Kendal Williams (Host 1): Welcome, everyone, to the Penn Primary Care Podcast. I'm your host, Dr. Kendal Williams, and I will soon have a co-host. We have recruited a co-host, the wonderful Dr. Amanda Swain, who will be joining the podcast, will co-host with me, but will also be hosting her own podcast on the Penn Primary Care Podcast. Should we call it a network now? And she's also going to be hosting a very specific thing, and that is what we're calling the PCP Roundtable. Instead of bringing in subspecialty experts to talk about their field, there's tremendous value in primary care docs getting together—and providers generally—getting together and talking about their practical experience and their own insights. I learn an enormous amount from my own colleagues in our various staff and faculty meetings. And so, we wanted to kind of bring that to the podcast.

This is our first PCP Roundtable. But more importantly, this is the first time you will hear the voice of Dr. Amanda Swain. So, Dr. Swain is an Assistant professor of Clinical Family Medicine and Community Health at Penn, in Penn Family Care. She is the Faculty Director for the Undergraduate Medical Humanities Curriculum at Penn, and she brings a lot of humanities background, but also is a family medicine-trained physician. She still sees kids, and she does gynecology and a lot of these other things that young adults and others that I, as an internist, don't see as often. So, I'm hoping it'll also broaden our topics. Amanda, thank you for agreeing to do this.

Amanda Swain, MD (Host 2): Thank you so much for giving me this opportunity, Kendal. I'm really excited.

Host 1: Amanda, tell us about yourself

Host 2: I've been practicing family medicine for just over 20 years now. I am from New York. I moved to Philly for my family medicine residency, and I never left. And as you mentioned, I've spent a lot of time working in adolescent medicine, but now I am based at Penn Family Care. So, I see all ages, what we call full-spectrum primary care, though I do not do obstetrics.

I also have a role at the medical school here at Penn, where I help organize medical humanities teaching, and that's where we use aspects of the arts to teach clinical skills like close observation, listening, communication, and empathy, among many other things. And then, I also write. So, you may occasionally see my opinion pieces in the Philadelphia Inquirer or essays in magazines.

Host 1: That's fantastic. I know you've been listening to the Penn Primary Care podcast for a while and found it helpful. And you're going to bring a lot to this project and in terms of your own background, but also just topics that we can address that are beyond sort of my area as an adult internal medicine doc, so...

Host 2: Yeah, I'm really excited. Thank you so much again.

Host 1: Co-host a few, and then Dr. Swain will also do her own program, and we'll be able to turn out more primary care podcasts, and go through the summer, something I haven't been able to do.

So as I mentioned, this is our first PCP Roundtable. We're going to talk about the thing that all of us, I think, talk about with our patients every day, and that's GLPs. And we face a lot of very practical questions as we both prescribe patients initially on them, but also help them navigate their weight loss journey and eventually try to get off of them. We thought this would be a great place to start for a PCP roundtable.

And in order to do that, we actually brought on an expert primary care doctor—two experts. Patrick Puliti has a specialty training and certification in obesity medicine. He is an internist by training. He practices primarily in New Jersey, doing some resident teaching out there, as well as his own practice. Patrick, thank you for coming on.

Patrick Puliti, MD: Thank you for having me. I'm excited to talk about this.

Host 1: Patrick is part of the Penn Primary Care community. And with us also is Nick Grillo. Nick is a PharmD. He is based at Penn Presbyterian and is the ambulatory clinical pharmacist for both weight management and addiction, and serving multiple practices, which is a big job. And Nick, you're behind the scenes doing a lot of work on helping people navigate the GLP universe. So, I know you have a lot of practical insights into that world. Thanks for coming.

Nicholas Grillo, PhD: Yeah, for sure. Thank you for having me.

Host 1: Let's just start talking about GLPs. we've all been using these now for several years, and we've watched the newer drugs come on the market, and I kind of wanted to go back through each of them out there.

And we'll just start with semaglutide, but we'll also talk about tirzepatide and the newest agent, Foundayo, as well. And I just want to talk practically about the use of it. So, let's talk about semaglutide, which of course initially came out as Ozempic, was then reapproved at the FDA as Wegovy, initially as a once-weekly formulation and then, more recently, as a PO formulation.

Let's talk about weekly subcutaneous injection, Patrick, with Wegovy itself. What is your experience with the drug? How are finding it useful in your practice?

Patrick Puliti, MD: This is something that I've been prescribing for quite some time. I mean, technically even going back to residency, I was prescribing Saxenda, which was the weight loss version of liraglutide, which has largely kind of been forgotten as of late. To be perfectly honest and pretty open with patients if they're interested in getting on it, with weight loss, I always try to be very caring and understanding that it's a heavy topic. A lot of patients are wary about coming into the doctor's office and talking about it. But as of late, probably because of marketing, a lot of patients have actually come in asking about it. And basically, I take that as an opportunity to have a larger conversation about weight loss, but I try to be very encouraging of it because I think there was a time when a lot of people were skeptical of it.

But at this point, having prescribed it hundreds of times, at least in the GLP-1 class, I feel very comfortable walking patients through the process. And it does end up being a pretty decently lengthed conversation. It does take about 20 minutes to really go through the full gambit, which I'm sure we'll touch on a lot of those topics today.

Host 1: I have this little thing that I do. And I guess we all have our speeches. I explain that these drugs came out of the diabetes universe of medications, that the actual class of medications is over 20 years old. So, we do have a fair amount of experience with these, and we know their risks, which are primarily gastrointestinal, but also their benefits. And I also reassure people that most of what we're seeing in terms of side effects are side benefits. Patrick, are you feeling as positive as I am about them?

Patrick Puliti, MD: I would say absolutely. As most of larger concerns that I think have come out about them from patients in terms of their side effect profile are things that, like you said, are gastrointestinal side effects. And I generally will walk patients through the fact that I take things relatively slowly.

