Oral or Injectable GLP-1s? What Doctors Say About Bioavailability, Gut Damage, and Results

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Welcome back. In this episode of Cell to Systems, we're going to be talking about oral GLP-1s. And it's really interesting because 19 to 25% of Americans report that they are needle phobic. And now we're seeing 10% of them who are just completely averse to doing a severe, severe phobia to needles. But this opens up a new door, a new pathway for people. And the topic today is what's going to happen in the market as oral GLP-1s start to find their way into that 25% of people, or will people switch off of injectables? What are the ups and downs, the goods, the bad, and the pitfalls? And I think I'd like to open it up right away for the team to talk about it. So, you know, let's start on the pharmacy side. Leonard, Dr. Pastana, give us what you're thinking, please.

Well, you know, I think my thinking now is a little bit different than it would have been maybe five or six years ago, in that I would always assume that an oral capsule would be way better for patients, for patient compliance. You know, five or six years ago, just injecting yourself or just receiving a vial in the mail and injecting yourself was kind of crazy talk. It was only for like the bodybuilders and kind of stuff like that. And then in the last five years, an oral GLP-1 would make all the sense in the world. But I honestly, for my opinion, don't think it makes that big of an impact on compliance just because I've seen over the last few years most of the population is on a GLP-1, or at least it feels like that, and they've gotten really comfortable with that subcutaneous injection.

Now, I do think that it hits an even much broader market because I know that a lot of these companies are trying to hit everybody. You know, they're not happy with just millions of people; they want everybody taking their drug. So I could be convinced that, yes, this is going to open the door up for a lot of people, but in my world, at least in my sphere, people have gotten really comfortable with that subcutaneous injection.

For years, GLP-1s have been like a weight loss conversation, but I am so thankful it's becoming more of a systems biology conversation. Injectable GLP-1s have changed the direction of obesity medicine, insulin resistance, cardiovascular health, and inflammation. But oral GLP-1s may completely change accessibility and patient compliance. I think I do have a few patients that never start the GLP therapy because of injection fear, or the stigma that "oh, I'm cheating because I'm using a GLP-1," and the convenience and lifestyle barriers. So I do think oral medications might remove some of that psychological barrier.

But from a longevity perspective, many providers are beginning to see GLP-1s less as diet drugs, thankfully, and more as metabolic signaling tools, right? I mean, these, as we all know, these medications influence inflammation, insulin signaling, mitochondria, cardiovascular health, and neuroinflammation. In my opinion, that's why it's getting so much attention in our world as far as longevity medicine.

However, my concern with the oral GLP-1s is, if it's easier, cheaper, and more mainstream, we might also start seeing more casual prescribing of it without really addressing the functional biology underneath—the dysfunction that those patients, we all see. If we normalize chronic appetite suppression without rebuilding muscle strength, improving mitochondrial health, and stabilizing the hormones, we're simply just creating a thinner but more metabolically fragile population. And that's the difference for me between weight loss and longevity medicine.

Leonard said something that was really profound to me at Calm that I wrote down, and so I hope I get it right. He said that future winners in this space will not be the providers who are prescribing the most GLP-1s; it'll be the providers who know how to protect muscle, preserve the metabolic rate, optimize recovery and nutritional status, and then transition patients into sustainable health long term. Because muscle is the currency of longevity.

Yeah. And as Frank said last time, that was a big concern around the muscle side of it. And I know some people who are actually taking GLP-1s—one person in particular—and not working out consistently. And I'm like, you can't do that.

But moving on to our doctor in Atlanta, Dr. Christy, you make such a great point. The concern for me also is, if these are as easily accessible as statins, then how are we going to be prescribing them? In the past, if you're a provider seeing 30 patients a day, you have 5 to 7 minutes to see a patient. Now you're talking about, am I able to prescribe it as quickly as I can a statin? The GLP-1s require a little bit of education, and now we're not requiring that.

We're putting these now, because of the accessibility like you were saying, into the hands of people who are not concerned about sarcopenia, people who are not paying attention to the literature around collagen loss and hair loss, and who aren't taking care of the entire person or making sure that the cells aren't dehydrated. While there's so many benefits and it's exciting that the accessibility is greater, when we put things like this into the hands of people who aren't sure what they're doing, then we're asking the consumer to be responsible for their own health. Which on some level is actually a really good idea—to make us all be responsible for our own health—especially since we all have access to things like AI, but you obviously have to be careful with what your sources of information are.

