How Do GLP-1 Drugs Override Our Biology?

FLORA LICHTMAN: This is Science Friday. I’m Flora Lichtman. Over the past couple of years, a class of drugs has dominated the headlines. I’m talking about GLP-1 medications, like Wegovy, Ozempic, Zepbound.

You might be taking one. You might know somebody who is. In a new book, former FDA Commissioner David Kessler aims to go beyond the headlines to take a close look at the science on metabolism, weight loss, and how these new blockbuster drugs actually work.

Dr. Kessler has a personal relationship with the subject. He’s taken a GLP-1 medication himself. His book is called Diet, Drugs, and Dopamine– The New Science of Achieving a Healthy Weight. David, welcome back to Science Friday.

DAVID KESSLER: Thanks for having me.

FLORA LICHTMAN: You wrote an op-ed on these GLP-1 drugs for The New York Times, and there were 740 comments as of the time that I looked at it. Why do you think this medication is a lightning rod?

DAVID KESSLER: Well, I think they’re an opportunity to reverse, for me, this epidemic of chronic disease, they are not a panacea. They are one tool in a toolbox. The one thing about these drugs that I think everybody can agree on is that they work through biology.

And that means this struggle that many of us have experienced throughout our lives, this struggle with weight, is not willpower. That’s what these drugs show. But all of a sudden, we have something that we’ve never had before. We have a very powerful, highly effective drug that does something that we’ve not been able to achieve on our own.

FLORA LICHTMAN: You know, one thing that really struck me in your book was a section you had about why the weight always seems to come back. And you talk about how when you lose weight, your body actually starts to burn fewer calories at rest. Can you walk me through that?

DAVID KESSLER: So there’s two central reasons why you keep on gaining back weight. First, there’s this thing, as you just alluded to, called metabolic adaptation. As you lose weight, the body is designed to defend that body weight. Your energy expenditure reduces.

But you also still have those addictive circuits. There are circuits in our brain. Call them the reward circuits, call them the addiction circuits, and they drive much of eating.

If you go back millennium, go back thousands of years, those circuits enabled us to survive. They were geared to have us look for food, to find food in an environment of scarcity. Switch that environment to an environment of abundance, energy-dense food, it’s not that our brains are not working well.

They’re working only too well. The human brain evolved to deal with scarcity, not abundance. So I have that biology working against that weight loss.

FLORA LICHTMAN: You make the argument in the book that you can get addicted to food, and you also quote a–

DAVID KESSLER: Just be careful. I’m sorry to interrupt.

FLORA LICHTMAN: Yeah, please.

DAVID KESSLER: It’s not food. It’s these ultra-formulated foods. It’s these highly processed, energy-dense, high glycemic foods, these foods that don’t occur in nature. It’s this perfect trifecta of fat, sugar, and salt. The enemy is not food. It’s these highly processed, energy-dense foods.

FLORA LICHTMAN: You don’t call them ultra-processed foods in the book. You call them ultra-formulated foods. Why that distinction?

DAVID KESSLER: It’s a nuance, but I don’t think when you think about processing, when you think about preservatives or stabilizers or emulsifiers, I don’t think those are really what’s driving overeating. I think it’s fat and sugar, fat and salt, fat, sugar, and salt. That’s the perfect trifecta.

So the food industry will say we’re just giving consumers what we want. They designed the foods to achieve this bliss point. But that bliss point is exactly the kind of stimulus that these reward circuits, that these addictive circuits, are designed to respond to.

FLORA LICHTMAN: When you were commissioner of the FDA in the ’90s, did you think about regulating ultra-formulated foods? I mean, it was a different time, but did it cross your radar, and do you wish you had done something then?

DAVID KESSLER: So what we did was we did the food label. I mean, that was the first iteration of just what’s in the food. What we missed, what I didn’t get, was that told us what was in the food.

List the fat. I mean, it lists the carbohydrates, it lists the sugar. It lists the calories. It lists the protein. It never told us what the biological effects were of those foods and what those foods were doing to our metabolism, let alone to those addictive circuits.

FLORA LICHTMAN: I want to go back to the GLP-1 drugs. How do they work? What is the mechanism for how they work.

DAVID KESSLER: I don’t think the companies have fully leveled with the American public. I think they worked pretty simply by keeping foods in our stomach longer. It’s called delayed gastric emptying.