I think there is a titration regimen that was FDA-approved. Generally, it's once monthly. I generally tell patients we go a lot slower and, as a result, I find that they tolerate them very well. And I'm very open with patients, like, "Look, if something is wrong, reach out to me." That's the benefit of the portal, and oftentimes we can troubleshoot them. And as a result, I even encourage patients—I rarely actually discontinue patients because of side effects as a result because they tolerate it when it's a much slower approach

Host 1: You mentioned something that's important. And as you note that when these came out, there was a titration schedule that you were supposed to increase. We even have an sort of an automated version of that at Penn where the pharmacist will do that for you. I found two things. One, I kind of wanted to manage it manually, both to manage side effects, but also I wanted to kind of exploit all the weight loss I could get out of a particular dose before going up. So, I would tell patients, "Okay, start at 0.25, go up to 0.5." If you're losing weight, I'll see you back in whatever, you know, a couple of months. But if you're not losing weight, let me know." And I'm curious to hear your insights on that, Patrick, but also then Amanda and Nick's input.

Patrick Puliti, MD: I agree. I think utilizing getting every ounce of benefit from each individual dose, because I think each dose increase winds up being a little boost for the patient. But I also find that I do a lot of nutrition counseling, which I'm sure we'll circle back to, and I use each dose as an opportunity to kind of make sure that we're hitting those nutrition goals. Because one of the things that I worry about is if we go too rapidly, we may be missing opportunities to make adjustments. And I find when I take that slower approach and I kind of weave in the nutrition counseling, it tends to result in a greater change for the patient that ricochets through more than just weight loss itself.

Nicholas Grillo, PhD: That is such an important point with those monthly touch points to check in to see how diet and exercise and behavioral modifications are going on that new dose. It's always important for patients to kind of conceptualize what is their purpose for losing weight, right? Is it just beyond dropping a few pounds, or is it something greater? Is it something to feel better, to live healthier? And each of those monthly touch points, I think, can serve as a great checkpoint for both providers and patients to kind of do a self-assessment. How did the last month go in terms of your weight loss journey? And what are some areas that we can tweak a little bit, which can prevent against side effects while also promoting more weight loss on higher doses or continuing the same dose if you're already seeing positive weight loss results.

Host 2: Yeah. I mean, the only other thing I have to contribute, I would say, is that I hope we talk a little bit more about this. But I think certainly in an older, more medically complex population, I also do get a little bit worried, are people hydrating adequately? Are they eating enough? Because sometimes the medication kicks in and it works so well that I've had patients that come in with an acute kidney injury. And then, we have to address that. So, I don't like to just kind of automatically increase because I think, for a lot of people, who've been struggling with weight for so long, the idea is "The more weight I lose and the faster I lose it, the better." And that's, as far as I'm aware, not necessarily the approach we'd want to take with weight loss at all, but certainly not with these medications.

Host 1: I remember when we had colleagues from the obesity center on and said that healthy weight loss is one to two pounds per week. So, you're talking five to 10 a month. And so, if anybody's greater than that, you do have to have some concern. Patrick, is there a specific nutritional counseling program you do? Do you send your patients to dieticians?

Patrick Puliti, MD: I actually do pretty much all of the counseling myself. This has been a topic that's been near and dear to me because I myself have had a weight loss journey. I have a printout that I provide each and every patient whenever we talk about these medications.

I generally follow a guideline of high protein, high fiber, adequate hydration, primarily because those three points could be adapted to any singular diet style that someone wants to adhere to, whether it's gluten-free, whether it's Mediterranean, whether it's different cultural types of eating. I try to make sure it's adaptable because the more restrictions I put, the harder it is for change. And I really focus on those big three because I think those three things have the largest impact on sort of health outcomes in terms of nutrition counseling.

Host 1: Protein, fiber, hydration. When you do protein, do you kind of do this number in your head, 0.8 times kilogram weight, and kind of get an estimate of what they should be getting and talk to them about how to achieve that number?

Patrick Puliti, MD: Generally, I focus closer to one gram per kilogram because that's generally what most data suggests is enough to sustain muscle mass. And I use that word pretty particularly because—and hopefully we get into a muscle training program—generally one to 1.8 grams per kilogram is where you start to see muscle growth. Above 1.8 grams per kilogram, you don't have as much benefit.

So, I generally tend to start with one gram. Sometimes it'll even just be as simple as 80 to 100 just because it's a little bit of an easier number for a lot of people, and it captures a wide group of people. And then, I can kind of tweak it from there as we move forward because some people see like, I calculated that for myself, it'd be like 150, which could be a lot for someone who doesn't even know what that looks like.

Host 1: I'm not sure I know what that looks like. I've struggled with this. I try to eat a vegetarian diet and just to get enough protein is challenging. So, you're talking about, I assume, for me, lentils are a staple because you're talking about 20 grams of protein per cup or something like that, and also 25 grams of fiber, which really helps with the constipation of being on these medications. So, I actually tell people about lentils. I say, "You know, you really should think about that as being a universally helpful thing." But then, I guess there's the Greek yogurts. Do you recommend protein powder drinks, that kind of thing?

Patrick Puliti, MD: Generally, the way that I start off and on my sheet, I recommend people track their food intake. And I do encourage food tracking apps. And I even tell them, "Look, there's lots of numbers on here. I really just want this to be a diary. I'm going to use these numbers more than you may." Because I'll even hold their phone and scroll with them and look at the days during the conversation, or I'll ask them to pull up the information.

So generally, I have people doing the tracking so that they can learn to kind of follow this stuff. But to go back to your previous question, if they can't hit that protein goal, I'll bring in protein powders, but I don't bring them in right away, because I do like people to try to integrate their own style of eating first so that we don't rely too heavily on supplements.

Host 2: I have a question for both Patrick and Nick actually about the starting of the GLP-1s and how you counsel folks about starting to eat differently and in terms of how fast or slow they're eating and how to manage those early side effects if they have them. Though in my experience, it seems like more people than not have some early side effects. But I'd be curious for your thoughts on the initiation of medications and how we do some initial counseling.

