Is there any good consensus on what the deal is with this drug yet? I don't know how to think about GLP-1. In the headlines it seems like every month it's a miracle cure for something new, yet we don't really understand it? But it seems like just generally...everyone, including me, would benefit from being on it...? The whole thing makes me uneasy but I'm not exactly sure why outside of it seems weird to have one drug that is so good at so much.
There is large-enough consensus on this drug for its main use cases (treating diabetes and obesity), but more importantly for this conversation: it's actually quite common for drugs to get new indications after their initial one --- at which point, there might be a new, broader consensus on what the drug is good for.
Clinical trials are designed to treat a very specific subclass of individuals; pharmaceutical companies very carefully choose that subclass in an attempt to help ensure the clinical trials are successful, which is a combination of the following:
- Positive, statistically-significant results.
- FDA approval with those results.
- Insurance companies willing to pay for the given treatment.
- A decent-sized addressable market.
Examples of drugs/medical technologies later getting other indications:
- Minoxidil was a drug that only later got its approval to be used as a hair loss treatment; there are currently clinical trials for a more "advanced" minoxidil oral pill for this use case.
- Re: GLP-1s: Tirzepatide later got an indication that it effectively treats sleep apnea. There are very many other clinical trials ongoing for GLP-1s, but perhaps most recently, Semaglutide (ozempic) failed to show statistical significance as a treatment for Alzheimer's.
- The Galleri blood screening/test. The initial indication they are going for is folk who are at highest risk for cancer (I believe that's individuals between the ages of 50 and 70); however, that's not to say it would be bad for individuals younger or older. But, this is a way to help ensure the earliest product has a successful outcome.
These are ones I know off the top of my head, but I suspect an LLM can give several more examples.
It’s miracle drug, I’ve been on it for a few years now, it would have been sooner but usage data wasn’t available at the scale I needed before the ozempic craze. I have hEDS and part of that is ME/CFS and uncontrollable weight gain, so naturally I was looking for help with weight loss with the understanding that drugs that help with weight loss could be treating an underlying mechanisms that was causing the weight gain. Low Dose Naltrexone is another drug that also helps with weight loss and hEDS, so I was looking for more of the same. I still don’t know the underlying mechanisms but my autoimmune conditions have largely been resolved. Like cheap solar electricity, I see GLP1s as basically an absolute win. Of course people shouldn’t abuse the drug and they should also change their habits.
Yeah, that's one of the reasons I waited for usage data is that I was pretty sure people with hEDS would have an overly strong reaction, and that did happen in my case and appears to have happened with other with hEDS. I started at 0.025mg (1/20th the 0.5mg starting dose at the time) and still got temporary gastroparesis which was indeed very uncomfortable. I had done long term fasting prior to semaglutide so I had to just stop eating for a long time while the effects started to wear off. Over the first year I ramped up linearly to 1mg and I've been at that dose since.
Thanks, highly recommended. I forgot to answer, I don’t have MCAS but I do get PEM which I do believe is another form of allergic reaction. I do like to eat histamine inducing foods and I wonder if has kept MCAS desensitized.
No, it's the worst, just fat but also because I was dieting so much I couldn't tell if I was tired from not eating enough or if I had ME/CFS. After I gained the weight people would blame my fatigue on me being fat, ignoring that I was fatigued before gaining the weight.
Anything dealing with the signaling systems of the body (GLP-1 agonists, DP-XX binders like Keytruda, IL-XX binders like Humira, etc and even HRT) all fall under this bucket. We have a great understanding of some effects of some signaling systems and we use that understanding to our advantage. But the fact is these signaling molecules and receptors do a lot, more than we know, and in overlapping and complex ways, that we are always finding “new indications” and “new side effects” with roughly equal frequency.
There are currently several hypotheses. Some say that it's just because it helps you lose weight, and obesity increases the risk of so many things. However while this is true, there are lots of examples where there are effects even when you control for weight loss. One of the more interesting theories is that it's down to their anti-inflammatory effects, because chronic inflammation is linked to so many conditions.
I had just assumed that all these new things this is a cure for are just down stream affects of being overweight, and losing the weight also reduces the incidence of these other issues as well.
One reported benefit from Ozempic is that it improves self control. For instance, there are some studies that show it's easier to stop smoking on Ozempic[1]. I can't think of any way that would be modulated just by being less overweight.
Correct. Reduced smoking, alcohol, and other behaviors have been documented. There's a complex relationship between the gut and certain behaviors. These drugs slow down gut processing, and delay the reward mechanism. With slightly less reward from the body, the scales may tip slightly in favor of self control.
Source: currently using GLP and seeing reduced positive feedback from alcohol (incidentally)...
It seems weird because we hate finding “bugs” in our bodies, but it happens all the time.