Now, they work– to do that, they work on the hindbrain circuits. They work on the gut. What does that do when you keep food in your stomach?

There’s this spectrum. I’m satisfied. I’m full. Then there’s this Thanksgiving fullness.

Then I can push you to beyond Thanksgiving fullness, like, uh, to that edge of nausea. And what happens when you have food, just staying in your stomach longer? What don’t you want to do?

I think we’ve all experienced this where we get the flu. You don’t want to put anything in your stomach. You lose your appetite. You get food poisoning. You really don’t want to put something in your stomach.

So, food stays in your stomach. I mean, that’s the result of certain circuits in our brain. Specifically, it’s the area postrema, the nucleus solitarius, the NTS. Those are part of the aversive circuits of our brains in contrast to those addictive circuits.

Everybody perceives this and experiences. Both when it comes to food and certainly these drugs, there’s great variability. We all respond differently and uniquely, and from a scientific point of view, that is very humbling for me.

I was sort of conditioning myself, I didn’t want to become ill. So I was eating smaller portions, knowing how I would feel. I mean, it wasn’t a conscious thing.

I mean, it was just happening. I was eating less. And many people eat much less.

I mean, one of the concerns I have about these drugs, and there’s not a lot of data out there. But when people are on them, there are many people, from what I can tell, where they eat less than 1,000. Some people eat down to 500 600 calories a day.

But that’s the stuff of semi-starvation. You have to do it carefully. You can’t just take these drugs. I mean, it’s absolutely essential. If you’re going to be eating much less, that has to be done under good both medical and dietician care.

FLORA LICHTMAN: You said the pharmaceutical companies haven’t fully leveled with the American public. What do you mean?

DAVID KESSLER: Well, I mean, the drugs work primarily, and I’m not saying this is the only way they work. They work essentially through their adverse effects. The adverse reactions are the mechanism of action.

FLORA LICHTMAN: The nausea– making you feel sick is actually, it’s not a side effect. That’s how they work.

DAVID KESSLER: Well, does it make you sick or just pushes you in that direction? The very early GLP-1 drugs, they were at different doses. When they injected these into animals, the animals didn’t move. They coined a term the scientists called visceral malaise, this just general ill sense, that the animals didn’t even move to the food.

And I think one of the great things about these drugs is they learn to titrate the dose. So I can push you to that level where you don’t want to put anything else in your stomach. I can quiet down those food noises. But for many people, I mean, if you’re not taking these carefully and you’re not titrating the dose carefully and you’re not under good care, you can push over that edge. And some people can’t tolerate these drugs because it gives them just too much distress.

FLORA LICHTMAN: You know, food feels like a key pleasure of life. And I think people could make the argument that these drugs deprive people of that pleasure, and that’s a serious downside to them. What do you make of that?

DAVID KESSLER: It’s not clear yet. Certainly for me, I could still get the pleasure. I still can get the taste.

I just was eating smaller amounts. But there’s a bigger issue here. For decades, nothing worked.

Let’s face it. I mean, diets just didn’t tamp down these circuits for the most part. I mean, again, you could white knuckle it. You can deprive yourself, but it would always come back.

And in the face of nothing working, I give a great deal of credit. A movement emerged, this body positivity movement. I mean, if there was no way to lose weight effectively, why put yourself through it?

And certainly with weight, shame, stigma, a very big part, it’s very hard to talk about these things. But this is not about weight. What really concerns me, what I care about, the reason I wrote Diet, Drugs, and Dopamine, was that it’s about health.

It’s about this toxic fat. That’s the fat that accumulates around our abdomen, that invades our liver, into our pancreas, that gets into layers of our heart. And that causes many of the cardiac, renal metabolic diseases.

Those are the chronic diseases that in our senior years cause great disability, if not mortality. We all knew that weight was not good for us, but we didn’t understand until now that it was causal in these chronic diseases, certain forms of cancer, potentially some of the neurodegenerative diseases. And we finally, finally, have tools. Again, no magic pills, no panacea, but we finally have the tools to deal with that. And we can reclaim our health.

FLORA LICHTMAN: We can reclaim our health, but only if we’re taking this drug, right?

DAVID KESSLER: Oh, hold it, hold it, hold it, hold it. This drug is one tool in a toolkit.

FLORA LICHTMAN: I just mean you can’t go off it.

DAVID KESSLER: Well, OK.

FLORA LICHTMAN: Let’s talk about that.

