What can we learn from the latest research on krill oil's effects on knee osteoarthritis? We dive deep into the study's transparency and rigor, exploring the impact of adherence rates and the significance of measurable markers like effusion synovitis. Our spirited debate covers biases in healthcare, the balance between skepticism and openness to new evidence, and the emotional responses tied to negative trial outcomes. This episode is packed with thoughtful reflections and expert insights, making it essential listening for anyone interested in evidence-based integrative medicine. Tune in for a comprehensive and engaging exploration of the complexities of clinical trials!
Learn more and become a member at www.DrJournalClub.com
Check out our complete offerings of NANCEAC-approved Continuing Education Courses.
What can we learn from the latest research on krill oil's effects on knee osteoarthritis? We dive deep into the study's transparency and rigor, exploring the impact of adherence rates and the significance of measurable markers like effusion synovitis. Our spirited debate covers biases in healthcare, the balance between skepticism and openness to new evidence, and the emotional responses tied to negative trial outcomes. This episode is packed with thoughtful reflections and expert insights, making it essential listening for anyone interested in evidence-based integrative medicine. Tune in for a comprehensive and engaging exploration of the complexities of clinical trials!
Learn more and become a member at www.DrJournalClub.com
Check out our complete offerings of NANCEAC-approved Continuing Education Courses.
Welcome to the Dr Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Continue your learning after the show at www. d rjournalclub. com.
Dr. Joshua Goldenberg:Please bear in mind that this is for educational and entertainment purposes only. Talk to your doctor before making any medical decisions, changes etc. Everything we're talking about that's to teach you guys stuff and have fun. We are not your doctors. Also, we would love to answer your specific questions on drjournalclub. com. You can post questions and comments for specific videos, but go ahead and email us directly at josh at drjournalclub. com. That's josh at drjournalclub. com. Send us your listener questions and we will discuss it on our pod. Hello and welcome to the Dr Journal Club podcast, where I've missed my podcasting partner lately. It's good to have you back, sir, I have to say.
Dr. Adam Sadowski:Hello, hello, hello. How are you?
Dr. Joshua Goldenberg:Good, good, you were well missed. I do have to say I don't know if you listened to the last um, the last pod, but I I had a ode to I owe to you in the middle. It's like, oh, this is so boring. I just it was so weird talking to myself about the, the paper, I just felt like it was uh speaking out into the ether like the the old days, or something like that that's probably gonna have the the most views or the most downloads to watch yeah, they're like hey, everyone, adam's not on this one, take a, take a listen.
Dr. Joshua Goldenberg:Yeah, although it's funny, like you get into your rhythm and then you just start talking and it feels normal, but at first you're like I'm talking to nobody. This is very, very strange right and I was realizing like we've done this for a long time, like it was kind of weird at that point because you know, basically I think we've been doing this for a year and a half, something like that, definitely over a year since last october, I think oct.
Dr. Adam Sadowski:Because I remember it was the fall or the winter of my final year of residency and I just remember us talking about studies and we were like let's just you know we already talked about all of this. Why don't we just share it with others?
Dr. Joshua Goldenberg:Yeah, let's just basically still do it.
Dr. Adam Sadowski:And then literally the next week week. We just started doing that.
Dr. Joshua Goldenberg:Yeah, and it's been fun. Man, it's getting easier and easier to podcast, I have to say, and now there's like technology that we can remove filler words and all this jazz, but anyway. So how are you? Briefly, how are you in life? It's been a while. The listeners haven't heard from you in like months and months and months and months. How are you doing? What are you doing? The rumor on the street is you are no longer training for triathlon. Is that true? Is that a blatant lie? Are you back on the saddle? What is going on?
Dr. Adam Sadowski:The rumors are semi-true. Overall, life is great, but with the triathlon training and working as a full-time clinician and doing a lot of other extracurricular things and wanting to also have a life, it's that last piece that's gonna get you every time yeah and it was just a culmination of things and just honestly started feeling really burnt out with it.
Dr. Adam Sadowski:Uh, when I first started I actually just truly enjoyed the training component of it and really just liked going to every training session, and then that only recently really um, started to dwindle to the point where I then just hated every single training session I was doing and then I was like, why am I actually doing this?
Dr. Adam Sadowski:I'm not a professional triathlon, you know triathlete if it's not fun, you gotta stop yeah and I was like I'm not trying to prove this to anyone and I know I can do all of the events because I I've, you know, I've done every single event on its own and I have done combinations of it.
Dr. Adam Sadowski:I've just never done the full thing, like at an actual iron man event. And then I was like, well, you know, if I, if I know I can do all these things, that was really kind of the internal motivating factor of it. I was like, well, can I even do it check? I don't need to prove it to anyone else. And then why do I have to bring it on a very specific day, right at a very specific time, when it at first is like, hey, I feel really good today, like let's just go, versus let me go to a race event and have all the stuff that I'm used to be, all these like weird variables in the way of like you know a different hotel room and like sleeping at a different hour and like you know nutrition's not the room, and like sleeping at a different hour and like you know nutrition is not the same versus like, hey, I just woke up, felt really good and went for it.
Dr. Joshua Goldenberg:Yeah, no, that makes sense. I mean, you, you hit your goals, so now you just got to find new, new goals, to have new things to hit from her. For, like, that's the thing I like about having some sort of like I hear what you're saying, but for me, anyway, I need that external like requirement, or I just don't get it done Because there's like you know, you have a couple races a year, you train up for it, and then there's always like I need a little break for a month or something right, like I kind of let things go, and then it's like, oh, you got another race in six months, josh, like you got to prep again, and so for me, like that is, especially with, like, the fear of death in water, is like enough of a motivator to like show up and do the the training sessions. But yeah, if so, that's for me.
Dr. Adam Sadowski:But yeah, if you're able to just get it done and that was your motivator, then you're good man also it's a very expensive sport, and so it is for the most part I was just kind of of you know winging it, like I have a lot of like used stuff and just like buying stuff on the very, very cheap. Yeah.
