A (3:52)

And it really has been remarkable, not just on the chemical side, the formulations, but even the engineering side, to have the devices that we have now that make it so easy for patients and are so much really better devices than the original exenatide device years ago. And a lot of people don't appreciate the amount of work that goes into all of that, from engineering to the creation of an orally available formulation of semaglutide. Can you share with us a bit about that process? What were some of the challenges in moving toward an oral formulation? How are those challenges addressed?

B (4:35)

First, in terms of prolonging the circulating half life, regardless of whether it's oral or injectable, there was amino acid substitutions, including an amino acid substitution that prevented degradation by DPP4. Then there was a spacer added attached to a long chain fatty acid. And this fatty acid adduct allowed absorption to albumin in the circulation and prolonged its half life in that manner. But it was a whole nother ball game in terms of bringing this into an oral formulation. We've been trying to get oral insulins for some time and it hasn't really worked out that well in other peptides. What happened here with Novo Nordisk is they contracted with another company that developed this product called SNAC S NAC and it was a matrix in which the semaglutide was embedded and it prevented digestion of the protein in the stomach. And when it approached the gastric mucosa, they changed the pH locally to a more basic pH which allowed absorption of the molecule semaglutide into the systemic circulation. The absorption isn't perfect. In fact, it's fairly poor, one and a half to 3%, something in those in that order of magnitude. And that's why the oral doses are, in terms of milligrams are so much higher than the injectable doses.

A (5:57)

It's fascinating and it just for us in primary care and Endocrinology to hear how that basic science moved along gives us a better appreciation of what goes into the medicines we use every day. Let's move on now to the clinical trials of oral semaglutide, which is the evidence that allows us to use it every day. And can you go over some of those clinical trials and of course, mentioning weight efficacy as one of the end.

B (6:24)

Points, Lisa, with oral semaglutitis, these are the Oasis trials and Oasis 1 was a dose of 50mg maximal treatment dose. And so it's 50mg a day. Once you achieve the full dose. This was very effective. It led to about a 15.1% weight loss. And this is using their treatment policy estimate, analogous to an intention to treat type of analysis. That's pretty good weight loss. You get into the 15% range. I call these second generation medications because once you get that sweet spot, you're able to treat and prevent a broad array of obesity complications. So this level of efficacy for weight loss really gives us a tool to improve quality of life and to prevent and treat the complications which really infer morbidity and mortality in our patients. So that was good news. Of course, this was at a period in time when the company had greater than expected demand for their drug and was having problems kind of supplying. And the 50 milligram dose compared to a 2.4 milligram dose injectable, that's a lot of semaglutide devoted to an oral preparation. So Oasis 4 explored at lower dose, half of that 25 milligrams a day. Of course, there's an escalation up to that we can talk about later, but once you get to 25 milligrams, and here we still had good news. The intention to treat type of analysis was 13.6% weight loss. If you looked at a completer's type of analysis, it was over 16% weight loss. Again, very good weight loss efficacy, maybe a little less than the 50 milligrams, but in a range where we're still able to bring a lot of health benefits to patients. And so the 25 milligram is what was pursued for FDA approval. It was approved January 5, not that long ago. And we've really seen a lot of patient interest in this oral formulation.

A (8:16)

There sure is. As recently as yesterday, I saw someone in the office who is actually asking about switching from their injectable to oral semaglutide. Can you go over some of the other endpoints? Because as you mentioned, these are Medicines where the goal isn't just weight loss, but is improvement of health outcomes. What are some of the metabolic endpoints that we're seeing in Oasis 4?

B (8:43)

Yeah, we had, we saw a lot of cardiometabolic disease risk factors improve. These patients in Oasis 1 and Oasis 4 did not have diabetes at baseline, but the hemoglobin A1C came down 0.3% units. Fasting glucose came down, of course, about 6 milligrams per deciliter. But another thing I was impressed by, and this goes along with all these GLP1 based medications, is the fasting insulin levels came down and these studies as well, 25 to 30% together with the decreased fasting glucose, and this is really indicative of a marked improvement in insulin sensitivity. Some of this, I guess this could be attributed to the weight loss, but perhaps there's other drug effects operative here. But regardless, as we know, insulin resistance is the core lesion in cardiometabolic disease. And when we see an improvement in insulin sensitivity like this, we can expect improvements in glycemia as well as some of the other benefits we saw. In Oasis 4, the triglycerides came down. The C reactive protein also came down. In this study, though, the blood pressure came down, but it was equal to placebo. There seemed to be a more pronounced effect on blood pressure lowering in this study in placebo. We're talking about 4 or 5, 6 millimeters of mercury diastolic, systolic, but there weren't significant differences there. Not quite sure how to interpret that. Usually with these GLP1 based medicines, we do see a significant decrease in blood pressure. Good, good. And then in terms of patients that started out with prediabetes, over 70, 70, 75% of those were converted to normal glycemia by the end of the trial. That's good news. This wasn't a trial designed to look at prevention of progression to overt diabetes, but I think given those results, we can predict that this medication might also have that beneficial effect.

