The Truth About GLP-1 Drugs and Who Should (and Shouldn’t) Take Them with Dr. Susan Brian

So you would have to be living under a rock to not hear about the GLP-1s and all the debate around them. And if you want to know why the debate is there, if you want to know what they're doing, what they're not doing, who should be taking them, who shouldn't be taking them, the role that they have in the intended use, but then maybe in cancer and maybe in longevity, then you are definitely going to want to tune in today's episode. So today I have Dr. Susan Bryan. She is an Ivy League trained endocrinologist who really has her fingers on the pulse of what these GLP-1 drugs are doing, the different, the different forms, what the implications are, who should be on them, who shouldn't be on them. How do— how should we be screening for who should be on them? And she really has a very, very welcome and grounded perspective in all of this. Without further ado, I welcome you to listen in to Dr. Susan Bryan. So, Dr. Bryan, welcome, welcome, welcome to the show. I've been so looking forward to having you.

Thank you for having me.

I have a particular interest in what's happening with the GLP-1s because of my work in the breast cancer population. And because obesity and breast cancer are highly tied to one another, right? They're, they're totally tethered. Um, and this story for all of us is really about metabolic dysfunction. So I want you to first talk to me about— because you've been an endocrinologist for a while now— like, talk to me about, from your standpoint as an endocrinologist, how has metabolic health changed over the last few years, and what are you seeing in your practical work?

It— metabolic treatment has completely transformed with the GLP-1s coming into the mix. Used to be all we had really for metabolic things was metformin, and I, I like to say to my patients, like, metformin would be like going to the Dollar General, and GLP-1 would be like going to Saks Fifth Avenue. I mean, you can get stuff at both of those places, but the quality is, you know, completely different. So is the price, of course. So we used to have, you know, just a little bit of treatment. And on the diabetes side, of course, that's like one of the worst consequences of metabolic disease is type 2 diabetes. We had no good way to treat that minus metformin and insulin and giving insulin, of course, increases weight gain, worsens metabolic disease. So by our treatment of diabetes—

it was kind of masking the symptom, right?

It was definitely treating the blood sugars but worsening other metabolic issues for sure, right? And, and all of the kind of precursors of type 2 diabetes or the, the other diseases involved in insulin resistance like polycystic ovarian syndrome, etc., we had, you know, metformin again for that. Um, really nothing. In my— when I was in 2003, I I was interviewing, I believe, for, yeah, interviewing for fellowship, interviewing for endocrinology fellowship at the NIH. And that was the first time one of the interviewers said, "Have you ever heard of GLP-1?" And that's the first time I heard it. And so it's obvious they've been studying, and she told me about the Gila monster, and I was like, "Okay, this is kind of weird," you know, like, and, but now I look back on that and think, "Oh my word, if I would have had any idea how that would've changed my life." as a prescriber. Um, and it used to be so much more frustrating to treat patients with PCOS and, and type 2 diabetes and all, you know, all the metabolic issues because we didn't have good things to use. And now it's almost— it's exciting again. It's, you know, diabetes actually used to be one of my least favorite things to treat. Now it's one of my most favorite things to treat because it's like, I, I know how to change your life, and I've seen lives changed over and over. So really GLP-1, the reason we make such a big deal out of it is because it really is life-changing. And as a provider, I've seen that, you know, I saw what life was like before we had that treatment for metabolic disease and what life is like now. And I could tell you, you know, dozens and dozens of stories about amazing life transformations, not just weight, but all the other cardiometabolic things and life quality. I had a guy the other day, this is an older guy, guy that, you know, type 2 diabetes, etc., and kind of wasn't doing anything active, had all this joint pain. And he came in the other day, he's like, I went duck hunting for the first time in decades. And I was crawling under fences and over fences that, you know, I felt so like my old self so long ago. And, you know, that's kind of silly, but it's like, that's what it's about, you know, to be able to, like Oprah just said recently in an interview, you know, I feel more alive than I felt in years. And I've heard that type of sentiment so many times.

Yeah. I mean, it truly has revolutionized medicine 100%, probably more than anything else that we've seen in decades.

Yes. I would say the thing that was the major thing before this was insulin. So insulin saves lives in type 1 diabetes. Absolutely. But I believe this is equivalent to the discovery of insulin in the metabolic world for sure.

Yeah. Well, now I want to talk about appropriate use and inappropriate use because the way most of us heard about GLP-1s is that it was being used by the population to lose 5, 10, 15, 20 pounds.

Right, right.

So what do you think? Are we— has the pendulum swung? Are we getting more appropriate? Or is this really just a drug for everyone? Like, how do you feel about it?

It's a great question. And I'm— I truly am not positive how I feel yet. I don't think we have enough research in maybe longevity spaces and normal BMI spaces to say. For sure, using it in the appropriate population is absolutely, the benefits far outweigh the risks for the, and how it's labeled, you know, is a BMI 30 or above without comorbidities or a BMI 27 or above with at least one cardiometabolic comorbidity. That could be high blood pressure, that could be prediabetes, you know, a high cholesterol, which a lot of people have. So that's definitely beneficial. What we, but also what is BMI? And so now, you know, the guidelines are saying what we need to reconsider what BMI is because plenty of people with a higher BMI have a lot of muscle and not a lot of fat. And a lot of people with lower normal BMIs have a lot of fat and not much muscle. So, and they're not metabolically healthy. So if we only followed the current guidelines, we are missing this kind of metabolically unhealthy lower BMI population.

And there's a whole skinny fat population, right?

Yes, yes. And we see a lot of those. I have lots of type 2 diabetes patients who walk through the door, and you would never guess it to look at them that that person has type 2 diabetes. You can't identify everybody. So, so definitely, I think using it in the way that it's labeled absolutely makes sense. I think the bad reputation it's gotten is kind of the Hollywood person that has lost—

Poppy Handler injecting her friends.