Dr. Adam Sadowski:And then I was like, well, if I'm actually going to do a race, the race itself is going to cause cost upwards of a grand, and then to get all this other equipment and like working equipment and stuff like that, it's gonna cost a pretty penny.
Dr. Adam Sadowski:and then when I, you know, calculated all out, I was like I would much rather fly first class round trip around the world vacation for two weeks with, like, my best friends and like, live it up, then endure, you know, eight hours of pain in one day, just to get a little piece of plastic that says you can do, just to say you did it, yeah, yeah.
Dr. Joshua Goldenberg:And then the classic line for triathlon is like oh, did you win the race Me? Like no, no, I finished the race. Yeah, oh well, did you come in like there? No, I was like 130th in my age group, you know. Yeah. But well, well did I. Briefly did I, speaking of cheap equipment, I told you about what happened with my bike on my first try, right, my first one and only try. Yeah.
Dr. Joshua Goldenberg:Yeah, yeah. So I think the having decent equipment matters. Like you can't really wing it and it's just like some things, like everything else that I've done in terms of this, I always just get the cheap stuff or like whatever, like I don't know that it really matters, and but I think here like yeah, ok, you don't have to buy like the $10,000 bike, but you should probably buy a nice bike, right, right, if you're going to, and then you should probably protect it when you travel and all that jazz.
Dr. Adam Sadowski:Anyway, this has nothing to do with what we're talking and yeah well, and also like just for anyone out there who's like also kind of going through anything similar, like it just quit, like it's it's okay, like I feel like there's this you know thing and with society of like, if you quit, yeah quitting is okay well, no, no, not that quitting is okay. Well, it is okay, but that like if you quit, you failed oh yeah it's like I didn't fail anything.
Dr. Adam Sadowski:I was like doing something that I just wanted to kind of like fool around with and see if I liked it, and at the time it was something that I really enjoyed doing, and then I didn't like doing it. So I'm not going to do a sunk cost fallacy where you're just going to keep investing into something that you're either not enjoying or just's just a failure, with the hopes that, well, I'm already down this far, let me just keep. At some point it's got to turn around.
Dr. Adam Sadowski:No cut your losses and like, move on. And so like I mean, I still went for a run today, I still do things I enjoy.
Dr. Joshua Goldenberg:It doesn't necessarily have to be, you know, grueling hours on a to be, you know, grueling hours on a on top of an already hectic, you know, work schedule. Yeah well, dude, you were training for half iron man, right? So that's like crazy hours, yeah, so that totally makes sense to me. What did I want to say about that? Oh, yeah, well, it's also. It's not well, I don't think you failed at all, but it's like or cutting your losses. I don't think there are any losses, but um, the.
Dr. Joshua Goldenberg:The other thing is like it's, it's what you're like, what are the outcomes that you've selected, right? Is it to get that metal at the end of a finish line, that like that piece of metal that probably cost them two dollars, right? Or is it to stay fit and healthy, or to prove that you're able to accomplish something physically? And if it's the latter two, like, yeah, nailed it, yeah, check, and so like, yeah. So I think it depends on like what, the what the outcome measure is right. So, to bring this back to clinical trials, it's like what is the, what is the clinically meaningful outcome here? Right? Like what's the outcome that that's meaningful to you? And you could even argue that, like to extend this obnoxiously, you can even argue that like the metal, or doing the actual race is just a surrogate outcome to like. Yeah, health and wellness, you know but I don't know.
Dr. Adam Sadowski:I just feel like, you know, looking back to, it's kind of silly of like, hey Adam, let's go hang out. It's like, oh no, hold on, I have to go sit on a saddle for three hours watching Netflix, but you go ahead, go have fun.
Dr. Joshua Goldenberg:Yeah, fair enough. I think it sounds like you've made the wise, smart decision and you've proven that you can pull it off, which I think is impressive.
Dr. Adam Sadowski:And I got better at three things. You know, I got better at running, I got better at swimming, I got better at biking. I'm going on. I still go on bike rides, but like they're more leisurely with friends, let's go check something out. It's still fun to do those things, but not with the mindset of, oh, I'm doing this because I have to do it for triathlon training, it's more so. Oh, I'm doing it because it's a night day, let's go on a bike ride.
Dr. Joshua Goldenberg:Yeah, we should just call this podcast the Triathlon Podcast at this point. But the one of the things I liked about switching to actually getting a proper trainer this year is that I used to just like go out and like put in those hours, thinking that that's what I needed to do. And I think that, um, what she has me on now is like, okay, you do 30, 40 minutes of like something every day and then you do your long ride, you know with a, you know with a brick or whatever, like you do at the end, but on the weekends and obviously that builds up as you get closer to the race. Yeah, I think it was just doing those continuous long runs every time was like so draining for me and to just like, oh yeah, I'm just working out for 3040 minutes a day, like that seems totally doable. And then, yeah, there is this one long thing on the weekend and as you get closer to race day, it gets like more and more owners, so it takes up more and more of your day plus recovery time. That's hard on families and life and all that.
Dr. Joshua Goldenberg:I think my total minutes of training is lower now but I feel better about it, like it's less of a drag, I guess, okay, should we talk about science now and medicine? Yeah, we can. Okay, sort of. So you know, we're only 10 minutes 20 seconds in. So, speaking of biking, speaking of knees, speaking of knee pain, we are going to talk about a. You see how I did that. That's professionalism, right there. It's a really nice transition. Just note that.
Dr. Adam Sadowski:We're talking about migraines today. People.
Dr. Joshua Goldenberg:Shoot did
Dr. Joshua Goldenberg:So my friend Adam here sent us this article on krill oil for knee pain and because of his contrary nature I'm suspicious that he sent it because it was a negative trial and he likes to be contrary about integrative medicine. Is that true? Or did you just see it and sent it before you saw the results?