So let's talk about what are the two different options that are available. One is the typical one that is broken down by DPP-4, and then the remainder is broken down by regular beta-oxidation. So we're talking about something that's going through kind of normal pathways. This is when we're talking about using the gut to use a medication that's going to daily change the way that medication is used, absorbed, and affecting things. So if now my system is affected slightly differently, my DPP-4 might work differently and my beta-oxidation might work differently depending on what's happening in the environment. So we have to remember the terrain of the person we're giving this to as well.

The second one that's available is a small molecule. It is not—Leonard, please correct me as this is your area of expertise—but it is not a GLP-1 receptor agonist specifically. It's orforglipron, I think is what it's called, and it works by affecting cyclic AMP. So the breakdown mechanism of that is by NADPH oxidation, and when I hear about NADPH reductase, I get concerned about increasing oxidative stress in the cell already by using one of these mechanisms.

Now, it's wonderful because it doesn't have the restrictions on diet. Orforglipron goes through cytochrome P450, specifically the 3A4 pathway. Now, if you've ever taken any other kind of medications, you realize that 3A4 is one of the pathways that lots of medications go down. So, especially in your longevity clinics, if your clients are taking rapamycin, for example, if they're taking fluconazole for whatever reason, if they're on a statin, if they're on a couple of antibiotics, or if they're on hormones—all of that is going to affect this 3A4 pathway.

3A4 is sort of like the guardian of the liver. And if you're going this NADPH reductase 3A4 pathway, now we're talking about increasing oxidative stress on the cells, and that's not what I'm trying to do for the body with the other options. This is something we all need to consider: that we're affecting the pathway that is helping patients absorb.

That was just a lot of great points there. Isn't it funny that once they went away from a peptide, which has a lot less drug-drug interactions, now we have to deal with all the traditional things that we've always had to think about when it comes to regular small molecules or medications? Looking at, you know, is it a CYP3A4 substrate, is it an inducer, is it going to increase the concentration, is it going to decrease the concentration? Now we have to think about all these other things.

That's one of the reasons why I just kind of fell in love with peptides as a pharmacist. We're constantly having a blinking red screen telling you all the drug interactions before you verify a prescription. So that's kind of like PTSD on that. It was so nice to see that peptides have less of these drug-drug interactions; they're still there, but not as much.

But there is so much more to consider, and I love your point about the monitoring. Typically, in traditional medicine, it is 5 to 7 minutes, like you say, write a prescription and out the door. And it's kind of backwards, I would think, in the thought process within the industry. Patients or doctors in functional medicine or in longevity aren't necessarily standardized like it is in conventional medicine, but I am much more afraid of these GLP-1s in conventional medicine for all the reasons that you stated.

When it came into the longevity and functional medicine space, we were like, okay, what's the impact on visceral fat? What's the impact on muscle? What are we doing about hydration? All the things that you mentioned. And we know that our colleagues—sometimes it's not their fault—are just not doing that in more conventional medicine, where they're walking in the clinic and stepping on that old-school scale, sliding the weight over to the side, and they're not really paying attention to muscle versus fat and other things that we've talked about.

These GLP-1s do take a lot of monitoring. They do take a lot of clinical pearls and a lot of patient education as to the foods to eat and how to titrate the dose. When these sales reps come in with this drug in more conventional medicine, they're going to ask, "Well, what's the dose?" And they're going to say, "The dose is this, and every four weeks you raise it to this, and every four weeks you raise it to this." There is no, "Hey, go double-check on the patient." There's no, "Let's see how they're tolerating it." That's dangerous. And so... Oh, hi Millie. But yeah, you brought up a lot of great points. It's really incredible.

Well, I want to take a step back here from a patient perspective, because you guys started talking about all sorts of things that I think many people, myself included, just simply don't understand. Hey, I'm a patient and now I'm at a point in time where I want to consider a GLP-1. Is there an advantage to—I mean, I look at it and I think to myself, well, there are days when I forget to take a certain supplement, so like Urolithin A, I missed it, forgot that one, somehow someway just didn't get it in today. I wonder if that's going to translate over to the oral GLP-1s. So if you don't have a phobia, it doesn't matter to you, what would be the recommendation just generally? Not giving medical advice to anyone here, but what's your opinion on the best route to go?

