Who should actually take a GLP-1? An obesity expert's honest take

Who Should Take GLP-1s? Weight Loss Explained | Dr. Robert Kushner & Mike Haney

In a recent episode of A Whole New Level, Levels editorial director Mike Haney sits down with Dr. Robert Kushner, professor of medicine at Northwestern University Feinberg School of Medicine and one of the country's leading obesity medicine specialists. Kushner has spent more than four decades treating patients with obesity and training clinicians in obesity care. He led the landmark STEP clinical trials for Novo Nordisk that brought semaglutide to market, co-authored the influential Lancet Commission framework distinguishing clinical from preclinical obesity, and has written multiple books on the subject — including a phenotype-based guide for clinicians and the popular Six Factors to Fit.

The conversation covers how our understanding of obesity as a chronic, relapsing disease has changed over the past 30 years, what the new clinical versus preclinical obesity framework means for how we diagnose and treat it, how GLP-1 drugs work and why they've succeeded where earlier medications failed, what the STEP and SELECT trials revealed about the disease-modifying potential of semaglutide, and how patients and clinicians should be thinking about who these drugs are really for.

"There is a strong biological basis for developing obesity. And I think we're still struggling to put it together — but what we are pretty much sure of now, which has been clarified over the past two decades or so, is that it's a very, very strong biological basis." — Dr. Robert Kushner

Obesity as a chronic, recurring disease

Mike Haney: So Dr. Robert Kushner, thanks so much for joining us today.

Robert Kushner: Thank you for having me, Mike.

Mike Haney: So we're going to talk a lot today about GLP-1s, but I want to start by talking about obesity in general because I want to sort of frame this conversation — you know, in this modern age of people being able to go online and get a GLP-1 prescription in 10 minutes, or micro-dosing it, or taking it for all sorts of different clinical implications. We want to kind of understand who these drugs are for and what we know about how they're working. But I think framing how we think about obesity is maybe the place to start.

You've been doing this for 30 years, and I think one of the probably biggest changes that have happened over the time that you've been working on obesity is that we've come to see obesity as a chronic recurring disease. You've also said — and I think this is something else we've learned over that time — that obesity is not one thing. So when is obesity a chronic recurring disease, and what are the implications of now being able to use that label?

Robert Kushner: Yeah. Well, obesity is complex. As you said, multiple factors lead to obesity. We've known for decades that it's a combination of biology, genetics, physiology, environment, social drivers of health. And we couldn't quite put that puzzle together. And I think we're still struggling to put it together. But what we are pretty much sure of now, which has been clarified over the past two decades or so, is there's a very very strong biological basis for developing obesity. And that comes from our ancestors — you know, we had to survive famine and drought and we had to have the biology to get through all of that. The problem would happen though is now in modern society where we don't have famine everywhere. We have food available in most parts of the world and very little need for physical transportation since everything is mechanized.

We are really good at storing calories. That's where that biology comes in. And our current thinking is that if someone's developing obesity, particularly moderate to severe obesity in this society, they most likely have a genetic predisposition from our ancestors to put on calories and they don't balance their body fat very well.

So to answer your question directly, there are some people who probably don't have that thrifty gene, but just the fact of how their lifestyle is — they're not physically active, they're eating a lot of highly processed food and so forth — they're gaining weight, but that can change quickly depending upon change in their behavior and in their environment. Others, however, are probably destined because of genetic loading to put weight on and keep it on. Those are the individuals that come to see me in the clinic because they're developing a whole host of obesity-related complications and diseases.

Mike Haney: I'm curious what you've seen. It sounds like one of the things that being able to call this a chronic recurring disease has helped with is that it's removed a lot of the stigma, right? That for so long obesity was — you're just being lazy, why don't you move more, why don't you eat better? And because we now understand some of those genetic drivers and that this can be a disease for folks, it takes that away. I'm curious what your experience has been as we've started to use this terminology from the patient's point of view. How do patients react to finding out they have a chronic recurring disease? Because it feels like on one hand that could be a relief. On the other hand, that could sort of bring an air of hopelessness — like, oh no, I thought I could just do a certain thing to get better and you're telling me I have a chronic recurring disease.

Robert Kushner: Yeah. It's a two-sided coin. On one point I can say it is not your fault, and that's probably the most important thing a clinician can tell a patient. It is not your fault for lack of willpower, lack of determination, lack of intelligence, sloth and gluttony and the moral implications of obesity. That is relieving to say it's not your fault. There is a biology to this and I think they take a deep breath and I tell them it's a non-judgment zone. Let's talk about that.

The other side of the coin, however, as you're getting to, is who wants another disease? When you go see a doctor, sometimes they feel good when you could put their symptoms and signs together and they name it something — to go, I knew I wasn't in my head. But in general, people don't want to be told, I have another disease. But weighing the two, seeing thousands of patients over this period of time, they really start to embrace the disease concept because for them it puts together — oh, now I understand why it is so difficult for me to reduce my calories long term and keep my weight off. I understand why I'm getting hungrier again, why I'm thinking about food again, why no matter what I do, my weight comes back. So it actually connects the dots for them that there is a biological basis.

But then I have to go from biology to chronic relapsing disease. That's that disease word that a lot of people don't want to give that label. They still have a sense of — I get it's a disease, but it's still my responsibility, right? I still should be able to take this on. And some of it's true, you do need personal responsibility, but that's typically not enough when you're dealing with a disease.

Redefining obesity: clinical versus preclinical

Mike Haney: And you also worked recently on a large article — essentially a paper for the Lancet — on defining clinical versus preclinical obesity. Can you talk a little bit about those labels and how that fits into this picture of different types of obesity we're talking about?

Robert Kushner: That article has been a paradigm shift and there's been so many follow-up articles in response to it with other types of studies that are addressing it. And what the paradigm shift is — we are looking at not just obesity being a disease based on body mass index. A BMI of 30 or more, at least in the western population, is obesity. We don't define disease by an anthropometric measurement in anything else other than rare endocrinologic diseases. So we really wanted to tackle: if obesity is a disease and we want to treat it as such, like we have other chronic diseases, tell me what the signs and symptoms are of that disease.

So if a patient comes to see a clinician and they have shortness of breath and they're wheezing, and you listen to their lungs and you hear wheezing, we make a diagnosis of asthma. But when someone comes in with obesity, what are the signs and symptoms? They have a disease, not just by elevated BMI, because that could be muscle mass — it doesn't have to be body fat.

So we take really the revolutionary step, a dividing obesity, which means excess body fat. So you identify that and you say: is there harm to your health by having an elevated body fat? If the answer is no — so this would be an example: running half marathons, good quality of life, blood sugars under control, lot of energy, blood tests are completely normal — do they really have a disease? Well, our thought is no, they don't. They have obesity, but it's preclinical obesity as a disease. In other words, it's a state. They can develop signs and symptoms over time. In fact, they have a higher risk of developing problems. You have to watch that individual, but may not need aggressive treatment today.

However, if that same individual comes in and they go, you know, I have sleep apnea, my knees hurt, I'm developing pre-diabetes, or a woman has PCOS, infertility and so forth — now there's harm to their health because of the excess body fat, and we call that clinical obesity. This has really set the world on fire. There's been so many articles about this.

