- Welcome back everybody to the Building Life Along Out These Podcasts. I'm your host Jordan Wrennke. Thanks so much for stopping by. If you've never been here before, the goal of this podcast is to help keep you active and healthy for life through actionable evidence informed education. And today we're talking about a couple different articles. So we're gonna dive into them right now. Okay, for this study, we're gonna talk about a article that came out looking at GLP-1 agonist for knee pain and kind of whether it can be helpful for knee pain and taking a step back here. Osteoarthritis of the knee is the most common form of arthritis and leads to chronic pain, reduced mobility and impaired quality of life. And obesity as we know is a major risk factor for knee OA arising from both kind of the increasing mechanical stressors on the joints and increased metabolic dysfunction and inflammation. And this presentation explores the potential of GLP-1 receptor agonist, specifically semaglutide as a treatment approach for patients with obesity and knee osteoarthritis. So let's dive in. So currently the current treatment guidelines recommend a weight reduction and physical activity as first line management for pain. I don't think anybody's gonna change any of that anytime soon. I think that's always gonna be a first line here. But as always, it's always better to have more options than less, so we're looking at that. And specifically, they talk about adhering to lifestyle modifications like diet and exercise are a staple of treatment of knee pain when we have excess adiposity as well. Well, here in this study, we're introducing semaglutide, which if you haven't heard of semaglutide yet, you're probably living under a rock 'cause it's everywhere, right? Talking about the brand names are Ozempic and Wegovy. This is a once weekly injectable GLP-1 receptor agonist. I've had previous podcasts about that, so you can go back and listen to that. And it is approved for weight management in people with obesity. That's what it is specifically. And in the US, semaglutide is also approved and improved to reduce the risk of major adverse cardiovascular events in adults with established cardiovascular disease and overweight or obesity. And obviously it's also indicated for diabetes as well. So that's like the general landscape of what these medications are. And here we're gonna see kind of a unique case, use case for it as well. So what was the design of the study? Well, this design was a double-blinded, randomized placebo controlled trial lasting 68 weeks with a seven week followup. So that's pretty much our gold standard right there. Double blind means nobody knows who's getting the intervention. The patient doesn't necessarily know and neither does the physician there. It's randomized, meaning it's hopefully very similar people in the control group versus people getting the experiment. And then placebo, once again, we have a placebo, which is great. And these participants, these were adults with obesity and moderate knee osteoarthritis experiencing at least moderate pain. And the interventions was a once weekly semiglutide injection at 2.4 milligrams or a placebo. Plus also both groups got counseling on physical activity and reduced calorie diets. So this wasn't just, hey, here's a medication, take it. They did that and they did lifestyle counseling as well. And the primary end points specifically looking at percentage change in body weight and change in WOMAC pain scores. And WOMAC is just an acronym for a very common test. It's a kind of a questionnaire used frequently, frequently for arthritis. And so we're looking at a very standardized test here. So we're looking at change in body weight and change in these WOMAC pain scores. In terms of weight loss, what do we find? Well, unsurprisingly, GLP-1s are very good for weight loss. Participants receiving semiglutide experienced significantly greater reductions in body weight compared to the placebo group. So about 13.7% reduction in the semiglutide group versus only 3.2% in the placebo. And a higher percentage of participants in the semiglutide group achieved clinically significant weight loss, meaning greater than five or 10%. And actually what's crazy means about 47.8% of participants lost more than 15% of body weight with semiglutide. That's big. And the reason this is big, and we're kind of jumping the gun here, but usually in clinical studies or anything like that, more than a 5% weight loss is clinically significant. We start to see health benefits in terms of blood markers and other functional things start to improve at about 5%. And so we're having people here who are losing more than 15%, which is huge. And so almost half of the people got more than 50% weight loss, which is really important because clinically that's gonna make a big difference. They also looked at pain reduction as well. And semiglutide led to significantly greater reductions in WOMAC pain scores versus the placebo, meaning that they dropped about 41.7 points versus 27.5 in the placebo. And what this is essentially, this is a big scale. And if you lose more points, that means you're not having as much pain. So you're doing better. On top of that, there was a subgroup analysis done that showed consistent pain reduction benefits across BMI categories. So, you know, depending on where you are with BMI, it didn't really matter. You seem to get benefits as well. Improvements were also observed in other pain-related measures like daily pain intensity and stiffness scores. And then they also looked at physical function as well. Right? 