Dr. Adam Sadowski:I wouldn't label it as a contrarian. I would label it as I'm a skeptic of a lot of things, and I think that there's too much direct to consumer nonsense out there, and so I really want people to question things when they see things, especially since at a lot of these integrative events there's a lot of lab testing industry, there's a lot of supplement salesmen, and I want people to actually understand what the evidence is for what they're using these supplements for, and not just taking it because some sort of fancy paper by someone who's wearing a suit and tie, who isn't actually a researcher, is telling you this is the next best thing and it's no different than a pharmaceutical rep doing the exact same thing. And so I think that really we need to question that and recognize that that is a big thing in the integrative evidence space that no one wants to talk about, and so I will happily talk about it.
Dr. Joshua Goldenberg:Excellent. I have to admit, it's really been weird, ever since we've been friends, to have someone more on that wing of things than I am. I feel like most of my well, all of my career in natural medicine, I feel like I've been that contrarian. What did you say? Oh, not contrarian, curmudgeon, oh wait, no, no, you said critical thinker. Okay, so I feel like I've been that one, but to have someone outflank me is impressive.
Dr. Joshua Goldenberg:Um, but at this point, like I think I sent you something the other day. I was like what we should do this? Like, um, colored noise analysis. Now, I was serious. I was just like no, I was serious about that. I was like you know, the white noise versus brown noise, versus pink noise, there might be some neat studies, like whatever, and you know, just an immediate response no, like that's ridiculous. Like adam, you haven't even read it. This could be a thing. You're like no, that's too weird, forget it anyway, all right, so we're going to talk about this study. So, let's talk about this study. Um, okay, pulling up here about this study. Okay, pulling up here, all right. So this was a JAMA paper, which was, you know, always nice, real JAMA, jama, jama, not JAMA. One of its myriad offspring, and this just came out this year. Do you want to set it up? You want me to set it up? What's the rationale for? Well, no, you don't read the introduction. Did you read the introduction? This?
Dr. Adam Sadowski:time. Yeah, I actually read the introduction. I also read the discussion. Whoa. I did because I wanted to see how it compared to the three other trials that they talked about in the introduction.
Dr. Joshua Goldenberg:Yes, yes, exactly the whole time, the entire time. Once I got to the results, I was like good study, good study, good study, good study got the results like huh, surprising, surprising, surprising. And all that was going through my head was well, how did you mess this up? What were the other trials that set this up? And yeah, and I think they did a good job of that in the discussion. So that's your foreshadowing. So set us up what was the rationale for this study design.
Dr. Adam Sadowski:Yeah, yeah, and just with that thought process, you and I are literally the same person. It's kind of scary, no, I agree on many levels.
Dr. Adam Sadowski:Yeah, but yeah. So basically, knee osteoarthritis affects a lot of people. Actually, in the paper they quoted, 654 million people above the age of 40 have knee osteoarthritis. They also said that there's no medical therapies that improve the natural history of it, meaning once it's set in stone, it kind of is this progressive issue. And so there's this also from a mechanism of action standpoint. You know, reducing inflammation may reduce pain, may improve outcomes in people with osteoarthritis.
Dr. Adam Sadowski:In omega-3s there's evidence that it reduces inflammation and because we love mechanism of action, if you can reduce the inflammation with something, then therefore we should have improved knee osteoarthritis. On top of that, krill oil, as opposed to fish oil, has improved bioavailability, so there's better uptake of it, and it contains an antioxidant called astaxanthin which also can help from, you know, inflammation, free radicals, yada, yada, yada. And then they had three prior randomized clinical control trials that showed daily krill oil reduced some aspects of knee pain in individuals with knee osteoarthritis. However, compared to this trial, none of those trials included individuals with effusion synovitis. So essentially, that joint space having some inflammation of that synovial fluid, the lubrication within the joints. So this way you're not, they're not grinding on each other. I think of it as like break fluid basically. Mm-hmm. Uh, they none of them actually like break fluid.
Dr. Adam Sadowski:Basically None of them actually measured that and that can be used as a surrogate marker for the structural progression of knee osteoarthritis. Yeah, and so what? Go ahead.
Dr. Joshua Goldenberg:No, I was just going to say like it's kind of nice right. So obviously the clinically important outcome is the pain. But you know, I always get nervous about subjectively reported outcomes, and so it's kind of neat that, even though the effusion synovitis is a surrogate marker, it is like a surrogate marker for an objective response like progression, and so I don't know, I kind of I love when you have these. Okay, yeah, the subjectively reported outcome is the clinically important one, but you pair it with something objective at the same time. So I just love that.
Dr. Adam Sadowski:Right. And then I do want to talk about those three trials without giving away the findings of this paper, so I do want to go into that next.
Dr. Adam Sadowski:Mm-hmm of this paper, so I do want to go into that next. But the whole aim of this paper was to look at two grams per day of krill oil versus identical placebo, and the placebo that they used in this paper was a mixture of random oils, including the quote unquote bad seed oils that everybody's scared of, even though there's really a lack of evidence to support that Watch a curmudgeon, yep. Are curmudgeons, are they? Do you think they're sea creatures which would be fitting for this podcast?
Dr. Joshua Goldenberg:They might be sea creatures.
Dr. Adam Sadowski:Yeah, that's very fitting.
Dr. Joshua Goldenberg:Okay, but yes that's what I envision. I envision someone on the bottom of the ocean, sort of like an angry mumbling. What is it? Spongebob, squarepants, plankton, plankton, just like fuming about things, about the research evidence, literature. Yeah, great, anyway, that's you.
Dr. Adam Sadowski:Yes, that's me, and so this was a randomized clinical controlled trial looking at two grams per day of krill oil versus placebo, as I said, on the primary outcome of a knee pain over 24 weeks in people with knee osteoarthritis who had significant knee pain and effusion synovitis. And when we actually compare the other three trials, which they do talk about in the discussion, they were of smaller trials and they used different amounts of krill oil. One small trial looked at 300 milligrams of krill oil versus two grams in this one, so 2,000 milligrams in this one. That trial was also only 30 days, whereas this one is 24 weeks. Another trial did look at two grams per day, but they only included 50 people with mild knee pain and they also had other comorbidities associated with that as well, so they couldn't necessarily say that it was due to knee osteoarthritis.
