It’s a miracle weight loss drug that’s been approved in the United States and the United Kingdom, and it has few side effects?
Ozempic is going viral on social media. Users are posting dramatic before and after pictures of their weight loss. An Ozempic trend is allegedly blossoming in Hollywood, and famous personalities like Elon Musk claim to have taken it.
Many remain doubtful, dismissing the craze as just another internet scam preying on people’s insecurities.
But earlier this month, semaglutide — the drug’s active ingredient — was approved as a weight loss treatment by the U.K.’s National Health Service. Even the most skeptical are taking note.
In today’s episode, Jonathan speaks with Dr. Robert Kushner, the lead investigator of the huge phase 3 clinical trial that evaluated the safety and effectiveness of semaglutide.
He has hailed the drug as a “game changer” in the treatment of obesity.
Dr. Robert Kushner is a professor of medicine at Northwestern University and a founder of the American Board of Obesity Medicine.
Please be aware: Dr. Kushner is also a consultant on the medical advisory board for Novo Nordisk — the company that manufactures semaglutide.
If you want to uncover the right foods for your body, head to joinzoe.com/podcast and get 10% off your personalized nutrition program.
The study we mention is:
Once-weekly semaglutide in adults with overweight or obesity published in The New England Journal of Medicine
Episode transcripts are available here.
Dr. Kushner’s book Six Factors to Fit: Weight Loss that Works for You! is available to buy here.
You can keep up with him here.
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[00:00:00] Jonathan Wolf: A miracle weight loss drug that's approved in the U.S. and the U.K. and has few side effects. Really? Ozempic, a drug originally intended to treat type 2 diabetes, is going viral on social media. Users are posting dramatic before and after pictures of their weight loss. Famous personalities, such as Elon Musk, claim to have taken it and an Ozempic craze is allegedly developing in Hollywood.
But many are doubtful. Dismissing the craze is just another internet scam preying on people's insecurities. But earlier this month, semaglutide, the drug's active ingredient was approved as a weight loss treatment by the U.K.'s National Health Service. Now, even the most skeptical are taking note. Could this be a magic bullet for weight loss?
Is it safe? Surely there are side effects, and do you put all the weight back on if you stop? In today's episode, we went straight to the source. Dr. Robert Kushner was the lead investigator of the huge phase 3 clinical trial that evaluated the safety and effectiveness of semaglutide. He is better placed than anyone to explain if this drug is the miracle cure that we've all been waiting for.
Bob is a professor of medicine at Northwestern University and a founder of the American Board of Obesity medicine. Also joining me today is ZOE's U.S. medical director, Dr. Will Bulsiewicz.
Bob, thank you for joining us today,
[00:01:48] Dr. Robert Kushner: Jonathan. It's a pleasure, and thank you for having me.
[00:01:51] Jonathan Wolf: Not at all. I can safely say that we had more questions on this topic than any single one that we've run before. So I'm excited to do it. It's fascinating. And what I'd like to do is start, as we always do with a quickfire round of questions from our listeners.
And these are always extremely difficult for professors because we have a simple rule, which is you can say yes, or no, or you can give a one-sentence answer if necessary, but not more than that. Bob, are you willing to give it a go?
[00:02:21] Dr. Robert Kushner: Let's go.
[00:02:22] Jonathan Wolf: Fantastic. Are Ozempic and Wogovy a massive breakthrough for weight loss?
[00:02:28] Dr. Robert Kushner: Yes.
[00:02:28] Jonathan Wolf: All right. We're already off to a good start. Do drugs like Ozempic and Wogovy mean the end of obesity?
[00:02:34] Dr. Robert Kushner: No.
[00:02:36] Jonathan Wolf: Can most people lose weight sustainably with calorie counting and willpower?
[00:02:40] Dr. Robert Kushner: Very challenging. That's why we are now starting to think of using medications
[00:02:46] Jonathan Wolf: and finally, if these weight loss drugs will keep me thin, can I stop worrying about what I eat?
[00:02:52] Dr. Robert Kushner: No.
[00:02:54] Jonathan Wolf: All right. Well, I think that's a brilliant way of sort of setting up the conversation. And what I'd like to do is just start right at the beginning. So there are these three different drug names that we've started to hear all over the place on the media and social media, which I'm probably pronouncing wrong.
So Ozempic, Wagovy, and semaglutide, what are they and how do they work?
[00:03:15] Dr. Robert Kushner: So semaglutide or semaglutide, both are acceptable on how to pronounce the name of the drug.
[00:03:22] Jonathan Wolf: All right, thank you, Bob.
[00:03:24] Dr. Robert Kushner: It mimics a naturally occurring hormone in our body that helps to regulate. So when this naturally occurring hormone is released into the bloodstream after you eat, it helps you start feeling full.
It helps you be content between meals. It helps to reduce appetite or hunger. So what the pharmaceutical industry has done is harness this hormone. Reproduce it synthetically into a drug which is called semaglutide, and give it back to an individual to enhance the reduction in appetite. Jonathan is very similar to taking someone with diabetes who has difficulty making enough insulin.
And then give them back enough insulin so they can handle their blood sugar. So it's very similar to taking something that's within our body, giving it back to someone in a pharmacologic sense, and improving their condition or the problem that they have.
[00:04:28] Dr. Will Bulsiewicz: I find it very interesting how effective these drugs are, these GLP one agonist drugs. You just made a comparison to diabetes.