Another example: low dose metformin is largely considered beneficial for most people, at least in a small way. But very few people who aren’t diabetic take it, as the drawback of possible side effects outweighs the potential benefit for someone who doesn’t have symptoms in the first place.
Same thing here. Would it benefit you? Possibly. Do the risks of side effects outweigh that benefit for someone without symptoms? Also possibly.
I agree with you. My point was simply that most physicians only prescribe if the potential benefits are obvious and outweigh the potential risks / side effects. Doing nothing is something better than doing something without an obvious benefit.
If you’re obese, have metabolic syndrome, have T2D, or any other number of issues that we’ve seen GLP-1s (or metformin) help with - then the medications can be a godsend.
Nobody understands why it all helps, they just noticed it does work for something, quickly pushed it to the market first to get patents and get all the profits from it before generics + derivatives hit their pockets. Now, everyone is studying it because there's all new funding coming in for it and finding other versions of it that they can profit off it.
Nobody knows what migraine really is, so this isn't a surprise to them that GLP-1 may help, the main question is; why? So they have another data point proving that gut health has a direct correlation to the brain.
Keep in mind that a lot of the benefits go away once patients come off GLP-1 and we have not seen any studies yet on what happens to people who come off it for long term effects. It may in fact make things even worse and for a lot of people, they may have to stay on it for the rest of their lives.
> [...] quickly pushed it to the market first to get patents and get all the profits [...]
Beyond what others have commented already, especially on obesity and cardiovascular disease, I have to correct this specifically, because it is a very common and honestly understandable misunderstanding people have about these drugs.
While only having appeared in the public consciousness comparatively recently, this class of drugs has been in use for two decades at this stage [0], showcasing a very solid safety profile with well established side-effects [1].
Continued research is important, as is proper prescription and use under the care of a Medical Professional up-to-date on current day evidence based practices (as is the case with all interventions), but to have a proper discussion about these, we shouldn't spread myths such as this being "quickly pushed" out, as these have undergone the clinical trials and regulations established across multiple agencies from multiple governments [2].
Again, it is understandable why these are considered rather new or appeared suddenly, especially if one doesn't take a look into their approval, but I don't see any evidence for them being rushed out or anything of the sort.
> Keep in mind that a lot of the benefits go away once patients come off GLP-1 and we have not seen any studies yet on what happens to people who come off it for long term effects.
Not if they increase muscle mass and change their lifestyle, like every physician (and the FDA/pharma companies) recommend.
> It may in fact make things even worse and for a lot of people, they may have to stay on it for the rest of their lives.
It does not. And some people may.
You know what’s worse than taking a GLP-1 forever? Obesity or metabolic syndrome killing you before you get to “forever.”
Benefits of reading, swimming, walking, playing an instrument etc. will go away too if you stop doing that thing.
Biology rarely awards something "forever". Maybe one day we can "fix" obese metabolisms permanently by killing off some receptors etc., but in that case, I would be afraid of intractable long-term effects even more.
All I know is I had some miserable side effects that started after a couple years that just progressively got worse while on them... when I found out it was the Trulicity/Ozempic I stopped, and the effects coming off were nearly as miserable... took almost a year to recover coming off and still dealing with the fallout.
Curious how you tied the side effects to GLP-1 when they didn't appear for a year and took so long to go away after stopping? Is it possible it was unrelated?
It's too soon to really know the downsides. Statins for example only recently are better understood and there's a lot more downsides we know about now.
Yeah... I think part of it is definitely that the profit margin is so high that there's a huge financial incentive to try to make buzz around it before all the patents expire. I guess we'll know for sure when it's available for pennies on the dollar if the buzz continues.
(i am hopefully that probiotics might be a future path to curating gut microbiota that meets an individual's GLP-1 in vivo production needs based on target metabolic outcome, but immediate intervention is welcome for obvious health reasons at scale)
GLP-1 is a naturally occurring hormone regulating blood sugar, satiety, and gastric emptying. Some people simply don't have enough naturally (which can be a result of diet composition and lifestyle -- there are diet and behaviour modifications to increase your natural production) and artificial supplementation is beneficial.
The overwhelming benefits from GLP-1 are courtesy of weight loss and better blood sugar control. Get those two things under control, with or without GLP-1 drugs, and an enormous array of complications are made less likely.
For people with healthy, ideal diets at an optimal weight and with good blood sugar control, there are only remote, hypothetical benefits. There is some evidence it reduces inflammation and might ward off neurodegenerative disorders, but those likely have more of a relationship with blood sugar spikes, and again lifestyle changes are more impactful.
I agree with most of what you are saying but we should also be clear that there some sources of inflammation that are not caused (or fixed) by diet and lifestyle. There is huge upside for some serious chronic conditions that may be helped by GLP-1 but we are still early on in studies for these things.