Nicholas Grillo, PhD: For initial counseling, so we know that the GLP-1 medications are going to slow down digestion. So, you're going to start to feel fuller longer. You're not going to want to eat more. So, the risk is that you're missing out on adequate nutrition as a result. So as it relates to diet, like Patrick was saying, encouraging protein, fiber foods that are going to make you feel fuller longer so that if you're not eating a lot throughout the day, what you are eating is providing that adequate nutrition.

And so, like we were saying can be tailored to any sort of diet regimen and whatever personal preference patients may have. And one of the things that we've seen too when initiating GLP-1s is that certain foods can cause some GI distress and some nausea. So, foods that are greasy, fried, fatty, spicy, overly processed foods are almost guaranteed to cause some side effects at some point throughout a patient's GLP-1 journey.

And so, by minimizing those foods as much as possible, again, not saying that if you can't have an ice cream cone as long as you're on a GLP-1 medication, but to recognize that certain foods may predispose you to having some gastrointestinal distress and kind of replacing those foods with foods that are going to provide a little bit more nutrition.

Patrick Puliti, MD: One big thing that I like to do is I try to explain the mechanism. Because I think if patients understand in broad sense how the medication works, they can oftentimes infer the side effects. So, I say, "Look, think of your stomach as a plumbing system. If I slow down your plumbing system, two things are going to happen. Stuff is going to back up. And so, you may get acid reflux, you may get nauseous." And I even say some people when they start it, they may vomit. Generally, I often warn patients that that can happen. Although in my experience, most of the time, it's because they misestimated how much. And so, that's why I always start them, "Have your plate first, and I'd rather you go back for seconds."

And then, on the other end of the piping system, constipation is not uncommon, and I often warn them, "You may find things are slower, but as long as you're not straining, I'm not generally too worried. It's when you start having to strain that that's a problem." And we should figure out a solution, and we workshop those side effects.

But I find that using the plumbing system tends to very visualize it for a lot of patients. Because oftentimes, they guess the side effects before I even bring it up. Now, that may also be because they heard about it on TV or in media. But I find that that's a very quick metaphor to get through the larger chunk of side effects.

Host 1: So, I'm curious how you deal with the constipation aspect. As I said, I encourage lentils and kiwi and prunes if people need them, although I think you need to eat six or eight prunes a day order to have some anti-constipation effect. Patrick, where do you go from there? I mean, patients just based on those dietary aspects alone, the high fiber, the protein, are still constipated, what do you do next?

Patrick Puliti, MD: So, I think severity is going to be the big answer or big kind of like fork in the road there. If the symptoms are very severe I'm starting to become worried that they're having like severe abdominal pain and cramping and they're not passing a bowel movement in a few days, first of all, I'm going to pause the medication and consider something stronger, oftentimes a combination of MiraLAX and osmotic laxative.

In terms of like more mild side effects, Metamucil or psyllium is my go-to. It's filling. Psyllium does have a little bit of cholesterol-lowering benefits, so another benefit. We all need more fiber. And it's very tolerated. So, I find Metamucil or any kind of like psyllium husk derivative is my go-to for more like mild to moderate constipation.

Host 2: I'm curious if you want to address any differences that you've seen, if there are any differences that you've seen in terms of the folks that are doing the weekly injectable GLP-1, versus the oral formulations

Patrick Puliti, MD: Because of how recent the oral formulations have largely come out, most of my experience actually comes from the diabetes version of semaglutide, Rybelsus. I find that the side effects have been fairly similar. I unfortunately have not had an opportunity to prescribe the newest one, Foundayo because it just came out. I haven't seen a massive difference between side effects. Some people who have a very strong early week side effect and a much lesser later week side effect, that's the couple of folks who I've seen the daily dosing actually works better. But for those who where it's, like, pretty consistent throughout the week, I haven't noticed much of a difference.

Nicholas Grillo, PhD: From what I've seen just with the oral Wegovy formulation, it tends to be that patients can tolerate the low doses fairly well without reporting any significant issues. But at the same time, a lot of patients report that they're not noticing a lot of weight loss. So, the patients that have tried the injection and the pill note a much stronger appetite control with the injection early on compared to the pill. Just balancing both aspects of it is important to kind of tailoring your GLP-1 selection for your patient.

Host 1: So when you start the pill, let's talk about the Wegovy pill specifically, and I want to circle back to Foundayo a little bit later. The weight loss was less. I think, with Wegovy injectables, we're looking at a 20% weight loss in 50 weeks. I think that was the data, whereas it's more in the 15% range on the Wegovy pill. Most patients, that are new to these medications, many of them at least, like the idea of taking a pill. But actually, those who have taken the injections seem to prefer that, because they don't have to take a pill every day. They just have to remember it once a week. I'm just curious if there's any other insights any of you have on the injections versus the pill and managing those, or what expectations folks could have in terms of weight loss

Patrick Puliti, MD: In my experience, the choice of using an oral pill has largely been more financial than anything else. If you were to talk to me two, three years ago, I think the conversation would have been radically different, I think because there's been a bigger shift towards talking about the injectable medications. A lot of people have actually been like, "No, I'd rather have the injection," which i If I talked to patients three years ago, most of them were asking, "Can you not prescribe a pill?" And the answer at the time was no. Because there is a cost saving with oral Wegovy over injectable Wegovy, albeit not large, generally, I always go with the injection, and my patients also want that as well, just because it's less timing-dependent. And most of my patients come back and say, "Can you make my blood pressure pill an injection?"

Host 2: If only.

Host 1: Actually, I don't know that's too far off. I think I saw some data on that recently.

Patrick Puliti, MD: The weight loss itself is a blood pressure agent in and of itself.

Host 2: Good point.

Host 1: That's very much true. that's one of the dramatic things that I've seen with the weight loss drugs, and it makes me wonder sometimes if it have independent effects on blood pressure. I know there's been some consideration of that because it almost seems like blood pressure drops before they've lost a lot of weight. I don't know. Nick, have you seen anything come out about that?