Dr. Adam Sadowski:Interestingly, in one paper with the 300 milligrams per day of krill oil, that significantly decreased C-reactive protein, whereas in the other one that looked at two grams per day of krill oil had no change in C-reactive protein.
Dr. Adam Sadowski:So for anyone who remembers this Shilajat paper that we talked about, we did talk about how it was really interesting to see a dose-response relationship where a higher dose of the Shilajat improved the bone mineral density as well as all of the inflammatory markers associated, relative to both placebo and a lower dose. But so we're not seeing that here. So there's some inconsistencies. And then there was a third randomized controlled trial that looked at four grams per day and that did seem to improve in individuals with moderate knee osteoarthritis over 26 weeks. However, in that trial they did not have people specifically with the synovitis as in this case, and they also had a little bit of a difference in the EPA and DHA content, but it seemed like those were just more so things to note but didn't really change much of the results that we'll see in this paper change much of the results that we'll see in this paper Thoughts.
Dr. Joshua Goldenberg:Yeah, I think I think you know to your point like this. So this study was done in the context of okay, we have studies that show benefit of krill oil in populations like this, not exactly like this, even at much lower doses we're seeing benefit. And we have like as low as 300 milligrams, as high as four grams, and we're going to shoot for two grams. So it doesn't seem like they intentionally undershot the dose or any reason like that, right. So it seems like, you know, it seems reasonable, and even the I think they even even the placebo comparators were similar to at least one of the other trials. So it does seem like they set this up based on an expectation that we have evidence that this works and so let's try it. Sort of a very rigorous, larger study, very rigorous design.
Dr. Adam Sadowski:This is also a larger dose than what we're seeing in over-the-counter products, because I did look at popular name brand fish oil supplements and krill oil supplements, a lot of which are used in the integrative space with sort of this you know idea that oh, it's not over the counter, so therefore it's a superior product and the dosing on those are significantly underdosed compared to what's being studied in this trial.
Dr. Joshua Goldenberg:Well, yeah, I mean, I guess it depends on, like, how many you take, Like I know, for I don't know how you use them, but I regularly. Will you know if I do? I don't really do fish oils, but when I do, or when I have, it's usually been the gram levels right, Like two grams a day would not be, it would not be crazy for me. So I feel like it's a hefty but not crazy dose. So I feel like it's a hefty but not crazy dose. But yeah, anyway, Um, okay.
Dr. Adam Sadowski:And also can we just plug in one thing real quick about fish oil.
Dr. Joshua Goldenberg:Sure. Yeah.
Dr. Adam Sadowski:For those who are giddy about super high doses of fish oil. So when I say super high, I'm saying at least four grams per day. There is an association there with AFib. So it's not.
Dr. Joshua Goldenberg:It's not a benign a hundred percent benign.
Dr. Adam Sadowski:It's not. It's not a benign, 100 percent benign. It's not. It's not a benign thing. You can cause harm with high dose fish oil, so please be careful, and this is not medical advice.
Dr. Joshua Goldenberg:Yeah, that was. My mom just sent me that New York Times article about that, that's. I think that's the next thing we should, we should look at. Look, the thing is we don't do this for money. This is pro bono and, quite honestly, the mothership kind of ekes it out every month or so, right? So we do this because we care about this, we think it's important, we think that integrating evidence-based medicine and integrative medicine is essential, and there just aren't other resources out there. The moment we find something that does it better, we'll probably drop it. We're busy folks, but right now this is what's out there. Unfortunately, that's it, and so we're going to keep on fighting that good fight.
Dr. Joshua Goldenberg:And if you believe in that, if you believe in intellectual honesty in the profession and integrative medicine and being an integrative provider and bringing that into the integrative space, please help us, and you can help us by becoming a member on Dr Journal Club. If you're in need of continuing education credits, take our NANSEAC approved courses. We have ethics courses, pharmacy courses, general courses. Interact with us on social media, listen to the podcast, rate our podcast, tell your friends. These are all ways that you can sort of help support the cause. So let's jump into the methods. Just some things to highlight. One of the things I really liked they had the entire trial protocol and the entire statistical analysis plan available online. I feel like they're being like super transparent. Not just that they had, like you know, a Prospero well, not Prospero, but not just like a basic clinicaltrialsgov registration. It was like the straight up entire protocol and the analysis plan.
Dr. Adam Sadowski:Honestly, I've been very impressed with research coming out of Australia. I'm not surprised that that is what happened. A lot of the Australians do a really good job with when it comes to the reporting of outcomes in the papers and whatnot.
Dr. Joshua Goldenberg:Huh, yeah, no, that's cool, I haven't. I hadn't noticed that I'm not seeing a lot out of Australia besides SIBO stuff. Actually, like they FODMAP stuff is really big out of the Monash University down there, but okay, so, yeah, so, really, like you said, very transparent, very good methods. We talked about the population. You had to be 40 years of older. Symptomatic knee pain you had to have like significant knee pain, like 40 points or higher on 100 point scale. So these aren't people where it was just marginal knee pain. And I think the biggest difference between this population and the other trials was A it was all people with knee arthritis, osteoarthritis specifically, and not a mix. And also that they all have this effusion synovitis. And I was wondering, like, do you? I mean it's not like I guess you would argue that that makes it more severe. Yeah, yeah, right.
Dr. Adam Sadowski:And so if you were to see a response, then you should see a response, right? So if you kind of think about it like as a secondary prevention type of population, you would expect to see a larger magnitude of effect.
Dr. Joshua Goldenberg:Right, and that's the only thing I could think of, like trying to play devil's advocate was well, maybe they were so extreme, Like sometimes, when disease is so progressed you know you just can't reverse it and maybe that's what we're seeing here, is that you have these anatomic evidence of severity of disease that's just no longer reversible, Whereas if it wasn't that extreme it would. I don't know, could just be that it doesn't work, but we'll see. So that was one thing. One question I had, because I think this is the only study that actually had that as an inclusion criteria, that they had to actually have this synovitis.
Dr. Adam Sadowski:Yeah, and that was one of the differentiating factors between this and the other three randomized controlled trials.