And what we took out, Mike, is the whole idea of overweight. Overweight currently is a body mass index of 25 to 30. You could find it on Google. We said, no, if you have excess body fat, it doesn't matter if you're overweight or not — that is obesity, but it may not be causing harm to your health. So this is currently being debated. In fact, it's debated in every meeting I've been to. I'm moderating a debate in the upcoming diabetes association meeting. I talked in last year's Obesity Society meeting. And that's exactly what we wanted — we wanted to start the conversation to move beyond BMI as the diagnosis of obesity, because you know what? A lot of people find that offensive. They have a BMI of 32, they can do everything they want, they're muscular, and you're saying I have a disease of obesity. Well, they probably don't.

Mike Haney: And that really focuses on the sort of outcome, right? The not eventual outcome, but the sort of state of the patient. There's also, as related to that, the sort of path to obesity. I think of the folks I know who have, you know, childhood friends who have been big guys since we were kids in elementary school and have sort of been big all their life and maybe struggled on and off with losing weight or getting it back. And then I think about, you know, a lot of the rest of us that maybe started pretty thin and then as age came for natural reasons, you start to put on weight and if you're not really careful about it, you can be the person who's now in their 40s and has 25 extra pounds. How do those paths to obesity change how we define it and then how we think about sort of treating it?

Robert Kushner: Yeah, it's a very good question. I have always thought, along with other colleagues for a long time, that you can start identifying groups that have lived with obesity for a very long period of time and they would somehow present differently metabolically and so on, and it would give us an understanding of what treatments would be better for someone, let's say, with long-term obesity versus someone with short-term obesity. That hasn't really come true. If I see someone in a clinic and they've been living with obesity for 15 years versus someone for two years, I kind of render the same treatments.

Where the differences occur though is probably their long-term risk. And we think of years lived with obesity now like smoking years lived with tobacco — we're starting to think of years lived with obesity not so much to change my treatment but to render the risk estimate that you have. For example, if you take an actor who puts on 30 pounds for a role for a movie and they develop obesity and they take it off a year later, they don't have the same risk as someone who's had it since emerging adult years, 18 to 25, or during child-rearing years, 20 to 30.

So treatment doesn't change much, but psychologically it may be different. Someone who's always grown up living in a larger body probably had bullying when they were younger, and psychologically maybe didn't have as much social interaction because of shame or embarrassment, and so on. They probably have other psychological issues perhaps, or they stayed away from fitness and sports because they were never good at them or they were embarrassed to do it, so they don't have the skill set and the liking of being physically active. So that's more behavioral and emotional and psychological — you really need to pay attention to — but as far as other treatments rendered, pharmacotherapy and so on, that really doesn't change much.

Mike Haney: Does that time with obesity tell you anything about that genetic predisposition we were talking about that might kind of separate disease from non-disease state?

Robert Kushner: It likely does, although it doesn't take away the physical exam and signs and symptoms and doing blood tests. But if I see someone who's lived with obesity for a long period of time, like years — as we said, years living with obesity — I'm going to pay very close attention to them about their disease risk. Having said that, other people may gain weight quickly because of change in diet, or they develop a disability and their physical activity goes down, or they're on a weight-gaining drug for diabetes or something — they can have rapid risk as well. So I think there's a lot of heterogeneity or variety in patients. So we're talking in stereotypes a bit.

Obesity phenotypes: a more targeted approach to treatment

Mike Haney: Yeah. Well, speaking of that heterogeneity, you've done a lot of work on obesity phenotypes, written a couple of books about it now — a popular book, Six Factors to Fit, and now a book for clinicians to use this sort of obesity phenotype framework as part of treatment. So what are obesity phenotypes?

Robert Kushner: So phenotypes — if this was a show on marketing I would use the word segmentation, right? Marketers segment the population. Phenotyping is a way that clinicians segment the population, so you could segment a population on various characteristics: physical characteristics, behavioral characteristics, time lived with obesity, psychological characteristics. And I'm a big fan of that because as a clinician you need some guide, some efficient and effective way to treat the patient in front of you. What separates out that patient from the person who's coming in next, or you just saw, who has the same body mass index?

So we use phenotypes, and the most common phenotypes people are probably familiar with is: is your body fat distributed in the upper body segment — that belly fat — or is it in the lower part of the body? That's a phenotype. It turns out that the high-risk phenotype is an individual whose fat distribution is in the upper part of the body.

I happen to be interested in not physical phenotypes but biopsychosocial phenotypes — and that is individuals who come in, and let's say you're taking in extra calories, but why are you taking in more calories? Well, one is called a food lover, or someone who has cravings for food. That's a different phenotype than someone who is consuming fast food all the time — it doesn't have cravings for it, but just eats fast food. Those are potentially two phenotypes. Or someone who has perfectionism, or someone who's not getting enough physical activity. So I've developed, in the popular book and the professional book, a 27-item questionnaire that a clinician could administer very quickly. It's filled out about a patient, it's scored by you or the patient, and you could identify the phenotype and then target your treatment directly to what the issues are that patient is facing.

Other individuals — although this is in its infancy — are trying to identify phenotypes when it comes to treatment: like what are the characteristics of that individual that are more likely to have them respond to a GLP-1 medication versus let's say an older oral medication. That's kind of in its infancy, but that's where we're going. And that's similar to cancer, actually, where you can do the genotype of an individual and identify what's the best chemotherapy or immunotherapy for an individual with, let's say, a certain kind of breast cancer. We're not there yet with obesity or obesities. But that's kind of where this whole idea of phenotype is going.

Mike Haney: You did something with this book that I wish all books that were trying to present a solution to obesity had to do, which is you came up with the idea and then you ran a study to validate it, and then you wrote the book about it. And I'm curious what you learned. I know this book grew out of your experience working with patients, and you sort of started to identify these phenotypes. And I'll say, reading the book — doing all the sort of thinking and research about GLP-1s and then reading the book — kind of felt like reading a book from another era. I mean, it is from, I think, 2019, when the popular book was published. So it is a little pre-GLP-1s being in the mainstream culture. And it made me wonder, how much success were you able to have? I've heard you say, you know, I spent 25 years treating this condition without a decent pharmaceutical option and five years with one. So in that 25 years, using frameworks like the phenotypes that you've actually studied, how much success were you able to have with lifestyle-focused treatments?

Robert Kushner: Well, Mike, I can tell you I became an expert in motivational interviewing, patient-centered care, behavioral change theories and techniques, and using my hands to try to encourage people to make changes. I became very good at that and I think we did the best we could. What we didn't understand — I started practicing in the 1980s — what we didn't understand in the 1980s, 1990s, in the 2000s we started to have a better understanding but we didn't have the right medication. We understood there is a strong biological basis for gaining weight and, most frustratingly for the patients, for causing weight regain — or we call it weight recurrence.

So we were good over those decades in helping people lose weight. They're motivated. They're starting at their highest body weight. They're making changes in their diet, their physical activity, their cognitions, social connectiveness, and getting support systems around them. But what got in the way is metabolic adaptation. And that is this drive for body weight to go back to where it started. No matter what the individual is able to do behaviorally or psychologically, they couldn't fight that.