A (10:36)

Yeah, that's pretty amazing. And so important because almost half of the population has either diabetes or pre diabetes, a substantial number having pre diabetes. So critically important. Did they look at physical function?

B (10:54)

Yes, there were some sub studies looking at changes in body composition and physical function. The body composition, I think it aligns with any, in my opinion, aligns with any modality producing weight loss, whether it's diet of bariatric surgery or obesity medications. When we measure body composition using DEXA scans, we see about a 1/3 decrease in lean body mass and about 2/3 decrease in fat mass with a preferential loss of fat from the visceral or abdominal compartment. In terms of the functional studies, this was really done with a sit to stand maneuver. How many sit to stand repetitions you can achieve over a certain time period. That was reassuring. Also, I think there was no decrease. In other words, the number of SITA stands at baseline was statistically similar to the number at the end of the study. So there was no weakness as manifest in that way. But I think in addition to that, there were patient reported outcome questionnaires assessing quality of life and physical function and those improved as well. Both of those improved and they also improved in people that had impaired physical function at baseline. So I think this muscle loss something we need to study more carefully. That's something we need to pay attention to and make sure our patients have adequate protein intake. And we advocate walking programs and particular resistance exercise. But it doesn't appear to be a clinical problem in most patients in terms of any kind of adverse effects on quality of life or activities of daily living and physical activity and functioning. We'll just have to see where the research takes us there.

A (12:43)

Yeah, and those are important things I think for our listeners to be aware of. In the studies, I'm assuming in the OASIS trials, as it was in all the other GLP1 studies, patients received regular advice on lifestyle on diet and exercise. Is that correct?

B (12:59)

That is correct. I would say. I think most sites had dietitians study. My site certainly had dietitians as study coordinators and able to talk to patients. And yeah, that was part of the protocol, kind of a standard advice type lifestyle intervention for both involved both diet and exercise.

A (13:19)

Yeah. And something that I think is so important is that these medicines, therefore, in order to achieve the results that they do really are optimally prescribed by people like those who listen to this podcast, clinicians who talk to their patients, not patients just going to some online site without any interface with any health care professional and getting medicines. And we've talked on a different one of our podcasts about all of the problems with compounded medicines with these online sites, but that it is very reassuring to hear that in the studies people maintained their physical function, had improved quality of life and all the metabolic parameters. Any other adverse effects? I imagine the same usual adverse effects we see in other clips.

B (14:09)

You're pushing a button of mine when it comes to online availability of these prescriptions without evaluation by a healthcare professional. So I know our this podcast is not designed to go there, but so I'll stop.

A (14:22)

We share the same concerns and there it's something we've talked about in detail. So I'm glad that we both share that concern.

B (14:30)

Yeah, this the same Glyp1 receptor that in the hypothalamus and brainstem that mediates a decrease in appetite is also the receptor in the area postrema that mediates nausea. So the oral preparation does not get around these GI side effects. That is also observed of course with the. So like the injectables there's about a 40, 45% prevalence of nausea, less so for vomiting, more like 30% and constipation and diarrhea are down there about 20% of patients. So a lot of patients do fine. But some, a significant proportion of patients do have these GI side effects. I don't think that was, that's not, that was to be expected, I believe. And again, like the injectables, they occur primarily during dose escalation and then get better over time, usually mild to moderate, only infrequently requiring discontinuation of the medication. So the GI side effects were not surprising and still in what would be expected with any GI based medication I believe.

A (15:33)

And I noticed in reading the paper there was something I was not as familiar with. Dysthesias.

B (15:40)

Yes. This occurred at about 5% of patients in the OASIS1 OASIS IV trial. We first began detecting this in the called step up trials with higher doses of subcutaneous semaglutide, up to 7.2 milligrams per week compared to 2.4 in those studies close up to 20% of patients have these dysesthesias. What does a dysesthesia mean? These patients, that's a general term, but these patients usually feel this sensation and they're just doesn't feel normal. It can be tingly, it can even have some painful characteristics to it. The worst I've seen is a patient who had problems putting on it was so painful. And this gets better pretty quickly once you decrease the dose or stop the dose depending upon how much it's bothering the patient. There may be higher incidences of this because patients just probably don't even mention it because often it's very mild and patients just brush it off and it can get better over time. I'm not sure what the mechanism of this is, I'm not an expert in neurology, but I did look this up and there are GLP1 receptors and peripheral nerves. I don't know if that's part of this, but I think that's something we have to be aware of in our patients. And I think this is true with any GLP1 based medication. We'll see a certain percentage of patients have dysesthesia, but the higher the doses, I think that's when we bring this out more.