It's just that when something is widespread enough you can actually study other effects it has. Sort of like how psilocybin and weed had all these other effects but we couldn't study them till they got a little less criminalized. All sorts of shit does stuff, but we grandfathered in substances and froze everything for a while. Then COVID came along and a bunch of people started doing telemedicine and before you know it compounding pharmacies were handing out GLP-1RAs as a substitute for the phentermine they were passing out. Not scheduled, absolutely effective, great stuff.
Then with all that use in the wild you could rock and roll. Only problem is that off-label use like me with my retatrutide makes some population studies less effective than before.
There is a growing body of evidence that this is the most significant class of drugs since the introduction of statins. Whatever it is doing, it is delivering tens of millions of quality adjusted life years.
The Alzheimer """cure""" claim was already disproven by another study. Aside from that, the people who stop taking GLP, 75% gain 50-75% of their bodyweight back and lose all concomitant cardiovascular, cancer etc. risk benefits.
No research out on, say, alcoholism yet, but I'd hazard a guess the results are the same.
This is not a cravings loss drug but largely a cravings management drug. Which is still pretty great but it saddles healthcare funding systems with an enormous burden for the next 20 years. Or you keep it private, which means you introduce an enormous gulf of health inequality.
I hate that our solution to obesity is not the way Iceland treated it's youth drinking problem: reduce access to the harmful thing, give people money and support to do the healthy thing. Stick with it instead of cancelling the program if it doesn't show results in 4 years.
Modern food (started in the 80s) has carefully been engineered to be as addictive as possible, health consequences be damned. Let's start fixing the problem there.
This is not a cravings loss drug but largely a cravings management drug. Which is still pretty great but it saddles healthcare funding systems with an enormous burden for the next 20 years.
Semaglutide goes off-patent in 2032 in the US, and in 2026 in Canada and China:
No they have been on the market for decades, but only recently have been found to be of use to non-diabetics. That's why you are hearing about them much more.
> the people who stop taking GLP, 75% gain 50-75% of their bodyweight back and lose all concomitant cardiovascular, cancer etc. risk benefits.
I don't think that framing is right, from another study:
* 17.5% maintained 75+% of their weight loss
* 25% maintained 50-75% of their weight loss
* 23% maintained 25-50% of their weight loss
* 24% maintained 0-25% of their weight loss
At least 75% (possibly more!) maintained some form of weight loss 25% to 75%+. That is tremendous. And 43% maintained 50%+! For reducing being overweight, that is just amazing.
> I hate that our solution to obesity is not the way Iceland treated it's youth drinking problem: reduce access to the harmful thing, give people money and support to do the healthy thing. Stick with it instead of cancelling the program if it doesn't show results in 4 years.
I don't think it's possible to "reduce access to the harmful thing" when that thing is "food".
Many people show long term results even stopping it. I don't understand this desire to say "people should suffer!" instead of taking something that helped them.
Plenty of people have tried (me included) but if it was easy to lose weight, nobody would be long term overweight.
Effects on Alzheimer’s have not been disproven; it was shown that there wasn’t a perceivable benefit from oral semaglutide at the doses prescribed for folks with a certain degree of progression of the disease.
“We think that, by modulating cerebrospinal fluid pressure and reducing intracranial venous sinuses compression, these drugs produce a decrease in the release of calcitonin gene-related peptide (CGRP), a key migraine-promoting peptide”, Dr Braca explained. “That would pose intracranial pressure control as a brand-new, pharmacologically targetable pathway.”
I'm not sure I understand what that means, but I wonder if this would work for people who are not obese?
They are positing that the GLP-1 agonist acts mechanistically to modulate CGRP release. But CGRP involvement in migraine is itself only one potential mechanism that causes migraine. I would like to know whether the subjects who responded to the GLP-1 therapy were also responsive to CGRP monoclonal antibody therapy.
My wife has chronic migraines which are successfully mitigated by rimegepant (gepants are CGRP antagonists), and didn't have any particular change in headaches from GLP-1.
What has helped, interestingly, is supplemented creatine HCl (she went with hcl because it's absorbed substantially faster than monohydrate). We've learned that depletion of neural ATP levels can result in an energy crisis which results in cortical spreading depression, which stimulates the release of CGRP. (https://www.sciencedirect.com/topics/neuroscience/spreading-...)
She's found that a) daily supplementation of creatine has reduced her headache days, and b) an immediate dose of creatine upon onset of a headache frequently aborts or mitigates it. Her need for the gepants has dropped to a tiny fraction of what it was prior to starting creatine.
She's tried everything under the sun, had all the scans, tried all the meds and procedures, and creatine and gepants are the only things she's found that have worked. She's not a placebo responder, and hasn't responded to about a zillion other therapies, so we're pretty sure it's not just placebo effect.