So fast forward to today, we now have effective medications to treat biology with biology — the biological problem, which is helpful. But the forgotten treatment is what we have done for decades. And that is, we can use a medication — very helpful — and the food cravings go down, the food noise goes down, I'm not struggling, I don't have to count calories every day. But how do I not only live a healthy life, but how do I keep that weight off long term and be all I can be? And that's where all those behavioral and psychological treatments start to come back and we add them back to the highly effective medications.

Let me end this part, Mike, with: we've always thought that the foundation is lifestyle management and then we have adjuncts of pharmacotherapy. We often are flipping it on its head. Now we have pharmacotherapy but the adjunct to that is lifestyle medicine or lifestyle therapies.

"We've always thought that the foundation is lifestyle management and then we have adjuncts of pharmacotherapy. We often are flipping it on its head. Now we have pharmacotherapy but the adjunct to that is lifestyle medicine." — Dr. Robert Kushner

Mike Haney: I definitely want to come back to the pharmacotherapies in particular, the concept of metabolic adaptation, which we've been talking about on the show a lot recently. But to stay on the obesity side of it and the lifestyle side of it — does the behavioral phenotyping that you've done, as you began to understand that there is a sort of biological component you're working against here, does that behavioral phenotyping become then more important? Because you can't just throw a sort of set of generic lifestyle suggestions at people, but you really do need to be kind of more targeted about how to help this specific person fight that biological imperative.

Robert Kushner: The answer is yes. Of the six phenotypes that we came up with — we try to simplify a 27-item questionnaire — one of the phenotypes is easily enticed eater. That's a love of food, and food speaks to me, and I get joy and reward out of food, and I live to eat — that type of thing. Medications are very good at tackling that. So if you put someone on medication, that particular behavioral phenotype is controlled with the medication by itself.

Of the other phenotypes — like convenient diner, fast-pacer, self-critic, all-or-nothing doer — the medications don't tackle those really at all. And what I've learned working with patients is if you take away the easily enticed eater and they don't have to count calories all the time, and they can start eating healthier because they're not driven to eat, they have the psychological and mental bandwidth to start tackling these other phenotypes that they have been unable to conquer, because they have the other ones under better control.

So I still find that using a phenotypic approach even with pharmacotherapy can be very advantageous for the patients because it really rounds out: how do I treat the patient in front of me, even though it's the same medication I use for the past five patients? How does this patient differ? And that's where that phenotypic work comes in handy.

The three stages of weight management

Mike Haney: Well, before we move on to the drugs, you mentioned maintenance, and I want to talk briefly about what I call sort of the three stages of weight management, right? There's prevention — I'm a healthy weight, I'm just starting to see those pounds creep on a little bit. I think this is what everybody deals with to some degree as they age. Even skinny guys like us, you start to hit your 40s and 50s and you go, wow, the weight's coming on in a way it didn't when I was in my 20s and 30s. So there's the prevention side of it. There's the actual loss side of it — okay, I've identified I've got some weight, I need to get rid of it. And then there's that maintenance part of it, keeping the weight off, which I think is the component that doesn't get talked about enough. What's the difference physiologically at each one of those stages? What is the kind of biological imperative that we are fighting? Or is there any difference at each one of those stages?

Robert Kushner: Well, in the first stage, which is that weight gain stage, you're in positive energy balance — and the only way you put weight on is you're taking in more calories than you burn off. From a physiologic point of view, you're in positive energy balance. And that could occur for a variety of reasons. People don't notice that, but if you listen to the story, they'll say, you know, ever since COVID-19, I'm working from home, so I don't have that walking commute I had every day. So I'm more physically inactive. I have access to the kitchen every day, which I didn't have when I went to work. I'm under a lot of stress because my company's downsizing. I think I'm nibbling more and snacking to deal with my stress, and I'm not sleeping as well as I did because I'm nervous. So all of those changes conspire to put weight on.

When you develop obesity and your weight is stable, you're now actually in energy balance. Energy intake equals energy expenditure because that's what balance is — except that it's at a higher level. So you're taking in more calories and you're burning a little more calories off, but it's because you are actually bigger. That's what's going on physiologically.

And then weight regain, of course, it's almost backwards — there you have the body having metabolic adaptation. The energy expenditure goes down when your appetite starts going up. So it's almost like riding a wave. You're riding a wave up, you're stable, and then riding a wave back up once you've gone down.

From a treatment point of view, there are clear differences. If I see someone starting to put their weight on — let's say preclinical obesity, they don't have harm to their health, but they're putting weight on — I'm going to be talking a lot about a healthy lifestyle at that point, about making smart choices. You don't have to become a vegan. You don't have to become a marathon runner to start making healthy choices. And you have to point it out to the individual. I actually may ask them to track their diet, maybe put a wearable on or looking at steps, maybe looking at their sleep if they're digitally minded. Small changes can make a difference. And preventing the weight gain may actually be easier than treating obesity, because the body changes during the obesity state. Then we have to become more invasive and more aggressive there.

Then you have weight maintenance, which is the rest of your life because it's a chronic relapsing disease — if you will — or condition. And there it's how do you — you're getting away now from the whoopee effect of boy, the weight's coming off, I feel good, I'm motivated — and now you're in how do I do this the rest of my life. And that could be often different kinds of counseling. And there, what I'm talking to them about mostly is stretch goals. Now that you've taken your weight off, where are you going to get your motivation to remain healthy? And it could be running a marathon, taking up ballroom dance, maybe going on trips and doing hiking, taking up different sports — pickleball or other things you'd like to do. Get yourself into different social clubs and hobbies. So really reinvent yourself. Some of these people have struggled with their weight their whole life. Tackle things that you never did before that you maybe can now start to do, to increase your motivation and enjoy your new life and your healthier body.

Mike Haney: That's interesting. So on the maintenance side, you were fighting this kind of metabolic adaptation, this biological imperative that your body is trying to get back to its settling point. And you know, the way around that is again, if we're not doing pharmaceuticals, is to maintain these healthy lifestyle choices. And what you found is that motivation, it sounds like, is what matters there. That you need to give people a reason that they should sustain these, because just doing it is hard, right? This is the thing we're always told about lifestyle is that it quote unquote doesn't work, it's too hard, people all go back. But sort of changing someone's identity, it sounds like, is a little bit the hack to keep that working.

Robert Kushner: It is. And you got it right, exactly. I will tell individuals, patients I'm working with — when you keep your weight off, what you want to do is have other people describe you in ways that typify health. Such as, if they say, boy, when I talk about Mary, she is always moving. She is the most active person I've ever seen. And when she's on that pickleball court, she is really working hard, and she's traveling and she's going out and she's being physically active and using the stairs. So it is an identity and you want to own that identity. If your goal is I want to take the weight off and just keep the weight off, you're missing the point of improving health, which is really what we're trying to achieve when we work with someone living with obesity.

