I am a physician who prescribes and follows this medication. I believe you significantly underplay the downsides. First of all, a life long drug is no joke at all; especially if my patient is not medicalized.
Starting a GLP-1 agonist on a late-life diabetic is a significantly easier chose than starting it on the hordes of 20 year olds asking for it. Why?
1) There are no studies that answer: ‘is this medication safe for 50 years?’ which is exactly what we’re offering here. Last time my field tried a ‘benign’ drug that made physiologic sense in an entire age group for decades (aspirin); it did not end well.
2) I can tell you from experience Mounjaro has significantly more discontinuation due to side effects than GLP-1 agonist. (Tirzepatide > Semaglutide > Dulaglutide). It causes severe acid reflux in many patients, one that only responds to high doses of PPIs (if it does)
3) And while your confidence in safe long term use of these drugs might be misplaced; there’s no evidence of harm yet. There IS evidence of harm for long term PPIs, which is what we’re being forced to do for people who want to stay on these drugs in a rapidly escalating cascade of medicalization
4) many Anesthesiologists have already started doing rapid sequence intubations on anyone using GLP-1s routinely because of the higher risk of aspiration. How many physicians tell patients starting these drugs ‘any future elective surgery you take will be slightly riskier’? How many discuss the lifetime use? The unsure risk of muscle mass? We at best discuss the risk of medullary thyroid cancer and gastroparesis/GERD.
5) I am seeing a lot of ‘GLP-1 gluttony’ that mimics the famous ‘statin gluttony’. No further words are needed.
There is too much positive spin on this and not enough caution. I am reasonably confident in saying when I revisit this in 5 years, the average American will not be much healthier but will definitely be much more medicalized.
Hi, this is a bit outside the points of the blog post, but, nevertheless, some thoughts:
1) I don't think anyone "has" to be on these drugs forever, any more than anyone has to follow a diet plan forever. In fact, I'd say the ability to get on and off these drugs (in contrast to the permanency of surgery) is a major part of their appeal.
2) I believe that you've noticed this, but the studies haven't borne it out so far.
3) Again, people can literally just stop taking these drugs and, at worst, end up where they started. They don't have to end up on long term, high dose ppis.
4) I'm unaware of this but would be interested to read about it if you have any literature.
5) GLP-1 gluttony is a contradiction in terms, I think.
1) I mean; we know the weight loss largely reverses if the medication is stopped as you yourself say. Can people use this as a gateway to lose weight and keep the weight off? Sure. Is this what the company's own evidence is showing? No. If I'm prescribing this for weight loss, the implicit argument is it'll be a life long thing. If I plan to stop it in a while, then I'm just wasting the patient's time by the GLP-1's own evidence base.
2) The tirzepatide study mentions 'In the event of intolerable gastrointestinal symptoms, mitigation strategies were implemented as described in the protocol and in a previous publication.'; ergo recommendations to do smaller meals and to not finish what's in your plate if you're full (good practice); and if that fails PPIs.
3) Usually the people who ask for this medication are desperate and would usually take the PPI and power through. If a patient asks for a GLP-1 for weight loss; I mention everything I've said here and give it to them if they want it. Not my life, as long as people know what they're getting into, I'm okay. I just don't like the aura of over-promise around these drugs.
In my father's case, he hilariously stopped trusting his excellent endocrinologist because the tirzepatide gave him severe reflux. Patients are weird and finnicky; if I didn't insist he go back his A1c would be in the sky. Over promising and under delivering leads to a loss of trust.
Both were issued in response to overwhelming anectodal evidence; and now the written evidence has to catch up. Practice has already largely changed on the ground and a lot of docs are doing RSIs (ergo 'full stomach precautions'). Problem is no one really knows how long of a washout period we need to improve gastric emptying; but we know it's definitely more than 1 week. Not really convenient to stop it.
5) GLP-1 gluttony is inspired from statin gluttony; which is a paper from 2014 asserting that people on statins become more cavalier with the quantity and quality of the food they eat because they feel 'protected' by the statins.