Yeah. And losing so much weight. You know, they look unhealthy and I'm sure they're having bad consequences because of that unhealthy weight loss. That's not how it should be done. And but, but should it be done in a healthy way for people who don't meet the current guidelines? I think there is a place for that. Because of this, you know, if we were getting body compositions on everybody, we would have a different understanding, I think, of who we would give it to. But we, several things are caveats. One is that we absolutely can't apply the known beneficial outcomes that we have for the studies that we have, like lowering, you know, heart attack and stroke and improving kidney function and liver function. All the things that we have are true, but they only apply to you know, those doses used in that population. So we can't say that someone with a normal BMI is going to have a significant lowering of heart attack and stroke. Maybe they will, but the research wasn't in that population. So interestingly though, in our patients with diabetes that received this and did show lowering of heart attack and stroke, there were patients with a BMI lower than 27 in that study, and they had this equal lowering of cardiovascular events as heavier patients. So, but again, those are— have patients have diabetes, so that's not the population we're necessarily talking about. I believe to do it in a healthy manner in someone who has a lower BMI, what probably is not being done in those kind of Hollywood situations is low doses, very slow weight loss, watching body composition, you know, thinking differently about that population because the negative things that we see almost all come from too high of a dose, too rapid dose escalation, you know, too quick of weight loss, even like the, you know, gallstones and risk of pancreatitis. That's from rapid weight loss, you know?

So, yeah, I mean, we, we see the same thing in gastric bypass surgery.

Right.

And it's why almost universally when we do that surgery, because that's my background, yeah, I'm a surgeon, when we do that surgery, we take out people, people's gallbladders because there were too many people with this rapid weight loss who got cholecystitis. And you don't want to have to set someone up to have a surgery and then have to go back and have another surgery, not to mention that there are complications associated with cholecystitis.

Right.

So, okay. I would like to start by delineating what are the benefits? Like what, what happens to people with metabolic dysfunction who then go on this drug? Like what are the clear benefits of these drugs?

The clear benefits are that they lower blood pressure, they lower cholesterol, especially triglycerides. They can help HDL improve through weight loss. They lower blood sugars. The tirzepatide studies, you know, like 99% of patients with prediabetes had normal glucose levels glucose at the end of the study. Then they lower the risk of heart attack and stroke. They help stabilize kidney function, prevent worsening of chronic kidney disease. They help obstructive sleep apnea. They cut moderate to severe sleep apnea episodes in half. They lower osteoarthritis. They cut inflammation markers. This is— these are all randomized controlled double-blind plus, you know, studies I'm talking about. So this is good information in the population, of course, that was studied. Cut inflammation markers, almost in half, I think 48% in two different studies. So lots of great hard data outcomes.

And conversely, what are the risks?

So patients with metabolic disease are at risk of usually up to 4 times higher cardiovascular disease, heart attack and stroke, higher risk of Alzheimer's. Remember we call Alzheimer's kind of tongue-in-cheek type 3 diabetes because it's completely linked to all the things that are linked with metabolic disease. Um, kidney disease, you know, diabetes is the number 1 cause of kidney failure and dialysis in the United States. High blood pressure, which is also a metabolic disease, is the number 2 cause of kidney failure and dialysis in the United States. So all of those— fatty liver disease, completely tied to all the metabolic syndrome. The risk of fatty liver disease, which we now call like metabolic metabolic-associated liver disease is cirrhosis and then liver cancer. And, you know, worldwide cirrhosis from fatty liver disease progressing is overtaking cirrhosis from alcoholism. So a lot, of course, obstructive sleep apnea, severe osteoarthritis, on and on. Lots of really bad things, which is why when we talk about the side effects, the risks, cost-benefit ratio when you think about all of, like, this is what I talk to people when I talk to my patients about thyroid cancer, they're like, oh, I heard about all the thyroid cancer stuff. And my thing about thyroid cancer is if there is a risk of thyroid cancer, if there is a risk, it is like less than 1%, if it's there, maybe. So far we really have not seen that, but maybe long-term, maybe long, long-term there's risk.

Why do you think they're talking about it if it's not really seen?

We, we've seen it in animal studies. In animal studies, um, the animals that were studied, they had, their thyroids have a a lot more C cells than a human thyroid. If you look at a human thyroid, C cells in the thyroid are kind of weird. That, that's what actually releases calcitonin in the thyroid. There's just a few random C cells, not very many. Well, C cell hyperplasia is what was seen in the animal study. So it was somehow stimulating those C cells, and C cells are the type of cell that become medullary thyroid cancer. So I take care of a lot of patients with medullary thyroid cancer. Um, it's just another kind of thyroid cancer, but—

But it's the least common of, of thyroid cancers.

Yeah. It's very uncommon. It's like, put it out there.

It's very treatable.

Yeah. I mean, you, there are genetic, like the IMiD, um, genetic autosomal dominant tumor. Yeah. And I have plenty of those, but that's, that's genetically driven. So that's where it came from because the animals that were studied had a lot, had different kinds of thyroids basically than what we had. But maybe, maybe it does. But even if it does, it's probably about 1%. And so I say the risk, your risk of taking thyroid, and it like, also we're aware of that. So I'm always feeling the thyroid at the exams, you know, we're aware of it. So that risk is like this, but your risk of those things we just talked about is like way up here and those things are so much more common. So that's that risk-benefit ratio. But to your point of like, who should be taking it? If you really don't have any cardiometabolic disease and maybe you have 2 pounds to lose and, um, you're just wanting to take it cuz you, you know, everybody's taking it and you think it might be great. What is your risk of that stuff? It's not up there. So that's when I think those, the, the risk benefit ratio really becomes appropriate. Like, is it, is it worth it? Because these things do happen even though they're less than 1%, like the rare eye disease and that sort of stuff. It's very, very rare, but that becomes more important if you don't really have a lot of benefits to gain from it.

Yeah, absolutely. So, you know, I think a lot of people who heard the risks early on, things like gastroparesis and an increased risk of bowel obstruction, like I, I, I think I was listening to Mark Hyman's podcast and maybe he said like 800 times more bowel obstruction and, and that kind of thing. And people who are not knowingly metabolically dysfunctional kind of said, well, why would I ever do that? So what are the real risks? I, we talked about the thyroid cancer and the fact that that comes from animal study data, rare eye disease, like What are the real risks that go along with taking these medications?