How GLP-1s work: the physiology

Mike Haney: Well, let's pivot into the drugs then. And I'd like to start here because I think most folks really don't understand how these work. So can you give us the sort of college freshman level physiology of what is a GLP-1 and what is it doing in my body?

Robert Kushner: Well, we're targeting a sweet spot in our biology, Mike, that we didn't really know was there, at least I didn't know what was there. And what we're targeting are naturally occurring gut hormones. So GLP-1 stands for glucagon-like peptide-1, and GLP-1 is one of several hormones produced in our intestines or in our stomach. And the way the body works is when you consume food and you start feeling full, hunger goes down, you're not interested in eating any more food, you really feel satiated. You're feeling that in the brain, but the signals to feel that are coming from your gut. So you're eating and food is causing the release of these hormones into the bloodstream targeting the nervous system, and that's what you're feeling in your head.

And that is basically what these new revolutionary drugs are. They're called GLP-1s, but there are many other ones there. So what we do is we take a naturally occurring hormone, we take it out, synthesize it into pharmacologic amounts, give it back to individuals, so we're able to amplify these satiety signals that someone's not quite getting, so they feel full.

And the best example I can give you, Mike, is someone with type 2 diabetes when we give them insulin. Someone with type 2 diabetes has insulin, but it's not enough insulin in order to bring their blood sugar down. So what do we do? We give them higher doses of insulin. They already have that — give it back to them at much higher pharmacologic doses and it brings their blood sugar down. And that's the best comparator. It's a naturally occurring hormone, we synthesize it pharmacologically, give it back at very high doses, and it amplifies the satiety or appetite signals so they feel less hungry. And that's how all these new generation medications work — by reducing appetite, which leads to reducing caloric intake, which then leads to losing body weight.

Mike Haney: So people may have heard, just on this physiology side, the word agonist — GLP-1 agonist. What does agonist mean? What work is that doing?

Robert Kushner: Agonist means it turns on the receptor for the GLP-1. So all hormones have receptors — you know the key and lock concept. So an agonist is it turns on the receptor, or the lock part. So it amplifies the signal that the GLP-1 is going to get at the lock part, or the receptor part. Antagonist would be the opposite — it blocks that lock or blocks the signal.

Mike Haney: So is it making the body more receptive to the amount of hormone it already has, or like insulin, are we literally injecting additional hormone into our body?

Robert Kushner: Yeah, great question. And my answer is going to circle back to what you asked me before about the disease of obesity. If we're giving something back to someone that they already have, why does it have such a profound effect on them? And our current thinking about obesity, and one of the components of the disease of obesity, is that some individuals — although they all have GLP-1 and these other gut hormones, amylin, glucagon, GIP, that's what they're called — that signal, for some reason, is not getting to the brain in ample amounts to tell the individual to feel full, satiated, and stop eating.

So even though you can find GLP-1 in someone living with obesity, it's not signaling the brain enough to modify their appetite. So the theory is if we give that same signal, a hormone at a higher dose, we can overcome whatever that barrier is — and it turned out to be true. So it's the same hormone but at amplified amounts — they now hear or feel the fullness and they actually start to reduce their body weight.

Now, if we took a GLP-1, we would get that signal loud and clear and also reduce our appetite. So it works in all individuals, but someone who's not living with obesity doesn't need it. Their signals are completely normal, their physiology is working. Someone with obesity, for reasons not entirely clear, that signal is muted — it's not loud enough. So we treat it pharmacologically and now they get this signal.

I see patients in the clinic all the time that will tell me after getting a GLP-1 — they will spontaneously say, now I get it. This is what it must feel like for someone who doesn't have to live with obesity, who has normal appetite regulation and is not thinking about food all the time, which we now call food noise. So they're getting that feeling that they've been searching for and they didn't know what was wrong with them. And now they have an understanding — I was not getting the signal all this time. That's why it's been so hard for me all of these years and decades.

"I see patients in the clinic all the time that will tell me after getting a GLP-1 — they will spontaneously say, now I get it. This is what it must feel like for someone who doesn't have to live with obesity, who has normal appetite regulation and is not thinking about food all the time." — Dr. Robert Kushner

Mike Haney: So getting back to that — we talked about obesity as a disease, and it's a disease in some part because our bodies were not evolved to live in such a food-rich, calorie-rich environment. So is the GLP-1 fixing a dysfunction? If we go back to like type 1 diabetes for instance, right — that person's pancreas is just not producing insulin the way that a quote-unquote healthy body would, and so we need to give them insulin to fix a dysfunction. Or is the GLP-1 essentially hacking a process that is working perfectly normally — our body wants us to take in more and more calories, we just live in an environment in which that's the wrong signal for us to be getting, because absent any other kind of control on it, we could all sit and eat Ho Hos and Cheetos all day long? So is it fixing something that in some people, for whatever reason we don't understand, that signaling is not working the way it's supposed to? Or is it essentially giving us a hack to live in the modern environment without taking in too much?

Robert Kushner: We think of it regarding the former description you came up with. We think of it as individuals with obesity have developed an appetite dysregulation. For some reason their regulatory process is not working. Someone without obesity has a normal regulation of body fat — that's why their body mass index and their body habitus seems to be within a healthy range. With an appetite dysregulation, caloric intake is higher than it should be, which is causing a disruption and therefore excess body fat. So we think of it really as a disease in which we have a treatment for it that we can hopefully put the individual — control it and hopefully put them in remission — but currently it only works if you take the medication.

All of the studies that have been done in which the medication is abruptly stopped — that's how trials are done, the trial's over, stop, thank you very much, stop the medication — the weight starts to go back up. So we don't cure it, but we're able to treat it, which actually is like many other chronic diseases: diabetes, asthma, hypertension, high cholesterol. If you stop the treatment, the disease comes back. And I use that analogy when I'm working with patients to really reinforce that it is a chronic relapsing — sometimes I don't use disease, people again don't like disease, I'll say condition — we can treat it but we don't know exactly how to maintain that healthier body weight without the medication long term in most people.

Beyond weight loss: the disease-modifying potential of GLP-1s

Mike Haney: So mechanistically it sounds like the outcome is the same as what we would be trying to achieve with lifestyle — which is essentially negative energy balance. Like at the end of the day we're not doing something here that maybe some of the earlier pharmaceuticals might have been trying to do, of burn fat cells or change the way we store fat. We're literally just trying to get to a place of negative energy balance, and the GLP-1 is essentially an assist for doing that. That maybe people who don't have the kind of diseased state, who are just trying to lose 5 pounds, could theoretically do with just lifestyle changes.

Robert Kushner: Regarding body weight, that's very similar. Individuals are able to reduce their caloric intake with more resolve and less difficulty, right? Because the appetite signals are intact. However, the other transformative effect of GLP-1 is not just on weight loss. The real importance is the gain in health. GLP-1 medications — and GLP-1 itself — has receptors, we talked about that, in multiple organs throughout the body: the brain, the pancreas, heart, and vasculature. So as one is losing weight, we're also treating the disease of obesity when it comes to a new term here, lipotoxicity — excess body fat, ectopic body fat, inflammation throughout the body. So not only is someone losing weight, but the true benefit of GLP-1 in obesity is they're gaining health. Sleep apnea improves, arthritis improves, heart failure improves, heart disease improves. And that's not just weight loss — that's also an independent effect of GLP-1. So there's added benefit of using this type of medication in someone who has obesity and has harm to their health.