A (17:05)

Thanks for going over that because that's new information that's certainly helpful to know if a patient has those symptoms. Let's now go on and talk about cardiovascular safety and efficacy. Where does that fit in?

B (17:18)

Yeah, this was also I think good news. We know the select study and this was probably one of the more important studies ever performed in obesity. It was a cardiovascular outcomes trial of course, in patients just with obesity, not diabetes. 17,600 patients internationally followed for four years and we saw about a 20% decrease in the hazard ratio for cardiovascular disease events with semaglutide 2.4 the injectable. And this was secondary prevention. So these patients for the most part had a cardiovascular disease eventually to come into the study, or at least were very high risk. And in the labeling for oral semaglutide, this indication for secondary prevention of MACE events, major cardiovascular disease events, was carried over to apply to oral semaglutide. So the oral semaglutide 25mg also has an indication, FDA approved indication for cardiovascular disease prevention.

A (18:15)

That's so important because my sense clinically, to be honest with you, is that a lot of my patients who we co manage with the cardiologist, that the cardiologists are not as quick to use GLP1s because they're hard medicines used. You get a lot of callbacks from patients and they don't have the years of experience that we in endocrine and primary care do. So we see a lot of patients with coronary disease who are overweight and obese. And it strikes me me that a lot of them are not automatically put on a GLP1 the same way as they are some other cardiovascular risk modifying agents. And I suspect that having an oral agent available will be very attractive and make that easier.

B (19:01)

I suppose in terms of the injectors, I've been a diabetologist for 35 years or whatever and I've had so many patients on injectable medications. Medications and we have a more of a. You're an endocrinology practice, your patients, you just have a cadre of patients that just don't mind injectables as much I think as the general population. I could be wrong about that. But I think the cardiologists this Isn't like a statin where you put patients on a stat and you check the lipids in three months and you're good to go. This is a medication where you're right, we do have to manage patients a little bit more actively, deal with their side effects, manage the weight loss. We want healthy degrees of weight loss, not excessive. And we want to reach our clinical health targets as well. And we need to adjust other medications. We may need to decrease any other blood pressure lowering medications the patient might be on, glucose lowering and blood pressure lowering medications that they're on. It is a little bit more involved. And a statin, for example, I believe in my opinion, yeah, the oral, they're still going to have those challenges in terms of managing the weight loss side effects, altering other medications, just integrating it into their overall treatment plan for their, whatever diseases they may have.

A (20:18)

That's a really good point. Let me ask you something that's on the edge of what we know, but I'd be really interested in your opinion. Increasingly we're doing coronary calcium scores in order to rest stratify. If someone has a calcium score of zero, they're at very low risk. But when you have a calcium score over 300, and this has been shown in a number of studies, the MISA study by Matt Rudolph and others, a calcium score over 300 has about the same risk of an event as someone who already had a heart attack or stroke. And based on data like that, the national lipid association 2025 guidelines state that for people with a calcium score greater than 3, 300, an LDL goal of less than 70 is recommended. Should we be thinking in this group to treat them if they have a calcium score, whether it's over 100, over 300, similar to the way that we should be doing for people who have established coronary disease, thinking about a GLP1 as a way to risk reduce in individuals who also have overweight or obesity.

B (21:29)

A lot of patients with obesity will have metabolic syndrome or one or two metabolic syndrome traits. We know they're insulin resistant. We know they're in a state of accelerated atherosclerosis before diabetes or the first cardiovascular disease event comes to the fore, I think so if they have overweight or obesity. And in the select study we know that almost all of these, I think 80% of these patients were already on statin. So this cardio protection is over and above what statin brings to the table. I think there's very good evidence to support that. Your contention there, we should think about adding GLP 1, 2 as an additional or if we're going to choose a medicine for obesity, let's choose one where there's evidence basis for cardio protection, particularly in patients that have already had an.

A (22:17)

Event that makes sense. Thanks for addressing that because I think that comes up and it's often not entirely clear. Let's go over now some practical aspects of prescribing oral semaglutide. What should our listeners know?