Okay, well, um, let's talk about the eye disease and then we can talk about the gastroparesis. So, the— there's two types of eye disease that we think about with these medications. One is specific to patients with diabetes, and that's diabetic retinopathy. And that is any medicine that rapidly improves blood sugars can, can cause the retinopathy to worsen in someone with diabetes. So we've seen that with insulin.

Why is that? What's happening there on a physiologic level?

It's, it's, it's probably a blood pressure and perfusion issue. So when— because you're—

when you're somewhat reliant on a higher blood pressure. And so as the blood pressure drops systemically, so does the blood pressure drop in the eye and they're not getting the perfusion they need.

Yes.

Okay.

And so that's specific to the retinopathy, even though it's like I literally have never seen a case of worsened retinopathy, only improvement. But that is a theoretical risk. And we've seen it with many type of diabetes medicines. But the thing that gets more press coverage is NAION, which is the eye blindness or the eye stroke. And that also, we think, is a blood pressure kind of perfusion issue. And it is— well, so it's more blood pressure perfusion probably than the retinopathy, but it is I, I've never seen a case of it and I, you know, I've been doing this for 18 years and long, long time, uh, using the GLP-1s. But in the, in lots of good studies now that they've looked at, probably the risk in general is about 0.04% of getting NAION. And for the general population, the risk is about 0.02%. So it, it is higher, it is a risk, and it probably is related to the, the dehydration and lowering of blood pressure acutely. And you could say, if you didn't understand the statistics, you could say this medicine doubles your risk of NAION. And that is true, but it takes you from having a 0.02% risk to 0.04% risk. Okay. So, so it is there.

It's a relative risk.

It's a relative risk.

It's not an absolute risk.

It's a relative, it's a very small absolute risk.

It's a way to sensationalize. The data.

Exactly. Exactly. But that, that did happen to patients. It was like, it was a Harvard specialized neuro-ophthalmology group that initially reported that, and it was semaglutide, a semaglutide study. But then subsequent studies have looked at it, and what they said about that group was like, that was probably a selection bias. Those, that group is like, you know, the world's specialty eye group. So they're seeing more of those rare cases. And then if you look at more general, everybody who's coming into my clinic, what percentage of them have the NAI1? That's where it's like, it's probably 0.04%. So it was, it was a selection bias basically for that study. But, but it probably does exist. It's just extremely rare.

Gotcha. All right. So what else? We talked about thyroid.

Gastroparesis.

Okay.

Yeah. So we used to worry a lot about gastroparesis with these meds because they do slow down the gastric emptying. So that is gastroparesis. It slows down. That is the way that it works. That is also one of the ways that we get a lot of benefit from it because you're not delivering glucose so rapidly to the GI tract and you're having some slower movement, some fuller sensations, you know? So there are some benefits of it, just, you know, some. But we did not give these medicines to our patients with gastroparesis for a long time because of that worry. Um, and then—

Interesting part is those people probably had gastroparesis because of their diabetes.

They for sure did. Yes. Yes, for sure they did. But we were worried it would make it worse.

Yeah.

So we didn't give it to them. And now, but now after, you know, after it being on the market for so long and realizing, oh, it's really a very, very low percentage risk of gastroparesis, then, then I started thinking like, I'm going to offer it to patients. You know, this person is uncontrolled and we've tried so many things and, you know, they would benefit. And now I freely— of course, we have the risk-benefit ratio discussion, but I have tons of patients with gastroparesis on it, and I would say 99% of them have improved their gastroparesis with these medications. And it's not because the medicine's improving specifically the gastroparesis, but weight loss improves nerve function, weight loss improves neuropathy. Activity improves gut health, the lowering of the blood sugar so you're not having the toxic damage to the nerves. So it's, you know, ironically, patients actually have a lot better outcomes. And I've had so— I just had this recently, a patient last year came to me and she was like, no one's ever allowed me to have a GLP-1. This is a new consult patient with diabetes because of my gastroparesis. And I just— she was like crying. I just want to try it. I was like, great. Today's the day. Let's do it. And she came back, you know, she's come back a couple of times and it's like her life has totally changed. And did it worsen the gastroparesis? No. And she's better with so many things, just like, you know, like it happens. Their blood pressure is better. We go off blood pressure medicines. Their cholesterol gets better. Their activity gets better. So, yeah, so the gastro and the whole, what do they call it, frozen stomach or whatever, all the stuff that's plastered I've never seen that. I have seen a couple of hospitalizations in patients that probably ramped up their doses too quickly. Um, one patient, for example, he just completely skipped all of the first dose. I don't know, just, we don't know why, but people, weird things, went to a high dose immediately. He ended up with like very slow gut, but not frozen, not anything like that. And just took a few days and he was better.

And he wasn't like stuck dead?

No. So I personally have never seen a bowel obstruction and I, you know, I'm the head of our inpatient diabetes service where we touch over 100 patients with diabetes a day in our hospital. So I'm in the know with a lot of this treatment. So certainly it does slow down the GI system. So it makes sense. And you again have to be careful with all of that. But that is so overblown. I never know, like, what are they talking about when they talk about this? Like, what are they talking about?

So, so I do think that there is a considerable amount of fearmongering out there.

Oh yeah.

About these drugs.

Why do you think that is?

I mean, why do you think that there was some intent to create so much fear around these medicines?

It's a very good question. You know, I don't know. That's one thing that bothers me about social media is I know I have to get off of it when I start seeing that. I'm just like, why are you saying that? Because so many of my patients—

Horrible.