There are two types of diabetes. There's type one diabetes where the person is not able to produce insulin, and then there's type two diabetes where the person has insulin resistance, and so they need a higher level of insulin to achieve the effect. If this is a similar sort of process in the body, is this GLP one more like type one where there's a deficiency in obesity or is this more like type two? where the body is resistant to GLP. So we need higher levels to achieve the same effect?
[00:05:09] Dr. Robert Kushner: Well, I'm not sure we know exactly and that gets back to the whole idea that the condition of excess body weight is not probably one uniform problem, like obesity. It's probably obesities. In other words, there are multiple types, you made it comparison to type one diabetes and type two diabetes.
In obesity, there are probably multiple types of excess body fat. There are likely those and this has been studied where the GLP one level is lower than you would predict after a meal, for example. You get the surge of, all this releasing hormone, and it's lower in individuals with obesity, but probably not all. There are others where that hormone may not be penetrating deeply enough into the brain where the appetite centers are.
So you give higher doses to penetrate those centers. Some of this is speculative at this point, but we do know that when you give GLP one hormone backed individuals who are struggling with their weight never feel full and hungry all the time, either there's a, uh, an insufficient release within their own body, or they just need a higher level, not necessarily resistance, but a higher level to achieve that. Interesting.
[00:06:20] Dr. Will Bulsiewicz: Okay, so just to play it back real quick, there may be some people out there that they're a little bit GLP one deficient, and therefore we're fulfilling this for them with the drug. But there may be some others that just need a higher level.
[00:06:32] Dr. Robert Kushner: Correct. We don't, we're not sophisticated enough to know who's who.
We call 'em phenotypes, like different presentations, of a particular condition. We don't know enough about that. That's cutting-edge information. If one day, we can have an. Who comes to their healthcare professional's office, and we can start categorizing these individuals or segmenting them into different types as we do with diabetes?
We will be able to treat them in a more targeted manner. We're not there yet, but that's the direction this whole field is going. At this point. We can give this kind of medication like semaglutide and we can't see differences. Some people are more super responsive than others. Some are less responsive.
We don't understand why that is at this. And
[00:07:21] Jonathan Wolf: Bob, a lot of people will have heard these names, Ozempic and Wego V. How does that fit into what you've been describing with Semaglutide?
[00:07:29] Dr. Robert Kushner: The drug semaglutide is actually in both of those drugs, the difference is a trading name and what they're approved for.
So Ozempic is a semaglutide that's approved for individuals with type two diabetes. Will was just talking about that at a lower. Wvi is also semaglutide, but this is approved for individuals with obesity and it's approved at a higher dose. So it leads to, I think, confusion in the marketplace. But they're the same drugs under two different trade names.
And approved for two different medical conditions. You know, this
[00:08:10] Jonathan Wolf: is like when I go to the supermarket and you're saying like there are different brand names for bleach or the peanut butter or whatever it is. And in this particular case, you've got two brand names. They have the same active ingredient but in different amounts.
Is that what you're saying, Bob? They're not licensed for the same thing, but they actually have the same sort of active ingredient, hence some of the confusion.
[00:08:31] Dr. Robert Kushner: Correct. Let me throw one more wrinkle in this whole story. You could take semaglutide orally, meaning by your mouth, and that's called Rybelsus, that's also approved for diabetes.
So you have three different forms. Two of them are used for self-injection shots, a third one orally, and they all contain semaglutide. So just to confuse the listeners enough that's what the current state is.
[00:08:58] Jonathan Wolf: And Rob you ran like a huge clinical trial on Semaglutide.
You were the lead author on this, and that was published in the New England Journal of Medicine fairly recently, which the listeners who aren't familiar with it are one of the absolute top clinical journals, extremely hard to get into. Can you tell us a little about how that trial was run and the results that you saw?
And of course, any disclosures that you want to share about it.
[00:09:22] Dr. Robert Kushner: I'm gonna throw in the very first rapid-fire question you asked me: is it a game changer? And I quickly said, yes, and you were taken back perhaps by that, but that's trial that you're referring to. Game Changer was something the media picked up on when it when globally was a game-changing drug.
First of all, the trial was called STEP, and it was a global trial of about 2000 individuals in the step one trial in which individuals, all of them who were overweight or had obesity, many with a medical problem, were randomized blindly to either take this new drug. Or a placebo, which is just an inactive, comparator.
And individuals were then studied for over a year, and all of them received lifestyle treatment as a foundation. So it wasn't just drugs, it was medication or placebo, and everyone got lifestyle counseling
[00:10:17] Jonathan Wolf: And Rob, that means like guidance about what? when you say lifestyle, treatment.
[00:10:21] Dr. Robert Kushner: Correct so they all saw either a registered dietician or a healthcare professional who's trained in nutrition and received guidance on diet.
They're asked to track their diet, increase their physical activity, and be aware of their surrounding social surroundings, and so forth.
[00:10:36] Dr. Will Bulsiewicz: From a dietary perspective, just to be clear, I believe it was with a calorie deficit of about 500 kilocalories per day. Is that right?
[00:10:44] Dr. Robert Kushner: That Is correct. Everyone got the same, treatments.
It wasn't tailored or targeted. Everyone got the same lifestyle management.
[00:10:53] Dr. Will Bulsiewicz: Right. So the group that received the drug and also the group that did not receive the drug were all recommended the same diet and the same lifestyle practice.