Nicholas Grillo, PhD: Yeah, I have not heard that as a causing hypotension, in an otherwise non-hypo or hypertensive patient. But what we're seeing is as a result of weight loss, we're seeing all those secondary benefits: dropping of systolic blood pressure, lowering of cholesterol, decreasing waist circumference, and all the other independent risk factors that are so common in many of our chronic diseases.

And so we're getting these added benefits from the GLP-1s that are—it's why they're so popular, right? Why so many people are asking for them to see those added benefits as a secondary result of weight loss. So no, as it relates to causing hypotension, but yes, in terms of beneficially dropping blood pressure.

Host 2: It makes sense, right? I mean, we probably will see less osteoarthritis and weight-bearing joints, and you can imagine that there will be trickle-down effects, I hope. the one thing I just wanted to say in reference to the oral medication, just in case the audience isn't aware, but one, I think, tripping point potentially for folks is the fact that you have to take the oral semaglutide on an empty stomach and then wait at least thirty minutes until you eat.

And so, that I think maybe makes it a little tricky just because sometimes that's really tough for people because of their schedule or other medications that they may take. But I do have some patients that are really appreciative of it coming in a pill form that the cost is a huge issue.

And obviously, we're not talking about insurance issues this episode because that would be its own episode. But the one thing I'll say about cost is that for the folks that are going outside of insurance and buying it from manufacturer, the cost of the oral medication does seem to be working quite well.

Host 1: Before we leave that point on, the dosing and timing of the medication, Nick, I wanted to ask you something. And this is interaction with other medications if you are taking Wegovy. So, I had a patient message me today. She's on a thyroid medication. She started on PO Wegovy. Now, she's feeling palpitations. She's wondering if maybe her thyroid medication is being absorbed differently now that she's on it, which is possible. So, I'm just wondering, how much should we know about that kind of interaction?

Nicholas Grillo, PhD: No, it's really important and not a lot of real world information on that potential interaction. Because the Wegovy is going to slow down digestion, it may make it more difficult for other medications to be absorbed. The extent and the rate at which it does that is unknown and it's pretty much impossible to tell for every patient how much of their other medications are getting absorbed and having an effect.

And so, that's why the recommendation for oral Wegovy is to take it at least 30 minutes before any other medications, completely empty stomach, and let the Wegovy kind of get absorbed and your body start to metabolize that before you introduce any other medications that you would normally take.

Host 2: Which for some folks is going to be really challenging

Host 1: And there are other medications that you're supposed to wait before eating as well, right? Like, I think even thyroid medication.

Nicholas Grillo, PhD: Yes. Even for thyroid medications, right? We want to take that—again administration is very similar, right? In the morning, you don't want to combine any other medications or anything else with that administration too. You have two medications that you're supposed to be taking at the same time. Which one goes first? We don't really have that information. Best thing you do is look at lab values, right, with the thyroid medications and see if we're still on the right track.

Host 1: We don't know it much about that yet. Patrick, you were going to say something?

Patrick Puliti, MD: And that's exactly what I—It's funny, I had this conversation with one of my endocrinologists who works at my clinic, or at the office that I work at. And generally, we both kind of were just going back and forth. And I think we both agreed that dose the Wegovy first, then dose the thyroid the 30 minutes after, and then we're just relatively quick in terms of checking the TSH to make sure that, if we have to make adjustments, we make adjustments and just make sure it's always going to be the same way so that if we're adjusting for it, it's always going to be under the same circumstances.

Host 1: Just to finish off on Wegovy, it does have specific cardiac indications, based on a trial in the New England Journal of Medicine, that showed a benefit to cardiac reduction. So, we're sometimes able to get it approved for that. But primarily, it's a weight loss drug. I don't know of any other specific indications for approval at this time. Nick, you could correct me on that, for Wegovy specifically.

For Zepbound, so that's tirzepatide, right? Mounjaro for diabetes, Zepbound for weight loss. Those two drugs, as we know, are exactly the same, right? Just the label, I believe, is changed on it, but they're dosed exactly the same in the same manner. Zepbound is the—you know, I tell patients this. I tell them, you know, the truth be told, if you look at sort of the overall picture, Zepbound's a better drug. I mean, it's more potent, and it does seem like some of the side effects, the gastrointestinal side effects are less with the tirzepatide products than with the semaglutide products. Is that fair?

Patrick Puliti, MD: A hundred percent. I did want to just go back to the Wegovy indication. Metabolic-associated steatotic liver disease, or MASLD, previously known as NAFLD, is an indication for it, and I've gotten that approved a couple times so far.

Host 1: Just Wegovy or is Zepbound as well?

Patrick Puliti, MD: Just Wegovy

Host 1: Amanda, do you have a favorite GLP? Is it Zepbound?

Host 2: I couldn't even possibly have a favorite if I wanted to because of the insurance shenanigans. So, I really am completely beholden to what insurance covers what medication. And only recently have I started to be in a situation where a patient has—I don't know if we would use the term—failed semaglutide, let's say, and we are then trying to get tirzepatide or dulaglutide or another one approved to see if that will actually have a better effect.

Patrick Puliti, MD: Generally, when I talk to patients, I say I very much appreciate the whole GLP-1 class of medications. However, if I'm going to start somewhere, I'm going to order Zepbound. Statistically, I believe actually the side effects are relatively similar. But anecdotally, I see a lot less side effects with the Zepbound. Because it's better tolerated, in my experience, more effective. I tell patients, "I'm going to start here. But if your insurance comes back and says, 'Look, we will cover Wegovy,'" I tell them, "That's still a win, and I want you to celebrate that." But I have to start somewhere because I can't start a prior auth without something. So, I always start with the Zepbound and then I kind of go from there.

Host 1: I do the same thing.

