Obesity Journal Club Save

Hello, everyone. Welcome to Tuesday Night Rheumatology. We're starting these back up because it's a campaign month and this month our campaign is the obesity imperative. We want to spend the whole month talking about obesity and its major effects as a comorbidity. As part of this series, we're going to do four weekly webinars here on Tuesday night rheumatology.

Our first one's going to be a journal club. I'm joined by our two discussants who are highly knowledgeable on both the papers we're going to discuss. I'm going

to ask everybody to introduce themselves. I'm Jack Cush from Dallas. I'm Doctor. Philip Meese, a rheumatologist based in Seattle where I direct rheumatology research at Providence Swedish Medical Center and conduct clinical practice at Seattle Rheumatology Associates.

Tom.

I'm Doctor. Tom Abelson. I'm a rheumatologist in London, get this Canada, the other London. I'm head of the rheumatology division at Western University in Canada, conduct clinical research trials and lead an osteoarthritis program trying to discover DMOs.

So before we get into our survey and some outlining, I want to ask Tom, because Philip and I are many, I like to think I'm like Philip, that we've done many trials over many years and a lot of different areas, including trials in osteoarthritis. So we're dabblers, but this is your career. Why have you chosen, or how did you get into choosing osteoarthritis as the focus of your research, teaching, and career?

Well, first off, I love rheumatology and that's been an incredible love doing all of rheumatology and getting to learn all there is about the breadth of it. I think osteoarthritis is a field that has really needed the input of rheumatologists for a very long time. It's had a tremendous amount of input from other experts like rehab experts, like pathologists, like orthopedic surgeons. But as the arthritis experts, truly rheumatologists, we bring a complimentary set of expertise, and I think that's so important for this field. The fact that it's the largest unmet need in all of musculoskeletal health to be able to find a medical treatment that actually modifies the disease, pretty attractive opportunity, think, and a big gap to try to fill.

So I'm just trying to do my part.

We are certainly glad that you are. Let me go to sharing screen right now. Hopefully I'm going to pull up the right set of slides. Here we are. All thumbs this morning.

We're going to do a journal club today where we're going to discuss two articles and we're going to intersperse that with survey results that we did in yesterday and having almost 200 responses. We want to say that not only this TNR series, but also the whole month of September and the campaign on obesity has been supported by Lilly. And our thanks to them for their interest in medical education and spreading the word about the impact of obesity on patients with inflammatory arthritis, degenerative arthritis, all kinds of arthritis. We think it's gigantic and that's why we're doing a campaign where you'll see a lot of content. For the audience, we want you to be an active participant in this program.

One in the chat box, you'll see the links to the two papers that we'll be discussing and you can pull those up and refer to those. We encourage your questions and we'll answer them throughout. For that, just click on the Q and A box. Then one more announcement, if you haven't seen today's room, room now in your inbox, Tom has a featured video as a feature piece. It's a really good, fast, I think five, seven minute listen about osteoarthritis and the new changes and new thinking, I think it's a really important read that you should look into.

We did a survey yesterday, we had 193 responses from many countries, ninety one percent are rheumatologists, you can see here in blue, five percent are advanced practice providers. We have a few fellows in there and a few others, not like 1%, two percent. Then we started off by asking them, the whole audience, have you ever prescribed? Again, this email survey goes out just to rheumatology HCPs, people who are practicing rheumatology either as an APP fellow trainee or rheumatologist, ninety one percent are rheumatologists. We ask all of them, have you ever prescribed a weight loss drug such as the GLP-one agonist?

And half said no, but thirty four percent said yes, they have. And eighteen percent said that they have referred patients to another for treatment with weight loss drugs. I want to ask our discussions, are you surprised at these results, Tom?

I think I'm becoming less surprised when I hear people saying that they are prescribing. And I think that's really testament to efforts like this one, like the obesity campaign, people trying to make obesity much more a hot topic, not just something we try to move past and get on with, managing the inflammatory disease. I think that the trials that we're gonna discuss tonight have, have made an impact on things like that, and I think it's going to change. I think if you asked this question six months ago, it probably would have been much less than that.

So Philip, you're not only doing the clinical trials in this area, you have been doing teaching in this area. In your travels, have you seen this trend of increasing use or does this surprise you as well?

This does not surprise me. When I asked this question to audiences two years ago, the number of hands that went up would be six. When I am lecturing to the audiences now, the number of hands that go up is 40. When I ask the question, are you beginning to prescribe these? It doesn't translate automatically into, are you successful in prescribing?

That's the second step. But there's a lot more conversation going on because I think there's a moral imperative that we have to be addressing this issue now that we're seeing this data coming out about how important addressing obesity is.

Yeah, and bringing up these journal articles in this whole month is really about the conversation that needs to happen. Physicians in general, I don't know a number on rheumatologists, but physicians in general who have a patient who's obese in front of them will only a third of the time bring up obesity in some way, shape or form. So that's a bit of a concern. So I want to frame this a little more by asking the audience as I did, you have an obese patient with a BMI of thirty nine who has arthritis, RA, PSA, whatever. The question was, who should initiate treatment for obesity?