[00:11:01] Dr. Robert Kushner: Correct. And after 68 weeks, when the trial, came to an end, we found what I thought was game-changing, remarkable and that is individuals who took a placebo, in other words, just received lifestyle counseling, lost about 3% of their body weight after about a year. Those on the medication on average lost 15% of their body weight in. One in three lost 20 or more percent of their body weight. We hadn't seen that before.
So in part, that is where that game-changing moniker came from. We've never seen that before. The other reason, I've responded yes to Game Changer is that, that trial heralded in a new direction for the treatment of obesity, and that is harnessing our intestinal hormones, which we talked about a little bit early.
GLP is one hormone. That's what it's called. What Semaglutide mimics. Is now showing the way for a new treatment direction for the treatment of obesity in which we are now trying to treat obesity hormonally again, like diabetes. I keep using that comparison.
[00:12:16] Dr. Will Bulsiewicz: And you know what's interesting About this all, Bob, you're an endocrinologist, so that means that you specialize in hormones, is that it starts to paint a picture that obesity may be a hormonally mediated disease. can you perhaps talk for a moment about why it's so hard for people to lose weight? reducing calories long-term or by exercising? How does the body adapt when we reduce calories or we start to exercise more?
[00:12:43] Dr. Robert Kushner: Well Will, to answer your question, we have to go back millennia. We have to go back to how the body is engineered.
[00:12:49] Jonathan Wolf: We've got time. Bob, we can just extend the podcast.
[00:12:53] Dr. Robert Kushner: I'm gonna shorten the hundreds of thousands of years, but where I'm going with this, Jonathan, is that we are engineered to maintain our body in times of famine and starvation. So if you go back a hundred thousand years ago when normally you would have times of famine, the body developed adaptive ways to survive when there wasn't enough food around.
So we're very, very good at hibernating, if you will, and surviving without a lot of food. So our bodies adapt. It shuts down. You don't burn as many calories to get through those times when there isn't enough. So fast forward hundreds of thousands of years, and we don't have famine anymore, but our body is biologically engineered that way.
So will, if you go on a diet and you try to lose weight, you could do that. Pretty successfully early on by reducing your calories, as you said earlier, a calorie deficit, so you start losing weight cuz you go into an energy imbalance. However, from a biological point of view, our body thinks that it is famine time or starvation time.
So it goes into this down adaptation to get you through this period. the body is biologically engineered and wired to conspire against you. It does not want to have you lose weight, so it will defend what you weighed before you went on a diet. Interestingly, even though you had excess body fat or excess body weight, the body thinks that's where you ought to be.
So as you lose weight from time zero down, the body fights you, biologically that is, and the. You feel it is, you start getting hungrier as you try to keep your body weight down so food feels and looks more enticing. You're not as content eating the same amount of food you did before, so it drives you to eat more, and it is even more difficult than that.
Your energy expenditure or your resting metabolic rate, the number of calories you burn starts to go down. So you don't need as many calories as you did when you started. And we also now have identified that your muscles become more efficient. So as you're on a treadmill and you know, you're 3.5 for 30 minutes.
You don't burn as many calories cuz your muscles get more efficient in what you're doing. These are all the factors of the mechanisms the body puts into place to try to maintain where you were before and prevent you or make it harder for you to lose more weight. And at some point, individuals start to eat more and changed their diet to what it was and over time, Weight starts to go back up again.
So long-winded answer that. It's very, very difficult to take the weight off and keep the weight off because of the weight. We are biologically wired.
[00:15:50] Dr. Will Bulsiewicz: This explains why many people can be successful with a 30-day diet. and then they bounce back and have that rebound weight gain because the hormones are changing and you become more hungry, your metabolism slows down, and eventually, it reaches a point where your body bounces back to that baseline.
[00:16:10] Dr. Robert Kushner: Right. Now there are different stories to hear if you think about an actor in Hollywood who gains 30 pounds for a role in a movie. They're often able to get their weight back down again. It was a short-lived weight gain. Weight comes back down. An individual woman who becomes pregnant will gain excess weight for the baby.
Her weight can come back down. You go on a holiday, you gain some weight, and you bring it back down, so you certainly can gain weight and bring it back down. What we think is happening in individuals who suffer from what we call clinical obesity or ongoing long-term obesity, is that it's over a longer period and may be in part from the food supply.
There may be inflammation that's going on in the brain and may be genetic that you are predisposed to gaining weight over a long time. So we don't exactly know the difference between individuals, but for individuals who we call suffer from clinical obesity, that it's affecting the quality of life: medical complications, they're medical problems associated with weight. Those individuals who have struggled to take their weight off and keep it off.
[00:17:14] Jonathan Wolf: Bob, I think there'll be many people listening to this. Who is saying it's really interesting cuz I've just sort of had this slow, steady increase in my weight?
I think back to what I was when I was 21 or whatever and in many cases just sort of slowly, steadily going up and it's always seemed hard to get back down. And what you're saying is this is a very unfair system, right? There's a sort of easy. Movement up and then there's this incredible biological system that is fighting back and that therefore, I think a lot of what, you know, certainly I was brought up to believe about weight loss, which is, well, you know, you just reduce your calories.
It's just willpower. It's easy. There are no scientists that I meet now who still seem to believe in this. Is that fair?
