People who don't get better with Placebo A get crossed over to Placebo B and people who don't get better with Placebo B get crossed over to Placebo A and people who don't get better with PT alone get randomized to A or B.
This study was blindingly lopsided and it is one of the problems with the GLP1a drugs. The emergency room is full of abdominal pain and loose stools or constipation from poorly instructed and some inappropriate patients. It has its place, but I feel there will be a cost of not addressing the psychological issues related to obesity. And if you lose weight, your knees hurt less, no kidding, that is less pounds per square inch hitting the ground.
I assume the reason for this trial is that most (maybe even all) medicare products do not pay for weight loss medications. If I were a manufacturer of a GLP1a, I would search for a common symptom in the over-65 crowd and do my darnedest to show that my GLP1a improved it.
An added benefit is that GLP1a coverage could be sold to insurance companies as a more predictable expense than knee replacements.
Such as SELECT and SURMOUNT-OSA, I think this STEP 9 just proves to us that weight loss is good to improve cardiovascular outcomes (SELECT), apnea outcomes (SURMOUNT-OSA) and osteoarthritis outcomes (STEP 9).
I agree that the non-blinding is a limitation to evaluate WORMAC....but I wouldn't be suprised if a 15% weight loss would lead to a similar (maybe lower effect size) improvement.
Anyway, if we already knew that the drug do makes people lose weight (A), and if we knew the weight loss improves a lot of things (B), I think it wouldn't surprise us to come from A and B to C!
The big question is always the same: should we, as a society, push for a drug leading a behavioral change or not?
Ivan Ilitch, a common cited author by you, would have a strong opinion on it :)
"What’s wild is that they cite a paper strongly warning scientists that unblinding is a huge problem in arthritis trials. The conclusion of this paper (as if no one would have looked it up) is this: (emphasis mine)"
Out of curiosity, what would the best methods of managing unblinding/measuring the placebo effect be for a study like this?
Could it be as simple as asking participants (at the end of the study) which study arm they believed they were assigned to? And then reporting the number of participants who accurately concluded which study arm they were in?
Imagine the results if you injected that saline placebo in their butt and then reloaded putting the saline placebo in the knee; $0.50 for the syringe and $0.05 for the saline - a deal at twice the price
Sure the trial is the BS but I’d argue that we don’t need a RCT for weight loss improving knee pain (or back pain, sexual function, or hell even whether or not your more likely to be hired for a job). Marketing disguised as research sure is a term that your team taught me that rings a bell. The problem is the obesity/lifestyle epidemic as a whole and the gut instinct that this expensive ‘fix’ may be little more than a transient non sustainable fad due to a combination of cost, long term tolerance, or unknown long term adverse effects.
Would a run in period of 4 weeks (in which both groups get treatment arm at low dose) followed by blinded placebo thereafter in control arm been a better method?
Sorry, but I must really wonder about this post.... Newton came up with gravity hundreds of years ago and the consequences we see until this day. I'm talking his 3rd law of motion!
Try to lift up 300 pounds sack of potatoes, first thing happens, you HAVE TO BEND YOUR KNEES.... And now move your head forward by few inches, while keeping the body straight, your spine gets all the weight pressed upon. To even try to explain Wegovy will help these struggling knees with lifting is like one of these jokes:
In case you see the above and start to laugh, your belly is moving, you are LOOSING WEIGHT already::)))
And now start to chase the producers of you donuts, ice creams, ready made with chemicals filled pizza's., sugar filled everything. You are getting better and better. At one point look into mirror, you don't see your knee, BUT it feels better, with every gram lost weight! Newtons laws work....
The patients were primed to expect less pain and, like anyone with chronic pain wished that expectation to be met. Who doesn’t want less pain? It’s a form of persuasion similar to hypnosis.