Yeah, it is. They come in and they're like, my, my cousin, my husband, my whoever, you know, said this is so terrible, you have to stop it. And I'm like, but the patient's like, but I'm doing so good on it. And I feel so much better. But these things reach the patients, you know, they negatively influence the patients. On my, in my cynical side, I think, I don't know, people are trying to make money from it. They, maybe they're like personal trainers, or they're in the nutrition space, or they feel maybe threatened by this, um, or they just think everything needs to be so natural. And I'm a big naturopath, like, I, I follow all kinds of natural stuff myself. So, um, but that's my— I don't know, that's kind of my cynical thing of must be benefiting them in some way. But what I tell patients about this, and this is what I would say to, like, naturopaths about it, the very best level I think that we can get to with our health, like, the very top level, is Excellent health without medication. That's like, if we can get there, fantastic. But right under that, I think, is excellent health with medication. And then I think way under that is poor health, no medication. No, that's way under good health with medication. And then of course, even that is, you know, poor health, you know, no medications. That's what I try to get, right? Yes. If, if the— if you can do that without medication, great. But so many people can't because we have multiple diseases in our— that's just the way it is. And if you would genetically test people with metabolic disease, there are often multiple— it's a polygenetic disease. There's multiple mutations that lead to metabolic disease. And that's just— it is a disease. Like, in, in, in— when your blood sugars are going up in metabolic disease and diabetes, your glucagon starts going up and your blood sugars go up further. Why does that happen? Because it's a disease. You know, it shouldn't happen. That's what it— that's what happens in a disease.

You know, a disease. Yeah. So what are we currently doing to screen for metabolic disease or metabolic dysfunction? And what, what do you think we should be doing?

Oh, that's a good question. That's definitely kind of a population health thing, which I'm probably not as good at because I'm a subspecialist. I'm seeing you know, the consults where they've already done X, Y, and Z and they've already often been screened. But there are the guidelines as far as, you know, if you're overweight, then you should have your lipids done every so often and your blood sugars done, you know, screening for diabetes. So those are there. That's more on the primary care kind of level. But I'll tell you, all the time I see patients come in and you can look back and see their chart forever. A high triglyceride, a low HDL, you know, those are metabolic disease. Certainly blood sugars, even in the higher 90s fasting. It's, it's a range. It's not just all of a sudden it's abnormal, you know, it's that range of impaired fasting glucose. There are recommendations now for screening for fatty liver disease with the FIB-4 score. That's like a calculation you do off of labs, but that's hardly ever done. But that looks for like fatty liver disease. So I don't know, that falls to the purview of the primary care doctor so often who have to do 50 other things and it's so hard, you know, to do that.

So really, the problem is it doesn't get done, and that's why they wind up in your office and in mine.

Yeah.

As much as, like, diabetes is downstream from metabolic dysfunction, so is breast cancer.

Yes, absolutely. Yes, yes, yes. And so let's— so we talk about that. That's a great point that when you look at the development of type 2 diabetes, for example, and insulin resistance, Insulin resistance is a big part of that, is genetic. Um, so you are born again, polygenetic, lots of risk factors for that. And then you have this underlying insulin resistance, and then, but with normal blood sugars. And then over time, as you continue to have that insulin resistance, your blood sugars will start to rise because you start to kind of burn out the pancreas, if you will, in a simplistic form. And so then your blood sugars start going up even though your insulin is still up. That's prediabetes. So typically you live in the insulin resistant state for 5 to 10 years, then you cross over to prediabetes for 5 to 10 years, then you cross over to diabetes. So it is a very long, slow burn that we can find people in, and then we can back things up, especially when we use something like GLP-1. And that's my great gift, I feel like, to people, is trying to help find them earlier and then back it up. And that, that's why I love the menopause space, because all the things we just talked about worsen naturally at menopause. All of the things— obstructive sleep apnea, type 2 diabetes, all of it. And those women are coming in wanting help, you know, and no one is helping them.

Yeah.

Um, so that is— and so I love finding people earlier in that metabolic kind of, you know, crash and being able to be like, hey, let's let's reverse some stuff. And I, I really do feel like I see people aging in reverse now. It's like so awesome because we never used to see that. You know, it was somewhat depressing. It was like, oh, now you've gained more weight and now you're having more swelling in your legs, you know, because we're giving you insulin and things are just worsening.

And so, yeah, well, I mean, unfortunately the system is set up to just not really intervene until people fail, right? That, that's the way that our system currently works, is wait to fail, and then we, we just do something.

Yeah.

So I do want to back up and have you explain why all of these symptoms worsen with menopause, why metabolic dysfunction worsens with menopause, because people rarely, rarely— like, it's very popular to villainize estrogen. And not have any insight or realization as to what benefits it's affording you all along the way.

Well, I'm an estrogen fan and user myself, so I definitely love it. Yes. So when you start having the lowering of estrogen, you have— we are, you know, we're protected cardiometabolically from with estrogen for a good like 10 years that the men are not. Estrogen does improve insulin resistance at the cellular level. And as estrogen starts to fall, you start having changes in body composition because of that, where you start, due to this insulin resistance that's now being worsened, having that abdominal deposition of visceral fat, which is, you know, risky cardiometabolically.

And people are putting fat, not so much like on the outside, but on the inside, around their organs.

That's right. That's right. So that starts to change. And that, that is something that estrogen is known in studies to decrease the risk of developing diabetes in the menopause transition because it improves insulin resistance. And also, even though estrogen doesn't cause weight loss, it does help slow that change in body composition. So people on the estrogen, uh, you know, menopause hormone therapy won't have as significant of change in that body composition, more visceral fat deposition, etc. So we know that the withdrawal of estrogen worsens insulin resistance, and giving it back can improve some of those risks.

Yeah, and so rarely is that concept understood, and that includes providers.

Yes.

So, so, so quick to villainize estrogen and not, and not think about what is happening on a physiologic level as estrogen goes away. Because as you mentioned, that is our protection. And it's why we don't see the, the, the— we don't mirror men in terms of cardiovascular disease.

That's right.