It should have been who should start the discussion, but I wanted to get to something really definitive, writing the prescription. You can see that more than half think that it should be done by primary care. But still, there's almost nineteen percent of rheumatologists who are willing to take responsibility. But overall, eighty percent of rheumatologists think it should be done by somebody else, not me. Very few are saying, this is the responsibility of the patient.

The second question I asked in the same vein is, what is the goal of treatment in a patient who has TSA who's obese, the patient who would get into the study we're going to discuss next? What is the goal? Is it an arthritis goal or is it a weight or BMI goal? You can see when it comes to the answers that rheumatologists gave, not surprisingly forty six percent plus twenty six percent, that's about seventy two percent, seventy three percent are saying it's an arthritis outcome, either MDA or remission. And that only sixteen percent plus six percent, twenty two percent said that the weight is the goal.

And I guess, I gave them a very blatant number of two fifty two BMI at 39, But if I gave them very blatant joint counts or skin scores, maybe they would have said more. Obviously both are important, but I want to know from rheumatologists, how much are they thinking about weight as the goal here? Do you want I think if

there was the possibility of answering the question with the top two or even three, but I'd say top two, I imagine you would have gotten one of each, you would have gotten arthritis and then you would close second, you would have gotten the 10 to 20% weight loss.

That's the failing of my surveys, but it's also the brilliance of my surveys in that I'm forcing them to give me single best answer, which means you might have several right answers, but to choose one is harder. And that could be right or could be wrong, I don't know. Tom, what do you think about these data?

Well, I think the same thing could be said actually about your first question that we could have asked multiple questions. And really my point is it gets down to what's the intent? Why are you prescribing this GLP in this case or this weight loss strategy? Is it because you're trying to achieve weight loss? Well, maybe that is a primary care role, or is it because you're trying to improve cardiometabolic risk?

Maybe that's internal medicine's job, or you're trying to target an A1C. There's lots of reasons to prescribe a GLP and they might all have specialists involved in this particular patient's care. But I think when it comes down to, I'm actually trying to get a better arthritis outcome. I think that's when it becomes essential that the rheumatologist is at least involved in the discussion, if not actually the one owning the script, because the intention now is really focused on the rheumatology problem.

So I have prescribed, these newer drugs, but I don't have a weight loss clinic inside my rheumatology practice. Do you think that a rheumatologist need to be that much of a weight loss expert to have a dedicated clinic or do clinical trials to be knowledgeable or using these drugs?

I think this is going to evolve. At the moment, I would say the most competent care is coming from rheumatology offices where one or more people in the office, either a physician and or an advanced practice practitioner, has taken on some responsibility to really learn about the biology of obesity, some of the issues around safety of the drugs, knowing, that if if the BMI is over 40, there should at least be a discussion about bariatric surgery and so on. But gradually over time, I believe that it's going to become kind of standard practice to prescribe a incretin agent along with our standard immunomodulatory as we see the trials coming out as we're going to discuss in a moment. And so I think that ironically, the level of expertise may come down a little bit as it becomes more common to use this. But I do think that it's really important for people to at least become acquainted deeply with the clinical trial data and to become acquainted deeply with the safety issues so that they can counsel patients on the gradual increase of dosing and that sort of thing.

Yeah. Let's get into the studies. The first paper was published in arthritis and rheumatology recently. Philip is the second author on this paper, the Together PSA study. We featured it on RheumNow when it first got released as the Together PSA study.

Then a few weeks later, Together PSA study came out. It's a phase 3B randomized open label multicenter trial. It was a fifty two week trial. The primary endpoint, however, is at thirty six weeks. They enrolled patients who had active psoriatic arthritis and they had to either be overweight with a BMI of thirty seven to fifty with a weight related comorbidity, or they needed to just be obese with a BMI of greater than thirty.

Patients were randomized to either receive, and they were allowed to be on background pain medicines, acetaminophen nonsteroidals, very few like less than ten percent took opioids at any time, but they were randomized. By the way, weight loss drugs or no other biologics involved here. They were randomized one to one to receive either ixekizumab IL-seventeen inhibitor with tirzepatide and the other half of the group, ixekizumab alone without the tirzepatide. The primary endpoint was a combined endpoint of a high level arthritis response, ACR50, and also achieving at least 10% weight loss at week thirty six. So on right, you can see that the arms are balanced here.

They use commercially acceptable starting doses, there was some dose escalation allowed in this. And these are the results, the primary endpoint-

Jack, before going on, just to add one comment. An important ingredient of all of the incretin trials is there is simultaneous counseling about diet and physical exercise. So that is sort of like, even though it's not a pharmaceutical intervention, there is an encouragement that, whenever you use these drugs, they're based on a foundation of also a good diet and exercise.

