Dr. Michael Smith (Host): Welcome to Meaningful Medicine, a podcast by Novant Health. I'm your host, Dr. Mike, and with me is Dr. John Cleek. In today's episode we're going to be talking about GLP1 weight loss shots. Dr. Cleek, welcome to the show.

Dr. John Cleek: Thank you. Appreciate your offer to be here.

Host: Before we get into all of the GLP1 stuff, weight can be a very sensitive topic for people. How do you help patients understand kind of the biology of it all and help them overcome some of the stigma and shame?

Dr. John Cleek: So the first thing I try to assure patients is that the major driver behind this is multifactorial. It's not just what they eat, it's they eat what they eat because of environmental factors, because of economic factors, cultural factors. And then on top of it, we have all the hormonal dysfunction that is created by not only the weight gain, by what we choose to eat, et cetera, but it's those hormones that really drive the weight gain, and that's what they need to understand.

Host: When a lot of people hear hormones, they're thinking testosterone and estrogen. I think we're talking about some different ones here, right?

Dr. John Cleek: Right. We are talking about the hunger and satiety hormones that are actually made in the walls of the intestine and distributed throughout the body. So these are hormones like ghrelin, which is the only hormone we know of that promotes hunger. And then satiety hormones like the injections GLP1 or glucagon like peptide1, amylin, et cetera that help us feel full and control appetite.

Host: So in a normal state, let's take somebody that's maybe normal weight, there's a balance between these hormones, correct? Between I need to eat and I'm full.

Dr. John Cleek: Correct.

Host: But as we get a little older for various reasons, that balance ain't there. Right? Is that the big story?

Dr. John Cleek: Well, I don't know that the balance isn't there. We tend to overcome it with some of our will, some of the loss of muscle mass as we get older, so our metabolism slows down. We lose taste sensation, so we look for more intense flavors, which means it could be higher fat, higher sugar, higher salt in order to satisfy ourselves.

Host: So I think at this point, it's fair to say most people have heard of the weight loss shots, right? I think that's how it's like marketed, right? These weight loss shots. Can you explain what these shots really are, what GLP1s are really doing in the body?

Dr. John Cleek: So GLP1, these shots are agonists, that is, they stimulate the receptors in the body that normally are sensitive to GLP1. The shots are not actual GLP1 hormone, but they act that way. GLP1 in the brain signals that we are not hungry. It interestingly, also reduces cravings, reduces alcohol intake, binge eating behavior and something that is called food noise, which is the persistent thinking of food. In the stomach itself, it causes a slowing of the stomach's ability to empty. So we eat, the food stays there so we get full more quickly, and because it stays there, we stay full longer. So that's how they work both with hunger and fullness.

Host: When were these first developed?

Dr. John Cleek: Back in the early two thousands, the first one that came out was called exenatide or Byetta back in the early two thousands.

Host: So they've been around a little bit longer than most people think, maybe, right? Because they've really hit the market hard in the last like two years.

Dr. John Cleek: Right. The current generation has been out two to three years. The semaglutide, the tirzepatide that we talk about as injectables now are only two to three years old.

Host: So why are these considered, why is GLP1 shots considered a major breakthrough?

Dr. John Cleek: Because they're the first medication that has shown significant weight reduction and long-term benefit if we stay on the medication, that is, we don't regain weight if we stay on the medicine.

Host: Let me ask you this though. Just because somebody goes on a GLP1 regimen, are they allowed to eat whatever they want to eat? Are they still told to make sure they're eating healthy, exercising, all that stuff?

Dr. John Cleek: Bottom line is you still have to have lifestyle modifications. If you don't do that, we're never going to be successful, especially long term. So lifestyle modifications simply means we have to make sure we're on an appropriate meal plan, generally a little higher in protein than most people are used to.

We have to be staying hydrated, getting our fluids in, and we have to be moving in order to maintain that weight loss. So all of those have to change if we're going to have long-term success.

Host: Is the goal to be on GLP1s forever or if they're following these lifestyle changes, they use the GLP1 to get to that normal weight, they get off them and they maintain with lifestyle. Is that the goal?

Dr. John Cleek: Well, that would ultimately be the goal. Unfortunately, we don't have the data to support that at this time. The data shows that if you stop the medicine and say you reach goal in six months and you stop the medicine at six months, there's a 90% weight regain over the next few months, so we know we have to stay on them longer term.

The question is to answer you, is whether we can taper off the medicine later on a year later, two years later, or whether we can stop it cold turkey later in time, or do we have to stay on it until the next best thing comes along to replace it. And that's something we just don't know at this point.

Host: Is all this being studied right now? Looking at like the length of treatment. Are there clinical trials going on?

Dr. John Cleek: Yeah. There are studies going on trying to look at this.

Host: So this is what's so interesting about medicine and science to me, Dr. Cleek is it's always evolving, right? Like we're learning more and more and we gather more data, as scientists and physicians, like, we never say something absolutely. Because we're still learning more, right?

Dr. John Cleek: That is correct.

Host: Let's talk about side effects. Because I know this is obviously, patients are probably asking you about this. What are the common side effects and what are some of those side effects that aren't so common but that can be pretty tough?

Dr. John Cleek: The most common side effect is nausea. And that's a quarter or more of the patients that will experience nausea at some point. Now the nausea tends to get better after the first couple of days with the shot, and the longer you stay on the medicine, the better the nausea gets. Second most common side effect can be diarrhea.

And third most common side effect, interestingly enough, is constipation. So it all depends on the person as to what the side effects are. Everything else is less than 5%, like fatigue or hair loss. Things like that are much less common. Now, if we look at the serious side effect, there are two that are warned about.