I do see GLP-1s achieve proper weight loss sometimes and not just a BMI 32 patient reaching a BMI of 29 and staying there. But that's usually in patients who already got through 80% of the journey and just need an extra push off the final hump. The majority of the patient who ask for this medication however do no effort and persist (or worsen) in their unhealthy habits when on the drug. GLP-1 gluttony.
I feel like "too little or too much can disrupt the 'intended' function" is kind of the norm for a LOT of the various compounds we're working with, no? Like several of the standard "vitamins" are poisonous if you get enough of them in your system. If GIP is serving some kind of regulatory role, with the "intended" (fitness-adapting) outcome of turning excess circulating glucose into triglycerides and then storing them in adipose tissue (so that you can store up energy in a feast year, to survive a future famine year), then potentially imbalancing it in either direction might mess with that process somehow... Though if that's right you potentially could have a situation where, say, you're still building triglycerides just as fast, or even faster, than normal; but then not storing them fast enough, which would mean a higher level of circulating triglycerides.... which might be a problem (High levels of circulating triglycerides are a heart attack risk, I think?)
Anyways, I'm just speculating... I suppose you'll address some of the possibilities in follow-up posts.
Eh....there are a few problems with what you wrote. First, it's not that "too little or too much disrupts the intended function", it's that activating the receptor or preventing the receptor from being activated (as long as the GLP-1 receptor is also activated) seems to have the same effect.
So, vitamins, which by definition aren't produced inside the body, aren't really analogous. They perform lots of functions but aren't specific to any one receptor, and the vitamins that are toxic in large amounts are because they are fat soluble vitamins that aren't easily removed and just hang around interfering with bodily processes.
If we extend the traditional "lock and key" method, we can think of like a machine that produces widgets when it's turned on, as long as the engine next to it is also turned on. In this example, the machine produces widgets when you insert the key and turn it on, but it also produces widgets when you start the engine next to it and then put a lock on the machine so nobody can turn it on. That's pretty weird, no?
I am a physician who prescribes and follows this medication. I believe you significantly underplay the downsides. First of all, a life long drug is no joke at all; especially if my patient is not medicalized.
Starting a GLP-1 agonist on a late-life diabetic is a significantly easier chose than starting it on the hordes of 20 year olds asking for it. Why?
1) There are no studies that answer: ‘is this medication safe for 50 years?’ which is exactly what we’re offering here. Last time my field tried a ‘benign’ drug that made physiologic sense in an entire age group for decades (aspirin); it did not end well.
2) I can tell you from experience Mounjaro has significantly more discontinuation due to side effects than GLP-1 agonist. (Tirzepatide > Semaglutide > Dulaglutide). It causes severe acid reflux in many patients, one that only responds to high doses of PPIs (if it does)
3) And while your confidence in safe long term use of these drugs might be misplaced; there’s no evidence of harm yet. There IS evidence of harm for long term PPIs, which is what we’re being forced to do for people who want to stay on these drugs in a rapidly escalating cascade of medicalization
4) many Anesthesiologists have already started doing rapid sequence intubations on anyone using GLP-1s routinely because of the higher risk of aspiration. How many physicians tell patients starting these drugs ‘any future elective surgery you take will be slightly riskier’? How many discuss the lifetime use? The unsure risk of muscle mass? We at best discuss the risk of medullary thyroid cancer and gastroparesis/GERD.
5) I am seeing a lot of ‘GLP-1 gluttony’ that mimics the famous ‘statin gluttony’. No further words are needed.
There is too much positive spin on this and not enough caution. I am reasonably confident in saying when I revisit this in 5 years, the average American will not be much healthier but will definitely be much more medicalized.
Hi, this is a bit outside the points of the blog post, but, nevertheless, some thoughts:
1) I don't think anyone "has" to be on these drugs forever, any more than anyone has to follow a diet plan forever. In fact, I'd say the ability to get on and off these drugs (in contrast to the permanency of surgery) is a major part of their appeal.
2) I believe that you've noticed this, but the studies haven't borne it out so far.
3) Again, people can literally just stop taking these drugs and, at worst, end up where they started. They don't have to end up on long term, high dose ppis.
4) I'm unaware of this but would be interested to read about it if you have any literature.
5) GLP-1 gluttony is a contradiction in terms, I think.