Well, it's just a conversation that you have with a patient first of all, to know a little bit more about them. But if they're asking my opinion, I'm going to lean towards the once-a-week injection. It's just that much easier. It's hard to remember to take pills every day. It's just one quick injection and it's over. And we just have a lot more studies when it comes to the injectables. We know the side effect profile; they've been on the market for a long time. Some of these newer ones, we just don't know. And then efficacy is so much better—I want to say so much better, though some of these orals are catching up. They're like at 11% weight loss, 13% weight loss, they're getting close to like 15%, but I'm always going to lean towards that once-a-week subcutaneous injection for those reasons.

That would be where I lead. And I think most—you know, I'm spoiled because most of my patients are used to doing some sort of injection, if not plain old testosterone or something, they're on peptides and that sort of thing. So they almost always are like, "Oh, yeah, one more injection is fine with me." Back when they used to be once a day, the liraglutide back in the day, that was certainly a different conversation. But now that we have the injectables, and most people are used to them, I think I will certainly offer the option of the oral that's available.

One of the things you have to think about is the SNAC. That's the little piece that's attached. Leonard, maybe you can give us a little bit more information, but my experience with using anything that has SNAC with patients that I have who have ulcerative colitis or Crohn's disease, they have a little bit of trouble with the SNAC. So that may be something that you can kind of help fill us in a little bit.

Yeah, the SNAC is something that's supposed to help with peptide delivery to get it to like 1 to 2% maybe. But the thing that we're worried about—and I've dug through all the literature about this because we have so many patients with leaky gut and GI issues—the mechanism is kind of scary when you're thinking about that because it's actually poking holes in the lining of the gut to improve bioavailability. Now, they say this isn't impacting tight junctions, but the last thing I want to do with anybody with any type of GI issues is start poking holes in what we're trying to close up. This is why we're using other peptides like larazotide to improve tight junctions. And so, I am a little bit worried about some of these that contain SNAC because if you look through the literature, there's not that much information on the safety of it outside of like a paper or maybe two.

Well, and the few patients that I've tried the oral on, most of them switch back because they just haven't seen the results with the oral. But the big symptom I get is people will say their stomach is on fire, that it's just burning them. I have one lady that's on it, but her job is international. She flies across the pond like I drive to just a normal flight. And so the oral works for her, but she admits it burns. I think it's interesting just watching her inflammatory numbers; they've actually gone up a little bit compared to when she was on the injectable.

And for me, the bigger picture is like the next evolution of GLP-1s, regardless if it's oral or injectable, truly belongs to the providers that understand muscle strength, recovery, inflammation, hormone balance, and mitochondrial health. I think the big risk with oral GLP-1s is not the medication itself; it's the temptation to oversimplify these complex metabolic diseases that we're seeing.

That is such an incredible point right there. I mean, I think we've been talking about this, right? Sort of this notion, as we've gone through all the episodes, the same thing keeps coming up: the sort of one-size-fits-all, stamp-it-out whatever, instead of really focusing in on the whole person, who they are, and what they really need. Suzanne, you've said this a bunch. Leonard, you've said it a bunch. Chrissy, you've said it a bunch. Frank said it. Craig has said it. The reality is that I think as a consumer, as just a regular Joe out here, and just seeing people every single day talk about this stuff, I just think people are missing it. I don't know, maybe I'm just really lucky to be so close to you guys and in this to know better, but I feel like—and I mean, I'm sure all of your patients probably feel the same way—they're seeing you and they know you, and they've got a better set of information than most people.

But going back to what you said before, Leonard, about the reps coming in and they don't really know, saying like, "Hey, if you can't get to 2.4, then you shouldn't be on it," which is sort of like, "Hey, if you just can't hang with it, then you're just out of the club," right? It's like max out or leave.