[00:17:54] Dr. Robert Kushner: It is fair. And I'm so glad you brought that up because it highlights the continuing societal myths or misunderstandings about what excess body weight or obesity is. Many people still think it's willpower, it's a lack of discipline.
You know, why can't you just stop eating? There's something wrong with your personality. Your compulsivity leads you to be overweight. We now know so much more that we do consider obesity at least in this situation as a disease. I think it's very similar to how we used to think about depression or alcoholism or opiate misuse.
Several decades ago. We used to blame people for their alcohol use or their depression, and we would no longer think of telling someone who's depressed, just think happy thoughts and just snap out of it. Why are you so blue? We wouldn't think that way anymore. We used to probably 50 years ago before we understood that depression was a disease.
With signaling problems and biological basis, we don't think of opiate misuse like that anymore. It's individuals on heroin or cocaine. We know they need rehabilitation. They need help. They need to see a healthcare professional. The same applies to individuals struggling with their weight. We have to get away from this whole stigma and bias that there's something wrong with them and just they need to be motivated and think of it as an underlying biologically and genetically based disease in many individuals and treat them as such, and that then opens the door to thinking about drug use like semaglutide.
[00:19:31] Jonathan Wolf: And Bob, on this show, we end up talking a lot about gut health. We talk a lot about the microbiome. We end up talking about foods particularly, the difference between ultra-processed foods and the sort of foods we used to historically eat a lot.
And I'm, intrigued that you're describing this drug as a mimic of a hormone that comes from our gut as I understand it. Do we understand whether There is any interplay here, because there has been this extraordinary explosion of obesity, which I think you rightly describe as a disease, and you see the statistics in every country, right?
Like when I was little, people used to talk about that very much in America. And what's striking now is you see the same statistics somewhere like France that used to claim that, that this wouldn't happen here. So there's a solution coming in that sort of mimics this existing thing created by our body.
Do we understand anything? Somehow why this might be more needed today than it was 50 years?
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[00:20:27] Dr. Robert Kushner: You are right. The prevalence of obesity has risen dramatically. I just looked at this the other day in the United States, the prevalence of obesity, in 1993 was 13%. It's now 42% in a projection, at least in the United States, that it will reach
[00:20:44] Jonathan Wolf: , it's amazing. So from 13% to To 42%?
[00:20:47] Dr. Robert Kushner: Correct. And a projection by 2030, if you use modeling, is about 50% in the United States defined by body mass index over 30. And Jonathan, as you're alluding to this, is a global problem. Obesity is the single most common non-communicable disease. So Covid, of course, would be commutable, right?
You passed it along non-communicable, like a chronic illness. Obesity is number one. Change in food supplies, socialization, urbanization. Engineering out physical activity and so forth are presumed reasons. You asked before whether semaglutide would cure obesity or bring an end to obesity, and I said immediately, no.
Obesity is a chronic relapsing condition or disease. That is now spread globally. Obesity is also a public health problem. The game-changing aspect of Semaglutide is from a clinical point of view, as an individual comes to see their healthcare professional, they're suffering from obesity with its complications.
Medication makes sense. We're not gonna unleash a medication for a public health problem. So you have to have all the stakeholders involved between regulation, food supply, leisure, and group-built environment, right? Transportation, air pollution. All these things are factors that may affect obesity. So it's a public health problem and it's a clinical problem, and we have to use the right tool in solutions for both of them.
[00:22:12] Dr. Will Bulsiewicz: Bob, you mentioned earlier in your New England Journal of Medicine paper, the Step one trial, and in that study, the people who did just exclusively the diet and lifestyle, lost about 3% of their body weight. Talk to us if you use these drugs. What did you find in your study? What can a person expect in terms of outcomes?
[00:22:30] Dr. Robert Kushner: So the primary outcome was weight loss. And that's what we talked about. As I tell my colleagues and my patients, my center which is the Center for Lifestyle Medicine is not 1- 800- thin. , that's not what we're trying to do. We're not trying to make people thin. We're trying to help them be healthier and weight is one of the metrics of health.
So the other metric of health that was seen in the STEP trial, is Reduction in blood sugar, although none of them had diabetes in that trial, those were pre-diabetes. It improved reduction in triglycerides, total cholesterol, LDL cholesterol, reduction in blood pressure improvement in C R P, which is an inflammatory marker, and a very important improvement in quality of life, particularly physical functioning.
So those were the outcome measures in the step trial. So at the end of the trial, individuals not only lost weight, they were healthier by all of the parameters we were able to measure... Now, that also comes at a balance of what are the side effects of the drug, which we didn't talk about, but it's probably worth mentioning now, is that these medications, all the GLP one receptor agonists, that's what they're called, these gut hormone mimics, all the side effects are gastrointestinal.
Although it was found to be safe and effective. Individuals were at risk of having at least temporary short-lived side effects, and they were all gastrointestinal, such as nausea, diarrhea, and constipation. Some even had vomiting and some had increased heartburn. In all of the trials, the individuals, have these side effects.
Early and they tend to subside as time goes on. There's also an increased risk of gallstones, or what we call gallbladder disease. You have to be aware of that. So it has to be prescribed by a knowledgeable healthcare provider who's gonna monitor you. And I would not be recommending this drug just to lose weight or be thin.
[00:24:33] Dr. Will Bulsiewicz: You know, one of the things that I find interesting as a gastroenterologist is that these are gI side effects. Nausea is the number one side effect associated with the drug, and there's a very clear explanation for this, which is that when you start taking this drug, it slows down the emptying of your stomach.