Anecdotes are not data, however I used to have one or more severe migraine headaches weekly. Debilitating migraines. I suffered pretty high blood pressure (which has a very direct relationship with cerebrospinal fluid pressure, which is why I mention this), but aside from that am very healthy and physically fit, exercise regularly, and so on.
I started medication to treat the BP -- telmisartan and amlodipine -- and my BP dropped from 150+/120+ to 115/80. The migraines completely disappeared. I still infrequently get the visual aura that would traditionally precede a migraine, but nothing follows. I haven't had a migraine in the years I've had my BP under control.
Candesartan is actually one of the most used medications for migraine prophylaxis, also for people with normal BP. Your doc might have chosen the med for that reason. Though it's widely used for BP even in people without migraines.
I've had the auras at least since a teenager, but not headaches. Thought is was completely normal, 'til a neurologist said No and that I has having vestibular migraines. Blood pressure was always on the low side of normal.
Family history of migraines and seizures, which some hypothesize have the same root causes. Would be interesting to see GLP-1 tests on epilepsy.
Oh man, I'd love for a reduction in that. I sort-of deal with it.
As a kid I had nearly daily migraines - go into a very dark quiet room and be happy when I fell asleep, since I knew the migraine wouldn't be there when I woke up.
These days it's just headaches, 99% sure it's muscle tension in my neck. Kinda doubt GLP-1 could do anything for that, but I'd be pleasantly surprised....
I had very similar issues, both as a kid and an adult. I now take 500mg of Magnesium (Malate or Glycinate. NOT Citrate, as that is a laxative) nearly every night, and my headaches are almost completely gone now. I still get one every once in a while, but it's infrequent enough that I no longer worry about my use of Ibuprofen to manage it.
Get your magnesium level checked. Those that suffer from chronic migraines often are deficient in magnesium and will see a significant reduction in events after 4-6 weeks on a daily Magnesium supplement.
Well, that depends on the effect size etc. right? There's a chocolate bar in front of you and your two buddies. You split it in thirds. As soon as one of your buddies eats his, he drops dead. Your other buddy says "Sample size of 1. Psh. Billions have eaten chocolate.". He eats his. Drops dead. The sample size is now 2. You eat yours or not?
If the answer is yes, well all right.
If the answer is no, weaken the effects until you see what crosses the threshold of "should we study this more?".
Obesity is associated with increased rate of migraine, so their symptoms could have gone away by virtue of losing weight. Let's see what it does for non obese.
When I developed pre-diabetes symptoms (having to drink a lot - like 5-6l per day, consequently having to pee a lot, when not doing the first: getting headaches), I noticed that cutting on sugar meant (next to other benefits) that the thirst-induced headaches were the first thing that went away. Not the thirst itself (still have it).
However, not an expert on headaches and can't say if it has anything to do with the migraines in the article. But the point that reducing sugar helps in a myriad of ways, stands and is worth repeating.
The article specifically mentions that the weight loss was not enough to explain the effect on the migraine:
"Importantly, while participants’ body mass index declined slightly (from 34.01 to 33.65), this change was not statistically significant. An analysis of covariance confirmed that BMI reduction had no effect on headache frequency, strengthening the hypothesis that pressure modulation, not weight loss, drives the benefit."
Is there any good consensus on what the deal is with this drug yet? I don't know how to think about GLP-1. In the headlines it seems like every month it's a miracle cure for something new, yet we don't really understand it? But it seems like just generally...everyone, including me, would benefit from being on it...? The whole thing makes me uneasy but I'm not exactly sure why outside of it seems weird to have one drug that is so good at so much.
There is large-enough consensus on this drug for its main use cases (treating diabetes and obesity), but more importantly for this conversation: it's actually quite common for drugs to get new indications after their initial one --- at which point, there might be a new, broader consensus on what the drug is good for.
Clinical trials are designed to treat a very specific subclass of individuals; pharmaceutical companies very carefully choose that subclass in an attempt to help ensure the clinical trials are successful, which is a combination of the following:
- Positive, statistically-significant results. - FDA approval with those results. - Insurance companies willing to pay for the given treatment. - A decent-sized addressable market.
Examples of drugs/medical technologies later getting other indications: - Minoxidil was a drug that only later got its approval to be used as a hair loss treatment; there are currently clinical trials for a more "advanced" minoxidil oral pill for this use case. - Re: GLP-1s: Tirzepatide later got an indication that it effectively treats sleep apnea. There are very many other clinical trials ongoing for GLP-1s, but perhaps most recently, Semaglutide (ozempic) failed to show statistical significance as a treatment for Alzheimer's. - The Galleri blood screening/test. The initial indication they are going for is folk who are at highest risk for cancer (I believe that's individuals between the ages of 50 and 70); however, that's not to say it would be bad for individuals younger or older. But, this is a way to help ensure the earliest product has a successful outcome.