Mike Haney: I want to come back to all of those other potential benefits — what that means for again that question of who are these for — but just to, I'm curious, as I've watched this: we talk about sort of harnessing the satiating hormones. I'm old enough to remember when leptin was going to be the key to all of this. We've tried other kinds of drugs. Why do you think this has worked? What is it that we kind of discovered with GLP-1s, which have been around to treat diabetes for a long time? How do you understand the trajectory of our understanding of this particular hormone within the context of the gut-brain axis?

Robert Kushner: Yeah, I call it the secret sauce. Again, I've been involved in this field for 40 years and we've had other oral medications that have not been as effective and they've had side effects. And it seems as though these gut hormones are so basic when it comes to physiology of appetite regulation. And you think about the way we were created — as we start eating, something has to tell us to stop eating, as well as something has to tell us to start eating. That would be a hunger hormone called ghrelin. So this hormonal change within our intestinal system turns out to be incredibly powerful signals that work neurologically and through endocrine fashion up to the brain that really tell us how to regulate our body fat.

Finding energy and calories and maintaining our health is so important for our overall health and longevity, finding fuel and so forth. So it turns out these hormones are just key physiologic signals. And I think that's really what it's all about. It just is finding how these hormones work, how they work together. And something we didn't know — which is a gift — is the fact that higher doses of GLP-1 have profound effects as anti-inflammatory markers or outcomes, and work in so many different organs that we really didn't think about. So it's not just appetite control, it's actually beneficial throughout the body, and that we didn't see that one coming.

Mike Haney: How are these drugs working in people with diabetes? Why was that the initial indication for these drugs?

Robert Kushner: Well, GLP-1 and its sister drug GIP were first identified actually in the 1980s. It was identified that these naturally occurring hormones were very important in releasing insulin and controlling blood sugar. So that's what really led the pharmacologic industry towards diabetes treatment — they figured if we can harness the effect of these hormones like GLP-1 and synthesize them, we can help individuals produce more insulin and manage their blood sugar. So that was the direction of the pharmacologic industry very very early on, and that started in 2005.

These drugs have actually been around for 20 years now, at least for diabetes. And it was during the trial of individuals with diabetes that it was noted that they were also losing weight and had a reduction in their appetite. So it was a kind of off-target observation when it was used for individuals with diabetes to then start studying it for obesity.

Now, it was a slow start though, Mike, because the history of drug development in obesity has been fraught with challenges. Many drugs going to the cemetery and being taken off the market, causing side effects and cardiovascular problems that caused them either not to be used or to be taken off the market. So the FDA and pharmaceutical industry were really shy in investing in more obesity medications. But some companies really took a gamble and said, let's see if these drugs — GLP-1 in particular — can really be used for obesity. And that turned out to be a very positive outcome. And of course, the rest is history now with hundreds of companies working in this space.

The STEP trials and the SELECT study

Mike Haney: So you were a really key part of that process in leading the STEP trials. Can you talk about what those were and what you learned?

Robert Kushner: The STEP trials were the phase three foundational clinical trials for Novo Nordisk that brought semaglutide to the market. And it's a series of studies with different designs and populations to look, in randomized controlled trials — that's the highest level evidence — at what this drug would do for individuals with obesity, individuals with obesity who also had diabetes, what about if we add intensive lifestyle therapy to it, what would happen if we stopped the medication, what about individuals living with arthritis or with heart failure or heart disease. So through different trial designs and populations, they helped me as an obesity medicine specialist really understand the biology of obesity, how to use these drugs, how to manage individuals on these drugs because of the GI side effects, and have hard outcomes that would actually lead to approval by the FDA.

Probably the game-changing study in the New England Journal, which I was corresponding author on, was STEP 1, which actually launched semaglutide to the world — which for the first time caused a result in a 15% weight loss at the end of a year. We had never saw that.

The second game-changing article that came out is called SELECT, in which it's the very first study that we could say these drugs are disease-modifying and change lives, save lives. And in short — that came out a few years after that STEP 1 trial — what we did for the very first time is take individuals with obesity and pre-existing cardiovascular disease, like a prior stroke, prior heart attack, or peripheral arterial disease, called PAD, and they're on maximal therapy for their cardiovascular disease or stroke, and then randomized them on top of that to either semaglutide or placebo. What we found for the very first time, after three and a half to four years of treatment, is that if we add semaglutide to that individual, we can reduce their chance of either dying of cardiovascular disease, having a second stroke, or a second heart attack by 20%. And that was the first time I was able to say as an obesity medicine specialist that if I give you this drug, I can likely improve your life and reduce your chance of dying from cardiovascular disease. We were never able to say that before. So this is kind of a gift that keeps on giving. It has more and more disease-modifying and health-gaining benefits.

Who should get these drugs?

Mike Haney: So the clinical indication, as I understand it, for getting one of these drugs for the purpose of obesity is a BMI of 30, or a BMI of 27 with another condition like diabetes. But when I hear clinicians talk about this and who the kinds of conversations they have with patients — it sort of comes back to that earlier conversation we had where I'll hear the phrase a lot: you know, they've got this BMI or this obesity and they've tried everything else and it hasn't worked and now we're going to talk about the pharmaceutical. But the indication for the drug isn't BMI of 30 and has tried a bunch of other stuff. So how do you think about when to start somebody on one of these drugs? Who is the right audience for starting this kind of therapy?

Robert Kushner: Well, the BMI classifications, the cut points you mentioned, have actually now been removed by the FDA for semaglutide and the other drug called tirzepatide, the two major drugs on the market. It now just says an individual with obesity and it leaves it up to the clinician to determine what that is. Now, you actually do back into BMI, but they actually took it out of the labeling. So to get it approved by your insurance company or another payer, you often need that criteria.

But as a clinician, we're thinking of someone with overweight or obesity. So the BMI is certainly a bit lower, particularly for some of the Asian population where the BMIs are actually lower regarding health risk. But I'm looking for softer indications as well — what is the overall disease burden you have, or family history of a problem. Let's say you have a strong family history of type 2 diabetes or heart disease, but you really haven't manifested it yet. I would still want to prevent those from occurring. I also want to know about what have you tried before, what is your awareness of your diet inactivity, are you a willing partner in shared decision-making to work with me with this medication? Because your responsibility is going to be to modify your diet to reduce those side effects. Stay in touch with me. Tell me when it's time to dose escalate or how you're feeling. What other needs or phenotypes do you have? We talked about before — do I need to think about bringing a dietitian in or a health psychologist?

So it really is more complex than going to a telehealth company and filling out a questionnaire and getting your drug within two days. It really is a chronic relapsing disease, and it's really that astute clinician who is really understanding: is this the right patient for that drug to prescribe today?