We catch up with them. If you don't go on estrogen replacement. But, but if you are on estrogen replacement, you have that cardiovascular protection. Okay, what was my next question for you? So we talked about the benefits and talked about the risks. I kind of want to get into a little bit of the nitty-gritty about each of the different drugs because there, there are a number of them and they actually have different functions. So, and I pronounce them differently than you do, so I'm going to let you say them because I currently have been saying semaglutide and that's not what you say. But there's semaglutide, there's tirzepatide, there's retatrutide, which I don't think is FDA approved yet.

Not yet. Not yet.

Did it just— is it, is it like on the edge? It's in phase 3.

It's in By the end, maybe by the end of the year. Okay. It's in phase 3 research. Okay. So, so if like we have older GLP-1s that have kind of phased out, they weren't as effective. And then we have like for diabetes, we had Byetta, Bydureon, those, those, you know, are less and less used.

Why would they be less effective? Like what's different? It's not—

The way that they're made in the lab, basically the, the, a strength at which they stimulate the receptor. It's different based on the different formulations. There was, I don't know if you remember, Tanzium. There was a Tanzium that was one of the early, early GLP-1s for diabetes. I was like, this thing doesn't work. So, I mean, and it's off the market now. So yeah, it's just this, the ability of it to hit at the receptor level, basically. So, and that's why really the two that have risen to the top are semaglutide and tirzepatide. Those are the two most powerful ones that we have on the market. Liraglutide is still around and liraglutide is actually generic, but liraglutide, it's the same cost as like tirzepatide if you use direct. So we just don't hardly ever use any of that anymore. So let's— so the two most powerful ones, the reason why you hear these, the semaglutide and tirzepatide, is because they're the most powerful ones. So they're the ones that have risen to the top. They are also ones that you can use both for diabetes and for obesity or the different things that have to do with the cardiometabolic complications. Semaglutide is just GLP-1, and so that is called Ozempic for diabetes, and it's called Wegovy for obesity. And that is the one that has just now been approved in an oral form for weight loss, also called Wegovy. Wegovy injected or Wegovy oral.

So what do you think of the oral forms?

I'm excited about it. They are, you know, we have an oral semaglutide for diabetes, which is called Rybelsys. We hardly ever use it. So because people in general, in my experience, would much rather have a once-a-week shot than another daily pill. Plus you have to take it on an empty stomach and wait 30 minutes before you eat or drink and have only 4 ounces of water. So it's much more cumbersome to take.

The oral one is daily.

Yes.

And the injectable one is once a week.

Yes, that's right. But the cool thing about the oral right now is that there's a coupon for $25 a month if your insurance covers it. So it's a good time to kind of get into, if you wanted to try it, if you've been, you know, wanting to use it or you're paying a gazillion amount of money for, you know, your dose, then that could be an option. But the highest dose of semaglutide is still only about equal to the second dose as far as potency of weight loss, about only equal to the second dose of tirzepatide. So, and in the studies it is suggested, and this is what I see in clinical practice too, that semaglutide has a little bit more nausea. So probably a little bit more nausea, not for everybody, but there are plenty of people who feel like this, a little bit more nausea. With less weight loss. But for someone who doesn't need to lose as much weight, someone who doesn't have as severe metabolic disease, it, you know, it's great. But if you kind of reach your top of the semaglutide and you feel like you're stuck, that's when we'll go over typically the same dose of tirzepatide, which is Mounjaro for diabetes or Zepbound for obesity. And so the top Wegovy dose is about 2.4 milligrams, and that's about equal to 5 milligrams of Tirzepatide, and the starting dose of Tirzepatide is 2.5, so it's about equal to 5. But then you still have 7.5, 10, 12.5, and 15 of Tirzepatide. This dosing is the same in that for diabetes or weight loss, and the 12.5 dose in studies is about equal to gastric bypass surgery, weight loss surgery results.

Now, retatrutide, are they the Same though?

No. So tirzepatide also has GIP in it. So semaglutide is just GLP-1. Tirzepatide is GLP-1 plus GIP.

What does that mean to people?

That is— that means that it has an extra effect at the fat cell level because there's receptors there and the potency is basically just stronger for all of the things. Because that's another gut-derived hormone. You know, we have multiple hormones and there's even— there's a lot more in research that aren't even, you know, we're not even discussing, but we have tons of those, the gut-brain access, you know, we have a lot of those hormones. So, so GLP-1 is one of them. GIP is another one of them. And then retatrutide, which is in phase 3 research, is the triple hormone. It's like tirzepatide. It has 2 plus it has a third, which is glucagon. And so the amazing thing about retatrutide is it has even higher weight loss than the max dose of tirzepatide. And, and it has this because of the glucagon. There's— the liver is full of glucagon receptors and we, we deal with glucagon all the time with type 1 diabetes because you give someone glucagon to bring up their blood sugars. How are you bringing up their blood sugars? You're, you're telling the liver to release its stored glucose. And that's the problem with fatty liver. You know, you get like a liver cell and it gets so full of stored energy that it just balloons up, and when it can't balloon anymore, it starts fibrosing, and that's when you can lead to that cirrhosis. So you've got to empty those fat cells of their stored energy, and that's what glucagon does. So retatrutide in the Studies so far is the most effective thing we've ever seen in fatty liver. It, it clears fatty liver, stored fat. Amazing. One study— normal liver fat is less than 5%. One study, it took, um, this was an animal study, but they had over 85% fat in their liver, and it took all of the livers to less than 5%. So it's going to be amazing for fatty liver, but also diabetes, weight loss. I, I'm involved I've been involved in two Phase 3 retatrutide research studies, so I've been able to use it a lot in the research setting. It's extremely effective. It's going to be for those patients who tirzepatide is not enough. And we do have those patients that even that highest dose of tirzepatide is not enough. So that's going to be where retatrutide comes into play, I think, and for fatty liver. But it's being studied in obstructive sleep apnea, osteoarthritis, you know, all kinds of other things too.

So I'm gonna ask you what was so alarming to me when I first heard that, um, podcast with Mark Hyman a couple of years ago. He said that the weight loss came along with a 40% reduction in lean muscle. Yeah. So what about muscle mass? Because isn't that the key to our metabolic health?