Was that like in the step nine that was done at every visit, there was a reminder on that. Was that done the same way in Together PSA or?

It was encouraged, it was encouraged, yes. Excellent.

The primary endpoint, as we said, was a combined endpoint ACR 5010% weight loss. And you can see on the far left that was highly significant, 32% on the combo versus only less than 1% on the single drug. I thought more interesting was, what about if you just looked at the arthritis? You would expect that everybody is getting ixekizumab here. Was there an added value to the GLP-one agent on top of the IL-seventeen inhibitor and shows that it was significant with an ACR 50 of 33 with the combo and twenty percent with ICSI alone.

Then if you just look at weight reduction alone, clearly only the group that got the GLP-one drug had significant weight loss of more than 10%, that was almost eighty five percent. The other important thing is that there were many other secondary endpoints in this study that clear win for the combination of ixekizumab tirzepatide. That includes ACR 20, you're looking at that sort of grayed out on the bottom there. These are all very significant. ACR 20, minimal disease activity, the PASI score, the health assessment questionnaire, the HACD I functional outcome, and facet, as well as a PASI 90 score, all achieve significance with the combo.

The other important thing that I like to look at when it comes to what I think is a combination biologic trial is, is there an added risk when you start combining biologics? Because right now there is no FDA approved combined biologic regimen that's out there. I think that this company and other companies will go for this combining a weight loss biologic, meaning parentally administered targeted therapy to existing biologic therapy. And in this study, the safety outcomes were the same between groups that serious adverse events, SAEs were lower in the combination group than with the ixekizumab group. There was no mention of SIE, serious infectious events, which was the killer in the combination IL-one TNF trials from a long ago.

But they did report opportunistic infections, which was the same, if not a tad lower. And there were no other safety signals and no deaths in either arm. Philip, was there a signal at all as far as the serious infectious events, but it's not in the paper?

No, there wasn't. And also, I think the key point is that there was nothing new other than what we already knew about the IL-seventeen mechanism and the GLP-one and GIP mechanism. So there... I I think the biggest issue is is the GI side effects that are common as you're ramping up the dose of the tirzepatide. The, and we try to avoid that by very gradual increase starting at two point five milligrams and then go...

Changing every month. That's why the primary endpoint was way out. It's 36. It's because it takes a while to get ramped up. But interestingly, eighty five percent of the patients in this trial made it all the way to fifteen milligrams, which is the max recommended dose for for greatest, effectiveness.

And I think that that's a testament to both the patients and the investigators that they were able to achieve that degree of many of the patients that I see may pause at lower doses to avoid some of these side effects.

Yeah, I wish that was some time related phenomena. It looks like that the actual separation between placebo the single arm and the combo arm was as early as week four. And that was maintained going all the

way out to week fifty two, and that was seen both for weight loss and for ACR fifty. So even though there was minimal weight loss by week four in comparison to what was achieved at week 36, we're already seeing a separation in ACR 50. This is provocative because it makes us think about what beyond just simply loss of weight might be going on, in the immunobiology of the incretins in relation to our inflammatory diseases.

Yeah, I want to point out all these asterisks indicate statistical significance at very early time points, including week four. Philip, what other secondary or laboratory outcomes were favoring the combo group? There were a number of them.

So we saw all the usual suspects in psoriatic arthritis trials like enthesitis, being better. We saw that MDA was clearly separated, minimal disease activity achievement, which we consider low disease activity, twenty three percent in the combo group versus a lower score withixekizumab alone. And so it was satisfying to see that all of the various clinical domains of psoriatic arthritis were being addressed, skin, joints, enthesitis, and so forth. Also, many of the patient reported outcomes, pain, fatigue, the quality of life measures, all showed separation. And then importantly, metabolic changes.

So there was significant separation in terms of glucose, hemoglobin A1c, cholesterol, triglycerides, systolic and diastolic blood pressure, as well as weight. And so it looks as though many of the types of comorbidities that we associate with psoriatic arthritis, much more so than rheumatoid arthritis, are being addressed in parallel with the weight loss and arthritis improvements.

Tom, do you have any questions or comments on this trial?

One thing that stood out to me as well about that four week time point is that the percentage of weight loss that happened at four weeks was actually really quite small. In fact, it's probably below the threshold where you would consider that to have a meaningful effect on any other features. So just doubling down on what Philip was saying about this really suggesting there may be additional mechanisms in play. For sure, feel better when you lose weight, but are there other immunologic mechanisms that are in play or cardiometabolic mechanisms that are in play here that are actually having an effect on the psoriatic disease itself? And it would be great to see.

I think this is also good hypothesis generating information for subsequent studies.

Yes, would add to that that everyone is slightly cautious about just coming out and saying, oh, this is clearly an immunomodulatory effect. It needs a lot more study, including biomarker analysis, tissue analysis for us to have a fuller appreciation of that. But when we look at certain translational animal studies as well as human studies, we see a lot of reduction of not only the expected reduced reduction of adipokine inflammatory molecules like leptin, but also a reduction in TNF, reduction in IL six and so forth, which are at least bringing up, as Tom suggests, the hypothesis generating, idea that there could be some immunomodulation going on.