Mike Haney: That makes perfect sense coming from a clinician, but I'm curious — why is that the case for the patient? Like, what is the argument against, given that we know how these things work? What's the argument against going on to one of these online sites? We'll set aside compounding for a minute, but let's assume we're getting the actual drug and just getting it because I know I'm heavy and I know that I've exercised and it doesn't really work, and maybe I just want to take it for 6 months and shed the 10 pounds. I know clinicians will say no, that's not what they're for, that's not why we're doing this. But why not?

Robert Kushner: Well, I'm going to give you one more clinician perspective and then I'll answer your question. If we use a comparator of diabetes, can you imagine telling someone: I want you to use the telehealth company and they will take an onboarding to find out about your diabetes? They're going to treat you with insulin. Never see you, just treat your insulin and treat your diabetes. I think most people go, that doesn't seem right — I have diabetes. Obesity is a chronic relapsing disease in the same way.

But to answer your question directly, the concern about getting medication without seeing a clinician or having more comprehensive care is: one, the medication is not teaching you anything about healthy living, how to be physically active, which is also important. It is not going to teach you how to modify or mitigate the side effects you're likely to have. It's not going to necessarily tell you what is the right dose for you regarding dose escalation or deescalation. And lastly, the medication really currently is meant for the long term. The notion that you can go off it in six months — this so-called quick-start approach, I got this, doc, just get me started and I'll take it from there — is not really how obesity is treated. That's not what the disease is.

So if you do it without any interaction or intervention, you're likely to have increased side effects. You may have other medical problems that are not being addressed because obesity causes multiple organ problems. And if you go off it, you have a very high likelihood of regaining your body weight, just like you would with diabetes if you went off that medication.

Mike Haney: So I just want to push on this a little bit more because again I think this is where the sort of popular perspective is. It sounds like, you know, the insulin metaphor I think is a little challenging because it'll literally kill you, right? If your blood sugar goes too low, you will die. I don't think we see — or tell me if we do see — the same kind of challenges of somebody going to an online pharmacy, getting the GLP-1. Are there the same kind of risks — that I'm going to overdose or I'm going to underdose and it's going to cause some kind of other problem with it? Again, it feels like there's kind of a proper way to do this, which is, as you say, to have a good lifestyle, adjunctive therapy, maybe deal with some of the muscle loss, maybe create some better behaviors. But also, this is a drug that as long as I take it, it's going to reduce my appetite and I'm going to lose weight. So why not just go get it and use it for six months and shed the 20 pounds? Aside from the side effects — and maybe that's the very real problem here, that you're going to get super nauseous and we can help you sort of mitigate that by being careful with the dose — but are there any other reasons why somebody shouldn't use it that way?

Robert Kushner: Yeah. Well, the side effects is a very good point. I wouldn't underestimate that. You could end up with nausea, vomiting, and diarrhea, which are fairly common if you're not mitigating it through diet and lifestyle. And depending upon your vulnerability, you may end up in the emergency room with what's called acute kidney injury — meaning your kidneys start, don't work very well at all. There's a risk of gallstones, pancreatitis. If you happen to be an elderly individual, the risk of losing muscle mass, frailty, bone health — those are real concerns and those are side effects of the medication. It really can't be underestimated. It's always a risk-benefit ratio when you put someone on a medication.

And the other argument you bring up, where you're pushing back, is: I'm going to use it for six months and go off it. I don't have any hard data that shows that you have a high likelihood of keeping your weight off if you just stop the medication. There has to be — if you go off the medication, then what are you going to do? You have to do something different. You have to eat healthier. You have to be more physically active. Your relationship with food likely has to change. Your social surroundings — called micro-environment, within your home, within your workplace — likely needs to change so that you are prompted and cued to eat healthier. I think it's unreasonable to think that you can go back the way you were and you're going to keep your weight off, because that's just not how physiology works.

Metabolic adaptation on and off the medication

Mike Haney: What do we know about coming back to the concept of metabolic adaptation? So as I mentioned, we've talked about that a lot on the show recently. We had Eric Ravussin on and we learned all about metabolic adaptation in general, but particularly from that hormonal side, right — that our body is going to start increasing those hunger signals, going to decrease the satiety, it's going to change physically how your body works to make you take in more food. Then we had Herman Pontzer on and we talked about metabolic adaptation from the burn side, right — the reason you can't marathon your way to weight loss because your body's just going to adjust.

What do we know about long-term metabolic adaptation? Again, we're fighting that biological imperative we've talked about. On either the hormonal side — if I'm on these for a while, is my body just going to start compensating to these different levels of GLP-1 that are now in my body and have been consistently for some time? Or on the burn side, is my body going to just bring my basal metabolic rate down because now it's living in a 1,500-calorie-a-day world instead of the 2,500-calorie-a-day world?

Robert Kushner: My understanding is both are actually occurring. Not only is there a change on the energy expenditure side, but also on the intake side. And both conspire regarding metabolic adaptation to start bringing you back up.

I think an important question for individuals though is: if I want to go off these medications — let's say I can't afford them anymore, I just want to get off them, I don't like taking them anymore, nor do I want to switch to the pill, which two pills are now available — how do I keep my weight off knowing there's a metabolic adaptation? And that lingers — we know that from other studies.

And here's where we bring in behavioral and physiologic evidence we know for decades, before these medications existed. And we are applying that information now to the GLP-1 users who want to go off the medication — yet to be studied in more detail. But here, what we're doing is recommending a higher protein diet so that you are maintaining the fuel for the muscle, which you're then going to do robust physical activity and resistance training. Again, the identity is: I am a physically active person. I'm going to be careful about what I'm eating. I'm going to look at ultraprocessed foods. If my problem was easily enticed eater, I'm going to be very careful about having those foods in my home. I'm going to maintain close contact with my prescriber and maybe a registered dietitian. Take up other sports, change your identity — we talked about that before. And let's see how you do. So if you're going to go off the medication, you're likely to struggle because of metabolic adaptation, but this is how you actually fight back to the best of your ability by adopting these new behaviors.

Mike Haney: So that's sort of metabolic adaptation in the context of going off the medication. I'm curious if we're seeing it for people who are staying on the medication. Again, we're sort of altering our body, right? And even if I'm on this for 20 years, I'm changing the sort of default level of GLP-1 that is in my system. And presumably evolutionarily our body doesn't like being starved and we're essentially just starving ourselves. So I get that we're hacking kind of that hormonal side of the metabolic adaptation, or at least one aspect of that hormonal. But why don't we see — or do we see — an increase? Why isn't the body shooting my leptin levels up to try to fight that GLP-1 signal, to say no, no, you're not taking in enough calories, we need more? Or why isn't it on the other side dropping my basal metabolic rate so now I'm still gaining weight, or I'm staying at a sort of consistent level even at this lower calorie intake that the GLP-1 is allowing for me to have?

Robert Kushner: GLP-1 appears to be a strong enough regulator, dealing with the appetite dysregulation, to really harmonize — my understanding — harmonize all these other factors you're talking about. When body fat comes down, leptin comes down. So it's not that leptin is driving the body fat — leptin is actually produced by body fat. So if you keep the body fat down, leptin stays down, and it seems to be regulating these other processes pretty well.