Yes, that's very true. Muscle mass is the number one driver of our resting energy expenditure, which is huge for our metabolism. So yes, the muscle part is very concerning and there's a lot of work being done in that space. One of these studies I'm telling you about is a body composition study, which is so cool, with retatrutide. So we are going to have a lot of this answer, but a lot of the studies so far, we haven't had a lot of body composition parts of the study, so we don't have a lot of information on that. But here's the muscle— I'll summarize the muscle research. So in general, for, you know, all weight loss, diet, exercise, medicines, whatever, in general, you know, if you lose weight, you're losing about 75% fat and about 25% lean muscle mass. And so that's normal. In the worst study, the worst outcome study in the GLP-1, you lost 60% fat and 40% muscle. And that's what Mark Hyman was referring to. So that is true. What they have found in some other studies is that the muscle mass does decrease But it, a couple of things. One is that the quality of the muscle on MRI imaging, this was a study released in 2025, summer, last summer, the quality of the muscle was so much better because you get in metabolic disease, you get fatty infiltration of the liver and the muscle. So you get a large fatty muscle. And so the muscle did decrease in size, but the fat went away. And the strength testing that they had was, maintained or improved even. So even though you did lose muscle mass, the quality of the muscle was thought to improve and the strength maintained or improved. Another study that looked at it showed that people did lose muscle mass, but it, it became equivalent to what people at that BMI's muscle mass was. For example, typically, except in sarcopenic obesity, um, typically the, the larger your BMI is, the bigger your muscles are. And then as you lose weight, the muscles are, you know, you look at the BMI, it goes down, the muscle mass goes down. So in another study, people did lose muscle mass, but it was equivalent to what the muscle mass was for other people of that weight. And again, strength doesn't appear. So it's not like the quality of the muscle is worsening. Strength is still there. Now in sarcopenic obesity, that's the area we really have to be careful about. Patients with sarcopenic obesity have a lot of fat mass, so they are— have a high BMI but very little muscle mass. That happens much more commonly in patients with diabetes and patients who are older. So our older patients with diabetes, we have to be really careful using these medications because they already probably have sarcopenic obesity and we could worsen that. So we have to be really careful. Um, the American Diabetes had a— American Diabetes Association this summer, the big annual meeting, had like the top researchers in the world with muscle, and they some great presentations and here's in essence what you need to do. You need to resistance train 2 to 3 days a week. That is more powerful than anything else that you could do to maintain your muscle mass. It's way more important than protein or anything else. It's resistance training. And ideally it's at least a moderate amount of resistance training. Even light resistance training is better than nothing, but moderate is kind of a, a good thing to shoot for. 20 minutes, 2 to 3 days days a week. So that resistance training— and there has been, there are plenty of times when you look at body composition, even though they are losing fat mass, they are doing the resistance training, they're losing slowly, you know, kind of doing it correctly, everything correctly, and they maintain their muscle mass. So it's not like you have to lose muscle mass. Most people do lose some, probably some of that is fat, you know, it's a, it's an unhealthy— that muscle becomes healthier The strength can remain good. What you want to make sure you're not doing is worsening sarcopenic obesity. Does that— is that a— does that make sense?

Yeah, it does. Is there a difference between the drugs? Because I have heard this repeatedly, that semaglutide is worse in terms of preserving muscle mass than, than tirzepatide and retaglutide.

That's only because the— that 40% that muscle mass loss was the Wegovy study. It was the semaglutide study. Tirzepatide has the same ability to do that, but we're, you know, I think that we're trying to be more careful with that now. But the more weight loss, the more risk of it. So the thing that may be different about retatrutide, this isn't answered yet, it's ongoing actively right now, but what we don't know is will the glucagon part somehow protect the muscle because you're emptying the liver of its stored content more? And so that's what the hope is, that maybe retatrutide won't cause as much muscle mass because of the glucagon component, but because retatrutide is so potent, then that might offset that with the, the weight. Yeah.

Yeah. So one of the questions that I, or one of the comments that I have heard repeatedly is, you know, isn't this just imposed anorexia? And do people need to change their diet? Are they changing their diet?

Yes. Well, yes, anorexia only as far as it lowers the appetite. Hormones in a wonderful way so that you can maintain weight loss. If you are, if you have too much of a dose, then yes, you can have anorexia and that's not what you want. You should not be on that dose. You should be on a lower dose, or if it's the very lowest dose, then off of it or more infrequent. So anorexia is not healthy. That's not what you want, but it absolutely lowers the appetite hormone. And that's the way that we need it to work. That's why people can't maintain their weight loss because the appetite hormones, you know, we have all kinds of appetite hormones that increase our appetite, that decrease our appetite. And when you lose even a little bit of weight, you know, your whole body goes like, we must regain the weight. And those appetite hormones do, you know, do their job. And that's why people will say, you've heard it, I'm sure, like, I went off Ozempic and I wanted to eat like the refrigerator because you had lost weight and now you don't have that mechanism by which you're lowering your appetite to maintain that weight loss. And so then, Now, now your body wants to go back. It always wants to go back up to that heavier weight because regardless, it just doesn't want to starve. It doesn't care about cardiometabolic disease. It just doesn't want to starve. So, so yes, there is that component and that is a very important component of the weight loss maintenance. That's also such an important component when people talk about food noise and the release from all of that. That is that component. But, but these medicines do so much more than just lower the appetite. So I think that's a very unfair statement to say this is an anorexigenic medicine because we know multiple things, uh, benefits occur before weight loss occurs early on with the treatment, and that cardiovascular is one of those. So this is in the medical communities and the research communities. There's a lot of talk about how inflammation improves quickly before you lose the fat, I mean, fat loss, you lower inflammation even more, but there is more direct effect and there's direct effect on the vasculature, which is— so you get benefit from these medicines, direct benefit. The weight loss absolutely gives you benefit, but there are other mechanisms by which you get direct benefit from these medicines. So it's so much more than, than just the lowering of appetite, but that is an important component of it.