Phil, do you think that that is suggested at all by the ACR 50 only data that if you're just looking at the

No. I I think if you look at the skin data Yeah. And that's best shown in the together PSO trial that you alluded to earlier, where we saw very similar kinds of differences between the combination arm versus the uni arm. And I think that both skin and the joints are bringing that question up for us. And so we really are pushing, and I know Lilly amongst other companies are really pushing to try to understand this more at a biomolecular level.

Yeah.

So let's go get the next slide, which is really the summary that obviously is a big problem with obesity in The United States. It's forty one percent of adults in The United States have a BMI greater than thirty. But if you include overweight with a BMI of twenty five or higher, it's seventy two percent. The endpoints were easily met here and strikingly, the secondary endpoints were a multiple win. The strengths of the study was that combination therapy can be given to these folks without an additional safety concern.

There was no new safety information, nothing that stood out in this trial or the next. This is a difficult to treat PSA population where BMI and obesity is a major comorbidity. That's missing from most difficult to treat definitions. I think this was strong and that they use a multi domain outcome. I think it does help us in some ways about the mechanisms of effect here and what's going on in these folks, but there are limited to study.

I mean, is an open label design that there were more dropouts in the ICSI only arm, thirty three percent versus fifteen percent in the combo arm. There was no placebo for the tirzepatide treatment, there was a placebo for execizumab group, you will. As is the case in many PSA trials, the amount of psoriasis going in was modest. Less than five percent of patients had moderate to severe psoriasis. I'll ask our panel if you have any other main points that you want the audience to take away from this.

One to mention is the abstract that was at EULAR from, the TruVeta database, a multimillion population. And what they found in that study was yes, the seventy two percent number, which was the overall population, that were overweight and obese. But if you looked at the PSA population, that was eighty two percent that were, both overweight and obese, which underlines the fact that there is a genetic proclivity toward obesity in the psoriasis and PSA population. So even though they try like crazy to lose weight from diet and exercise, it appears that in many cases, having some aid from a medical agent would be helpful.

Think, and this is an issue as well when it comes to osteoarthritis we're going talk about next in that there have been a few other reports that say how much of a problem this is in osteoarthritis. And then there are of anecdotal reports or small study reports of benefits of GLP-one, and we'll discuss that with the next study. But I wanna get to

a few- One other point I would like to quickly make, Jack, is the fact that when you look at the cellular constituency of visceral fat, it's full of not only fat cells, but also macrophages and lymphocytes. And in visceral fat as compared to lean fat, those macrophages and lymphocytes are now... Are activated. They have become angry, and they're putting out not... They're putting out our usual suspects, TNF, IL six, interferon, and driving inflammation in addition to the leptin adipokine that is put out by fat cells.

And so you've got two pathways of pro inflammation going on.

I think that's really important. I think that's probably one of the reasons why we might actually hit a bit of a ceiling with our conventional therapies and our biologic therapies and treating patients with PSA. I mean, I'm sure everybody experiences this every day. Like you get to a point where you can only get so good and switching from biologic to biologic, switching to a JAK, I mean, you only get so far with it and the patient still has unmet symptoms, unresolved symptoms. And part of that could be these leaky visceral fat macrophages that, are driving especially innate immune cytokines and we just don't have a good treatment for that.

So this could be a bit of a game changer in that way. I wanted to ask Philip one quick thing if I could, Jack. Yeah. So I was really interested in the design of this study when it came out and I kind of thought, you know, if I was designing this trial the first time around, I probably would have just naively said, all right, let's take people who have been on, let's say, ixekizumab or IL-seventeen and haven't quite gotten to the best possible state. And then at that point, randomize them to going on to thornepatide or placebo at that point in time, because that might a little be a little bit more like what I think I might do in practice is adding the GLP or GIP, after we've tried to optimize things with biologics.

So why was this trial designed this way?

So first of all, I think we've got multiple trials that are pending, and you may be already anticipating one of those. But the other point to make is that it would probably have required a larger number of patients than were recruited to this trial to achieve a more understandable difference. And so the patients had not failed an IL-seventeen mechanism, but many of the patients had already been on one or two previous biologics, TNF inhibitors especially, and had inadequate response. So already we're getting into a more difficult to treat population. More females, BMI average was like 38.

The number of tender and swollen joints, this was a very active population. And so I think this gave us one of the best chances with an EM of two seventy seven to see the outcomes that we did.

I like Tom's design, but it would get to the question that's already been answered by other studies in psoriatic disease. That is, if they lose weight, does their disease get better? That's been pretty well proven, but now you'd be proving it with this intervention specifically as opposed specific diet. We ask questions of the audience that pertain to some of the things that we just brought up. What is the mechanism that basically where obesity results in increased PSA activity?