Nicholas Grillo, PhD: Yeah, I think what we've been seeing too when patients, to Amanda's point, who've kind of got all the benefit you could out of a semaglutide product, we are able to switch over to a tirzepatide product. Then, at a middle-of-the-road dose, you don't even have to start all the way at the lowest dose and see additional benefits starting at a middle dosing of Zepbound. We usually switch from Wegovy 2.4 to Zepbound 7.5 or Zepbound 10 milligrams, see additional weight loss benefits from there. And so, I think what we've seen in both real-world practice and in clinical trials, that the Zepbound causes less side effects in the general population and is associated with more weight loss over a long period of time, compared to Wegovy

Host 2: I'm so glad you brought that point up about the interruption or lack thereof in dosage. I'll follow that up with a question. What is your recommendation for patients in terms of how long they can go without needing to decrease and kind of restart the process of titrating?

Nicholas Grillo, PhD: Yeah, really good question. And one of our ambulatory care pharmacy residents was working on a research project on this, looking at patients that we made dose adjustments for after they've missed two or more doses. And on average, our group of patients missed about three doses, and the most common dose reduction was by one step decreased. About ninety-five percent of those people tolerated that adjustment perfectly fine. Our touchpoint that we tell patients is if you miss two doses, to reach out to either the pharmacist or your doctor, and we can have a discussion as to whether we should decrease the dose or not.

For someone who has never had any side effects whatsoever on a GLP-1 and just had some insurance issues causing a lapse for two weeks, we can usually continue the same dose and not introduce any new significant bothersome side effects. Longer than that, if we're looking at three or four doses, I usually err on the side of caution recommending a lower dose, one step decrease even if there was no other issues previously.

Outside of that, we're really unsure a little bit as to how many steps to decrease for every single patient. We don't necessarily have an algorithm to which one, what is the best dose to decrease to, but we can consider side effects and, of course, how long they were off the dose.

Host 2: Thank you

Host 1: Nick, I just wanted to highlight something you said. And that is if somebody maxes out on Wegovy, has stopped losing weight, that you potentially could switch them to Zepbound and get additional weight loss, right? Did I hear you there?

Nicholas Grillo, PhD: Yes. Absolutely. The higher doses of Zepbound are associated with higher rates of weight loss, and patients can usually tell fairly quickly after switching over to the new medication. And one of the reasons we don't have to start all the way at the starting dose of Zepbound is because it is a little bit better tolerated.

And so, patients have had a GLP-1 medication in their system already, kind of know what to expect with the class of medications as a whole. And of course, tolerability for individual medications differs from patient to patient. But in the general population, we've been able to switch over to 7.5 or 10 of Zepbound and continue on the weight loss progress.

Host 1: Patrick, this brings up a question that comes up, and that is patients are at the top dose of whatever. It sounds like if they're at the top dose of Wegovy, they could potentially be switched over to a Zepbound to get more out of the medication. But what happens if they're at the top dose of Zepbound and they're sort of stabilized? Where do you go from there?

Patrick Puliti, MD: Yeah. I do want to just very quickly point out that I have not had a great chance to order it yet, but there is technically Wegovy HD, which is a 7.2 milligram dosage. I don't have experience with that one, but that is technically an option that is in the toolkit, although I don't know many people who have prescribed it yet, nor do I even know much about coverage. I'm curious, Nick, have you seen any authorizations for the Wegovy HD come through in titration?

Nicholas Grillo, PhD: I have seen a few of them. I have not been able to track how patients are doing on that dose. The clinical trial showed greater weight loss compared to the 2.4 milligram. But I will point out a side effect that was seen in the trials that is a little bit alarming. About 20% of patients had this dysesthesia, so like tingling, burning, itching, or pain on their skin as a result of the injection.

And presumably, the reason is it's a higher concentration going subcutaneously causing that irritation to the skin compared to the 2.4 milligram of Wegovy. And that is the one thing I am little cautioning patients about, is that we don't know if it could happen to you, but this is what was seen in much larger rates compared to the former high dose of Wegovy.

Patrick Puliti, MD: To circle back to the prior question, so when patients are maxed out on whatever agent and we have nowhere to go up, generally, that's my opportunity to really move back to a lot of the nutrition and the activity counseling and see if there's anything that we can do to optimize what they're doing.

I oftentimes will talk with patients and say, "Look, the medication makes you fuller, so let's optimize that." And so, we go back to the fiber conversation. We go back to higher volume meals that fill the stomach up more to capitalize on the fact that that GLP-1 is still in fact working in the background.

It can be frustrating, and there are situations where it does become very difficult to help to the patients lose more weight. And if I'm continuing to have struggles, depending on where the patient is, that's when we consider what other tools are in our toolkit. For patients with a severely elevated BMI, we may talk about at least having them meet with a bariatric surgeon, at least to have that conversation.

Host 1: One of the things that I've learned to do is to sit down and pull out the basal metabolic rate calculator, which I actually find quite helpful because it really helps benchmark folks. You know, I say, at the end of the day, this is all going to be about calories in and calories out. And let's just find out roughly what are the amount of calories that your body needs in order to sustain your weight were you to do nothing all day, and let's go from that point.

It helps with people that have a lower BMI to begin with and are saying, "I can't lose weight," and their BMI may be 26, and I say, "Well, let's actually look at how many calories you have to stay below in order to lose weight." And it ends up being they can only eat, like, 1,000 calories a day. And I say, "Well, that's why you're not losing weight, because it's very hard to eat that few calories." And so, I find that exercise to be quite helpful, and I think patients seem to appreciate it.

Patrick Puliti, MD: And that goes back to the logging and why I oftentimes tell patients in the beginning, "Don't worry about all these other numbers." And at that point, I'll circle back and say, "Let's take a look at calories now," so that we can then kind of look at that other number and kind of contextualize what that looks like.

Host 2: That's a tough conversation too, right? Because then you're getting into that conversation about, well, what does healthy mean really, right? Is it really the number on the scale or how are we measuring it? But I think that's a tough conversation to have after we've been—these medications are a blessing. But in some ways, they can be really tough to manage in terms of conversation around weight and health, which is already quite a complex one.