And we know that in other disease states or conditions when a person's stomach emptying slows, they can feel nauseated. And it's because you get full very quickly. So it's not a big surprise, but this is part of the reason why when a person initiates the drug, they started a very low dose, a fraction of the ultimate dose they're gonna land on.
Then they gently work their way up, and if they run into these side effects along the way, they can slow down that dose before they ultimately get to that higher dose that allows them to achieve their goal.
[00:25:25] Dr. Robert Kushner: Correct. That's a very important point. Will all of them across the board start low?
Build up slowly and we're able to mitigate or reduce those side effects by doing it. And there's also another important message regarding how to better tolerate these drugs and get into the diet nutrition interface is that if you must consume or you should consume a lower fat diet, cuz that also slows gastric empty, don't overeat.
So when you start feeling full, moderate the amount of food you're eating and don't skip meals. So those are three things that help to reduce the side effects in addition to starting at a low dose. So we've learned all this through the trials, and now this has spilled over into clinical care.
That's how we counsel individuals.
[00:26:09] Jonathan Wolf: And Bob, I would guess a lot of people listen to this and are saying, Those side effects don't sound that bad at all. You are saying I can lose 15% of my body weight. I might have a bit of nausea, might have a bit of diarrhea. It's probably gonna fall away. I think most people listening are gonna say, well, those sound like quite good balances.
I was expecting it to be much worse. In terms of the side effects, is that what you're also experiencing as you're now, I guess both in the trial? In terms of, people sticking with it. And then after the trial, as you and your colleagues are also giving this to patients,
[00:26:39] Dr. Robert Kushner: we learned a lot about side effects in the trials.
And now of course, we're learning about in clinical practice, one of the most important things that we tell patients, or some of your listeners who may be starting on this drug, is to have realistic expectations when you use this drug. And that is you are likely to have side effects early on.
Pay very careful attention to your diet. I tell patients it's not a race to continue to escalate the dose, which is done by the way the medication is given once a week and then we escalate every month. So you take four doses at one dose and then you increase to the higher dose. You give four shots and then so forth.
I tell individuals if they are not tolerating as well as they would, You don't have to race to get to the next dose, they could stay there. The other thing we've noticed, interesting is that there are some super responders, and there are some individuals who don't have to get to a very high dose.
They have to benefit from appetite suppression. Some people are so responsive they will tell me, I don't get hungry anymore. I don't even feel I have to eat. That's too much for them. So we have to titrate the dose and lower those individuals.
[00:27:50] Jonathan Wolf: But just to make sure I've, I've got that right because I think a.
The way I've heard about it, it's sort of like this, okay, it's an eject, but it's like a magic pill, and we're used to sorting over-the-counter pills you just take and there's nothing that needs to be managed. You're describing something we're actually like. There's quite a lot of management that needs to happen in the first few months with lots of different results despite the way that it's working so well and that you're saying the side effects are relatively low.
This is something that needs to be quite carefully taken on because it's gonna change the way that you feel.
[00:28:21] Dr. Robert Kushner: Absolutely. Yeah. I fear a little bit that as some of the primary care providers start taking this on, I strongly encourage them to do so because. Many patients who would benefit from this kind of treatment is that they have the awareness, familiarity, knowledge, and bandwidth in their practice.
To manage patients carefully. I am concerned about the internet distribution and use of this medication because it's the opposite of what we're talking about on this podcast, right? That is just take the shot and go on your way and get thin. That is the wrong message.
[00:28:57] Dr. Will Bulsiewicz: So, for the listeners, there were a series of STEP trials.
There have been multiple clinical trials using this drug at this point. I think it's important for people to understand that for every single one of these trials, diet, and lifestyle were part of what was done. And this should be a part of how we support our patients when they transition to these drugs.
That we shouldn't exclude diet and lifestyle, and these are not mutually exclusive choices.
[00:29:19] Dr. Robert Kushner: Let me add something to that. Will, as someone who runs a Center for Lifestyle Medicine at my institution, Had the opportunity to work with individuals who have struggled with their weight for years, if not decades.
We talked before about weight regained, and biological adaptation. They know nutrition because we've talked about it repeatedly, but they struggle following or adhering to the diet and lifestyle recommendations we've talked about when we use now a medication like semaglutide for the first time in their life, and I hear this all the time.
I'm not struggling. I'm not hungry. I don't feel as compulsive to eat. I'm content. I'm not thinking of food all the time. And now they're able to follow the healthier diet that we've been talking about for years. And that's where the fun begins, will, where we could talk about the nuances, of reducing ultra-processed foods.
Using foods that will increase satiety naturally, like higher protein-based foods, more plant-based diets, getting in more physical activity, and doing resistance training. So for many of these individuals, it opens up the opportunity, to adhere to and start to explore a lot of the lifestyle recommendations we've talked about for years, but they've been unable to do it. Successfully.
[00:30:39] Dr. Will Bulsiewicz: That makes complete sense. Bob, we were talking a moment about the side effects associated with this drug and we've talked mostly about the GI side effects, but one of the things that come up on social media and people are concerned about is the connection between this drug and risks of cancer.
So could you comment on that, and unpack that for us so that we understand that better?