Philip alluded to a depo kine inflammation was sort of the runaway that most people are tuned into. But I think there's more to be learned there about the biology. I'd ask both of you to comment on that. Philip, you want to start?

Well, again, to make the point that, there's also TNF, IL-six, etcetera, that's coming out of the activated macrophages and lymphocytes to that point that I just, made. We're going to see, I think more biomarker analysis in which we are able to document reduction of all of these pro inflammatory cytokines, but that is yet to come. It's gonna come partly from this study, but also others that are planned for the future. I think it's interesting that our rheumatology colleagues already are so much clearly onto this, that the importance of these pro inflammatory molecules.

Tom, in your video today on RheumNow, where you talk about, what's going on with OA, the systemic disease OA, that there are these arms that are weight related and inflammation related. Why don't you get into that?

Yeah, I mean, might be a good dovetail point here between the two conditions and might actually be more shared or overlapping mechanisms among the two conditions. Certainly everybody knows that there are lots of people who present with psoriatic arthritis that can look often like osteoarthritis and vice versa, the clinic can sometimes even be hard to tell apart.

Yes, I can attest to that.

Yeah, exactly. The the other thing I was gonna add here is, there's definitely that visceral adiposity, that visceral fat that we think is coming from the host. But there's also a factor here to be played with the gut microbiome. And the way that our microbiome responds to the foods that we eat, not just how much, but also the types of food that we eat, is also affected by the use of the incretin therapies. And there's a really nice, actually osteoarthritis study that's a little bit more preclinical mechanistic that's looking at types of metabolites that are released by the microbiome in the presence or absence of incretin therapies and how that changes and how those metabolites can actually act on tissues themselves.

So, there might be a little bit of a host mediated effect like the adipokines and things that are released from visceral fat, but there might also be, a sort of a host independent effect of changes in the microbiome as well. So I'm looking forward to seeing more of those studies come out, especially in PSA. I know some of that stuff's in the works.

We also did ask, what limits the use of a GLP, GIP weight loss drug with arthritis biologic and everybody immediately runs to cost insurance formulary. That's always the big excuse, the big worry. But how do you guys see this going forward?

Yeah, I thought that the slice for patient reluctance would have been bigger. Maybe it's just because I talk to people about this stuff in the clinic all the time and the number of people who will say, oh, my neighbor was on that stuff. I wouldn't try that. I wouldn't be interested in doing that. And it's because of nausea or the other GI side effects and things that people have heard about.

And that's what's talked about. And all you have to do is just open Facebook or open your newsfeed and you'll see some sort of article about incretins, whether they're good, whether they're bad and the different side effects and those sorts of things. So everybody's got an opinion about this sort of stuff. So I actually see that as a little bit bigger of a barrier. Philip, what do you usually see?

So I think when we open this conversation, I would say ninety percent of our patients are relieved and excited about talking about it, because it's been on their minds. And we have a trusting relationship, and they want to talk. And either they've thought about going on one of these agents or they are already, it's surprising how many times we find, oh, I've just been started on one of these by my internist. So I think there's a more receptivity out there than we realize. The big issue that has plagued us historically has been insurance shooting us down and saying it needs to come from a PCP or an endocrine or weight loss clinic practice, but I'm already seeing that changing a little bit.

The other small point is that because tirzepatide is approved for obstructive sleep apnea improvement, if our patients have that, it appears to me that we get a little bit better chance if we include that in the application. The other thing that I wanted to just comment is that, and this is again a recent EULAR abstract from Italy. And it was a smaller study and it was just an observational study. But what they found was that this isn't an IL-seventeen combination phenomenon alone. They had patients who were on TNF inhibitors, on JAK inhibitors, as well as IL-17s and upon addition of tirzepatide, they had better outcomes.

So some people have asked me, Oh, does it need to be an IL-seventeen? And no, it looks like it's going to be helpful in combination with any of our drugs.

Lanka Barbosa in Dallas makes a good point. It's a little bit like nutraceuticals and vitamins and whatnot. If you don't ask about this stuff, you may not know that they've already been prescribed either by their primary care or they've been getting it over the internet through a dial in number and telemedicine. Philip, what are the general numbers on psoriasis in The United States and how many of those people get psoriatic arthritis?

Three point two percent of The US citizens get psoriasis or have psoriasis. And of those, between a low percentage of ten, but a more realistic percentage of about thirty percent will have psoriatic arthritis.

Right. These are highly prevalent problems, but then again, so is osteoarthritis depending on how you slice the pie. There's either thirty two million in The United States with osteoarthritis or fifty seven million, and then radiographic numbers or autopsy numbers, why don't you even know those? But this study appeared over a year ago in the New England Journal, once weekly semaglutide in patients with OA of the knee and obesity. Again, an important study because knee OA is driven by many factors, not just weight, it's mechanical factors, it's metabolic factors, and inflammation plays an important, but hard to corral and wrangle.