Are these medicines forever? For the majority, yes. Rebound effect when people stop taking them and they just want to consume everything that's in the refrigerator. And I, I totally get it that this is a protective medicine. I mean, I know a protective characteristic because we are here by virtue of the fact that we could survive starvation. Right?

Yeah.

From an evolutionary standpoint, the people that are alive are alive because they had a great ability to eat and store fat when food was plentiful so that they could survive starvation.

Yeah, that's a very deep, deep thing there. Yeah, it's in there.

Yeah.

So, okay, there— the— I have had— I have seen patients be able to go off of it, and there have been several studies, you know, about this. In my experience, the patients that are able to go off of these are not— they did not have maybe the greatest activity before, or they have other disease states going on. Something else happened, you know, big fracture, big life thing, gained a bunch of weight, became unhealthy, went on these medications, lost weight, started exercising, started eating right, you know, got out of depression, got into these better situations, and then we slowly wean them off, often using another type of anti-obesity medicine to help on the way, uh, getting off. And then they are able to maintain. Those patients with less to lose, less metabolic disease, etc. There was a study where they did that and they used other anti-obesity medicines for a year and people were able to wean off. People who are not able to wean off typically are those who have a lot of cardiometabolic disease who have, who lost a lot of weight, who were already doing all the things before, and the medicine just helped it be more effective for them. Then they, all of that stuff the same. The only thing that's different is the medicine. You take the medicine away, it's very hard not to go back to where things were, especially if there's that underlying polycystic ovarian syndrome, type 2 diabetes, metabolic disease, you know, all of the things. Those things are still there. They're, it's just like we say with type 2 diabetes, you know, we can get into remission, but it, it's still under there. So we still have to fight against it.

So let's shift a little bit because I wanna, I wanna know what role you think these medicines have in cancer or breast cancer.

Um, I, the, the breast cancer data, I, every time we get like an, um, this study, you know, these are all like retrospective and cohort and stuff, so there's not the the greatest because, you know, we just don't have long enough for prospective stuff with them. But when I, all of, you know, lower 10 types of obesity-related cancer, I'm always like, is it gonna be breast cancer this time? You know, I want, I so want, because you know better than I know, but you have all these poor breast cancer patients and, and they know that, they know that if they lose weight, it improves their outcomes and their recurrences. But how can they lose weight, especially if now they're like in premature future menopause and they can't take anything, you know, it's just like, oh, it's just awful.

It's awful for them.

And that is the patient that I love to be like, what do you think about GLP-1? So I'm— I, I would hope— I— it seems— it makes sense to me scientifically that as far as the weight loss, because we know that losing weight improves out breast cancer outcomes and, you know, lower recurrence and all of that. And that—

firstly, we know that people with metabolic dysfunction have worse outcomes across the board. They Yes. More recurrence, they have more metastatic disease, they have lower survival. We, we know all of that. I mean, it's clearly, clearly demonstrated.

In multiple cancers, multiple type of cancers, that's true. Yeah. Yes. So, so, and, and there have been, you know, there are some studies showing like 10 types of obesity-related cancer all decreased risk with GLP-1 use, just breast cancer hasn't been one of them. Um, there is some, you know, like preclinical and animal studies that suggest that GLP-1s do through like the immunologic tumor mechanism, which also kind of makes sense to me. We see that with different autoimmune conditions also. So, but my belief is that through that obesity mechanism, long-term use of these medicines would likely lower breast cancer recurrence and all of that through the mechanism of weight loss. But we definitely don't have that data. Saying that.

And then let's just shift to what about these drugs as longevity support in microdoses, in subtherapeutic doses? What do you think of them?

Okay, well, there's my, my like Ivy League trained, very scientific side of me that doesn't ever want to, you know, part from my my roots of that because I'm very much a scientist in that regard. Asking that side of me would be like, there's no data. You know, longevity is not something that we talk about in science like that. And you start saying longevity and then, you know, scientists start getting like, you're crazy and I don't want to talk to you. So that part of me is like, there's no data, there's no data on microdosing We just don't know. They're expensive. They have possible side effects. You know, everybody shouldn't be doing them, that sort of thing. But the other side of me that is going to be 50 this year and, you know, very much I'm a healthy eater, exerciser, believe in all of the things. That side of me is like, what is wrong with longevity talk? What's wrong with thinking about that? I mean, we are all aging. What's— I mean, and the healthy diet, exercise, lifestyle stuff we do is longevity stuff, why can't we put, why can't we combine the two of those? It is kind of like there's two sides and they don't want to, you know, mesh too much. But, but I do have a lot of patients that microdose for maintenance and they, you know, mostly for cost. But, um, they do great and they're able to maintain all their benefits as far as what we can see and measure, um, with those microdoses, which is the typically kind of the maintenance sort of doses. And they feel better on the medicine and they definitely do better, um, from all the things that we can measure. So, um, but of course we haven't studied in that way, so we couldn't say that scientifically, But I think, I do think in the future, there are some, you know, studies, maintenance studies, or I think there's going to be a lot more research on this in the future and probably will show that, especially for the people, person who has the risks of this or has dealt with any of this kind of cardiometabolic stuff, that long-term they probably will do better with some chronic microdosing or maintenance therapy of these. But I don't, I don't think it's for everybody, but I do think it's for probably more people than, um, we certainly than the FDA has it approved for right now.

Who is it not for? Who do you have concerns about it in?

I have concerns about older patients who already probably have some sarcopenic obesity. The sarcopenia does worry me, and I have seen that in older patients. I think we have to be really careful. With that. Patients who have eating disorders and are already thin and do use these as an anorexigenic agent.

That's really scary. I, I thought that was urban legend.

I mean, I, I personally have not known patients like that. I mean, I've known patients like that, but not— I'm not prescribing these medications. But, and I don't know, you know, people in Hollywood, I don't know any of them, but looking at some of them from the outside, people who were already very thin and then appear to be quite unhealthy with the supposed use of these medications, that would be a person that I would worry. And I've seen some, you know, videos and things about like this person was already thin and now they've got, you know, bone loss and all that other sort of stuff. Like, I, I do think for, for a, a thin, healthy person, um, that that probably doesn't, you know, has no reason to take it, that that's how we have to, I think we have to be careful about them and older patients who already have low muscle mass.