And they didn't stop there. I mean, if you look at what they did, they started doing trials at 7.2 milligrams. They went to 2.4, and now they have studies where they're tripling the dose. And that's dangerous. Not to say that some people might not need bigger doses. We saw a great presentation by Dr. Greg Jones on some people that are resistant to GLP-1s who might need higher doses, but that's pretty rare. Big pharma, good or bad, they make life-saving drugs—we can go back and forth—but this is one of those scenarios where, do they have the people's best interest at heart when they're getting things up to like 7.2 milligrams? I don't know, because there's no conversation around the things that you guys are talking about, the other things that we're measuring.

But I want to ask you guys a question about that. What happens when you say 7.2? So let's say for some reason somebody makes a mistake and they double dose on a GLP-1. What happens?

They end up in the emergency room feeling really horrible. And that happened a lot early on when GLP-1s were first getting compounded, and there were a lot of compounding pharmacies with different concentrations. Some had 2 milligrams per mL, some had 5 milligrams per mL. And somebody bouncing from one pharmacy to the next just took the same amount of units and got three times the dose. And so they got very, very sick. They feel pretty bad for a while, and they end up in the emergency room.

And so it's just another reason why there has to be a lot of patient education when it comes to this, and there has to be a lot of thought behind what pharmacy you're using. Even for the physicians, and I've seen this. This is like a pharmacist's worst nightmare. Every time I saw within the pharmacies where it's like, "Okay, we're going to start carrying another concentration or having to switch something because something was on backorder," that keeps a pharmacist up at night. They know that people are just going to be like, "Oh, I take 20 units, I'm going to take 20 units again."

We're always trying to think of what can we put on the screen in big bold letters, what type of stickers can we put on the bottle to say, "Hey, this is a higher dose concentration." Because there's nothing worse than starting a patient on a GLP-1 that could be life-changing for them, having them have a horrible experience, and they never want to take it again.

Hey Christie, how do you counsel your patients on traveling with their peptides or with their GLP-1s?

I mean, I just saw one this morning. I tell them they can either get a little insulin pack, or the other option—and even myself—I get a Yeti cup. I make it through TSA and then I go fill it full of ice. That's what I myself do, and I think a lot of my patients do. And then we always give them another prescription just in case, depending on different countries that want to see a prescription. We always print off actually a handheld prescription that they can show to whatever TSA agent or whatever country they're in. In that case, you literally would take the bottle, put it in something cold or just put it in the bag, get through TSA, put it into a Yeti cup of ice, and then you're off to the flight.

These peptides—and Leonard, please correct me if I'm wrong—but room temperature is okay for a little bit. These peptides are more stable than what we think with the temperature. Am I correct?

Yeah. No, I mean, everybody freaks out about, "Oh, it has to be cold, it has to be cold." I get those texts all the time: "I left it out last night. Is it okay?" Every peptide is a little bit different, but it's okay to be left at room temperature. Now, if it's in a hot car in the summer in Florida, maybe that might be an issue.

Okay. So, guys, I'm curious. What do you think—there's some other stuff. I was talking to another friend of ours over the weekend, and there was some talk about nasal GLP-1s. I was just curious what your thoughts are there.

You know, I can imagine it would be really helpful. One of the original purposes or study purposes of these drugs was for neurodegenerative diseases. So I would imagine if you have access to the cribriform plate—which is kind of debatable, as there's some evidence that over the age of 60, the cribriform plate's not really that penetrable—but if that was accessible, then that would be a really great way to administer it for your patients who have neurodegenerative diseases like ALS, Parkinson's, or Alzheimer's disease. What do you think, Leonard?

I think sometimes compounding pharmacies will get a little creative on different routes of administration because that's kind of their thing before we know anything about it. I haven't seen anything yet on a nasal delivery, but it does make sense and I hope somebody studies it. It would be nice to be able to personalize these routes of administration depending on what we're trying to do with the GLP-1 outside of weight loss.

Chrissy, I love what you said about the fact that the GLP-1s are going—and Suzanne, you just talked about it, Leonard, you just talked about it—but the notion that this is so much bigger than weight loss, you know, there's so much more to it. And I think that's one of the things that's super exciting: the origins of GLP-1s to where we are today. And as you just mentioned, Dr. Suzanne, the notion of someone with a neurodegenerative disease being able to actually get something that would work perhaps better would be sort of exciting, interesting. And the open-mindedness of this group is so cool because from where I'm standing, it's just like you guys are open to whatever works best for the patient.