Dr. Joshua Goldenberg:Yep, yep. So as we try to compare and contrast, so remember, like, if you have disparate results, it could just be that like, well, the early studies were wrong, like that happens or not wrong, but just like randomly positive right, especially smaller trials. But again, it could be that the populations are just very different as well, and so that's always something that you have to sort of consider. So I thought they did a good job with randomization, with treatment assignment, with blinding. I was all pretty happy with all that.
Dr. Joshua Goldenberg:You know, one thing that comes up when I hear you know people complain about integrative medicine trials, I hear you know people complain about integrative medicine trials, about oils or about integrative. You know, anything is the is be careful about the placebo. And like, what is the placebo? Is it truly inactive or not? So, like you said, this was vegetable oil, it did have olive oil, so it did have things that you know you might suggest would be negative, but also it has olive oil. So what about the argument that? Well, maybe the placebo itself had a benefit here, although the point, because it's maybe anti-inflammatory. However, it doesn't have any EPA, dha, and maybe that's what you're measuring here.
Dr. Adam Sadowski:It also has corn oil, which everyone loses their mind over. So I don't, I really, I really, you know, if you're gonna, if you have one good oil, then you have three other not good oils. I feel like it all cancels out. And I'm not gonna lose sleep over the fact that these contain olive oil yeah, okay, fair enough.
Dr. Joshua Goldenberg:So adam's not losing sleep over it. I'm not like I don't know, like I I always wonder about this sort of thing and I feel like there's always this battle between well, you can find one thing that explains a negative result, and it can sound rational, but at a certain point you look just like.
Dr. Adam Sadowski:But then you can't argue anymore that seed oils are pro-inflammatory.
Dr. Joshua Goldenberg:Yeah, I mean. So there's that, and then there's, you know, also, you just can't truly prove a full negative right, like you can always find something that if it was done differently it would be positive, and so I feel like at a certain point you just have to say on net that this looked like an excellent study, well designed, decent placebo, you know, and if you're comparing it to just taking some seed oils, it seems as if krill oil doesn't add much to that.
Dr. Adam Sadowski:We can put it that way, I guess I mean I would also say like okay, well then, go compare, go get funding. To say, the difference between our study in the previous study was that they had a mixed oil and so we're going to use straight up canola oil. Right, right, the canola oil study. No one's going to fund that. That doesn't make any sense.
Dr. Joshua Goldenberg:Yeah Well, interesting, I wonder. Actually I don't know who funded this one. They'll look at the bottom. I forgot to check the funding.
Dr. Adam Sadowski:It was publicly funded. And then the Krill Oil Company gave them product for free but had no role in the methods data collection, whether or not they were going to publish or not, so it was publicly funded.
Dr. Joshua Goldenberg:Cool yeah, and I just want to point out like that is totally okay and normal it's a multi-million dollar study probably and you know, someone donates some krill oil like that's not going to influence things, but to like, so that people say, well then, why, why do you get it donated? Because, pragmatically, when you do these studies, you need all the quality assurance documents and certificates for safety, and so you need to be working with the company that makes the product to provide those analysis to give to your ethics board. And also, when you're manufacturing a placebo, it has to match as much as possible right for blinding, and so the usually the best way to do that is to have the facility that makes the actual product also make the placebo, so that everything else is kind of the same. So, again, that's totally reasonable, I think. So, yeah, okay, so we have okay.
Dr. Joshua Goldenberg:Another thing I wanted to point out we did have a lot of dropout right. So you have 262 people randomized, half to crow oil, half to placebo. They did a good analysis, like their primary analysis was. You know, everyone that was randomized, but I think they lost, like what, 24 people in one group it looks like 23 and another, which is a significant percentage of the total.
Dr. Adam Sadowski:I think it's easier to look at it from a percentage standpoint. I think it was like 15% and 17% in both groups and overall only 85% of people completed the trial. So I do think, from a you know, bias standpoint, that is something that has to be taken into account, especially as they did not use an intention to treat analysis.
Dr. Joshua Goldenberg:I want to ask you about that. Like, that seems like a. I mean 24 weeks it's a long time and I guess 15% doesn't sound so crazy, but still that seems to be a lot of people to just drop out of the study and at least it's balanced, right. And if we look at the reasons for dropout here, they say dropped out for adverse. So seven dropped out for an adverse event in one group versus eight in the other. That seems balanced. Perceived lack of efficacy four in one group, six in another. Six cannot be contacted. So it seems like balanced as far as the number of people that dropped out and the reason.
Dr. Joshua Goldenberg:So it doesn't appear on its face that the intervention itself was driving dropouts. So that's what you worry about from a bias perspective. You just kind of wonder, well, if you're just missing this many data points, maybe it's not a bias issue, but maybe it's like you're just you know it'll, you're not going to see the effect as well, right, you're just kind of losing your power. So yeah, I don't know Any thoughts on like why they had such a large, relatively large dropout. Is it just the length of time, you think, or maybe just the people running the trial? I mean they were run through different. You know, I think clinics, but I think primary clinics.
Dr. Adam Sadowski:Yeah, I mean it may have just been a time issue. I'm really not sure, because when we even look at the adherence rates, they were so high 99% in the krill oil group and 96% in the placebo group. So you know, the adherence to treatment for those who were taking it was so high. It would have been interesting to see what was the adherence rate in those who dropped out. Like, did they also have a high adherence rate and then just, for whatever reason, dropped out of the study? Or yeah, I don't know. It's a shame that that happened and kind of a bummer that they didn't do it in ITT.
Dr. Joshua Goldenberg:Yeah, right, so they did. So they sort of did intention to treat, but they didn't do like a sensitivity analysis, I guess across it, but it was an. It was a null finding anyways, as we'll talk about, so I guess it's less of an issue, okay. And then primary outcomes was the 24 week change in self reported knee pain. So I like that the primary outcome, even though it's subjective, is clinically relevant. I loved that they predefined their minimal clinically important improvement. Did you see me like in your mind doing a little jig when you read that? Because I was like, yeah, I did, I did. Yeah, I was beyond thrilled and they actually picked the right number.