'Cause you know, if you just have pain, that's good, but like, can you do more with it? And they found that semiglutide significantly improved physical function as measured by once again, the Womax scores and the SF36, which is another validated form. So long story short, it didn't really matter, but they seem to show improvements in physical functions, things like a six minute walk distance. So get up and go. When you have a six minute walk test, it's like, hey, how far can you walk in six minutes? They improve that. And that's a big thing, right? We're improving actual function of patients. So that's why we really care about that. They also looked at use of pain medication as well. And it looked like overall for the use of pain medications, particularly nonsteroidal anti-inflammatory drugs or NSAIDs and acetaminophen or Tylenol, both the use of those drugs decreased more in the semiglutide group compared to just the placebo, suggesting a potential Ed said sparing effect, which is great 'cause those medications also have side effects as well. And from a safety perspective, the incidence of serious adverse effects was similar between semiglutide and placebo groups. And there were no unexpected kind of safety signals seen. And side effects wise, we did see some side effects. We always see side effects with any medication. I tell someone, if you have no risk for side effects, then that's not a medication worth taking. And I say that in kind of, I'm kind of joking, but people say, oh, there's no side effects to this, you know, whatever natural supplement or whatever. It's okay, if you don't have any potential for side effects, that means we're not actually doing something physiologic. So we're always gonna have side effects in anything we do. And there were ones and the common ones we usually see. We saw gastrointestinal disorders were the most common adverse events leading to discontinuation of the semiglutide group. But you know, that was the highest one. It wasn't huge or really significant, but you know, the side effects that they did complain about most were GI side effects. Usually people have either nausea or vomiting, sometimes diarrhea. Usually that can be well tolerated if you start low and kind of increase from there. But sometimes people have that and can't tolerate these medications. And so how are these medications working? Well, it's probably a combination. The real answer is we don't really know, right? We just looked at studies and we're kind of extrapolating from there. You know, we think that when we lose weight, we are reducing mechanical stress on the knee. You know, I'm not a person who believes strictly in the biomedical idea of pain that like, it's just structure that's risen, causing pain. But if you think about it, it definitely makes sense. If we're reducing mechanical load on the knee, that may be helpful. Time and time again, we see that weight loss tends to improve neostroarthritis outcomes. But is it because of weight loss or is it because when you lose weight, you're typically losing some amount of adipose tissue. And by doing that, you're probably decreasing inflammation in the body. We know that losing weight probably improves inflammation. And so GLP ones may have this anti-inflammatory property as well. And is it just because of the medication or it's because we're losing weight? Not sure there, we're kind of yielding that in the future. That's kind of what we're looking for. But it may be this combo of reducing mechanical stress and also decreasing inflammation, which may be leading to benefit. And so what are the big takeaways here for clinicians? Well, I want to reiterate that semiglutide seemed in this study to be effective in alleviating pain in those who had neostroarthritis and obesity as well. So this population is people who had obesity and moderate neothritis. Like that's the group we looked at. The important thing to understand is we cannot extrapolate this to people who do not have obesity and have arthritis or people who have really severe arthritis. That's not the population we're looking at here. We have to understand the sample you looked at in your population and how you can apply that. That being said, would it be a reasonable thing to try with someone with severe OA? I think absolutely it'd be very reasonable to try. I wouldn't see this and be like, well, I can't do it 'cause it's not there. But I just understand that's who we looked at here and it seemed to be helpful for them. And I think this does have some potential implications for primary care. I think semiglutide for the right person who has maybe struggling with obesity, maybe has some arthritis, this could be a reasonable option. This wouldn't be something we're prescribing just straight for arthritis. It's for all the other things. 'Cause when we have that excess adiposity, we have lots of increased risk factors as well down the line. So it's not like, hey, you come into my sports medicine clinic, I'm gonna prescribe this just 'cause you have a new arthritis and you're a regular BMI. No, we have other comorbid things as well. But it's kind of cool to think about. And I think really this is gonna open up the flood gates to what I think in the future is gonna be called essentially metabolic orthopedics. I see it time and time again, I have the luxury of being a primary care physician in terms of family medicine and sports medicine. So I see both. My overlap is huge on these. And I think that's gonna be a big thing. We're starting to realize that increased adiposity leads to lots of orthopedic issues and from an inflammation standpoint, from a mechanical standpoint, it's not good. And so kind of, I'm trying to, how do I tailor my approach as a sports doctor to say, hey, when you come to my clinic, I have to carefully address that. As a primary care doctor, you see them, you have a built relationship. For me, I'm a specialist when I'm in sports and it's kind of hard. I don't have that relationship. I don't have the rapport to say, hey, something that may be helpful is weight loss. That's a hard thing to necessarily say to someone you've just