Yeah. I don't think it's a matter of whether or not GLP-1s work. I think it's a matter of whether or not medicine is mature enough to use them intelligently, right? Have we advanced far enough to be able to address the way the cell uses this, the way that the tissues are going to respond, and the way that the organism is going to be different as a result of it?

Yeah, for sure. Well, today where are we? I think Dr. Suzanne brings up a great point in the way that she described it: is the medical community okay with wanting to answer those questions? You know, how is the cell going to respond? Is that good enough? Because traditionally trained, we wait a lot longer before using that type of information. We're waiting for big trials to be done; we're waiting for guidelines to be updated. Medicine moves at the speed of consensus, but patients just aren't wanting to wait that long anymore. They're just not okay with it.

And this is actually why, as much as we complain about it, they go to these research peptides and they go to influencers for information because they're seeing positive benefits out there. They're looking for physicians that are thinking the way that Dr. Suzanne is talking about—understanding, you know, what is the impact of GLP-1s on the efficiency of the cell or on tissue. They want a doctor that's thinking like that for them and making those decisions when it comes to risk versus reward on what we know and we don't know.

I think that there used to be two worlds. There used to be this world of kind of cellular medicine, longevity, functional medicine, which was like a polar opposite, and then there was traditional conventional medicine where we all came from. But now there's three worlds. We went from being on one polar end to now we're in this weird middle place where now there's like the research peptides and the people that aren't even licensed that are practicing medicine basically. And we're in this weird middle part where we're too conservative for them—and it's weird for us because we've never been conservative—and we're not conservative enough for the traditional medicine folks. And so we're just kind of like in this limbo part in the middle.

But I think this is where patients want to be. They want to be with somebody that has been trained traditionally but is thinking outside the box for them to help them make decisions. That's the state where I see us in. It's kind of this limbo area.

And for me, there are still concerns surrounding the long-term dependency on these GLP-1s. I mean, you talk to a patient and you're like, "Okay, let's try to start transitioning," and they lose their stuff on you because they're like, "How dare you try to stop this?" How I describe it is just like, you don't need to be in this underfed state for a long period of time, which can contribute to lean muscle loss, the emotional reliance on chronic appetite suppression, and bypassing lifestyle medicine completely. To Leonard's point, I never really thought about it, but there are kind of these three worlds, and that was a great way to break it down. In my opinion, the danger is when providers view these GLP-1s as the entire protocol instead of one tool inside a much larger metabolic strategy. I actually love young providers getting into this area, and I tell them the courses and what organizations to join, but it's not just this one-size-fits-all GLP-1 entire protocol.

All right, I'm a new patient, or I'm a person who's just heard about GLP-1s. I'm interested. What should I be looking for in a provider?

As a patient, I would say that there are several bodies that give us education. I think the original one was probably the American College of Advancement in Medicine, where they were talking about chelation—so this was kind of way back in the day—but now there's several. I think they have really good fundamentals for learning cellular medicine, and I think that it needs to be a daily practice of reading articles. I used to think it was really important that we had a certification from one of these organizations, but more and more as they become more popular, I get concerned that it's also not for the benefit of the patient. So I think more important than that, while I think it was important back in the day, what's more important now is how much are you doing on a day-to-day basis to continue to keep up with the research?

What is your exposure to the most recent data on how the drug is processed in the body, how the peptide is used, and what is its mechanism of action? Are those things that you're looking at? How will this interfere with my hormones that I'm taking also, or with my program that I'm following for MCAS or Lyme disease remission?

Yeah. I mean, I think that's a really interesting point. The other side of it, too—and now this is the agency side of me coming out, right?—stands on the other side communicating that kind of information for doctors to patients. And the question is, can they actually even find that information from most providers out there? Is there some place where we're eventually going to have a list of providers who really meet the criteria? Sure, you could go to that organization, and you could go to a couple of others, but I think there's going to be some sort of competition for that directory in the future where people meet a certain standard—those who are going to address me holistically rather than just going online to some organization out there that just wants to, again, treat you with a one-size-fits-all approach, hit you with one thing, and not give you the full spectrum. I wonder how that happens for them. That's an interesting question.

Most of the organizations—like A4M, IFM, SSRP, and even Cellular Medicine Association—do have these provider lists. So if you are a patient and you're looking for at least a provider who's been affiliated in some way, that's probably where you can go. The fact that they're on that list doesn't necessarily mean anything specific about them.