Patrick Puliti, MD: I do try to set the stage, and I really try to let patients define what their goal weight is because I want them to have an idea of where they're going. One thing I always warn patients is, "Look, my biggest concern is to make sure that number is not too low." If you set a number and I could go on about my issues with the BMI metric in a lot of—that could be a whole podcast.

Host 2: Yes. We'll have you back. I would love to talk about that

Patrick Puliti, MD: I'll say like, "Look, if my number still has that little BMI number popping up as red, meaning it's elevated, but you're comfortable there, at that point, I agree, we focus on how you feel health-wise." I had a patient once come in and said, "My goal weight is being off of my blood pressure pills." And I actually said, "You know what? I applauded that because I think that was a non-numerical focus or like a non-scale victory as we oftentimes call them."

Host 1: I have several disconnected, topics I wanted to sort of either come back to or make sure we covered and so forth. I wanted to just go back to the exercise piece, Patrick, and Amanda as well, whether or not you specifically recommend an exercise regimen for folks while they're on these drugs.

Patrick Puliti, MD: Generally, I'll tell patients, "I want to focus on nutrition first. I want you to be active. I want you to keep doing whatever you're doing. If it's not currently anything, then just go for a light walk. But I want to focus on nutrition first." When we have nutrition in a pretty good place, then I start—and I even tell them, "I'm going to kind of bring it up and then bring it up, and then like slowly kind of morph the conversation throughout visits to be more focused on it." I do eventually give an exercise prescription. But I avoid giving a nutrition prescription, a literal prescription, and an exercise prescription all in one or even two visits, because I just feel like it's overwhelming

Host 2: That makes a lot of sense.

Host 1: I also think that starting an exercise regimen other than strength training, which does not necessarily require a great deal of sort of energy, right? Like, you can go in and lift weights and not necessarily starting a running program or something like that. I mean, it's hard, right? It's hard. It requires a great deal of exertion. And if you're trying to diet at the same time, it's actually really challenging. It's almost easier to just focus on one or the other. I do think strength training is easier. Strength training and walking are easier to integrate in where you just say, "Listen, just go take a few walks a week. Get out there, enjoy the outside. Go to the gym twice a week, exercise every muscle in your body, but don't kill yourself." That's generally what I say. And then, maybe if they've lost a little too much weight or I'm worried about where they're at with sarcopenia, I'll really push them on the weight strength training.

Host 2: Yeah. I mean, my population tends to—when we're talking about this medication, because I also have so many patients with diabetes, they just tend to be older and less active to begin with. But I also like to talk about the difference between being physically active and exercising. That I really want people to be physically active, and that can look very different than exercise.

And to your point, Kendal, that it's very difficult to lose weight when you're training for something or really trying to get into an exercise program. So, like, let's not muddy the waters, so to speak.

Host 1: Because you're hungry.

Host 2: Exactly.

Host 1: I mean, I started running a few weeks ago, and I was like starving all the time, you know? So, it's hard to lose weight in those circumstances.

Patrick Puliti, MD: One, thing I was going to say is there's actually been a couple of articles that have come out regarding that. And for a lot of people, up until about, I think, like 300 minutes a week, you upregulate your hunger. And so, generally, anything below that, your body is going to try to compensate that even in spite of the GLP-1.

So, that's why I agree. I like the physical activity. And then, kind of take that physical activity and as they lose weight, they feel better, they move better, all the joints seem to move simpler, then you can guide them into more of a formalized exercise program. But I agree, like, physical activity is really the focus in the beginning.

Host 1: So, the other topic, I wanted to circle back. We talked about semaglutide or Wegovy, both in PO formulation as well as an injectable, and we talked about Zepbound or tirzepatide. We haven't talked about Foundayo, which is the newest one. This is the Lilly drug, Eli Lilly drug. I actually realized just right now that I've never said it out loud, but it is orforglipron or orfoglipron. I'm not sure how you say it. The Eli Lilly folks are going to be mad at me right now. We all don't have a ton of experience with it. It does seem to be effective. It is an oral agent. It's sold as you don't have to worry about when you take it in relation to food. So. That 30-minute delay you don't have to use when you're doing Foundayo. I believe the weight loss metrics were similar to oral Wegovy, or is that not right, Patrick?

Patrick Puliti, MD: It's a little bit lower. I want to say oral Wegovy was around 13%, and I want to say Foundayo was closer to 10% or 11% absolute body weight loss.

Host 1: There's also been some concern that the side effects that people are experiencing may be a little greater than even the oral Wegovy. Is that correct?

Patrick Puliti, MD: I'll be curious what Nick's—I unfortunately have not had a chance to prescribe it yet because it only became orderable in Epic, I think, like, a week or two ago.

Nicholas Grillo, PhD: Yeah, I haven't had any patients on it just yet. But I think the headline with that is that it is associated with less weight loss in totality compared to the other GLP-1s. But it doesn't mean it's obsolete or it shouldn't be used at all, because I think what we're seeing now is a wide spectrum of GLP-1s that can kind of tailor an individual patient's weight loss goals and what their preferences are. So, I think there absolutely is a role for it. But as of right now, just don't have a lot of information on side effect profile.

Patrick Puliti, MD: I think it'll be a toolkit for when we get towards maintenance.

Host 1: So, the thing we haven't talked about, but a lot of patients around the country are on, are compounded semaglutide in particular. I don't know—I've never seen compounded tirzepatide. You guys can correct me on that. But nevertheless, folks are getting them from Hims or Hers or Ro or some of these other online programs, or they're getting them through weight loss centers that are more private. What is your general feeling about this as a class? Are there some sort of take-home points there?

Patrick Puliti, MD: Substantial concerns, if I had to distill it into two words. Every patient that's come to me on some form of compounded GLP-1, It's first of all very difficult to understand what dose they're on sometimes, because I literally need the vial. Because they'll say, "I'm taking 20 units," and I need the vial to understand exactly, like, what they're pulling up.