Dr. Joshua Goldenberg:So, like there's a lot of new research on minimally important differences, we used to think the VAS scale, okay, it's like 10 points, right, you just do 10%. But actually it depends to do it properly. Like you need to look at, you need to actually ask the population that's relevant to you. So you know, find a group of people that have knee arthritis and ask them like what's the minimal difference that would matter to you? And and they use the 15. And most of the studies that I've seen, whether it's shoulder pain or knee pain or something like that. It's somewhere between like 13 and 18, or something like this, so 15 sounded really totally legitimate. They had that. Initially. They had a lot of secondary outcomes, including the change in effusion syncytitis, and then, like I think, up to like 60 other secondary outcomes. That's the other thing. Like they definitely went fishing, like they had lots of things they looked at, but they were so upfront and honest about it so that I feel like I wasn't too worried.
Dr. Adam Sadowski:Yeah, I mean. They even said, due to the large number of secondary outcomes, results for secondary outcomes should be considered exploratory. So they straight up said like hey, yeah, we're looking at a bunch of stuff, please don't look into it. Really, what that means is we're setting up future trials and future research questions. That's pretty standard.
Dr. Joshua Goldenberg:Yep, yep, yep and it's like so I always wonder with this sort of thing if it was the peer reviewers, if it was the referees that, like, required them to temper their thoughts about secondary outcomes. But just basically reading between the lines here, I feel like these authors were, like you said, super legit. Probably was their original language and yeah. So it's okay to explore and have exploratory outcomes. Just don't pass them off as what you intended to see, and I think they did a good job of that.
Dr. Adam Sadowski:I think too, if they had 60 secondary outcomes to look at. They really are, are trying to be as thorough with this as possible, and so even if there's like the slightest noise of a positive secondary outcome, you know they're going to go down exploring that.
Dr. Joshua Goldenberg:Exactly and they saw a couple things that didn't really make sense and we're probably just like random. Oh, the other thing I really liked about the MCID is the minimal important difference. They set them as well for lab values, which is so cool and you rarely see. We did that with our paper a couple years ago on on low carb diets and, as far as I know, we were like the first people to do that. We had like a big discussion about should we do this? Should we apply this concept to lab values? Can you do that? What's your justification? I mean, I'm sure we weren't the first, but we didn't know of anyone else and it's neat to see other people doing that now and actually using very similar thresholds to what we used, which I think is kind of cool. So, yeah, it's this idea that you know. You just have to start setting these thresholds that matter one way or another, and that is analogous in labs. It's obviously not patient important, because you can't tell the difference, but it is clinically important and they actually use these. People are great man. They actually use different languaging around that right, so that you have the minimally clinically important improvement, which is a very specific phraseology there, versus the minimal clinically important difference for the labs.
Dr. Joshua Goldenberg:Yeah, they did a great job. They clearly were well versed in MCIDs and all that. Yeah, I like these authors. I don't know any of them. I don't recognize any of those names, but I'm impressed as well. Alrighty, what else did you want to talk about? That's pretty much everything I wanted to talk about on results, besides some comments on adherence. Anything you want to touch on first?
Dr. Adam Sadowski:No, that was it, and we already talked about the adherence too.
Dr. Joshua Goldenberg:Yeah, and the adherence right, the adherence was excellent, you know. The other thing I'd say is they looked at, not just at counting pills, which is what almost everybody does Like. Okay, return the bottles when you're done. Let's count up how many are left to figure out how adherent you were. But they actually had a biomarker for omega-3 as well, which I thought was great. So they had like proof that not only were you taking the omegas, but it was getting into your bloodstream and bioavailable enough to have an impact, which is it's really nice when you can have that biomarker as well, alrighty.
Dr. Adam Sadowski:So let's talk results. You want to walk us through the results? Sure, so the primary outcome, which again was the change in knee pain based on the visual analog score. And so again, that visual analog score goes from zero to 100. 100 is maximal pain, zero is no pain. In order to be included in the study you had to have a score of at least 40. And when we look at our demographic table, score of at least 40. And when we look at our demographic table, the average knee pain for the two groups was a 48 in the in the krill oil group and a 50 in the placebo group. So basically the same. And then when we look at the primary outcome, so the change in that there was no difference between the two groups. From baseline to 24 weeks it changed by 20 points. It went down by 20 points in the krill oil group versus 20 points in the placebo group. Absolutely no difference.
Dr. Joshua Goldenberg:Yeah, so both improved significantly. But there is no difference between placebo and krill oil there. It's not too surprising to see a clinically important improvement from baseline to endpoint. In general like not when you're comparing across groups, but just because this is subjectively reported outcome they know they're getting something and so when you ask them how they're feeling, like they're going to report feeling better, right, Like that's just, that's the placebo effect. So it isn't crazy to think that, yeah, you would drop 20 points when you're in a study, when you're taking something. But that's, of course, why we do these placebo comparisons, because the drop with the krill was exactly the same as the placebo group.
Dr. Adam Sadowski:Right. And then when we look at the secondary outcomes, of the 60 secondary outcomes that were looked at, two were different, 58 were no different. Of those two, one favored krill oil and it improved triglycerides at the 12-week mark but not the 24-week mark. So it didn't really do anything there. And then when we looked at effusion synovitis volume at 24 weeks, the placebo group actually improved that over the krill oil group.
Dr. Joshua Goldenberg:Interesting right.
Dr. Adam Sadowski:To all the corn oil haters it improved inflammation.
Dr. Joshua Goldenberg:Yeah, that was interesting, and they kind of talk about when I guess we could talk about that in the discussion. Like they kind of talked about why that, why in the world the placebo would improve it, and I think they just kind of concluded at the end that it was probably a random, random result. Yeah, alrighty, so that's that probably a random, random result. Yeah, alrighty, so that's, that's basically it. Ladies and gentlemen, um, I let's look at the anything. I think we discussed most of the discussion as we went through. Um, I want to see if there's anything else here I want to talk about. Yeah, so, basically in the discussion they're going through, they're like okay, why didn't we see an effect here?