These are ones I know off the top of my head, but I suspect an LLM can give several more examples.
> but I suspect an LLM can hallucinate several more examples.
FTFY
(great comment otherwise)
It’s miracle drug, I’ve been on it for a few years now, it would have been sooner but usage data wasn’t available at the scale I needed before the ozempic craze. I have hEDS and part of that is ME/CFS and uncontrollable weight gain, so naturally I was looking for help with weight loss with the understanding that drugs that help with weight loss could be treating an underlying mechanisms that was causing the weight gain. Low Dose Naltrexone is another drug that also helps with weight loss and hEDS, so I was looking for more of the same. I still don’t know the underlying mechanisms but my autoimmune conditions have largely been resolved. Like cheap solar electricity, I see GLP1s as basically an absolute win. Of course people shouldn’t abuse the drug and they should also change their habits.
GLP-1s seem to induce/mimic gastroparesis, which also can occur with hEDS. Has that been an issue? Also, do you have MCAS?
(Also have hEDS.)
Yeah, that's one of the reasons I waited for usage data is that I was pretty sure people with hEDS would have an overly strong reaction, and that did happen in my case and appears to have happened with other with hEDS. I started at 0.025mg (1/20th the 0.5mg starting dose at the time) and still got temporary gastroparesis which was indeed very uncomfortable. I had done long term fasting prior to semaglutide so I had to just stop eating for a long time while the effects started to wear off. Over the first year I ramped up linearly to 1mg and I've been at that dose since.
Wow. Glad it panned out for you.
Thanks, highly recommended. I forgot to answer, I don’t have MCAS but I do get PEM which I do believe is another form of allergic reaction. I do like to eat histamine inducing foods and I wonder if has kept MCAS desensitized.
Does having uncontrollable weight gain help you get jacked? Being jacked and fat is tons of fun, better than being skinny.
No, it's the worst, just fat but also because I was dieting so much I couldn't tell if I was tired from not eating enough or if I had ME/CFS. After I gained the weight people would blame my fatigue on me being fat, ignoring that I was fatigued before gaining the weight.
Anything dealing with the signaling systems of the body (GLP-1 agonists, DP-XX binders like Keytruda, IL-XX binders like Humira, etc and even HRT) all fall under this bucket. We have a great understanding of some effects of some signaling systems and we use that understanding to our advantage. But the fact is these signaling molecules and receptors do a lot, more than we know, and in overlapping and complex ways, that we are always finding “new indications” and “new side effects” with roughly equal frequency.
There are currently several hypotheses. Some say that it's just because it helps you lose weight, and obesity increases the risk of so many things. However while this is true, there are lots of examples where there are effects even when you control for weight loss. One of the more interesting theories is that it's down to their anti-inflammatory effects, because chronic inflammation is linked to so many conditions.
I had just assumed that all these new things this is a cure for are just down stream affects of being overweight, and losing the weight also reduces the incidence of these other issues as well.
One reported benefit from Ozempic is that it improves self control. For instance, there are some studies that show it's easier to stop smoking on Ozempic[1]. I can't think of any way that would be modulated just by being less overweight.
[1]: https://www.goodrx.com/classes/glp-1-agonists/semaglutide-fo...
Correct. Reduced smoking, alcohol, and other behaviors have been documented. There's a complex relationship between the gut and certain behaviors. These drugs slow down gut processing, and delay the reward mechanism. With slightly less reward from the body, the scales may tip slightly in favor of self control.
Source: currently using GLP and seeing reduced positive feedback from alcohol (incidentally)...
Once you have proven to yourself you can eat less and lose weight, you believe you can do the same with other things like smoking.
Makes sense
That's not how it works.
so its a cure for the body positivity movement and all of the proponents reverted back to default understanding of health
It seems weird because we hate finding “bugs” in our bodies, but it happens all the time.
Another example: low dose metformin is largely considered beneficial for most people, at least in a small way. But very few people who aren’t diabetic take it, as the drawback of possible side effects outweighs the potential benefit for someone who doesn’t have symptoms in the first place.
Same thing here. Would it benefit you? Possibly. Do the risks of side effects outweigh that benefit for someone without symptoms? Also possibly.
Metformin's side effects are pretty minor, I find. So don't let that possibility stop you if you think you could benefit.
I agree with you. My point was simply that most physicians only prescribe if the potential benefits are obvious and outweigh the potential risks / side effects. Doing nothing is something better than doing something without an obvious benefit.
If you’re obese, have metabolic syndrome, have T2D, or any other number of issues that we’ve seen GLP-1s (or metformin) help with - then the medications can be a godsend.
Nobody understands why it all helps, they just noticed it does work for something, quickly pushed it to the market first to get patents and get all the profits from it before generics + derivatives hit their pockets. Now, everyone is studying it because there's all new funding coming in for it and finding other versions of it that they can profit off it.