The very idea that this was funded by the company is outrageous. You, and Dr. Prasad have made this septuagenarian much more cautious. Now I read entire papers instead of just the abstracts. A story about UV Light for CDI marketing. If you look at the “studies” cited in the marketing deck there actually was very little evidence for the effectiveness of UV light sustained lowering of CDI incidence. All studies had confounding variables, sampling bias, non-significant improvements or didn’t even address the issue - lab studies. But the administrators desperate for a quick fix went for it, to the tune of hundreds of thousands of dollars. The people in this study wanted less knee pain and that’s what they got. Everyone gets what they want, right?
Lose 10% body weight and arthritic pain usually decreases simply due to the fact that the arthritic joint is bearing less of a load. It would be a bigger surprise if there had been no decrease in pain.
Wow. Novo wasn’t just the sponsor here. They designed the protocol, ran the trial, analyzed the data, and co-wrote (at a minimum) the paper. Did NEJM have the decency to at least use different font and label it as an infomercial?
This is no different than the StepHFpEF studies….if you lose 11% of body weight (average about 20 lbs), your soft endpoints like QoL are gonna get better. Doesn’t make it a disease-modifying HFpEF drug. And similarly here, starting from a BMI of 40, it’s hardly shocking that losing a bunch of weight would improve joint symptoms.
Maybe they should do a study of the effect of Semaglutide on pant sizes. I’m guessing they can show that sema causally reduces pant sizes too.
It is truly a face-palm that something like this could end up in NEJM.
Apparently the NEJM has now abandoned even the pretense of having scientific standards. Even a schoolchild can see that this is a tautology. "Weight loss has been shown to alleviate some of the pain in osteoarthritis of the knee. Our drug helps weight reduction. Our drug, therefore, helps alleviate some of the pain in osteoarthritis of the knee." The many other gross violations of scientific principles in this study are beside the point.
Should all non-life-threatening conditions always be treated with a placebo first?
Apparently, some placebos are better than others (bigger the pill and red colored), even when the patients know they are getting a placebo!
I'd like to see a trial for an orthopedic condition (like knee, back or shoulder pain), placebo A with PT vs. placebo B with PT vs. PT alone.
If we can improve symptoms with placebos why not!
People who don't get better with Placebo A get crossed over to Placebo B and people who don't get better with Placebo B get crossed over to Placebo A and people who don't get better with PT alone get randomized to A or B.
This study was blindingly lopsided and it is one of the problems with the GLP1a drugs. The emergency room is full of abdominal pain and loose stools or constipation from poorly instructed and some inappropriate patients. It has its place, but I feel there will be a cost of not addressing the psychological issues related to obesity. And if you lose weight, your knees hurt less, no kidding, that is less pounds per square inch hitting the ground.
I assume the reason for this trial is that most (maybe even all) medicare products do not pay for weight loss medications. If I were a manufacturer of a GLP1a, I would search for a common symptom in the over-65 crowd and do my darnedest to show that my GLP1a improved it.
An added benefit is that GLP1a coverage could be sold to insurance companies as a more predictable expense than knee replacements.
I think I am more in the middle ground here.
Such as SELECT and SURMOUNT-OSA, I think this STEP 9 just proves to us that weight loss is good to improve cardiovascular outcomes (SELECT), apnea outcomes (SURMOUNT-OSA) and osteoarthritis outcomes (STEP 9).
I agree that the non-blinding is a limitation to evaluate WORMAC....but I wouldn't be suprised if a 15% weight loss would lead to a similar (maybe lower effect size) improvement.
Anyway, if we already knew that the drug do makes people lose weight (A), and if we knew the weight loss improves a lot of things (B), I think it wouldn't surprise us to come from A and B to C!
The big question is always the same: should we, as a society, push for a drug leading a behavioral change or not?
Ivan Ilitch, a common cited author by you, would have a strong opinion on it :)
Your link in this paragraph seems broken:
"What’s wild is that they cite a paper strongly warning scientists that unblinding is a huge problem in arthritis trials. The conclusion of this paper (as if no one would have looked it up) is this: (emphasis mine)"
Not to sound naive, but wouldn’t losing weight, regardless of how, reduce knee pain? Isn’t this just a ploy to sell more wegovy?