1) I mean; we know the weight loss largely reverses if the medication is stopped as you yourself say. Can people use this as a gateway to lose weight and keep the weight off? Sure. Is this what the company's own evidence is showing? No. If I'm prescribing this for weight loss, the implicit argument is it'll be a life long thing. If I plan to stop it in a while, then I'm just wasting the patient's time by the GLP-1's own evidence base.
2) The tirzepatide study mentions 'In the event of intolerable gastrointestinal symptoms, mitigation strategies were implemented as described in the protocol and in a previous publication.'; ergo recommendations to do smaller meals and to not finish what's in your plate if you're full (good practice); and if that fails PPIs.
3) Usually the people who ask for this medication are desperate and would usually take the PPI and power through. If a patient asks for a GLP-1 for weight loss; I mention everything I've said here and give it to them if they want it. Not my life, as long as people know what they're getting into, I'm okay. I just don't like the aura of over-promise around these drugs.
In my father's case, he hilariously stopped trusting his excellent endocrinologist because the tirzepatide gave him severe reflux. Patients are weird and finnicky; if I didn't insist he go back his A1c would be in the sky. Over promising and under delivering leads to a loss of trust.
4) I can give you the ASA's short statement: https://www.asahq.org/about-asa/newsroom/news-releases/2023/06/american-society-of-anesthesiologists-consensus-based-guidance-on-preoperative
And this quick editorial: https://pubmed.ncbi.nlm.nih.gov/38390914/
Both were issued in response to overwhelming anectodal evidence; and now the written evidence has to catch up. Practice has already largely changed on the ground and a lot of docs are doing RSIs (ergo 'full stomach precautions'). Problem is no one really knows how long of a washout period we need to improve gastric emptying; but we know it's definitely more than 1 week. Not really convenient to stop it.
5) GLP-1 gluttony is inspired from statin gluttony; which is a paper from 2014 asserting that people on statins become more cavalier with the quantity and quality of the food they eat because they feel 'protected' by the statins.
https://pubmed.ncbi.nlm.nih.gov/24763487/
I do see GLP-1s achieve proper weight loss sometimes and not just a BMI 32 patient reaching a BMI of 29 and staying there. But that's usually in patients who already got through 80% of the journey and just need an extra push off the final hump. The majority of the patient who ask for this medication however do no effort and persist (or worsen) in their unhealthy habits when on the drug. GLP-1 gluttony.
I feel like "too little or too much can disrupt the 'intended' function" is kind of the norm for a LOT of the various compounds we're working with, no? Like several of the standard "vitamins" are poisonous if you get enough of them in your system. If GIP is serving some kind of regulatory role, with the "intended" (fitness-adapting) outcome of turning excess circulating glucose into triglycerides and then storing them in adipose tissue (so that you can store up energy in a feast year, to survive a future famine year), then potentially imbalancing it in either direction might mess with that process somehow... Though if that's right you potentially could have a situation where, say, you're still building triglycerides just as fast, or even faster, than normal; but then not storing them fast enough, which would mean a higher level of circulating triglycerides.... which might be a problem (High levels of circulating triglycerides are a heart attack risk, I think?)
Anyways, I'm just speculating... I suppose you'll address some of the possibilities in follow-up posts.
Eh....there are a few problems with what you wrote. First, it's not that "too little or too much disrupts the intended function", it's that activating the receptor or preventing the receptor from being activated (as long as the GLP-1 receptor is also activated) seems to have the same effect.
So, vitamins, which by definition aren't produced inside the body, aren't really analogous. They perform lots of functions but aren't specific to any one receptor, and the vitamins that are toxic in large amounts are because they are fat soluble vitamins that aren't easily removed and just hang around interfering with bodily processes.
If we extend the traditional "lock and key" method, we can think of like a machine that produces widgets when it's turned on, as long as the engine next to it is also turned on. In this example, the machine produces widgets when you insert the key and turn it on, but it also produces widgets when you start the engine next to it and then put a lock on the machine so nobody can turn it on. That's pretty weird, no?
Where did you hear about BioAge being spooked?
Read change history at the bottom: https://www.nature.com/articles/s41587-024-02176-5