It's mixed with a wide variety of substances, whether I've seen B6, I think I've seen B12, I've seen N-acetylcysteine. I've seen all sorts of mixtures, and then the dosages are not the dosages that are typically prescribed, because it's another way of the compounders to navigate around the patent infringement. As a result, I tell a patient, "I have no idea what you're taking, and I have no idea what these substances are doing to the original molecule." And I believe the data suggests that the side effects are quite a bit higher in the compounded population.

Nicholas Grillo, PhD: Yeah, I think there are significant concerns with sterility and stability issues with using compounding pharmacies. And I absolutely do not recommend this practice, and neither does the FDA. As you were saying, Patrick, there's higher rates of side effects. And that's mainly attributed to either a non-sterile product that patients are injecting or the added ingredients in that are having some other type of adverse effect on patients.

Dosing concerns are pretty significant too, because we're used to dosing in milligrams. A lot of those are dosed in units. Really easy for patients to kind of mix that up when pulling up the medication from the vial into a syringe, leading to patients unintentionally getting much higher doses than what was intended.

And to ensure that a product is sterile and stable for whatever the expiration that the compounding pharmacies are putting on the vial requires a lot of monitoring, a lot of money to go into ensuring adequate clean rooms that we cannot verify, we cannot guarantee.

The manufacturers need to undergo strict tests and verification that every batch of their product is sterile and stable. I used to work in a fairly large compounding pharmacy and kind of understand what goes involved in making sure that the environment, not just what's in the vial, but the hood that the vial is compounded in and the clean room suite as a whole is sterile, requires a lot monitoring, and a lot of verification that I know that a lot of other smaller compounding pharmacies can't do.

Host 2: All of that makes so much sense, and I usually just make a blanket statement of stay away from compounded medications. Though I will clarify, I mean, you said this, but it is worth noting that there are ways for patients to get the actual medications from some online sellers. So, I make a point to educate patients about that. It's not that you can't buy them from certain places, you just have to be very careful that they don't say that the medications have been compounded, which is where the problem lies.

Patrick Puliti, MD: Ultimately, and I'm very gentle with this, I recognize that the point behind getting a compounded medication is affordability. And I try to be very gentle, because I don't want to sit here and say, "You don't get access to this medication, because you can't afford it." And it's always a hard place. I will say that with some of the pricing changes, they are largely in line with compounded. Oftentimes I actually have to tell patients, "I can get you this for $50 cheaper a month, and it's the real thing." And they kind of look at me surprised because they remember a year ago when a lot of these were $1,000 a month, and that has largely come down, I think, because of the pressure of compounding on these pharmaceutical companies.

Host 1: That's one point I wanted to hit on, and that is just cost generally. Very quickly, I think we all know roughly the cost that oral Wegovy is starting out at $150 a month or so. The Zepbound product has been available through Lilly Direct. It's now $299, I think, for the lowest dose, $349 for the second highest dose, and goes up from there. So, people are getting access to these medications at numbers that are a lot better than the $1,000-so a month.

But actually, as we had this big announcement last fall that Medicare would start covering these, I had heard that was April 1st, and then it was put off. I googled it, April 15th, and it said, "No, no, it's going to be summer." And then, have you heard any updates on that, Patrick?

Patrick Puliti, MD: Yeah, that's going to be, I believe, July 1st. It's called the Bridge Program. It's going to run from July 1st of this year to the end of December next year. We don't know what will happen after that. The hope is that it's not a bridge to nowhere, it's a bridge to something. There are pretty clear guidelines on the Medicare website. However, I believe it's kind of unclear what the system in terms of approval is going to be looking like because it's not run through the Part D plan. It's run through a whole separate program. So, I'm curious to see what that's going to look like. And oftentimes I just tell my patients this is on its way, but it's going to require a learning curve from staff and providers. But it's supposed to be $50 a month, and it does not count towards your copay or deductible.

Host 1: And that'll be consistent again across different Medicare Advantage plans as far as we know, 50 bucks a month. And that's Zepbound or tirzepatide and semaglutide?

Patrick Puliti, MD: And Foundayo.

Host 1: And Foundayo.

Patrick Puliti, MD: Yeah, all four of the ones we've talked about so far are included in the Bridge program.

Host 1: That's great. We don't know exactly who's going to qualify, you know, your BMI, some of those others. Do we know that yet?

Patrick Puliti, MD: It's like a tiered system. If I were to say anything, it wouldn't be—I fear to not be 100% correct. But generally, I believe there's like a tier where if you're above 27 with certain criteria like poorly controlled hypertension I know was one of them. And then, there's a 30 category, and I believe it's any BMI above 35 doesn't need anything else. But it's pretty clearly laid out on the Bridge website, and they've been posting that.

Host 1: What do you do with a patient who reaches their goal weight? To sort of front load this, I'll tell you what I tell patients. I say, "You're going to have three choices." I say, "You can stop it, but there is a belief out there by a lot of folks, and it's justified, I think, by some evidence, that people gain a fair amount of their weight back." On an individual case, folks, that doesn't necessarily need to be the case. I mean, you can probably avoid that if you work at it. Second option is to just stay on the medication at the dose you're at. And then, third option, which I see a lot of folks experimenting with, is some sort of weaning program, or they just use it when they feel like they're slipping or some variation of intermittent use, either extending dose, taking it every couple weeks or every 10 days, or just waiting until their hunger really comes back. So, that's what I'm seeing out there. Can you guys correct me on any of that?

Patrick Puliti, MD: Generally, my approach for most patients is if they don't have a preference, I continue them on it. At least I want them maintaining their weight for a year because after a year, a lot of the habits that we've talked about have solidified. They're kind of ingrained, because at that time, we're going to be working on all the things, strength training, continuing adequate protein intake, eating a well-rounded healthy diet.

And then, if they want to come off of it, then I work with them. But for most people, I tell them, "If your insurance is going to cover, it's going to act as a bubble," because we see greater than—I think it's usually about two-thirds weight regain if you come off of these medications without any kind of like counseling or anything like that. So generally, I encourage patients to stay on it, and I only wean them off if they really want to.