We talked about that, that most of the screening for metabolic health is happening at the primary care level. And I think a lot of the prescribing of these GLP-1s is also happening at the primary care level. This is kind of our wrap-up here. So I just want to know if you could leave clinicians and patients with, with some guiding principles around GLP-1s, what would they be?

Gosh, that's a big question. Guiding principles. I would say definitely, as you're talking about screening, you know, people, people should know, primary care doctors should know their BMI. If there's any way to get a body composition on someone, if you're suspecting it, your blood pressure, like a DEXA scan. Yeah, DEXA scan for body composition.

Okay.

And you, you basically have to pay for it out of pocket. But most places, if you just Google one close to you, has, has one close to you. And, you know, knowing what your glucose is, if there's any suspicion, doing a glucose tolerance test, that is such a helpful test and the most sensitive in diagnosing diabetes. So glucose tolerance, lipids, And then if there's any question about liver stuff, a Fib-4 score, which is very easy to do in about 1 second, just by— most people could do it themselves by just looking at their labs. It's an easy calculation. So assessing the risk, noticing the risk. On exam, do they have skin tags on their neck? You know, do they have abdominal, central, more central obesity like an apple shape? Do they have acanthosis hands on the back of their neck, you know, looking a good, a good physical.

And then as far as weight, waist circumference, or waist to hip ratio as, as your guidelines.

Yes, waist circumference and waist to hip, both, both of those have been shown. And if you look, you know, if you just Google what is metabolic syndrome, all of those things are on that, you know, so easy to, easy to look at that list. And, and even for yourself, evaluate that yourself. Yeah. So I think having a good understanding that this— and when I tell patients like, oh, you have the metabolic syndrome, oh, you have insulin resistance, it's like a light goes off and I'm thinking, have you never— you never know that? Like, and it's like, oh, that's why I am, you know, struggle with that. Yeah, that's right. Yeah. Um, and so, and then on GLP-1, I think you have to get educated to prescribe these medications. There they are special. They are— you have to do it in the right way. You can't just give someone a prescription and then, you know, send them on their way. Not everybody needs to go up on the dose. Not everybody needs to go up every month. Some people could do less frequent than every week. They need to be doing their resistance training. You need to be checking in on how much are they losing of weight. So I think I do—

they be losing like, what do you say?

I tell my patients a pound a week, don't lose more than a pound a week. It's really 2. But I feel like if I say that, you know, initially you'll lose a little bit more at the beginning, but that— but if they're losing more than a pound a week, I want them to be like, oh, I don't need to be losing more than a pound a week, you know?

Yeah.

And, and if we are in that way, they're knowing, like, if I'm getting that more rapid weight loss, oh, this is way more than what she wanted. I better call her and I'm going to back things down because that's really when you, when you get the hair loss Yes. When you get a lot of these negative things that people are complaining of, we— you're just losing weight.

Melted candle.

Yes, melted candle. That's right. And, and, you know, the, the, you get telogen effluvium that, you know, like after a birth, hair loss, because it's so traumatic on the body. But you don't have to do that. You don't have to get all of those things. So I say a pound a week. It's really 2 pounds a week. But, but I like to say that just to get them thinking, like, let's do this very slow. And that's what I say. We want this to be slow because in the studies, the slower you do it, the more likely it's going to stay off and the healthier you are going to be. We do not want this to be a fast thing.

Well, I thank you so much for your time today, for your, for your guidance and for what you do, because I have heard you say that you only take care of people at your hospital in Kansas. You're not doing telemedicine for everyone everywhere. And you, you, you lead a pretty righteous life and practice in a, in a righteous and beautiful way. And I know that you're very dedicated to improving the health of your community and you're doing a wonderful thing.

So that means a lot.

And you're, you're putting some real beautiful educational content out there in the world. And, and serving great purpose. So thank you so much.

I appreciate that. Thanks for having me on.

It was my pleasure, and it was my pleasure to be with all of you today. And if you enjoyed this, make sure that you share it with someone who needs to hear it, and know that I will be back next week, same time, same place. It's Dr. Jenn. Bye for now. I thank you so much for listening to today's episode. If you are looking for help on a breast cancer journey, I want you to visit my new website, it's JennSimmonsMD.com. And there you're going to find all our new programming. And no matter where you are, whether you are a previvor and trying to prevent a diagnosis because you're a BRCA mutation carrier or you're at high risk for whatever the reason, or you've had a biopsy that is abnormal but not cancer, or you've had the ARIA test and it is clinically positive, then you're going to want to look into my prevention program. If you have been recently diagnosed or you've already been through treatment and you want to get to the rest of your life, you need to think about the foundations and putting all of those foundations in place that you can build on, build your health on for the rest of your life. So that is the Foundations Program. And if you don't know where to go and you're just looking to get started, try the 3-day experience. It will change your life as much as it has changed mine and the hundreds of women who have been through that program already. Of course, if you are recently diagnosed or you know someone who was recently diagnosed, you're definitely going to want to pick up a copy of The Smart Woman's Guide to Breast Cancer, and that is available on Amazon. And if you are looking for breast cancer screening, you know that I recommend self-breast examination, the ARIA test, the Tears test, and that is at ARIA, A-U-R-I-A,.care. And you're going to use the code DRJENN20, D-R-J-E-N-N-20. And if you're looking for 100% safe, painless, and accurate imaging, we want to see you at Perfection Imaging, and Perfection is spelled with a QT in the middle. And lastly, if you're looking for hormonal health, Perfection Imaging is now Perfection Imaging and Wellness, where we are paying attention to and catering to the population that no one else is listening to, and that is the population of women who have had breast cancer. So we'll see you next week where I'll be back, same time, same place. As always, it's Dr. Jenn. Bye for now.