Data shows that 1% reduction in body weight will improve almost by 2% pain function and stiffness. So this trial was designed as a prospective double blind randomized placebo controlled trial where semaglutide is given versus placebo. It was done in multiple countries. It was a two to one randomization, more people being put on the GLP-one drug. They started at 0.24 and escalated to a target of two point four milligrams once weekly.

That was like Philip mentioned in the other trial, that was achieved by ninety percent of participants. Then the other third of the participants received placebo. Both were receiving counseling on a reduced calorie diet and physical activity augmentation, and that would occur at each visit. This was a sixty eight week trial with a seven week follow-up. You had to be an adult with a BMI of greater than thirty to enter the trial.

You had to have clinical and radiographic osteoarthritis of the knee with Kellgren Lawrence grade two or three, meaning not too mild and not end stage, just right as in Goldilocks. Their pain score had to be 40 or more on a zero to 100 Rheumat scale. They enrolled four zero seven knee OA patients, two seventy one got semaglutide, one hundred thirty six received placebo. The average age going in was 56, eighty two percent were women. The mean BMI was forty and the mean Womack was seventy one on a zero to 100 scale.

The goal of the study was the change in body weight at week sixty eight and the other co primary endpoint was change in Womack pain score. They had other secondary outcomes, including clinical function, percentages of weight loss, and other things within SF-thirty six and other important outcomes. I'll stop there and say, Tom, are there any other important considerations about the design of the trial?

There's a few things and I was even just going to throw in another seven million patients in Canada along to bachelors in The US. Of course, we're about 10 times smaller than you guys population wise. Yeah. I think there's a couple of key features about this. First of all, remember that semaglutide is actually a GLP one receptor agonist only.

Whereas tirzepatide that we were just talking about is a dual agonist. You've got the GLP-one receptor agonist and the GIP agonist. So there's a potential difference there. I think you might see that kind of play out. It's hard to compare these head to head, but you may see that in terms of the magnitude of the weight loss effects.

Something to just keep in mind there when we look at the results. Fact that people were eighty one percent women, think is, first of I think it's a strength of the study. The majority of people with osteoarthritis are women and tend to have worse outcomes and things like that. So it was good to see that actually come through in the demographics here, but the BMI was very high. You know, the mean BMI of most of the osteoarthritis population is probably between thirty two, thirty two and a half, something like that.

So this is well, well north of that. In fact, seventy five percent of the patients in this trial were above BMI of thirty five. So we have to keep that in mind as a bit of a limitation when we look at this extending this to the general OA population, very high BMI in this case, and a very high pain threshold, which of course you want going into a clinical trial where you're trying to get a positive result. Makes sense, you're trying to enrich your population, but you know, Womack pain scores, by the way, Womack was, developed at our centre.

Western Ontario, right?

That's right, Western Ontario and McMaster, Nick Bellamy in the 1980s. So, you know, Womack pain score of 71 is very high up around the range you would see going into an arthroplasty patient population. These people had severe osteoarthritis.

Yeah, most OA trials you need a WolMac pain score greater than 40 and they're usually a little bit above that in their mean. This is, as you said, very high and surprisingly high. So when you look at the outcomes of the trial, on the left, the week sixty eight mean change in body weight was minus 14% versus minus 3% and that being highly significant. The graphics show you the percentage of people on the far left who had greater than 5% weight loss, then greater than 10%, 15%, 20%. So extreme weight loss greater than 20% was still highly significant at week 68, 22 versus one percent.

And then when you look at the pain reductions at week sixty eight on the right, Again, on a 100% scale with mean of 71 going in, they dropped 42 points out of 100 or from a mean of 71 down to 28 or something with semaglutide and they dropped 27 points with placebo. Again, everybody's paying something so you expect the placebo response and you'll see in the next slide what that looks like on a percentage basis, but they're showing you the number of point drops in those two different groupings on the right bottom graph. The other important outcome was going to be safety. There were no major safety differences. Serious adverse events were the same really between groups and the discontinuation was higher with the semaglutide than for placebo, six point seven versus three percent.

Another way of looking at this data is shown with these changes over time. On the left, you're seeing again significant changes at week eight as far as reductions in body weight. On the right, it really seems to get as pain scores. It doesn't seem to happen until after week eight, maybe at week sixteen and week twenty where it starts to get really significant. I'm interested in Tom, what you think about those results.

I'll stop there and Tom, other major considerations on the results and outcomes of the study?

There's a few things to look at here for sure. First of all, week sixty eight feels like a long time, quite different than the TOGETHER PSA trial that ended in week thirty six. So, you know, you're looking at a sixteen week titration period to get up to that maximum dose of two point four, and then a much longer time on the maximum tolerated dose of semaglutide in the study to, to get to this endpoint. But if you look at the trends, so, know, the primary endpoint, sure, at week sixty eight is very, very different. It's a huge difference.