[00:30:57] Dr. Robert Kushner: In the preclinical trials. In other words, in the animal studies, there was one cancer that was identified, which is called medullary thyroid carcinoma, in certain animals. That has to do with, in part the way this drug works., the cells that activate.
That has not been seen in humans. There's a warning that any individual with a history of medullary thyroid carcinoma in their family should not take this drug. So that's only cancer that came up as a concern.
Another concern that came up earlier is pancreatitis, not cancer, but I'm thinking of in form of side effects that still have a warning when you use the drug that hasn't been seen in any of the STEP trials, so that's the concern regarding that.
Whether it reduces the occurrence of cancer in some individuals. I think it's yet to be seen. We don't know about that, but I can tell you my cancer colleagues or oncology specialists are very intrigued by this medication because obesity itself is a risk factor for many types of cancers.
Breast cancer, gallbladder cancer, uterine cancer. So they see this as a potential adjunctive treatment to reduce the occurrence of cancer or the recurrence of cancer in a woman, let's say, who's post breast cancer, as, another long-term treatment.
[00:32:21] Dr. Will Bulsiewicz: Yeah, I think it's very exciting to see where it goes because so many different forms of cancer are tied to obesity.
About thyroid cancer, real quick, there is a genetic condition, multiple endocrine neoplasias, type two MEN type two, which is a contraindication to use the drug because that condition is associated with this type of thyroid cancer. But Bob, if a person is in your clinic and says, I have a family member who had thyroid cancer. how would you approach that? Is a family risk something that would stop you?
[00:32:53] Dr. Robert Kushner: So I'm glad you brought up MEN two along with medullary thyroid carcinoma. Those are the absolute contraindications. There is no connection that we are aware of, of thyroid cancer that someone's more likely to have follicular thyroid cancer.
We don't see that as a connection, so that would not be a contraindication. So if I see someone in the clinic who take a family history of thyroid cancer. I try to clarify what kind of thyroid cancer that is, so that is not a contraindication.
[00:33:22] Dr. Will Bulsiewicz: But if it was a medullary thyroid cancer, would you have a concern?
[00:33:26] Dr. Robert Kushner: Yes, I would. I would not give it to someone with a history or family history of medullary thyroid carcinoma. Bob,
[00:33:33] Jonathan Wolf: I'd love to take the chance to maybe come to this question that I think is gonna be on a lot of listeners' minds, which is maybe I don't have obesity. But I know that I'm overweight.
I've tried all of these different ways to lose weight and I haven't been able to do so. This sounds amazing and it's having a lot of, you know, my weight is having a lot of effect on my life. What's the right message for those listeners today?
[00:33:56] Dr. Robert Kushner: Two messages. One is probably worth mentioning. What is the actual indication to prescribe this medication?
Let me start there. And it's based on something called Body Mass Index or BMI, which I think is an awful way of describing a disease, which is a height and weight relationship to body size. But it is indicated for an individual with a BMI of 30 or more. Or 27 or more with a medical complication like diabetes, high blood pressure, high fats, and blood, that gets you in the door for the prescription.
If you don't meet that, then you'd be, the prescriber would be using an off-label or you don't have that indication if someone has an increased body mass index and no medical problems whatsoever. I have a long discussion with them. First, I double down on lifestyle, eating a healthy diet, balanced diet, calorie deficit, and reducing ultra-processed foods.
More plant-based, is the way that I, think about it. Robust physical activity, and good sleep hygiene. Don't use substances like alcohol, tobacco, and social environment. I talk a lot about that. They're already following that and they still have an excess body weight or body fat, and medication is potentially indicated by the BMI.
I will make it very clear to them the medication works only as long as they take it. So I talk to them and I say, are you prepared to use a medication long term even though you just wanna lose, uh, 20 pounds or 10 kilograms? Uh, are you prepared to use this medication long-term? Because we don't think of it as a jumpstart.
Many people come in, I just need a jumpstart doc. This is not a jumpstart. This is a medication used long-term for a chronic relapsing condition called obesity. So I make sure they understand that I still may end up using a medication. Always touching base with them about why are we using it. What are your expectations?
What are your goals?
[00:35:49] Jonathan Wolf: That thing about the stopping is something that I really wanna follow up on because everything around this is so magical. Like it is extraordinary. You can lose this weight. There's this sting in the tail, right? Like ideally. , you would take this and it would treat your problem but this feels classic for a pharmaceutical drug. Like you have to keep taking it and if you stop taking it, it stops working. Could you tell us a bit more about what happened? Because I think a lot of people are probably thinking about this. Like, I can take it for a bit and it's gonna solve my weight problem, and then I'm not going to take it anymore. what happens if you stop?
[00:36:25] Dr. Robert Kushner: It's important to frame the conversation of what obesity is before I get into what happens when you stop it. I used to compare it all the time to either hypertension, asthma, or diabetes. And that is, these are chronic medical problems that you take medication for.
And if you stop taking the medication. Those medical problems are likely to come back, whether it's diabetes, asthma, or hyper. I think people understand that. So if you go on a statin agent for high cholesterol, most people say, okay, I get it. I need to use it long-term to keep my LDL cholesterol down. So I frame it in the same context.
Obesity is like a chronic disease like that. If you stop taking the medication, there's a high likelihood the obesity's gonna come back. So how does it come back? It comes back primarily and it's very subtle. People will say, I'm starting to eat a little more food because I'm not as content as I was when I took the medication.