I do want to mention one other thing that we've noticed in observation and has also been studied now. Individuals who remain on GLP-1 medications long term — and we actually measure their perceived appetite through questionnaires — what we're noticing now is even though their body weight is remaining stable, their appetite starts to come back online. In other words, they tell you, you know, I'm starting to feel hungry again, which I hadn't at all when they started these medication. I didn't know what hunger was and now I'm starting to feel hungry again. So they get scared because they think I'm going to regain my weight, but they don't.

And I think what's happening, interestingly, is a new norm is occurring where they're starting to get hungry again, but they're not overeating. They're eating just enough to maintain their normal body fat. So they're coming back into a new normal within a narrow range instead of these wide swings in hunger and appetite. And they will say, I go to a restaurant, I have my hunger cues, but I'm satisfied with much less food than I used to eat before, and my body weight is maintained. So GLP-1 seems to regulate a lot of other processes that maybe were not working normally. It seems to be maybe a super switch for them.

Mike Haney: So is it in a way sort of then creating a new settling point — if we like that sort of term for where your body wants to be? And is that why we see the levels that we do, that with a GLP-1 we're seeing about 15% and I think with the GLP-1/GIP combos we're seeing maybe 20 to 30% weight loss? Or is there a lot of individual variation in those numbers, that some people are seeing 5% and some people are seeing 50% weight loss?

Robert Kushner: I think both are correct. I think that we do think of it as a settling point — they're settling because of the medications bringing them down to a certain level. And the percentages you just stated were the mean or average weight losses in the trials: 15%, 20%. But within that is a great deal of variety or heterogeneity, and we don't really know why. Pharmacogenomics, other phenotypes — we don't really know why some people only lose 5% where some people are super responders and losing 30% of their body weight.

I will tell you, in the phase three trials, anywhere from 8 to 15% of individuals in the trials — so we know they're taking the drug — do not lose at least 5% of their body weight. So we call them insufficient responders or poor responders. I'm not sure what word we want to use. And we don't know why they did not respond like someone who was a super responder, but for whatever reason they settled at that point for some reasons we don't quite understand.

Mike Haney: When you talk about stopping the medications, what do you think about the concept of metabolic whiplash?

Robert Kushner: Do you mean the more rapid you lose weight, the more rapid it comes back on?

Mike Haney: Yeah. And essentially there's an idea — there was a paper relatively recently, I think, that was finally studying this concept that people have been kind of floating around — that if you stop them you'll end up in a worse state than actually where you started. Your body's going to sort of snap back, whether that's insulin or glucose levels or whether that's weight.

Robert Kushner: I haven't seen that paper, but what I can say — which I thought you were getting to — is that when we look at the categorical weight loss in all these trials, so some people lose 5%, 10%, 20%, 25% over the course of the trial, if you then stop the medication, the individuals who lost the greatest amount of body weight actually are the ones that regain it the quickest. Not necessarily back to baseline, but the trajectory of weight regain is more rapid the more weight you lose. And it's probably not that surprising — if you really had significant change in your body weight and you now have metabolic regulation coming back in, it's going to conspire to regain your weight.

I haven't really seen a lot of data that you end up worse off than you were. In fact, it looks as though the data shows that you regain about two-thirds of your body weight within a year on average, and then over the subsequent years, you're likely to go back to where you were unless you do some other intervention.

Mike Haney: And what do we know about the sort of implications of long-term use of this? So we just did a show, for instance, on statins, and one of the arguments you'll still hear against statins is, well, hey, you're telling me I've got to take this my entire life. What's it going to do to me after 40 years of taking it? And with statins, we're getting pretty close to having 40 years of data. As you said, with GLP-1s, okay, they've been around for 20 years for folks with diabetes, but diabetes is kind of a unique context. We have less time treating them only for obesity. What do we know about what the body is going to do after 25 years on this drug, or how it interacts with some of the other natural aging processes, the way our bodies are naturally going to change when we're in our 60s or our 70s and we've been on this for 20 years?

Robert Kushner: We don't have that information. Obviously we do have 20 years, as you said, although it was with lower doses with individuals with type 2 diabetes — using that as a group to compare to — we have not seen any development of concerns that have emerged. We know individuals who should not take it: medullary thyroid carcinoma, a very rare endocrine disorder called MEN1. We know it can cause increase in gallstones and gallbladder disease. It potentially can cause pancreatitis. So we are aware of that.

In other studies, particularly the SELECT trial we talked about earlier, with cardiovascular disease in elderly individuals, particularly elderly women, we saw an increase in osteoporosis and fractures. And that has to do really probably less with the GLP-1 and more with losing weight when you're 75 years old, regardless of why you're doing it.

So we always do post-intervention surveys to look for these types of things. I take a little comfort that GLP-1 is a naturally occurring hormone, although we are giving it as a peptide and now as a small molecule orally, so it's not a compound that's foreign to the body, although at higher doses in individuals.

But I think we just need to observe people. Everything that's coming out, Mike, so far is an improvement in health outcomes, generally driven by weight loss, by reduction in inflammation, the ectopic fat in the muscle and in the heart and in the pancreas and in the liver. We do have to be careful about excess body weight loss, which we know — sarcopenia, bone health, and so forth — but we really haven't seen any other signals to date, and we're going to continue and look for those.

Mike Haney: How much do you care about the muscle loss side? I feel like that's been one of the arguments from some portion of the medical community against sort of long-term use of this. And then I've also heard people say, look, as long as you are pairing this with — and everybody should be pairing this with increased — everybody should be doing resistance exercise anyway, but you definitely, if you're on a GLP-1, should be doing resistance exercise and taking in enough protein. Having actually run the studies on this and seen real patients, how much do you worry about the muscle loss component?

Robert Kushner: I worry about it mostly in an elderly individual, 65 years or older, because starting at about age 30 or so we start losing muscle mass. It's very hard to build it back. And so if I'm treating someone 65 years old, 70 years old for obesity and obesity-related complications, I am concerned about how much weight they're going to lose, because part of it will be muscle and they're not going to be able to build it back likely. So I'm certainly concerned about daily activity, frailty, falling, fractures, and so forth.

The other part is that muscle health — I think we're just really in the beginning of understanding the importance of muscle, the myokines, the signals that come from muscle. You mentioned leptin before, which was really a game-changer regarding how the fat talks, fat through leptin talks to the brain. We have myokines which are also signals from muscle that we don't really quite understand much, although some medications are now starting to address muscle health and block some of those signals that break down muscle.

So I do pay attention to it — it is important — but it's really certain groups I'm very concerned about. Most of the studies — in fact, all the studies — that we've seen now where we use patient-reported outcomes, meaning how's your physical functioning, in the trials they all go up across the board. People feel more physically functional and improved quality of health.

And the studies are now starting to look at the muscle during weight loss using things like MRI and other imaging. And what we're finding is even though the muscle mass or the total muscle may be going down, the quality of the muscle is improving because the fat is being removed from the muscle, and function where we're looking at it is starting to improve. Although we need to do many more studies looking at muscle function as people go on GLP-1s — like resistance training and squeeze my hand and sit-to-stand and quadricep extensions, all these things that we do to look at function.