met saying, hey, I think if you lose weight, you're better, it sounds insensitive sometimes. And like I'm just missing their pain. And so I'm trying to figure out how to better practice from my perspective. How do I incorporate this in my practice saying, hey, there's been studies that show weight loss can be helpful for arthritis. And so trying to do that as well and understand that this is a new tool in the toolbox. If a patient is in a lot of pain and maybe they can't do as much exercise or less job to lose weight, this may be helpful. And so just kind of a cool thing to think about in a new tool in our toolbox. But once again, it has to be for the right patient. I'm not just gonna prescribe this 'cause you have arthritis. It's gotta be other risk factors as well, like obesity or overweight or diabetes, something like that. But it's kind of cool to think about, it's all becoming interconnected. Is there an underlying cause of all these things? This metabolic dysfunction, is it causing the adiposity, the diabetes, the arthritis? Who knows? But it's kind of cool to think of a unifying theme. In this article, we're gonna talk about the intricate relationships between physical activity, cardio respiratory fitness and cardio metabolic health and kind of how they're all weaved together. So let's dive into it. For a little background, what is cardio metabolic health? Well, cardio metabolic health, it's kind of a cluster of interconnected risk factors, including things like waist circumference, obesity, blood pressure, cholesterol levels, triglycerides, blood sugar, and all these things and how they increase your risk of having heart disease, stroke, type two diabetes, or any sort of what we call kind of cardio metabolic disease. That's kind of the bucket we look into. So that is cardio metabolic health is the absence of those things. Cardio metabolic disease is, hey, we see these things kind of grouped together, causing these bad outcomes. And what we're looking at today is specifically the role of physical activity and cardio respiratory fitness and how it's related to cardio metabolic health. And so there are definitely established benefits for improving cardio metabolic health, right? We know that. But the central question in this study is, how are physical activity, cardio respiratory fitness, and cardio metabolic health interconnected and what role does intensity play as well? So what we mean by that is physical activity is like, I just got up and took a walk. I'm going on a walk. You're physically active, but it's not gonna do a whole lot to improve your cardio respiratory fitness. Cardio respiratory fitness, we think about like, hey, your VO2 max, how much oxygen intake, just essentially your quote unquote cardio, like how good and how good a shape are you in and what is your fitness? That's a cardio respiratory fitness. So the question is, are we getting benefits from just being physically active or do we need to do more than that? Do we need to have a higher intensity to improve our actual fitness level to get the biggest improvement for cardio metabolic health? So that's what the studies we're looking at here. So we'll dive a little more deep right here. And stepping back, there's definitely been research done on this before, but there's kind of some conflicting evidence. There's conflicting findings on the relationship between physical activity, cardio respiratory fitness, and cardio metabolic health. Some studies suggest that cardio respiratory fitness fully mediates the relationship between physical activity and cardio metabolic health. What I mean by that is that the fitness is responsible for the benefit and physical activity is just kind of a, hey, if you're improving your fitness, you're being physically active. So like, it doesn't really matter if you're physically active at a low level, it's only your fitness. But others show independent associations between physical activity or fitness, meaning that, hey, you see benefits with physical activity and not just with things that improve your fitness. So that's what we're looking at here. And there are differences in how we measure physical activity which is kind of challenging, right? So we're gonna, in this study they measured physical activity and cardio respiratory fitness. There's different ways to do that, whether it's self-report, accelerometry, which is like people wearing stuff around like pedometers and walking around or things like heart rate, VO2 max, there's lots of different things we're looking at there. But really what we're looking for here is we're trying to understand the interplay of physical activity, intensity, and cardio respiratory fitness and if it's critical or not for kind of, you know, really getting the most benefits. And with these understandings, hey, if we find that this intensity is important, how do we use that to then improve our clinical outcomes and then also public health recommendations? So the study population, this was about 4,100 people from this escapist study, which is a Swedish cardiopulmonary study on adults age 50 to 64. And what they did, they essentially compiled what they call a cardiometabolic risk composite score or a CS. And this score is constructed using five key risk factors associated with cardiovascular disease and type 2 diabetes. Things like waist circumference, systolic blood pressure, total cholesterol to HDL ratio, more info on that in previous podcasts, triglycerides and your HbA1c. And so what they did is they kind of used these numbers and they use these variables and they convert them to a standardized Z score. So kind of a standardized process. This process of getting this, puts all the variables on the same scale, allowing for them to be combined for analysis that gives equal weight to each risk factor. So what they're trying to say is, hey, they did some math