Nobody knows what migraine really is, so this isn't a surprise to them that GLP-1 may help, the main question is; why? So they have another data point proving that gut health has a direct correlation to the brain.
Keep in mind that a lot of the benefits go away once patients come off GLP-1 and we have not seen any studies yet on what happens to people who come off it for long term effects. It may in fact make things even worse and for a lot of people, they may have to stay on it for the rest of their lives.
> [...] quickly pushed it to the market first to get patents and get all the profits [...]
Beyond what others have commented already, especially on obesity and cardiovascular disease, I have to correct this specifically, because it is a very common and honestly understandable misunderstanding people have about these drugs.
While only having appeared in the public consciousness comparatively recently, this class of drugs has been in use for two decades at this stage [0], showcasing a very solid safety profile with well established side-effects [1].
Continued research is important, as is proper prescription and use under the care of a Medical Professional up-to-date on current day evidence based practices (as is the case with all interventions), but to have a proper discussion about these, we shouldn't spread myths such as this being "quickly pushed" out, as these have undergone the clinical trials and regulations established across multiple agencies from multiple governments [2].
Again, it is understandable why these are considered rather new or appeared suddenly, especially if one doesn't take a look into their approval, but I don't see any evidence for them being rushed out or anything of the sort.
[0] https://www.ncbi.nlm.nih.gov/books/NBK572151/
[1] https://pmc.ncbi.nlm.nih.gov/articles/PMC5397288/
[2] https://pmc.ncbi.nlm.nih.gov/articles/PMC6667915/
> Keep in mind that a lot of the benefits go away once patients come off GLP-1 and we have not seen any studies yet on what happens to people who come off it for long term effects.
Not if they increase muscle mass and change their lifestyle, like every physician (and the FDA/pharma companies) recommend.
> It may in fact make things even worse and for a lot of people, they may have to stay on it for the rest of their lives.
It does not. And some people may.
You know what’s worse than taking a GLP-1 forever? Obesity or metabolic syndrome killing you before you get to “forever.”
> You know what’s worse than taking a GLP-1 forever? Obesity or metabolic syndrome killing you before you get to “forever.”
Bingo. Being obese has so many downstream effects. Anything that helps that is tremendous.
Benefits of reading, swimming, walking, playing an instrument etc. will go away too if you stop doing that thing.
Biology rarely awards something "forever". Maybe one day we can "fix" obese metabolisms permanently by killing off some receptors etc., but in that case, I would be afraid of intractable long-term effects even more.
> Keep in mind that a lot of the benefits go away once patients come off GLP-1
All medicines taken for chronic conditions as this way.
Oh no, my psoriasis will come back if I stop taking my psoriasis biologic. Oh wait, why the fuck would I want to do that?
Do you know what else stops working if you stop taking the therapy?
Diet and exercise.
All I know is I had some miserable side effects that started after a couple years that just progressively got worse while on them... when I found out it was the Trulicity/Ozempic I stopped, and the effects coming off were nearly as miserable... took almost a year to recover coming off and still dealing with the fallout.
Curious how you tied the side effects to GLP-1 when they didn't appear for a year and took so long to go away after stopping? Is it possible it was unrelated?
I’m sorry you went through that
It's too soon to really know the downsides. Statins for example only recently are better understood and there's a lot more downsides we know about now.
It's likely going to be true for GLP-1 as well.
I don't know if it will. These drugs have been on the market for decades.
Yeah... I think part of it is definitely that the profit margin is so high that there's a huge financial incentive to try to make buzz around it before all the patents expire. I guess we'll know for sure when it's available for pennies on the dollar if the buzz continues.
I agree with you. All I can think is that it's affecting some central mental or physical aspect that has many different outward benefits.
It patches the reward center in the brain, which improves everything downstream of that (as mentioned in llm_nerd's sibling comment to yours).
https://news.ycombinator.com/item?id=45907422 (citations)
(i am hopefully that probiotics might be a future path to curating gut microbiota that meets an individual's GLP-1 in vivo production needs based on target metabolic outcome, but immediate intervention is welcome for obvious health reasons at scale)
Reminds me of aspirin. It started from willow tree bark thousands of years ago. I'm pretty sure it was not understood for most of that time either.
I wonder when the first person understood how it worked. (if anyone understands it now?)
It's Gila monster venom. You may become a druid while taking it.
GLP-1 is a naturally occurring hormone regulating blood sugar, satiety, and gastric emptying. Some people simply don't have enough naturally (which can be a result of diet composition and lifestyle -- there are diet and behaviour modifications to increase your natural production) and artificial supplementation is beneficial.