Host 1: Do you mean by two-thirds? do you mean the umber of pounds they gained is two-thirds of what they lost or do you mean two-thirds of people gained back?

Patrick Puliti, MD: Oh no, it's two-thirds. Yeah, it's like 66 % something around that range of weight gain of the original weight. So, some weight loss is still maintained, it seems. But the majority of the weight comes back on.

Host 1: Nick, how are you advising the folks you're advising with this?

Nicholas Grillo, PhD: Yeah. My best recommendation wherever possible is to not stop cold turkey, especially at higher doses of the medications. We are almost guaranteed to see weight to return in some form, appetite to increase. Obviously, insurance and access issues limit that to a large extent. However, if we have the choice, we don't want to stop it cold turkey.

Now, what we could do and what we've seen has worked fairly well is to slowly decrease the dose to a lower maintenance dose. It does a couple of things, like Patrick was saying, like while patients were titrating their way up to goal weight while on the medication, it became a little bit easier for patients to kind of make those diet and exercise modifications and instill that as part of their daily routine. So now, once those habits are formed, we're able—and most of the time, patients tell me they want to come off of medication or they don't want to need to take that high of a dose of a medication anymore. And it's understandable, right? It's a weekly injection for the rest of your life sounds a little daunting to a lot of people. But if we're able to go to a lower maintenance dose where we can maintain the weight you've already lost, not require as much of the medication, and let diet and exercise be the driving factors in maintaining weight loss, I think, that's the best way to go at this point. And not to put any pressure on patients as well, right?

Not to feel like you have to decrease the dose at this point on your weight loss journey, because that's not the case. There's no real evidence to support that, right? So if you're happy with that, with this medication as a maintenance medication, think of it as a blood pressure pill, right? Because if a patient's reached their blood pressure goal, we don't immediately take them off their blood pressure medication. We can adjust the dose. We can pick a different one that's maybe not as potent. And I think the same can be said with GLP-1s.

Host 2: That makes a lot of sense. I think it's also one of those things where there are different reasons why people end up being in a situation where they want or need to lose weight. And that nuance can be really challenging, right? There are the people—is it really just genetics? Have they just been at a high weight for their entire life? Is this someone that just has always struggled with a lot of food noise? Is this time around menopause where there maybe was some metabolic changes or something else going on? I mean, it's a complicated conversation no matter who you're having it with and nuanced.

Patrick Puliti, MD: And I think a big thing that I use is I use that as an opportunity to talk about how weight is not what we're really focused on. We're focused on adipose tissue. When I do wean patients down, the biggest thing I focus on is actually take this as an opportunity because if you're going to regain weight, it means you're in a caloric excess. It's very hard to build muscle substantially at a caloric maintenance or deficit. And I actually use this oppor- opportunity to say, " You may gain weight, but if we can channel this into a strength-building program, your body fat percentage is actually going to continue to go down despite weaning off of it because we're going to take that caloric excess and channel that into strength building and muscle building." We kind of flip the script on what weight gain and weight loss really is and really try to emphasize that just because you're going to gain weight doesn't mean it's necessarily bad.

Host 1: That's a really good insight, Patrick. You're sort of reversing any sarcopenia that might have occurred during the weight loss process and helping to reframe their bodies. You know, it's a really good way of thinking of it.

Patrick Puliti, MD: And it restores some of the metabolism because we know that more heavily muscled bodies tend to have higher metabolism as well. And muscle also acts as a glucose sink. So if that's also a concern in terms of hyperglycemia, increasing muscle mass has a lot of benefits on that as well.

Host 1: There seems to be—and certainly in my practice, there has been a pattern of me talking more and more about strength training, and I think part of it is because GLPs and I'm seeing people lose weight. But part of it may also just be my experience of folks are living older. And if they want to be strong into their late 80s, they really need to build some muscle. And so, I'm pushing that quite a bit, and it sounds like you guys are as well. We're kind of at the end of our time. But I do want to just ask if there's any other aspect of this that you think is sort of a burning thing that we need to just at least get out there.

Nicholas Grillo, PhD: Yeah, I'll just say, from my perspective, seeing a lot of the access resolution pieces. There's a whole team of people behind it submitting prior authorizations, following up on the status, and all that good stuff. But my main point is to not be discouraged for any providers that constantly hear from their patients that their GLP-1 medication is denied. Not to be discouraged to—I don't want to say—forget, but not emphasize enough diet and exercise and all those adjustments that can be done and start that habit stacking now even before starting the GLP-1. Because as we're seeing with the Medicare Bridge program, access may expand, and that may enable a lot more patients to get these medications if those habits are already forming, it makes it that much easier to do well on a GLP-1 medication. So, it's not to be discouraged. Hopefully, as prices come down, a lot more people have access to these medications that many people feel are miracle drugs and are life-altering.

Host 1: The prices are definitely not going to go back up. I mean, they'll continue to get cheaper

Patrick Puliti, MD: I think the biggest thing for me is that I just always remind my students and when colleagues ask me about how I approach this, I always try to approach it with an air of positivity. I always talk about what food can we add? How can we expand what we eat? I try to take as much negative language out of the equation because I think the topic is very emotionally charged.

And I think, if you do anything when talking about nutrition, always try to approach at bare minimum replacement. But I always talk about adding food. And I find that patients really respond to that, because they then get ideas instead of feeling restrained.

Host 2: I love that.

Host 1: Yeah, we always feel better when we broaden our perspective, you know? We're broadening our opportunities. That's why we all love traveling. And the framing it that way, I think kind of keeps it light and positive. So, that's great. Thank you all for coming to our first Primary Care Roundtable. You all have heard the voice of Dr. Swain, and she'll be hosting these in the future. But Patrick and Nick, I really appreciate you coming on and sharing your wisdom with us today.

Patrick Puliti, MD: Thank you so much.

Nicholas Grillo, PhD: Yeah. Thank you.

Host 1: And with that, I want to thank the audience as well for joining the Penn Primary Care Podcast. Please join us again next time.