DAVID KESSLER: All right. I mean, that’s fair. The data that I have seen suggests that the average period of time that someone’s on these drugs is eight to nine months. And let’s again recognize that the premise of these drugs was they only work when you’re on them.

You go off them, they stop working. The companies expect people to be on these for life. The reality is–

FLORA LICHTMAN: It serves the companies for people to be on these for life.

DAVID KESSLER: Right? I mean, that’s the business model. You’re on these drugs for life.

But people go off these drugs for many reasons. They can’t afford these drugs. Insurance will cover it.

These drugs, they have adverse events. Yes, those adverse events get reduced over time.

Just the general view of drug burden– do I want to be on a drug for life? The reality is most people do not. So we have to learn how to use these drugs in the real world. I think my agency, my old agency, has to do more to get the data, how to use these drugs in the real world.

FLORA LICHTMAN: And the long term side effects, right, that we don’t yet.

DAVID KESSLER: Absolutely. I mean, I am very humbled. Now, now the companies will say, these drugs have been around for two decades. That’s true, but we’re using them at higher doses more recently for weight than they were used originally for diabetes.

And there are adverse events that emerge only over time. So the question is how to use it. I was on these drugs seven or eight months, I lost significant amount of weight, and I had some abdominal pain.

I wasn’t sure was it related to the drug. We all have this experience of constipation. But constipation in certain instances, in rare instances, I mean, it can lead to obstruction and perforations.

So I just decided to go off these drugs. But the question is, what do you do then? And that’s why we’ve lived in a world where there’s diet on first, and then there’s drugs. But I think there’s a third way here.

FLORA LICHTMAN: What’s the third way? What’s the third way?

DAVID KESSLER: The third way is getting good care and having a range of tools to be able to use. So I go on these drugs. I learn to condition myself.

It happens automatically to eat smaller. But then I can use nutrition therapy. I can use diet.

I can use physical activity. I can use behavioral changes. I eat small even when I’m off these drugs. But eventually, that fades.

Maybe I need to go back on the drugs. We have to learn how to do that at the right doses. We got to get the data.

But the most important thing is, look. Just because I was born without this kind of satiety level of hormones that someone else had, There shouldn’t be any bias about my using these drugs. This is about biology.

So, no shame or stigma. I mean, it’s not a matter of choice. These GLP-1 drugs are an important tool. Ultra-formulated foods are addictive. These GLP-1 drugs can help tamp down the addiction.

FLORA LICHTMAN: But should it be the job of those drugs– should it– let me ask you this, though. Should it be the job of individuals to take on what is actually a structural problem? If the problem is these ultra-formulated foods, why should it be on individuals to have to suffer the side effects, the uncertainty, the risks, the expense of dealing with that problem?

DAVID KESSLER: It should not be. But if I wait– and the reason I wrote this book, if you’re going to wait for the day that our food environment changes, I don’t have time. I mean, if I’m sitting there as the average American and I’m suffering from these chronic cardiac, renal, metabolic diseases, I mean, what am I going to do about my health in the interval?

Look, you are right. There is no doubt. You have one industry making billions of dollars making us sick. You have another industry that comes along and makes equal profits by treating what that pharma industry does.

I mean, if you were from Mars and came down and you saw that problem, you would say, fix the root cause. Absolutely, we need to do that. But what are we going to do in the interval?

And I just wanted to be able to give people understanding the kind of tools are out there. But you got to be able to put it together. You can’t do it yourself, but you really can reclaim your health.

And we also have to work on that obesogenic food environment. Look, what was the great public health success? I mean, it was tobacco. How many years did it take–

FLORA LICHTMAN: Which you had a big part in.

DAVID KESSLER: It was a bunch of chapters. Yes, we were part, one chapter. But it took 75 years to change that story with tobacco. We changed, society, how we view tobacco. We’re going to have to do the same thing.

FLORA LICHTMAN: We need you to use your playbook again.

DAVID KESSLER: We need to use the playbook again, but we also need to be able to give people, if they want, the ability to reclaim their health.

FLORA LICHTMAN: David, thank you so much for taking the time to talk to us today.

DAVID KESSLER: Thank you.

FLORA LICHTMAN: Dr. David Kessler is the former commissioner of the FDA and the author of the new book Diet, Drugs, and Dopamine– The New Science of Achieving a Healthy Weight. If you want to read an excerpt of the book, go to sciencefriday.com/dietdrugs.