But if you go through even at week 20, you know, there's clear separation between the groups here. Even at week 16, you could say there's probably, you know, nominal p values, we can't necessarily claim anything about the statistical significance there, but, you know, definite separation much earlier on. And I think this is really encouraging for patients who are looking for an improvement in their symptoms well beyond, you know, fifteen months out after starting a therapy. So, so that's, that's point number one. Point number two is the magnitude of the effect.

So if you look at the delta between the placebo group and the semaglutide group out at week sixty eight, you're looking at a 14, just over a 14 difference between placebo and semaglutide. Is that clinically meaningful? And the answer to that is yes. So minimum clinically meaningful difference in Womack pain score is somewhere between eight and nine points depending on which studies you read. And certainly this would be getting close to the effect size that you would see in some of the average effects after even arthroplasty.

So this is a large effect that we're seeing, and we haven't seen this before in osteoarthritis trials with medications. It's just we've seen small effects. We've seen maybe small to moderate effects, but this is around a standardized mean difference of about 0.7 to almost 0.8. So, you know, for the osteoarthritis field, this was a notable improvement. The discontinuations as well, I mean, you absolutely would expect there'd be some discontinuations, due to the GI intolerance, but flip it the other way around, over ninety percent stayed on the therapy.

I think overall quite encouraging.

I think that's somewhat of a testament to the fact that although the nausea and either diarrhea or constipation can be very prominent toward the beginning of therapy, as your body gets used to the medicine, though these side effects tend to dissipate. And I think that the... It's... The testament of that is is how many... What high percentages were able to get to the max dose in both of these studies.

That's a great point. And I think it's also coming back to what you were saying earlier that as you develop more and more skill sets in how to manage the obesity parts of this, whether it's psoriatic or osteoarthritis or other rheumatologic diseases, these principles will extend across and being able to be reassuring for the patient and have that trust relationship that we'll get through this, we'll go slowly, we'll get to the target together, I think can be a really effective strategy.

The study was strong in its design and being blinded and really well done, well powered. Weight loss is a desirable goal in many forms of arthritis and inflammatory arthritis and even in autoimmune crystal conditions. But I don't think it's any as much as PSA and OA. This is a very appropriate study population to come up with a very significant result as they did. Again, strengthened by having co primary endpoints harder to achieve two endpoints at the same time as opposed to a single endpoint, very high retention rates on the drug, higher with the semaglutide versus the placebo 87 versus 78.

It might've been nice with a long trial to have some imaging, but OA, I don't know what to expect in OA imaging trial, especially with plain radiography. It might need five year outcomes and I don't think that anyone's going to fund that. I don't know that we're any closer to understanding the mechanism of action. Is this pure weight loss leading to clinical benefits or as we have already intimated, is it the adipokine macrophage effects, anti inflammatory immunologic benefits that are yet to be really spelled out that could be in play here? I think we'll be seeing more of that in the next two years because people are doing trials where they're trying to look at that.

Then the other thing was, as with the other study, this study gave instruction on diet and activity. But again, its role and its impact was not ascertained throughout the study. Like what if people were not compliant with that? What if they were compliant with that? Would that have changed any of the results?

Do any of the panelists want to add to, the takeaway points in this trial?

I'd like to ask Tom a question. So we know that there are neural effects of these medications. In fact, some people even think that the most prominent, like recent lecture by Will Hsu about the really prominent role that the CNS, plays, in in the action of GLP ones. I'm curious about what led to the pain reduction. I mean, I don't think that it could purely have been mechanical, or maybe that was only a small part.

We've highlighted the pro inflammatory nature of its effects and potentially in PSA. They were really controlling inflammation in a better way. But here it's less clear. And I'm curious where you think some of the inputs are coming from for reduction of pain.

I really like that hypothesis that there could be a CNS acting or centrally acting mechanism that is actually modifying pain experiences. Great hypothesis. And, you know, the good thing is in the osteoarthritis field, there are people who are expert in being able to ascertain those kinds of effects. People like Tahina Nyogi in Boston come to mind, you know, really good at separating peripheral nociceptive mechanisms from central nociceptive mechanisms. There may be a role for some fMRI kind of, analyses and things here.

But I think all we can do at this point in time is speculate about that. But you're absolutely right, GLP-one receptors are expressed in neural tissues. So it's entirely possible there could be some sort of effect there. I guess what we can go back to, and you know, I wish this trial had included a mediation analysis. I wish this trial had included an imaging endpoint as Jack alluded to.

In fact, I wish the Together PSA trial had included an imaging endpoint, and we could talk about disease modification. We're not there yet, but hopefully we'll be able to get there in, in subsequent trials. But you know, the Shanghai osteoarthritis cohort was a place where a mediation analysis was done in people who are on GLPs compared to match patients who are not on GLPs. This was a number of years ago, and they actually showed that indeed weight loss itself, just the number of kilograms loss does mediate the effect of the semaglutide or other GLPs were included in that study on the Womack pain endpoint. But only about 30% of the effect was mediated by that.