Other potential uses: addiction, dementia, cancer

Mike Haney: We mentioned before some of the other sort of non-weight benefits that we're seeing with this. I just literally heard a podcaster say the other day — she's somebody who doesn't have any weight issues, is in her 30s, and is now micro-dosing it for Alzheimer's prevention because Alzheimer's runs in the family. So maybe I'll sort of ask it this way: of the cardiovascular, dementia, addiction — all the sort of potential other uses — what do you think is the most promising and the most probabilistic when we think about how these mechanisms are working? Versus some other, I don't want to say just, but a weight-related benefit — if we bring down the weight, we get rid of the obesity, we get rid of that fat tissue, we're going to get a whole bunch of side benefits. But of the non-weight related benefits, what are you most excited about?

Robert Kushner: All of the above you just said. I just read a paper on a reduction in addiction across the board, you know, from heroin to cocaine to cigarettes to alcohol, which is really going to be a game-changer in our society regarding treating addiction.

But the two that I'm particularly excited about really have to do with disease-modifying and saving of lives. The two biggest killers in our country is cancer and cardiovascular disease. We have very good signals and studies showing a reduction in cardiovascular disease — in myocardial infarction, heart failure, preserved ejection fraction, atrial fibrillation. These are real serious concerns.

The next horizon really is going to be cancer. It's going to be much harder to study because the length of time between developing cancer cells and developing clinically developed cancer is a very long period of time. But if we can see, by reduction in insulin resistance, reduction in inflammation, reduction in hormone-based cancers — an improvement — that is really going to be exciting.

"The two biggest killers in our country is cancer and cardiovascular disease. We have very good signals and studies showing a reduction in cardiovascular disease — in myocardial infarction, heart failure, preserved ejection fraction, atrial fibrillation." — Dr. Robert Kushner

Mike Haney: Do you see a world in which a much bigger portion of the population is taking these drugs? And maybe this is a place to bring in micro-dosing — you could talk about that in the context of either weight loss or for other kinds of prevention. But do you think that's a likely path for these?

Robert Kushner: We are really living in the GLP-1 generation now. Very very rarely does a medication change society, and that's really what this conversation has been about. It's usually high-tech, right — computers and smartphones and digital age and all that. The last medication that really changed society was 80 years ago or 60 years ago — and that's birth control pills. In my opinion, that changed women's lives, women in the workplace, family planning. That's what I mean by changing society. I think that's what GLP-1 has an opportunity to do now. Whether it's the fitness industry, food industry, shopping, where we spend our money, disease reduction and so forth.

I don't really think of it though as like fluoride in the water — it's not really meant for public health, and that's why public health has to be a partner with clinical medicine. You have to change the food supply and how we eat and the cost of food and so forth.

But micro-dosing is a very interesting concept which has not been studied much at all. Micro-dosing just means using smaller doses than what's recommended by the company when you read the package insert. And it's very likely, I think, that micro-dosing will find its way in some of these areas like addiction or perhaps Alzheimer's disease, where you're really amplifying the anti-inflammatory aspects of the drug and not so much the appetite-reducing effects. So I think that's what we're looking for over the next decade or two — what other areas in society and in medicine can these drugs be beneficial for.

Compounding, online prescribing, and how to talk to your doctor

Mike Haney: So we mentioned earlier the reasons that you may not want to just jump online and get a prescription for this, and I mentioned the word compounding in there. Can you explain what compounding is and how you think about that?

Robert Kushner: Yeah, compounding is something that the FDA approves when a medication needs to be modified for a particular individual. So you have a pharmacy that will take a medication that you could buy off the shelf or get a prescription for and change it in some way. That's called compounding. Best example: you have a child who needs to take a medication but can't take a pill. So you compound it by making it into a slurry or into a liquid. That would be compounding.

The other area that compounding is approved is when you have a very important medication that a group of individuals are unable to get — like a shortage. So you allow other pharmacies to compound that medication, make it in their own facility, until the supply and demand are both rectified. It's that latter scenario that was the loophole for compounding the GLP-1. So when they were launched on the market, they rapidly went into short supply — they couldn't keep up with the number of prescriptions. So compounding pharmacies filled that gap. They took semaglutide, came up with their own formula, made it in liquid form, injectable, and then companies just took off with it and sold compounded medications.

So it's meant to be semaglutide or tirzepatide-like, but it's not the actual drug. Those drugs are no longer in short supply. The FDA now says there's no reason to compound medications that have a patent and that you can get supplied. However, they have not all disappeared from the marketplace. Some pharmacies are still getting compounded medications.

The problem with them is that you don't know exactly what is in them. You have to trust the pharmacy that they are making it — that they took the same recipe for semaglutide and made it within their own pharmacy with the same substances, liquefied it and so forth, and are giving it to you. The trouble is you cannot be assured of that because you don't really know what's going on behind the door at the pharmacy. So I actually dissuade people from using compounded medications because I can't guarantee it's the real deal and it's completely safe.

Mike Haney: So maybe as a way to wrap up — we've talked about the different kinds of obesity, different paths to obesity, different types of folks who might be thinking about one of these drugs or some kind of treatment for obesity. I think if you are somebody who has severe obesity or has struggled with this all their life, I feel like most of those folks are probably either on a GLP-1 or on the path to it because the success level is so clear. But for that other group of people that has 20 extra pounds that have come on and they want to get rid of it, how should they start thinking about this? Or what should the conversation be with their doctor? And how prepared are primary care physicians? Again, you just wrote a book to try to help primary care physicians think through this, but how prepared are primary care physicians now to have this kind of conversation in which we consider seriously lifestyle and what that can accomplish, but also we don't just either rush to the GLP-1 or say no, you don't need that?

Robert Kushner: Well, the conversation should start with your health care professional. I really think that's where it should begin — someone who you know, someone who you trust, someone who knows you. And have that conversation proactively. Don't wait for the clinician to bring it up to you. And ask them questions like, is my weight affecting my health? That gets back to the preclinical and clinical obesity. Are there any signs or symptoms or anything in my blood work that you think my weight is affecting my health? And you're going to take into consideration my family history because you already know who I am. Am I a candidate for the medication, or what should I be doing to improve my health — diet, physical activity, sleep hygiene, stress, and so forth? If I am a candidate for the medication, are you someone who can help me with that? And if not, can you refer me to someone who can have that conversation?

On the clinician side, clinicians need to be informed and become competent in this area. I think there's a mad dash for them to learn about it because there's so much social attention — patients are coming and asking about it. Having said that, I would say a good deal of primary care clinicians are not aware enough about these medications. And then if you add the extra burden of prior authorization — you know, the paperwork required, dealing with insurance companies — many of them may want to get involved but stay away from it completely because it's just beyond their bandwidth to take care of it. Now you're getting into the health care system problems with the medication.

But it really begins with having that interaction with your health care professional. Am I causing harm to my health? What do you think about my weight? What would you recommend? And am I a candidate for medication like this?

Mike Haney: I think that's a great place to wrap it up. So thanks so much, Dr. Kushner, for joining us today.

Robert Kushner: Mike, a pleasure. Thank you for having me.