For the group, because I can never keep the terms straight:
Semaglutide is one specific drug within the class of GLP-1 agonists. Other examples include Liraglutide (Victoza, Saxenda), Dulaglutide (Trulicity), and Tirzepatide (Mounjaro, though this is technically a dual GIP/GLP-1 agonist).
Semaglutide is available under several brand names for different uses: Ozempic (type 2 diabetes), Wegovy (weight management), and Rybelsus (oral form for type 2 diabetes).
Of all things my taxes go to, I would love it the United States Government would buy the patent for this drug and make it freely available to anybody who wants it.
The number of things it apparently just cures is staggering.
I have been on compounded GLP-1 for a month, prior to this I was a highly functional alcoholic, basically starting drinking after work every night and going until I passed out. I've drunk well over 50 beers (probably more) a week for the last 20 years. I have not had a drink since going on it.
I have been reading obsessively about this drug since going on it. I have been fortunate enough not to suffer side effects on it, save for one -- frustration with the cynicism around it. A cynicism I shared prior to experiencing its effects.
I am convinced that, barring any life threatening long term side effects, this is the most important drug of our lifetime (from a first world perspective) or until a silver bullet cancer drug is found. The potential to be the tide that lifts so many boats and alleviates so much physical and emotional pain and suffering on a population level is almost overwhelming to think about.
> barring any life threatening long term side effects
There's the rub. We have not been prescribing semaglutide very long, and I won't trust it until we've had enough time to suss out long term side effects.
My father was on a long-term maintenance dose of immunosuppressant (I think prednisolone, but I could be misremembering) following his kidney transplant. When it was first prescribed to him, the long term side effects were either not known at all or not widely known. By the time these side effects were more widely known, it was too late, as he was already losing his vision (cataracts) and mobility (cartilage was being destroyed). He spent his last few years in pain.
I am very cautious about the potential for damaging long-term side effects.
> There's the rub. We have not been prescribing semaglutide very long, and I won't trust it until we've had enough time to suss out long term side effects.
We've been prescribing GLP-1s for almost 20 years now. Not to say they all should behave identically, but from a Bayesian inference perspective these things really do appear to be quite safe.
Risk factors for NAION are basically all the things that you go on these drugs to treat - type 2 diabetes, sleep apnea, cardiovascular disease, blood pressure, etc. One observational study that shows some correlation isn't enough for me to be particularly concerned about it.
> As of March 31, only 4 cases of gastroparesis were recorded for semaglutide—the active ingredient in Ozempic and Wegovy—in the FDA Adverse Event Reporting System (FAERS), a surveillance database updated by healthcare professionals, consumers, and manufacturers. For tirzepatide—the active ingredient in Mounjaro and Zepbound—there is just one case logged.
I don't have more recent numbers, but these seem pretty low.
I don't think anyone is saying that there is no chance of significant side effects in people, but when measured against the risks of being obese, they'd have to be very bad and impact a significant number of people taking the drug.
Gastroparesis is a serious, life-threatening side effect.
It occurs in a small number of patients, sure, but maybe that just means I am more risk averse than you. My calculus is simple. I don't need wegovy. I can lose (and am losing) weight without it. Sure, it would be easier with wegovy, but it is not necessary. I am not going to take an unnecessary drug that has a nonzero chance of killing me.
Excellent! A huge chunk of people try and fail to do this for a wide variety of reasons.
If you can lose weight without the help of a GLP-1 drug, then yeah, that is likely the safest option. But most people aren't choosing between using a GLP-1 drug to lose weight or losing weight without it - they're choosing between staying fat and using the GLP-1.
> I am very cautious about the potential for damaging long-term side effects.
This is fair. But I'll ask you this: how long would it take for you to trust it? Assuming there are no side effects beyond what we know now, which are:
* gastroparesis is a small number of patients
* elevated thyroid cancer risk in mice
* nausea and general uncomfortableness when taking it (some percentage, not all)
* muscle and bone loss which seems to be roughly on par with any rapid weight loss approach
* a small percentage of people develop malaise, anhedonia and suicidal ideation
* a propensity to gain some percentage of weight back and/or relapse in addictive behavior when going off the drug
These are the side effects we know about with over a decade of prescribing GLP-1 agonists. Assuming these continue to be the primary side effects, how long would you wait until you are comfortable in trusting they are the only ones?