The overwhelming benefits from GLP-1 are courtesy of weight loss and better blood sugar control. Get those two things under control, with or without GLP-1 drugs, and an enormous array of complications are made less likely.
For people with healthy, ideal diets at an optimal weight and with good blood sugar control, there are only remote, hypothetical benefits. There is some evidence it reduces inflammation and might ward off neurodegenerative disorders, but those likely have more of a relationship with blood sugar spikes, and again lifestyle changes are more impactful.
This is absolutely correct. I couldn’t have said it better myself.
(Except I’ll note that’s true for more than one hormone, as tirzepatide is both a GLP1 and GIP agonist, and I believe retatrutide is also Glucagon?)
"Incretins" is the keyword here.
Indeed! Thank you!
I agree with most of what you are saying but we should also be clear that there some sources of inflammation that are not caused (or fixed) by diet and lifestyle. There is huge upside for some serious chronic conditions that may be helped by GLP-1 but we are still early on in studies for these things.
It's just that when something is widespread enough you can actually study other effects it has. Sort of like how psilocybin and weed had all these other effects but we couldn't study them till they got a little less criminalized. All sorts of shit does stuff, but we grandfathered in substances and froze everything for a while. Then COVID came along and a bunch of people started doing telemedicine and before you know it compounding pharmacies were handing out GLP-1RAs as a substitute for the phentermine they were passing out. Not scheduled, absolutely effective, great stuff.
Then with all that use in the wild you could rock and roll. Only problem is that off-label use like me with my retatrutide makes some population studies less effective than before.
There is a growing body of evidence that this is the most significant class of drugs since the introduction of statins. Whatever it is doing, it is delivering tens of millions of quality adjusted life years.
The Alzheimer """cure""" claim was already disproven by another study. Aside from that, the people who stop taking GLP, 75% gain 50-75% of their bodyweight back and lose all concomitant cardiovascular, cancer etc. risk benefits.
No research out on, say, alcoholism yet, but I'd hazard a guess the results are the same.
This is not a cravings loss drug but largely a cravings management drug. Which is still pretty great but it saddles healthcare funding systems with an enormous burden for the next 20 years. Or you keep it private, which means you introduce an enormous gulf of health inequality.
I hate that our solution to obesity is not the way Iceland treated it's youth drinking problem: reduce access to the harmful thing, give people money and support to do the healthy thing. Stick with it instead of cancelling the program if it doesn't show results in 4 years.
Modern food (started in the 80s) has carefully been engineered to be as addictive as possible, health consequences be damned. Let's start fixing the problem there.
This is not a cravings loss drug but largely a cravings management drug. Which is still pretty great but it saddles healthcare funding systems with an enormous burden for the next 20 years.
Semaglutide goes off-patent in 2032 in the US, and in 2026 in Canada and China:
https://journals.library.columbia.edu/index.php/stlr/blog/vi...
https://www.ncbi.nlm.nih.gov/books/NBK602920/table/t03/
Wait, what? I thought these were extremely new drugs, only approved for a couple of years now.
No they have been on the market for decades, but only recently have been found to be of use to non-diabetics. That's why you are hearing about them much more.
> the people who stop taking GLP, 75% gain 50-75% of their bodyweight back and lose all concomitant cardiovascular, cancer etc. risk benefits.
I don't think that framing is right, from another study:
* 17.5% maintained 75+% of their weight loss
* 25% maintained 50-75% of their weight loss
* 23% maintained 25-50% of their weight loss
* 24% maintained 0-25% of their weight loss
At least 75% (possibly more!) maintained some form of weight loss 25% to 75%+. That is tremendous. And 43% maintained 50%+! For reducing being overweight, that is just amazing.
> I hate that our solution to obesity is not the way Iceland treated it's youth drinking problem: reduce access to the harmful thing, give people money and support to do the healthy thing. Stick with it instead of cancelling the program if it doesn't show results in 4 years.
I don't think it's possible to "reduce access to the harmful thing" when that thing is "food".
Many people show long term results even stopping it. I don't understand this desire to say "people should suffer!" instead of taking something that helped them.
Plenty of people have tried (me included) but if it was easy to lose weight, nobody would be long term overweight.
It should be treated like other important drugs. The U.S. buys the patent (or other variant) letting it become generic
Effects on Alzheimer’s have not been disproven; it was shown that there wasn’t a perceivable benefit from oral semaglutide at the doses prescribed for folks with a certain degree of progression of the disease.
These medicines reduce the cravings for sugar. Is it possible that all of these beneficial side effects are just benefits from not abusing sugar.
They are positing that the GLP-1 agonist acts mechanistically to modulate CGRP release. But CGRP involvement in migraine is itself only one potential mechanism that causes migraine. I would like to know whether the subjects who responded to the GLP-1 therapy were also responsive to CGRP monoclonal antibody therapy.