One is you cannot use a GLP1 with a history of a specific thyroid cancer, follicular thyroid cancer and specifically because in mice there was an increased incidence of that particular cancer. It hasn't been shown in humans to date. The data's not there to hold up that risk because it was done in the preclinical trials, that is a warning. The other serious side effect can be pancreatitis, which is just what it sounds like. It's irritation, inflammation of the pancreas with symptoms of severe abdominal pain, nausea, vomiting and that's another reason to stop the medicine.

Host: Is there anybody else who should be careful here when taking GLP1s?

Dr. John Cleek: Well, the only other population that would need to be careful are Type 1 diabetics and it's being, again, looked at in that population, but we don't have really any experience to rely on.

Host: Couple of things that I've seen pop up recently. You got more pill forms of these drugs, and then there's also this idea of microdosing. What are your thoughts about those two?

Dr. John Cleek: Well, first of all, microdosing generally refers to using compounded medications, and that is semaglutide or tirzepatide compounded and trying to play with the dose. That's really what microdosing is. The problem for me is we don't know the source of the medication that's used in the compounding, and there are no quality controls regarding the medication. So we don't know it's purity, contaminants, things like that. So I'm not a user of microdosing or compounded medications.

Host: Okay. What about pill forms, though? That may not be microdosing, right? Or is it?

Dr. John Cleek: No, pill forms have actually not been released from the FDA at this point. It hasn't been approved for use in this country. It will come out sometime next year an oral GLP1, so I don't know where they get a GLP1 pill at this point.

Host: Okay. Now back to the microdosing. Just so the audience understands. That's just using smaller and smaller doses, right? Like to begin with, is there any clinical data showing a benefit, doing it that way?

Dr. John Cleek: No, there's not any clinical data at this point.

Host: Okay. So that's a strategy that does not have a lot of support at this point. I guess we could say.

Dr. John Cleek: No, it does not.

Host: Now here's something interesting, Dr. Cleek, there's a lot of research looking at additional benefits of GLP1s, and something that's just come out recently is maybe even a lower risk of colon cancer. What do you think about all that?

Dr. John Cleek: I don't know if that's directly GLP1 action somehow in the intestine or whether it's a weight loss. Because we know weight is a risk factor for colon cancer, so we don't know which it is at this point, and it's going to be hard to separate the two out because if you're on a GLP1, hopefully you're going to be losing weight. So how do you separate the two? It's going to be difficult.

Host: I guess a lot of the proponents of that are thinking the GLP1s may have some anti-inflammatory effect and maybe there's a link to some colon cancers being very pro-inflammatory, all that kind of stuff. So maybe that's w

Right.

with that,

Dr. John Cleek: That may be, but remember the fat tissue in the belly, especially deep in the belly, is also pro-inflammatory. So as we reduce that, we're still reducing the inflammation. So again, I don't know how we're going to tease that out.

Host: A lot of concerns about the cost and availability of GLP1s. What's the reality for a lot of patients seeking these medications?

Dr. John Cleek: Well, I think the major barrier to access is the cost, without a doubt. There's only about 50 to 60% of insurance companies that include those medicines in their formulary for weight loss. So that leaves 40 to 50% and some big ones like Medicare that don't cover the weight loss at all. So now we're starting to see though, a little business competition as the makers of Wegovy, Novo Nordisk announced a price cut on Monday to $199 a month for the first two months, then $349 for the months after that.

They reduced it $150 a month. If we look at the competitor, Lily and Zepbound, their first month is $349 and subsequent months are $499. So I'm hoping the pressure from one will transmit to the other and continue to bring down prices.

Host: Yeah. And that's what the market does. So there's a good chance that's going to happen.

Dr. John Cleek: Right. And with the release of the oral pill form next year, that's already going to be cheaper than the current injectable prices. So again, hopefully that will help drive down more of the price.

Host: What do you say to a patient who feels this is cheating?

Dr. John Cleek: I say that you still have to do the other work, it goes back. You still have to do the lifestyle things in order to be successful. The people who don't do the lifestyle things are the one we read about who've lost a lot of muscle, for example, because they're just doing what they want to do. And not stay into a long-term plan.

And unfortunately, muscle loss then makes you weak, tired, and slows your metabolism, making it even more difficult to keep the weight off.

Host: You're going to gain that right back at the end of the day.

Dr. John Cleek: Yes. Mm-hmm. As fat.

Host: Yeah.

Dr. John Cleek: Going to have lower muscle.

Host: When you're treating patients on GLP1s, do you suggest other things like maybe besides exercise right? Maybe protein supplementation. Is there anything you do maybe for their uh, gut health, enzymes, probiotics, anything like that?

Dr. John Cleek: The only thing we really focus on is the protein component of the meal plan, and generally it's about a gram of protein per every two pounds of body weight.

Host: Okay.

Dr. John Cleek: Is generally the recommendation.

Host: And most people are probably just fine with that. We love our protein intake right here.

Dr. John Cleek: Yeah. Some people do have to use some protein drinks or protein powder or protein bars, and that's fine in order to get it in.

Host: Dr. Cleek, any last words for the listening audience?

Dr. John Cleek: Oh, I just think they should be hopeful that we have medicine that makes such a significant impact on weight and therefore on people's lives. And I think that's really the take home message.

Host: Fantastic. Yeah. Dr. Cleek, this has been awesome information. Thank you so much for joining me today.

Dr. John Cleek: You are welcome.

Host: For more information, you can visit novanthealth.org. If you enjoyed this podcast, please share it on your social channels and check out the entire library for topics of interest to you. This is Meaningful Medicine. I'm Dr. Mike. Thanks for listening.