I'm starting to snack a little bit more. Or nibble throughout the day, which I wasn't doing for a long period. I'm starting to have the enjoyment of food, an enticement of foods that I didn't have before. Very, very subtle, but that's how the medication works. It alters your perception of how much food you need.
And that's what keeps you in a calorie deficit to lose weight and a lower calorie intake, thereafter. So it's very subtle and when I see patients come back, either they ran outta the medication or they couldn't find it in the pharmacy, and they'll come back two weeks to a month later and say, I've already gained a few kilograms or a few pounds, and I explore with them, what's going on, and that's what they tell me.
I'm just starting to eat a little bit more food. So that's how the drug works and changes your sense of appetite.
[00:38:18] Dr. Will Bulsiewicz: A quick comment first. So we mentioned earlier the indications for, this drug and the indications that you mention. Of body mass index of 30 or 27 and above with comorbidity.
Those are the FDA approvals in the United States, but just for the UK listeners, approval in the UK is slightly different. So as this drug gets reaches approval in different countries, each of the individual countries may have slight differences in how they're bringing it to market. With regards to what you were just talking about, you just published a paper on this specific topic, which is weight regain after discontinuing the drug.
You published it in October of 2022, and I found it to be very interesting. There was one particular graph in the paper where you could see the weight coming back, and it appears to me that eventually, everyone gets back to almost the same baseline. So it's almost like the baseline that was established before you started the drug is where your body thinks you're supposed to be.
Do you have any thoughts on that?
[00:39:23] Dr. Robert Kushner: Yeah, what you're referring to is the step one extension trial. And, just to bring all listeners up to, speed, we took about 300 individuals who were in that step trial that we described before the 68-week trial and follow them for a year, with no intervention.
Just follow them as if they stop taking it. And what we found will at the end of one year, is that individuals on average regained two-thirds of the weight that they lost over that first year. And if we follow them long enough, they would probably get back to baseline, which is what you're saying. So that speaks to this whole idea that there's a biological set point.
That's a new term we're introducing today in the podcast. A set point that the brain has of where you ought to be. That gets back to that whole famine and starvation concept I talked about before. So the body doesn't forget. It's under the category of unfair. But the body, the brain doesn't quite forget where you started, and it works its way very slowly over one to probably five years to get you back. To where you were. Now you can introduce change in your, diet. Again, reduce calories, and increase physical activity. Drive the body weight down again. But again, over time it's likely to go up. Will we see this in animal studies all the time? We change the rat chow. We change how many times, they're on the treadmill and the rats go back to the weight that they started at.
And we are biological beings, and our bodies behave in very similar ways. There are only two interventions that I am aware of. That changed this set point of where the brain thinks you ought to be. One is medications. We're talking about that today. The other is bariatric surgery. ,
[00:41:06] Dr. Will Bulsiewicz: Yeah, that's what's interesting.
And bariatric surgery is a part of this conversation too. There's gonna be some people for who these medications don't achieve the fact that we're looking for or we may achieve 15% weight loss, but we want more than that... I think bariatric surgery is a model that we understand with much more clarity because we have more experience with it.
There is a problem in bariatric surgery with weight regain that takes place. Now. One of the ways that you can prevent weight regain is with a high-quality diet such as a Mediterranean diet. With these drugs, Bob, is it too early for us to tell if weight regain is a possibility in the future?
[00:41:47] Dr. Robert Kushner: We don't have that answer right now.
I can tell you definitively that. At least two years of medication, which was the step trial individuals maintain that weight loss as long as they're on the medication for two years. That's the longest data we have now. We have other data from individuals with type two diabetes who have been using these drugs much longer, although weight loss was not the primary outcome, more diabetes control, and they tend to maintain a lower body weight as well, it's not as clear whether it's the same weight.
We don't have that information. I would hypothesize that weight will be maintained lower than when you started, but whether it'll be maintained, the exact weight you achieved after one or two years, I don't know.
[00:42:33] Jonathan Wolf: I think it's fascinating. So firstly there is this like it is a magic bullet. It's extraordinary compared to anything I think we've seen before, and yet it does have this sort of sting in the tail, right? Which is that you have to keep taking it. I guess the other thing that I've stuck by having been in a lot of these podcasts as I think many listeners have, where a lot of the story comes up from a lot of different scientists in their research is that there seems to be something profoundly wrong in our current environment compared to a hundred years ago almost nobody would get obesity. And you are telling us this story that I think in another 12 years, 50% of all Americans will have obesity.
And so that's part of the food that we eat, the environment we're in, what may be happening to our microbiome, all of these sorts of things. And so then the pharmaceutical industry does come up with what is a wonder drug. Right. And I think, you know, Bob, it's really clear. You're very, very excited about it and you can see that it can have a profound impact on a lot of people's lives, which is wonderful.
And I guess what I feel is if we were talking about cancer, we will be talking about treatment for cancer and all the great drugs to treat cancer. But we would also be spending a lot of time talking about the causes of cancer. And in fact, we put a great deal of effort to remove all sorts of things in our environment that might cause it.
Is there a danger that we say, Hey, problem solved, we've got this drug, in a few year's time everybody will start taking this when they're, 18 for the rest of their life and we forget about the other half?
[00:43:56] Dr. Robert Kushner: I don't think that will occur. I mentioned earlier that we think of obesity.