Dr. Joshua Goldenberg:Like the dose was you know right between these two studies that we've seen that showed benefit? There was. There were studies that showed benefit of exactly two grams a day. They all had knee pain, they were improving. So like, what's the difference? And I think, at least in my reading, the only major difference if you assume that dose is not responsible, then because you were seeing effects at like two grams and 300 milligrams in other studies was the population. Like it wasn't. The other populations were more mixed. Maybe they had some rheumatoid arthritis, maybe they had knee pain that wasn't necessarily osteoarthritis knee pain, and then also they didn't have this synovitis piece, and so those seem to be the most like if it's not truly negative, and those initial results are true, and this is true too then that was the take home that I had, that it's like, well, maybe it's the difference in the populations here that if we're really talking about a knee arthritis where you're having synovitis, then it's just not gonna help you essentially.
Dr. Adam Sadowski:Yeah, yeah, yeah, yeah. I don't have anything else to add to that.
Dr. Joshua Goldenberg:Cool, I think that's everything just going through here. Yeah, that's everything as well. They also looked at adverse events. There wasn't any major difference between groups there and they talk about how, um, what they saw with the placebo, that's the placebo thing. So that's the placebo thing. So that's another thing I wanted to highlight. So and I thought I think I talked about this earlier so they have this study of two grams a day showing benefit, right. So that's what? Again, that's what they're doing and they're like, okay, well, maybe you know you messed up the placebo pill. Maybe the placebo pill was actually beneficial and that's why you're not seeing a difference. But again, they use a placebo pill they claim very similar to that used in the study that had the two grams that showed benefit, right? So again, in theory, it's not that either. So, yeah, I think, at the end of the day, if you've got knee arthritis and you've got synovitis, krill oil is probably not going to help more than placebo, according to the findings of this study. And I think that's pretty much what I want to say about this paper.
Dr. Joshua Goldenberg:Anything else you want to add? Is it practice changing for you? No, well, I mean, I don't. I just, I'm such a specialized population that I don't I don't really see people for arthritis. I'm such a specialized population that I don't really see people for arthritis, although I have to say my laziness, because I see people with basically one condition small intestinal bacterial overgrowth. If they happen to mention arthritis, pain here or there, I will often say lazy things like oh well, you might consider some fish oil or something like that acryl oil, and so maybe this will be practice changing. Maybe I'll kind of check that reflex a little, a little bit more. How about you You're? You see patients like this every day, probably.
Dr. Adam Sadowski:Uh, I mean I, I see knee osteoarthritis a lot, um, I see people on omega threes. I have not yet seen anyone specifically using krill oil for anything, but I, you know, I, I go to conferences, I see, I see the salesmen and saleswomen yeah, we've got this thing against salesmen. So I always just yeah, I always just roll my eyes. Here's what I would say. I would say I, I would not consider it. Um, if someone was already on it, I'd be like you know, if you don't want to be on it or you don't know why, it's fine to discontinue, but I personally would not be making the recommendation to start this.
Dr. Joshua Goldenberg:Yeah, and and you know, to your earlier point, like there might even be a little bit of a harm there with AFib signal. So we should, maybe we should do that paper next to continue with the curmudgeon theme, just because, like, sometimes it's like okay, yeah, like it's overblown and over promoted, and when you look at good quality studies there's nothing there and usually it's just like okay, but it's benign. You're probably fine if you want to stick with it, right, but that's not always the case when you do have these harm signals. So I am curious personally to kind of look at that a little bit more. Maybe we'll do that next week or something like that.
Dr. Adam Sadowski:Also, I wouldn't say I'm a curmudgeon. I really do think I'm just a healthy skeptic because so many people are. They want to believe these things work.
Introducer:But if we?
Dr. Adam Sadowski:don't have the data to support it. We have to stop. We have to challenge our biases. If we don't challenge our biases, things don't change, things don't evolve and you get left behind. I'm sorry, but if you want the profession to change, if you want to be a better provider, you have to challenge your biases and everything.
Dr. Joshua Goldenberg:Yeah, yeah, it's true, it's true, I think.
Dr. Joshua Goldenberg:You know, I just I feel like I'm just steeped in this assumption, cultural assumption, that fish oil, omegas, like that they work, and I don't know where that comes from.
Dr. Joshua Goldenberg:I think that just comes from, like that's the societal milieu. And you know, you hear some papers or you hear your professors in school and you know, and then I just never was in a field where I was prescribing it a lot, right, and so I never really looked into it much, and so it is kind of interesting to actually look at these papers and be like, no, not really, and oh, you know, there might even be harm signals here. So, you're right, it is important to question these things. I guess it's. I guess you can't, so you can't question everything, and so, yeah, I think I think you just question the things that are high value and also that you see every day, right, so, like for you, I think it makes sense to be doing, to be looking at that and to have these conversations. And I'm curious, dear listeners, because I think that, um, there'll probably be a lot of hate mail after this one, I would suspect, and they're going to be giving us good papers.
Dr. Adam Sadowski:So, yeah, so with your hate mail, but then good, but like then, I'm glad that's happening. Send a good paper, send good papers.
Dr. Joshua Goldenberg:Yeah, send good papers, yeah, yeah. So here's, here's, the other thing is okay. So we have this our own. Our own tendency is to be to be critical of everything and to just assume it's all randomness, right, that, at least that's my tendency, and that most of the higher quality, larger studies will basically show that almost nothing works. But you know where I go with this evidence nihilism thing.
Dr. Joshua Goldenberg:However, I also want to own the fact that I'm not an expert in fish oil research. I haven't looked at a lot of fish oil studies and it could very well be that this is an exception to the rule, and in fact, this study followed apparently three studies that were positive. I don't know if they're well done. One of them at least had over 200 participants, I don't know. But I also want to own the fact that it could be that we're looking at a true subgroup phenomenon where populations with osteoarthritis of the knee, where you have the synovitis is just not going to benefit it's too far gone, or something like that Whereas more mild cases maybe it does. I don't know. Is that an apologist for the krill oil? Possibly you should look at my disclosures. I just got a huge new tri bike from Big Krill and I call it my Big Krill, big Grill, and so anyway, but yeah, but I think that's.