If you're a provider and you're trying to figure out what's my next educational step, I think there's a lot of ways to go, and I think some direct mentoring is helpful. I think there's a lot of really great courses that are available online. Some stuff, like Paul Anderson's stuff, is amazing. I love the webinars that are on Cellular Medicine Association; I think that's great. I think Lexi U's whole program is awesome. I mean, there's so many great programs out there that are available, but I think it is really right now kind of piecemeal and requires you to listen to your patient. What does my patient need? And now I'm going after that education.

Okay, now I'm listening to my patient; what do we need? Like, our whole team is going to Krishna Donaparthi here in town who does a lipid exchange, so we're all going to learn this. How do we use phosphatidylcholine and the other products that are available in that same vein, and how do we best optimize patients' cellular membranes? I just feel like that's the next thing for us, but the way we're doing it is by going to a course and making that a priority.

With that in mind then, let's just go right to Cellular Medicine Association and the lists that are created. Those are people that are attending the conference which happens in February in Florida, and those are providers that are coming to that, having had the opportunity to be invited to be there as a guest just to see it. So impressed with that. But there's a list that you have, Dr. Pastana, right, of providers that patients could source in their area? Correct.

Yeah. Well, we're very hands-on. We don't have like a directory where you're clicking buttons, but you can contact anybody at any time and say, "Hey, I'm in this area, this zip code," and they can look up all the doctors that are members for Cellular Medicine Association in that area. Then we might be able to give personal recommendations because we're very hands-on with all our physicians. We're on one-on-one calls with them, we're going over case studies with them, they've been through the certification courses, and we're hanging out with them at events. We know what they can do and what they specialize in. And so, it's just a kind of conversation. Anybody can reach out at any time and talk about if it's easy to find someone that's perfect for them in their area. But yeah, we'll have a database of where all the physicians that have been through the education are at.

That's great. I mean, I think it's so important for patients to find the right providers. As you said, there are these three different types; you guys are sort of somewhere in the middle, and ultimately those are the patients that want to find you, in my opinion. But that's just my opinion. I reserve the right to be wrong, but I feel like that's the right way to go based on my experience. So, hey, it's time to wrap up as usual. Let's go around and let's give that last burning desire on this particular topic.

Well, the last thing I'll say is that everything that we talk about is typically personalized. These oral GLP-1s, there's a place for them. But the one thing that we didn't mention is the fact that they might be more affordable. And I'm all for it being that kind of gateway into better metabolic health for someone that maybe wasn't engaged in this world, especially if it's something that they can save money on. I know there's a lot of coupons for like $150 a month. Maybe it's affordable to some people that wouldn't have it any other way.

Also, there are so many other things that we want to help people with, and it can get expensive. And so if this gives them a little bit of relief where that GLP-1 is not very expensive or it's covered by insurance, I'm all for it because I think that's where it's going to go. It's going to be a commodity; they're going to be covered. It's going to be a lot less expensive, but like Chrissy is saying, it's not about the GLP-1. It's everything else that we can do. And if we can make that GLP-1 less expensive and accessible, it just opens up the door for the other things that we can do to help people out.

I fully believe that medicine in the United States today is moving at such a fast pace because we have no choice, and that we are going to elevate all the others around us. We're going to begin to see physicians look at different ways of practicing medicine so they can actually give really good care, where we all are taking the best care of the patient possible.

Yesterday, an orthopedic surgeon in my area came in—and I've seen a handful of his patients—and he stopped by and said, "Can we schedule a meeting?" He says, "Why are the patients that are seeing you recovering faster with ACLs?" He does some shoulder replacements too, and I love it when specialists come and ask questions, especially, you know, a cardiologist. When they refer patients to me, to me that's the biggest honor you can have—that we're not this Wild Wild West, and we're not considered the crazy people anymore.

Really, really good. Okay. Well, it's time to wrap up. Another great episode of Cell to Systems. Thank you all, team, so much. It was phenomenal to see all of you and get this information out. For those of you watching, please remember to like, share, and subscribe. We really appreciate your comments when you leave them; it gives us direction on where we want to go next or where you'd like us to go next. And we'll see you on the next episode.