behind the scenes to say, we're gonna try to standardize each of these values and it gives us equal weight for each risk factor. And this cardiometabolic risk composite score, the CS, a higher CS represents better cardiometabolic health. So that's what we're looking at there. And from a cardiorespiratory fitness measurement, they did a submaximal cycle ergometer test or since they're on a bike and they were measuring the cardiorespiratory fitness. It's not the gold standard, which is usually like a treadmill VO2 max, but like it's a very reliable test and much more feasible for people to do so they don't have to go into max effort. So this was a submaximal based off of the numbers they can kind of extrapolate what your fitness is. So that's how they measured that. From a physical activity measurement, they had accelerometers that were worn on the hip for seven days. And then they also had advanced data processing to capture the full spectrum of physical activities as well. And for statistical analysis, they ran through something called a partial least square structural equation modeling. It's kind of fancy, but what it does is it essentially handles collinearity of physical activity intensity variables, which means that the model helps correct for the fact that exercise intensity is not completely independent. Meaning that when you're exercising, if you're exercising intensely during the day, that will affect how much sedentary time you have. So you can't just necessarily have only looking at physical activity and only looking at cardiorespiratory fitness. A lot of times they're interconnected and this kind of fancy mathematical modeling kind of helps adjust for that as well. So overall, what did they find? Well, first starting with physical activity and cardiometabolic health, they found that higher levels of physical activity were linked to better cardiometabolic health. That's great. This association though was weaker after statistically correcting for the influences of age and sex. And this adjustment kind of suggests that while physical activity itself does contribute to better cardiometabolic health, age and sex also play an independent role in shaping this cardiometabolic health as well. And what they did find is that moderate intensity physical activity most strongly linked to cardiorespiratory health. And so the standardized physical activity pattern, which captures the overall contribution of different physical activity intensities compared to cardiometabolic health, it peaked in the upper moderate intensity range. So they found that to get the best bang for your buck, you started to see the most improvement in cardiometabolic health when you were in the moderate, moderately high intensity range. And what did they find for physical activity and cardiorespiratory fitness? Well, there was a positive association between physical activity and cardiorespiratory fitness, indicating that individuals who engage in more physical activity tend to have higher cardiorespiratory fitness. Makes sense. People are doing more things that are active. It leads to being more fit. And similar to the relationship between physical activity and cardiometabolic health, this positive association between physical activity and fitness became even more pronounced after dressing for age and sex. And the strengthening of this association suggests that age and sex might confound the relationship between physical activity and cardiorespiratory fitness. And accounting for these factors provides a clear picture for the true impact of physical activity and cardiorespiratory fitness. And what they did also find was that vigorous physical activity most strongly associated with cardiorespiratory fitness, which is not really surprising at all. The harder you work, the more intense you work, the better your fitness is probably gonna be. And the standardized physical activity pattern for cardiorespiratory fitness peaked at upper vigorous intensity ranges, which once again highlights the importance of higher intensity activity for enhancing your fitness. And then what about cardiorespiratory fitness and cardiometabolic health? Well, there was a strong association with improved cardiometabolic health without more fitness you had with a coefficient of 0.59. So this is a path coefficient. And essentially what this does, this quantifies the strength and direction of the relationship between variables in some sort of statistical model. A value of 0.59 suggests a substantial impact on cardiorespiratory fitness on cardiometabolic health. This finding aligns with the well-established understanding of the higher levels of fitness you have, the better cardiometabolic you typically have. So not a huge shock there by any means, but the more fit you are, the better outcomes you'd typically have. And what they did after this was kind of cool. It was called a mediation analysis. And this mediation analysis is trying to step back and say, okay, cool, I see these associations, but like what actually causes, what's actually the most important thing and what percentage of these improvements in cardiometallic health can be equated to either physical activity or cardiorespiratory fitness. And what they found was that cardiorespiratory fitness mediated about 82% of the association between physical activity and cardiometabolic health. And that moderate and vigorous physical activity densities jointly influenced this mediation model. So this mediation implies that the effect of physical activity on cardiometabolic health is not entirely direct, but rather it operates in large part through its influence on cardiorespiratory fitness. So cardiorespiratory fitness dominated the relationship between cardiometabolic health, meaning that they think about 82% of the improvement of this improvement in cardiometabolic health is due to your fitness increase. And