So it leaves 65 to 70% of the effect mediated by something else. So maybe it's central nerve acting mechanisms, maybe it's direct actions on the joint, maybe it's the peripheral adipokine mechanism. All of those things are interesting and tantalizing hypotheses, we just need more data.

I want to make two comments about this one. Think without a doubt, the target organ that incretin therapy has effect on is the brain. I think that's going to be shown undoubtedly across the board with its many indications. It's an active trials throughout neurology right now, including in addiction and Parkinson's and other things like other movement disorders. The other thing about this particular trial, the STEP nine trial, for years I've wanted someone to give a great lecture on disease modifying therapy for osteoarthritis and we don't have one, we do now.

I think this is disease modifying and I think it is because of many effects which could be on the brain, but might be other mechanisms as well. We have a few more questions to close with. If you have any questions, you can put them in the Q and A box. Have one, let me see what this is. Philip, the question came up.

Tom brought up the ideas that there's single GLP-one inhibitors and there's dual inhibitors, GLP-one, GIP, and now there are triple inhibitors. Do you think that that's going to be a factor in how these drugs are going to be used? Because they're not all equal as far as their weight loss or other outcomes. There seems to be a hierarchy and these newer double and triple inhibitors seem to be even better. What do you think?

I agree. The data that I've seen so far would be consistent with that, that dual and triple mechanisms, I think there was a head to head between semaglutide and tirzepatide that was published in the New England Journal. And it's clear that tirzepatide was superior in that regard. I know enough about the difference in side effect issues to know whether or not there is more. I think my understanding or sense is that they're pretty comparable from an adverse effect point of view.

But we don't have all the dating in yet with the triple agent. And so we're waiting that to see if it's even seems even better than the dual agent.

Yeah, we've got the retatretide data, at least top line out, but not peer reviewed format. But Lilly's released their retatretide data from the TRIUMMPH-four trial and shows very similar results to the effects that we saw in step nine.

Let's end on this. Catherine Garcia comments that she's noticed that fibromyalgia patients on these drugs are also doing better as far as pain and that could speak to the issue we just discussed about neural pathways being affected. Let's look at this last question.

By the way, that was supported by a big TriNetX analysis that was presented at ACR last year. And although there were some flaws in the analysis, the direction would suggest that it does benefit fibromyalgia. And again, brings up all this neural stuff that we've just been talking about.

This final question, obese OA patients, we asked the rheumatologists who should be eligible for these new novel therapies. And I must say, you rheumatologists are very liberal. Although minority of you are prescribing this, majority think that two thirds think all overweight patients, not just obese patients or obese patients who need surgery or obese patients who have uncontrolled pain. You're saying it's all overweight patients. I doubt it's going to be that liberal if this happens.

Would either you like to speculate on where the first indication will be from the FDA and what the rules of use may be in the future? I mean, right now you treat OA, PSA, RA as you want to, but if they're eligible for one of these agents, for diabetes, cardiovascular risk lowering, weight control or sleep apnea, they can go on the drug. So those are the already existing indications.

I just want to speak to the, again, the concept of having a team, an interdisciplinary team here that is probably going to answer this more broadly. There certainly may be people who have symptomatic enough osteoarthritis or psoriatic arthritis to warrant considering a GLP, and we think that the obesity is standing in the way of them achieving the best possible outcomes. And, yeah, rheumatologists probably is gonna end up leading the charge there, but there'll be other patients that we're following for their psoriatic arthritis or other types of rheumatologic disease, and they have a cardiometabolic or like was suggested earlier, the sleep apnea indication. And so just good communication, I think, the specialists, among the care providers is gonna be really key to get people onto these medications and passing the baton, I think.

Philip, once you prescribe one of these drugs to one of your patients, who else do you get involved?

So sometimes if the patient is open to it, psychologist for counseling through when you think about the combination of PSA, psoriasis, obesity, what does that equal? Depression. So although a sensitive subject, think as sensitive as discussing weight loss, think mental health is an important part of the teamwork. I also, in some cases do want to engage an endocrinology person who is skillful in this arena. Ironically, our area, it's really difficult to get in to see

an

endocrinologist. And so we have to go it alone for a bit, but I'll say, get on their schedule because I'd love to have someone looking over our shoulder as we're prescribing these to bring more skill set to the management of obesity in you.

Yeah, I want to thank our experts, Drs. Appleton and Meiss for their advice and their perspectives on these two papers. I think it's been immensely useful for those of us who are considering these therapies and seeing patients. I want to remind the audience that next week, Touzanic Rheumatology will feature a panel discussion on obesity and inflammation. On that panel will be Juliana Simenetti, who's an endocrinologist, Lihi Eder from Toronto, a rheumatologist, and doctors Naved Sattar and Lee Kaplan who are endocrinologists.

Again, they've researched this area, they're experts on this. We'll do a survey next week and discuss many issues coming up next Tuesday night. With that, I'll conclude our panel and ask each of you to tune in next week for our next TNR. Good night.