I think of it as a two-pronged problem. First and foremost, it's a public health problem that is now spread globally. We're never gonna have a medication approach to a public health problem like that. It's too deep-rooted, as you said, in our environment, our food supply regulation, how we live our lives, the air plastics, and all these types of things, we're learning more and more that it's gonna need multiple stakeholders.
I kind of look at that as a moonshot. We need to put everyone in the room, block the room until we come up with some solution, and then give it a trial and see how that works. I don't ever think of it that way. The way I think about medication is when I see an individual come into my office, who is suffering from obesity, sleep apnea, type two diabetes, fatty liver disease, arthritis, where their knees hurt, and urinary incontinence.
It goes on to 200 medical problems. What do I have to offer that individual who's coming in with me today who has high-risk morbidity, mortality, and reduced quality of life? I have something to offer that individual. But by no way do I think I am solving the public health problem of obesity. We need to deal with those both together, and at the same time.
[00:45:15] Jonathan Wolf: So Bob, maybe to conclude, if some of our listeners are worried about their weight and they feel that based on today's conversation, these drugs could be relevant for them, what would be the next?
[00:45:26] Dr. Robert Kushner: Make an appointment with your healthcare professional. Be prepared to ask very targeted and specific questions.
How can you help me? Are there medications that can assist me in losing weight and improving my health? Have you heard of these new GLP one receptors? Semaglutide would be an example. Or there are others, what other resources or referrals do you have for me? So I could be more successful in taking control of my own life.
And lastly, if you don't have answers to that, who can you refer me to that can't provide that support?
[00:46:04] Jonathan Wolf: Brilliant, Bob, look, this has been fascinating. One of the things we always do at the end of the podcast is to try and sum up, so I'm relying on both you and will to keep me honest as a non-doctor in the room.
So I think the first thing that I learned is that Semaglutide mimics a natural hormone that is created in our gut that makes us full. That is a game changer. It's not just the media hype. Here we're talking to a doctor who's been in his field for decades, did the trial, and you're saying, look, this is a really big change.
And that's because it's profoundly addressing this really big challenge in weight loss, which is. Yes. Partly how much do you lose weight immediately? But this way in which you're trying to fight, your body's trying to fight back against it, and with these drugs, you're just not hungry all the time.
You're not struggling all the time and therefore you're able, instead of losing 3%, as you gave an example on the other arm, you're losing 15% of your weight, which is an enormous amount. It needs to be injected. So it's not just a pill you are injecting, but you can self-inject. It's once a week.
There are some side effects, and I think you said they're mainly sort of gut-related, like nausea, and diarrhea, but, in many people, they subside. And this is part of managing the treatment in the first few months. Now, all of that is amazing, like its side steps, all of this human adaptation to try and, react to famine by keeping on your weight.
But there is one big downside, which is you don't just do this for a couple of months and stop. This is basically at the moment it's like you've gotta do this for the rest of your life because if you stop, you just depressingly slowly, put the weight on sort of month on month and get back to the beginning.
And so it's potentially amazing drugs, but it's treating the symptoms of something which is going on in our society. And I think the figures that you shared were, obesity in the US was 13% in the 1990s and will be 50% by a dozen years from now... And I think the final thing you said is if anybody's listening to this and is interested, then they need to go to their doctor and ask some really clear questions.
And I think I also heard a lot of concern about people who might be trying to do this sort of over the internet in a way that is not well, managed.
[00:48:10] Dr. Robert Kushner: Well said. I think you did a wonderful summary.
[00:48:14] Jonathan Wolf: Well, Bob and Will, thank you so much. Spending the time, Bob, I'm sure that the phone has been ringing off the hook over the last few months on this topic, so really appreciate it and it's wonderful to understand, I think some of the facts.
[00:48:27] Dr. Robert Kushner: Thank you for having me. It's been enjoyable.
[00:48:30] Jonathan Wolf: We'll be able to have you, you're back again in the future. Cause it sounds like this is still relatively early. Right? So over the next year or two, we're starting to have a lot more data about long-term follow-up. And I think as will also mention, there's an enormous amount of sort of farmer industry in this area, isn't there?
So there are like even more, potentially even better drugs that are going to come in the next few years.
[00:48:50] Dr. Robert Kushner: This is the beginning of a whole range of Compounds that are mixing and matching multiple gut hormones with the likelihood of even more effective treatments around the horizon.
[00:49:02] Jonathan Wolf: I love it. Well, the power of the gut, we like to talk about that, so it's very exciting.
Thank you so much. Thank you.
Thank you, Bob and Will, for joining me on ZOE Science & Nutrition today. I think it's clear this is a pretty amazing breakthrough in understanding the science of weight management, with huge potential for many people living with obesity. And I'm excited to see what the future holds. If based on today's conversation you're interested in improving your health and perhaps achieving a healthy weight without drugs, then you may want to try ZOE's personalized nutrition program so you can feel more energetic, improve your gut health, and reduce the risk of long-term disease.
Your ZOE membership gives you meal and recipe recommendations and scientifically backed nutrition advice on how to eat for your best. Your personalized nutrition program is based on our scientific research and the results of your at-home test. If you're interested in learning more about ZOE, you can head to joinzoe.com/podcast and get 10% off your purchase.
As always, I'm your host, Jonathan Wolf. ZOE Science & Nutrition is produced by Fascinate Productions with support from Sharon Feder, Yella Hewings-Martin, and Alex Jones here at ZOE. See you next time.