Out of curiosity, what would the best methods of managing unblinding/measuring the placebo effect be for a study like this?
Could it be as simple as asking participants (at the end of the study) which study arm they believed they were assigned to? And then reporting the number of participants who accurately concluded which study arm they were in?
Imagine the results if you injected that saline placebo in their butt and then reloaded putting the saline placebo in the knee; $0.50 for the syringe and $0.05 for the saline - a deal at twice the price
Sure the trial is the BS but I’d argue that we don’t need a RCT for weight loss improving knee pain (or back pain, sexual function, or hell even whether or not your more likely to be hired for a job). Marketing disguised as research sure is a term that your team taught me that rings a bell. The problem is the obesity/lifestyle epidemic as a whole and the gut instinct that this expensive ‘fix’ may be little more than a transient non sustainable fad due to a combination of cost, long term tolerance, or unknown long term adverse effects.
Semaglutide Deaths are rising in FAERS
https://geoffpain.substack.com/p/stop-it-or-you-will-go-blind-nonarteritic
Would a run in period of 4 weeks (in which both groups get treatment arm at low dose) followed by blinded placebo thereafter in control arm been a better method?
Sorry, but I must really wonder about this post.... Newton came up with gravity hundreds of years ago and the consequences we see until this day. I'm talking his 3rd law of motion!
Try to lift up 300 pounds sack of potatoes, first thing happens, you HAVE TO BEND YOUR KNEES.... And now move your head forward by few inches, while keeping the body straight, your spine gets all the weight pressed upon. To even try to explain Wegovy will help these struggling knees with lifting is like one of these jokes:
https://www.youtube.com/watch?v=GjkWN-PG6K0
In case you see the above and start to laugh, your belly is moving, you are LOOSING WEIGHT already::)))
And now start to chase the producers of you donuts, ice creams, ready made with chemicals filled pizza's., sugar filled everything. You are getting better and better. At one point look into mirror, you don't see your knee, BUT it feels better, with every gram lost weight! Newtons laws work....
Congratulatuions.
The patients were primed to expect less pain and, like anyone with chronic pain wished that expectation to be met. Who doesn’t want less pain? It’s a form of persuasion similar to hypnosis.
The very idea that this was funded by the company is outrageous. You, and Dr. Prasad have made this septuagenarian much more cautious. Now I read entire papers instead of just the abstracts. A story about UV Light for CDI marketing. If you look at the “studies” cited in the marketing deck there actually was very little evidence for the effectiveness of UV light sustained lowering of CDI incidence. All studies had confounding variables, sampling bias, non-significant improvements or didn’t even address the issue - lab studies. But the administrators desperate for a quick fix went for it, to the tune of hundreds of thousands of dollars. The people in this study wanted less knee pain and that’s what they got. Everyone gets what they want, right?
Lose 10% body weight and arthritic pain usually decreases simply due to the fact that the arthritic joint is bearing less of a load. It would be a bigger surprise if there had been no decrease in pain.
Wow. Novo wasn’t just the sponsor here. They designed the protocol, ran the trial, analyzed the data, and co-wrote (at a minimum) the paper. Did NEJM have the decency to at least use different font and label it as an infomercial?
This is no different than the StepHFpEF studies….if you lose 11% of body weight (average about 20 lbs), your soft endpoints like QoL are gonna get better. Doesn’t make it a disease-modifying HFpEF drug. And similarly here, starting from a BMI of 40, it’s hardly shocking that losing a bunch of weight would improve joint symptoms.
Maybe they should do a study of the effect of Semaglutide on pant sizes. I’m guessing they can show that sema causally reduces pant sizes too.
It is truly a face-palm that something like this could end up in NEJM.
Apparently the NEJM has now abandoned even the pretense of having scientific standards. Even a schoolchild can see that this is a tautology. "Weight loss has been shown to alleviate some of the pain in osteoarthritis of the knee. Our drug helps weight reduction. Our drug, therefore, helps alleviate some of the pain in osteoarthritis of the knee." The many other gross violations of scientific principles in this study are beside the point.