My wife has chronic migraines which are successfully mitigated by rimegepant (gepants are CGRP antagonists), and didn't have any particular change in headaches from GLP-1.
What has helped, interestingly, is supplemented creatine HCl (she went with hcl because it's absorbed substantially faster than monohydrate). We've learned that depletion of neural ATP levels can result in an energy crisis which results in cortical spreading depression, which stimulates the release of CGRP. (https://www.sciencedirect.com/topics/neuroscience/spreading-...)
She's found that a) daily supplementation of creatine has reduced her headache days, and b) an immediate dose of creatine upon onset of a headache frequently aborts or mitigates it. Her need for the gepants has dropped to a tiny fraction of what it was prior to starting creatine.
She's tried everything under the sun, had all the scans, tried all the meds and procedures, and creatine and gepants are the only things she's found that have worked. She's not a placebo responder, and hasn't responded to about a zillion other therapies, so we're pretty sure it's not just placebo effect.
I wonder if the drug itself reduces CGRP or perhaps the altered diet is the cause.
I was wondering the same thing. Might be a mix depending on person.
Anecdotes are not data, however I used to have one or more severe migraine headaches weekly. Debilitating migraines. I suffered pretty high blood pressure (which has a very direct relationship with cerebrospinal fluid pressure, which is why I mention this), but aside from that am very healthy and physically fit, exercise regularly, and so on.
I started medication to treat the BP -- telmisartan and amlodipine -- and my BP dropped from 150+/120+ to 115/80. The migraines completely disappeared. I still infrequently get the visual aura that would traditionally precede a migraine, but nothing follows. I haven't had a migraine in the years I've had my BP under control.
Interesting to hear as someone who gets the aura thing, but never the migraine pain, and has good blood pressure
Candesartan is actually one of the most used medications for migraine prophylaxis, also for people with normal BP. Your doc might have chosen the med for that reason. Though it's widely used for BP even in people without migraines.
Agree. Candesartan was one of the first line of migraine treatments given to me. Propranalol was the other one. Neither worked in my case.
I've had the auras at least since a teenager, but not headaches. Thought is was completely normal, 'til a neurologist said No and that I has having vestibular migraines. Blood pressure was always on the low side of normal.
Family history of migraines and seizures, which some hypothesize have the same root causes. Would be interesting to see GLP-1 tests on epilepsy.
Oh man, I'd love for a reduction in that. I sort-of deal with it.
As a kid I had nearly daily migraines - go into a very dark quiet room and be happy when I fell asleep, since I knew the migraine wouldn't be there when I woke up.
These days it's just headaches, 99% sure it's muscle tension in my neck. Kinda doubt GLP-1 could do anything for that, but I'd be pleasantly surprised....
I had very similar issues, both as a kid and an adult. I now take 500mg of Magnesium (Malate or Glycinate. NOT Citrate, as that is a laxative) nearly every night, and my headaches are almost completely gone now. I still get one every once in a while, but it's infrequent enough that I no longer worry about my use of Ibuprofen to manage it.
Get your magnesium level checked. Those that suffer from chronic migraines often are deficient in magnesium and will see a significant reduction in events after 4-6 weeks on a daily Magnesium supplement.
Is there a centralized tracker for all these off-label benefits of GLP-1? Besides meta-reviews and one-off Deep Research reports
how is 26 people statistically relevant??
Well, that depends on the effect size etc. right? There's a chocolate bar in front of you and your two buddies. You split it in thirds. As soon as one of your buddies eats his, he drops dead. Your other buddy says "Sample size of 1. Psh. Billions have eaten chocolate.". He eats his. Drops dead. The sample size is now 2. You eat yours or not?
If the answer is yes, well all right.
If the answer is no, weaken the effects until you see what crosses the threshold of "should we study this more?".
It's relevant in that it's enough to cause them to plan to do a bigger study so we can say with more clarity how if it actually helps.
Obesity is associated with increased rate of migraine, so their symptoms could have gone away by virtue of losing weight. Let's see what it does for non obese.
When I developed pre-diabetes symptoms (having to drink a lot - like 5-6l per day, consequently having to pee a lot, when not doing the first: getting headaches), I noticed that cutting on sugar meant (next to other benefits) that the thirst-induced headaches were the first thing that went away. Not the thirst itself (still have it).
However, not an expert on headaches and can't say if it has anything to do with the migraines in the article. But the point that reducing sugar helps in a myriad of ways, stands and is worth repeating.
The article specifically mentions that the weight loss was not enough to explain the effect on the migraine: "Importantly, while participants’ body mass index declined slightly (from 34.01 to 33.65), this change was not statistically significant. An analysis of covariance confirmed that BMI reduction had no effect on headache frequency, strengthening the hypothesis that pressure modulation, not weight loss, drives the benefit."
how is 26 people statistically relevant???