B (22:31)

Well, some people like the oral semaglutide because it looks like they're going to be lower cost than the injectable vulva. But that's a big changing field right now. We'll have to see where all these costs level off. But it's, it's still a GLP1 based drug. We're going to need dose escalation with oral semaglutide 25. We begin with a dose of 1.45 for a month, daily for a month, then go up to four for another month, then to nine and then on the fourth month we're at 25 milligrams a day and they're prescribed in the pills or in bottles with 30 day supply for each of these doses, like single dose injectable pens, we may have patients we want to keep at a lower dose before we escalate to the next higher dose. Then we're going to have to get two prescriptions for a lower dose and it's only the 25 milligram dose. It's a pretty approved for treatment. Again, it's a challenge for clinicians to work our way through pre authorizations and insurance companies and all of this stuff to get the medicines that our patients need. We're familiar with those problems and with the oral preparation because of the snack matrix and the way this medicine is absorbed, we need to take these oral semaglutide in the morning before we've had anything to eat with a half a cup of water, about 4 ounces of water and not eat anything for the next 30 to 60 minutes or so, at least 30 minutes. So we're going to need to delay breakfast and that includes coffee. Patients I've had, they do very well with that. It's not a big imposition and they seem to do okay with that. But it is if you're, if you don't adhere to that, your absorption is not going to be what you want and so your therapeutic efficacy might fall off. So it is important to pay attention to that. Okay.

A (24:18)

And the half life of semaglutide on the oral Pills is the same as semaglutide by injection, is that right?

B (24:26)

That's correct. Once it gets into the bloodstream, it's the same.

A (24:29)

And then a question that I've heard asked, if someone is switching from injectable semaglutide to oral semaglutide, do you just guess that they're in that same dose range? If they're in a middle dose, convert to the middle dose of oral. If they're at the max dose of 2.4, go to the 25 or something different here.

B (24:51)

Yeah, we don't have any data for guidance there. But just think about the half lives with the injectable once a week. The half life is five, six days. If you just stop the injectable on day one and start with the same dose of pillow, those pills are going to be adding on to the dose, the full dose. It's going to be additional to what you achieve with the subcutaneous dose. So I would wait at least a week. A week, I would say, at least before you begin the oral semaglutide after injection, it's number one, just helpful, just making sense of the PK and if it's a patient that's not having any GI problems, I would go to the. They're on 2.4. I just go to 25. If the patient is having kind of some GI problems and intermittently just not dealing with that top dose of the injectable as perfectly, I might start at a lower dose of the oral just because. Just to be on the safe side. I mean, it's. Remember, it's not a race here to get patients up to the maximal dose. These patients have a lifelong disease and we don't want to make them disconcerted through precipitating GI side effects unnecessarily. So it's always better to be more conservative, I think. Take your time.

A (26:13)

Yeah, it makes a lot of sense and thanks for going over it in that detail because I think that is going to be happening and it's helpful to have just logical guidance about how to approach that. We're about out of time. Do you have any final thoughts for our listeners?

B (26:31)

Two things, Neil, if I may. First, I've been fortunate to give several in the last six months, been to several foreign countries giving talks to doctors about obesity. And these doctors in some of these countries don't have some of these drug medicines available. They know the data, the papers are published and they really want to get their hands on these medications. I was in Peru in particular and concomitant with the launch of an injectable Glyp one. And we're driving around Lima, Peru, and I see these pharmacias, these little pharmacias about every second block. And I say all these pharmacias have refrigerators to store the injectable. And they said, no, only about one in five do. And those are the ones we're going to have to work with. The advantage of the oils is they don't need to be refrigerated. So I think in terms of worldwide distribution and accessibility, this is a very good thing. And even for our patients in America, here for travel, it can just less easier to store the medication and travel issues and you can travel with the medicine better. When you look at real world data and we see that half of patients don't stay on these medications after we prescribe them, after a year, you realize we're treating this disease very poorly because we know that most patients regain weight and lose the health benefits of the weight loss. So we'll have to see how this plays out. Hopefully, if patients prefer oral medications, we know that they're more likely to be adherent to a medication when it's delivered in the format that they prefer. Maybe this will enhance adherence over a longer period of time. We'll have to see. But that's another hope of mine with the advent of these orals.

A (28:07)

Dr. Timothy Harvey, thank you so much for joining us.

B (28:11)

My pleasure. Thank you.

A (28:13)

And most of all, of course, thanks to our listeners. Thank you for joining us on this special edition of Diabetes Core Update, discussing new exciting information about the now available oral GLP1 semaglutide for obesity. This special edition of Diabetes Core Update is sponsored by Novo. We have gone over both the data and Dr. Garvey has really been wonderful in going over not just just the evidence, which he knows better than anyone, but also practical hints about this medicine and even issues of worldwide distribution and the importance of that for the American diabetes association. I'm Dr. Neal Skolnick. Till next time, stay safe and keep learning.

B (29:05)

Sa.