Dr. Joshua Goldenberg:The other thing is that, and this is okay, well, okay, I want to go on this tangent a little bit longer.
Dr. Joshua Goldenberg:When you're in the evidence evaluation world like I am most of the time, you know, doing systematic reviews, teaching critical eval it's so easy for me to like say, ah, this is just randomness, yada, yada, yada, and maybe that's good to have that distance.
Dr. Joshua Goldenberg:And then, whenever it's a it's a clinical question about a clinical field that is very dear to my heart, that I like know well and know the literature, I'm always much more skeptical of people's attempts to like poo, poo it, and I think that's a natural inclination. But I also feel like I don't know there's like benefits of being removed and looking at something purely from a methods perspective, but also there's obvious harms. Right, like you're not a content expert, you don't necessarily know the literature well, and that's one of the things I like about doing systematic reviews is like you always include content experts in your team for exactly this reason. Right, you've got your methodologists, but you also have your content experts to like keep you honest or keep you from being like overly critical, I guess. Anyway, thoughts on that, or is that just me rambling?
Dr. Adam Sadowski:no, I get where you're coming from. Um, I always kind of used to be the opposite, where I was like oh, supplement in jama, bet you it's going to be a negative trial, because, like 99 of the time, it's a negative trial yeah, right to now where I'm. I mean that was a very like emotional response because I'm in the integrative profession. It feels like an attack on me. Yeah.
Dr. Adam Sadowski:To now me being okay, it's a negative trial. Let's actually see if it's something to be up in arms about. Were there huge flaws or was this just a really well done trial? And we're just upset about our emotion, and the more I look at it, it's usually the latter rather than the former. Now, of course, there's always going to be instances of the former and you know, I think people also have to realize that because we're so in the integrative space, we're looking at integrative things and so I keep saying this doesn't work, this doesn't work, et cetera, et cetera. There's inadequate evidence to things. The opposite is not also true, that that means that all medications work. We're critical of all things. It's just that we just so happen to be in the integrative space. So we're looking at these things and if they're not working, we're going to say that they're not working or not providing the magnitude of effect that we want it to. And it's very sobering.
Dr. Joshua Goldenberg:And I think that people need to come to that conclusion as well. Yeah, I think that's well said, right, because of our area of interest, this is what we talk about, but, as longtime listeners will know, we're equally critical of a lot of different interventions and tend towards the evidence nihilism position for all of medicine. We were excited for Shiljat yeah, that was a surprise. That was kind of cool. Yeah, every once in a while you see it. Or Kirk Heumann was showing some pretty cool stuff too. We did that one paper on.
Dr. Adam Sadowski:Yeah, we're shills for Shiljat Big Shiljat jack. Come sponsor us. So how is that?
Dr. Joshua Goldenberg:I thought it was sheila jeet. How do we print we don't know, no one will know. Nobody will know, no one will know. No one knows. Unknown, unknown. It's one of those. It's like uh oh, you're probably too young for that. You know the um. How many licks does it take to get to the center of a tootsie pop roll or whatever?
Dr. Adam Sadowski:I'm old enough for that. Yeah, with a little with the owl, with the owl, yeah, yeah, yeah with the owl, with the owl right.
Dr. Joshua Goldenberg:Some things are just unknown, right? So anyway, um so interesting can't.
Dr. Adam Sadowski:I think between now and the next podcast, one of us needs to get a Tootsie Roll Pop and find the answer.
Dr. Joshua Goldenberg:Yeah fair enough, I'll put Theo on it. I think he'll be thrilled. He's all hopped up. Today was his last day of kindergarten and so I went in for the kindergarten party and so they brought in like pizza and cupcakes and like juice boxes and I had already packed him a cupcake in his lunch for his like last day, so like the kid. Well, the entire class are hopped up on sugar, like literally bouncing around the classroom jumping on each other, and I'm just look, did they also? What was that?
Dr. Adam Sadowski:did they also come. Everybody get a free sample of ozempic.
Dr. Joshua Goldenberg:Here's your cupcake and ozempic well, it or or like a benzo or something to calm the freak down. It was, it was totally nuts and I just I was like I turned into something. Other parents and I was like I am just so glad that he's got two more hours here before he comes home, because he's gonna have to, like, burn off this sugar crash with his kindergarten teacher not me, although he'll probably be a half asleep in a coma by the time I get him isn't it kind of funny how we go from like kids being hopped up on sugar to then we just transition to caffeine as adults?
Dr. Joshua Goldenberg:Oh yeah, I'm hopped up on caffeine right now, right, so it's like you know I I have nothing to say about this. All right, ladies and gentlemen, we will talk to you later. Adam, it is wonderful to talk to you. I missed you. I'm so glad we were back on this thing likewise my friend all right, take care bye thank you, everybody.
Dr. Joshua Goldenberg:Please do us a favor and let them know about the podcast and, if you have a little bit of extra time, even just a few seconds, if you could rate us and review us on Apple Podcast or any other distributor, it would be greatly appreciated. It would mean a lot to us and help get the word out to other people that would really enjoy our content. Thank you, hey y'all. This is Josh. You know we talked about some really interesting stuff today. I think one of the things we're going to do that's relevant.
Dr. Joshua Goldenberg:There is a course we have on Dr Journal Club called the EBM Boot Camp. That's really meant for clinicians to sort of help them understand how to critically evaluate the literature, etc. Etc. Some of the things that we've been talking about today. Go ahead and check out the show notes link. We're going to link to it directly. I think it might be of interest. Don't forget to follow us on social and interact with us on social media at DrJournalClub DrJournalClub on Twitter, we're on Facebook, we're on LinkedIn, etc. Etc. So please reach out to us. We always love to talk to our fans and our listeners. If you have any specific questions you'd like to ask us about research evidence, being a clinician, etc. Don't hesitate to ask.
Introducer:And then, of course, if you have any topics that you'd like us to cover on the pod, please let us know as well. Thank you for listening to the Doctor Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Be sure to visit www. d rjournalclub. com to learn more.