has been suggesting, are they doing much the same thing? That carbohydrate restriction does because the carbohydrates, the sugar, and the grains are actually the sort of environmental trigger of these diseases and these epidemics themselves. 

David: 
So we do know that people lose quite a bit of lean mass.

A debate is this outer proportion to the fact that they’re just losing a lot of weight and so you lose some muscle and organs as well, it looks like you’re probably losing more than one could account just for weight loss, although the final verdict there is not in. But John Speakman, who’s a researcher based in Scotland and in China, has an interesting paper, a review that just came out in the last week or two looking at the consequences of calorie restriction.

So long-term calorie restriction, on longevity and health, it says that yes, we know that if you underfeed rodents, they live longer. And there are different models from fruit flies up to chimpanzees where we can see some effects. So what about humans? And we don’t ultimately know, but he emphasized in his paper, it was written with somebody else in his group that there are a number of downsides of long-term calorie restriction.

All of the organs, the lean organs in the body, including the brain shrink and the consequence could be frailty and the downsides of that. and of course brain shrinkage. It doesn’t sound like a good thing to me even without the specific outcomes. So it gives, it leaves the question, why are these, why are there downsides when we eat, we want the calories to wind up some in fat so that we have enough stored?

To get us through if there’s an interruption of food, if there’s a famine and so forth. We just don’t want to overdo the fat storage. We want many of those calories to wind up in the critical metabolically active organs, the muscle, the liver in the brain. And why is it that in many diets and with these drugs, it looks like we’re borrowing, we’re there are not enough calories getting to the critical organs. This is where a low-carb diet looks very interesting because a central premise of what’s called the carbohydrate insulin model, which is considered one of the fundamental explanatory mechanisms for why a low-carb diet works.

There’s sort of a turnstile when your insulin level goes up by eating too much of the wrong carbohydrates, those calories are preferentially deposited in fat. There aren’t enough for the rest of the body, and that’s why we get hungry. And if we resist our hunger and don’t eat, our metabolism slows down.

And either way, it makes weight loss very difficult. Whereas if you cut carbs, the turnstile shifts in the other direction. More of those calories wind up where they need to be. You don’t lose the muscle mass with weight loss. So this is all, this is, some of it’s demonstrated and there’s evidence for some of this.

We don’t have proof. This could easily be demonstrated in trials including that two by two study that we talked about earlier. 

Bret: 
Yeah, that sounds like it would be a very powerful study, and I’ve seen people relate the 40% of lean mass weight loss with GLP-1s to the same as, gastric bypass surgery and severe calorie restriction.

So therefore it’s okay because it’s the same as those other methods, but I think as you’re saying, it doesn’t have to be that way. We can find a better way to lose weight and maintain muscle mass. 

David: 
We want to starve the fat cells. We don’t want to starve the rest of us.

And there’s potentially a way to do that, not based on restricting total calories, but by restricting carbohydrates if poor, and possibly other ways. If that produces the hormonal changes in the body, that shift where those calories wind up. 

Bret: 
It is a good place to stop and we’ll transition to, a future conversation.

But as we wrap again, Gary, please let us know. Everybody can find you your Substack and your Twitter and so forth. 

Gary: 
I’m on Twitter is Gary Taubes @garytaubes. In the Substack, it is called The Uncertainty Principles. 

Bret: 
Very good. And David, where can people find you to learn more about your work? 

David: 
I’m on social media.

I’m, I can be, found. my website is, drdavidludwig.com and that has links to Social media and my books and the like. 

Bret: 
Very good. And most importantly, if anybody out there wants to fund his study, please reach out to him right away. We need those answers. So thank you both for joining me.

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