so physical activity is kind of coming along for the ride and it's tough. Once again, how do you completely parse this out? It's just doing data analysis, which is never concrete, meaning this is definitive. But what they're saying is those people who are doing higher levels of fitness tend to have better cardiometabolic health. And you'll also notice higher levels of physical activity in these people as well, 'cause that's right. If you're doing more high-tensy work, you're doing more overall work. And so it seems to be not necessarily just the overall level of physical activity, it's really getting those adaptations from a cardio perspective, which seem to increase the outcomes of cardiometabolic health. And so, I thought it was interesting. There was also a weak, but statistically significant direct association between physical activity and cardiometabolic health, even after considering fitness. So I'm not saying physical activity is not worth it, that's all. So there is partial mediation where, cardio respiratory explains most, but not all of the links between physical activity and cardiometabolic health. And so I'm not saying, if you're not working hard, you're not doing anything, no, that's not the case at all. There's still some benefit, there's plenty of benefit from physical activity, but it seems like the biggest improvements we get are when we increase our fitness. And so overall, the sources point out that both moderate and vigorous physical activity intensities contributed to the complex mediation model, meaning that both moderate and vigorous seem to improve things. And while vigorous exhibited the strongest link to increased cardiorespiratory fitness, moderate intensity physical activity also showed a significant association with cardiometabolic health and fitness as well. And overall, it suggests that engaging both moderate and vigorous physical activity is beneficial for overall cardiometabolic health, which is pretty much what the physical activity guidelines talk about. And the specific physical activity pattern that maximize the association with the cardiometabolic health, start in the mid-moderate intensity range and peak in the upper moderate. So low level, very light walking, although can be beneficial in some regards, isn't gonna move the needle a lot improving your fitness unless you're really deconditioned. And so once again, like the physical activity guidelines talk about moderate to vigorous activity, that's pretty much where we're gonna go and we're gonna see the biggest benefits. And so what were the strengths and limitations of the study? Well, the strengths, well, they used objective measures, which is great, things like accelerometers, and they did an ergometer test of looking at your actual cardiorespiratory fitness, those are awesome. They had, they did detail, data analysis, which is great. And they used kind of sophisticated statistical modeling, which is also kind of one of the limitations in that like when you do really sophisticated statistical modeling, it's like how much is this is actually real world and how much is this, how do you tease out all that stuff? It's kind of challenging. From a limitation perspective as well, there was a cross-sectional design and so it wasn't interventional by any means. So we can kind of generalize ability is kind of a little challenging there. And also this study kind of excluded participants with cardiovascular disease. So generalize ability, meaning, hey, is this gonna improve people with cardiovascular disease? We can't quite know that from the study. That being said, exercise is good for pretty much everybody. Healy will probably see improvements as well, but we can't extrapolate these findings to that. And so what are the big take home points from this? Well, first of all, I think cardiorespiratory fitness can kind of serve as a proxy for cardiometabolic health. Obviously there's gonna be exceptions, like people in the NFL who weigh 320 pounds, but are incredibly fit. Like they're not necessarily healthy, but on average, people who are incredibly fit and have high cardiorespiratory fitness are probably gonna have better cardiometabolic outcomes. And on top of that, we also have to focus on hitting the right type of exercise to improve these measures, right? So emphasizing moderate to vigorous physical activity is gonna be optimal for increasing our cardiometabolic benefits. And so understanding as a physician here, prescribing, hey, like any physical activity is good. If we're doing nothing, let's do something, but if we're doing something, let's do more. Let's do something to get your heart rate up, let's get you working a little harder. So that's kind of the takeaway I had from these specific lessons here. And I thought it was a really important and kind of cool article to talk about. And that's gonna do it for our podcast today. Thanks so much for stopping by, I really appreciate it. If you found this helpful with me in the world, so maybe if you either gave us a five-star review on your podcast platform or choice, or if you shared it with a friend, that'd really, really helped get the word out about the show. But I really appreciate you stopping by and I'll get off your phone and get outside and have a great rest of your day, and we'll see you next time. Disclaimer, this podcast is for entertainment, education, and informational purposes only. The topics discussed should not solely be used to diagnose, treat, or prevent any condition. The information presented here was created with an evidence-based approach, but please keep in mind that science is always changing, and at the time of listing this, there may be some new data that makes this information incomplete or inaccurate. Always seek the advice of your personal physician or qualified healthcare provider for questions regarding any medical condition.