Agreed. The constant cynicism about everything, framed by some stupid moral hazard nonsense, is exhausting.
It reminds me of the British reaction to the famine in Ireland - the good ministers were concerned about the moral health of the Irish. If they were provided with charity food, it would be a terrible tragedy if they became dependent. Just let them starve to death, with a clean soul.
Can you describe what happened that you don't want to drink (many people who are addicted to something don't actually enjoy it anymore)? Did you still enjoy drinking before? Do you have the desire to drink?
I do not have ADHD. I am not sure exactly why I drink so much -- there are a number of alcoholics on both sides of my family, but I also spent many years drinking in bars in a big city, living a very social life. During COVID I became much more of a solitary drinker and over the last five or so years I have drank out of a sense of malaise. Every morning became the day I was going to take a break and every night there was an excuse to start drinking again.
The strange thing about GLP-1s effect on my desire to drink is how it manifests: I just don't care about drinking. I actually _could_ drink and be fine I think, I haven't tested it. I don't go through life with the burden of the knowledge of my own addiction. I don't have to be vigilant about triggers and self-assess my actions. I just don't drink.
I noticed that I did not want to drink the day after my first shot. It was that fast. If anything the closest I came to drinking came from routine, not desire. That is to say, what is an afternoon watching football if not with a beer in hand? But I was able to move past that.
One thing I should make clear, no matter how heavy a drinker I have been at times in my life, including with liquor, I have never had a physical addiction. A person deep in the throws of physical addiction will need to approach this carefully.
Novo Nordisk's market cap is $500 B, mostly on the basis of GLP-1 drug profits, and the US' entire discretionary budget is $1,700 B. Even if Denmark would allow the sale, and even if somehow the US did not need to pay a premium to shareholders (typical in acquisitions), that would still be a very substantial expenditure.
Voting majority is also controlled by the Novo Nordisk Foundation. It's already the wealthiest foundation on the planet so they're unlikely to give up their flagship enterprise.
The EU loves to ransom US tech companies for budget money. It's very clear that this is an opportunity for the US to similarly damage a big EU company by threatening its patents in the US, or otherwise hitting Novo for tens of billions of dollars in ransom money. The US market is by a huge margin the most important drug market in the world, and especially for Novo.
Find an abusive excuse to invalidate their patents if all else fails. Let Europe learn a valuable lesson in trade wars.
At this point in time, you are in no position to be teaching any lessons to the rest of the world, other than cautionary tales of wasted potential and the self-inflicted wounds of a belligerent populace.
First-gen GLP-1 goes off patent in 2031 (e.g. semaglutide). Seems far off, but is frighteningly close for Novo. Tirzepatide gets genericized in 2039 and has better efficacy, which is why Lilly is in such a strong position right now.
There is an enormous amount of biotech work to develop next-gen versions that have better half-lives, lower adverse events, and most importantly, have long patent lives. But it seems base GLP-1 are good enough that we should see massive societal change starting next decade.
Lilly is probably in an even stronger position if retatrutide continues to look as good as it has in the current trials. Better weight loss than tirzepatide, and recent results have shown it has excellent results on reducing fat deposits in the liver... and NAFLD is the leading cause of severe liver disease in the world.
This is the question and for people that are older the scales steadily tip towards just taking the damn drug because in 20 years they're likely to be dead anyways.
Seems like you need to increase the usage of it as your body starts adapting to it and the weight loss plateaus. IMO, I think the hype around this drug is a bit much and I expect a significant number of users won't be able to meet or maintain their weight loss goals with it.
I’ll make my usual response: we know that being obese is basically the worst possible thing you can do to yourself, and the longer you are, the worse it is. The side effects are going to be pretty awful just to negate that, much less all the other things they seem to be good for.
>> being obese is basically the worst possible thing you can do to yourself
Lol. I can think of dozens of worse things. Drinking. Cocaine addiction. Meth. Winding up in prison for some reason. Riding a motorcycle without a proper helmet. Getting into a plane flown by Harrison Ford. Even simple unprotected sex can lead to massive medical problems. Ever looked up the average life expectancy of professional athletes, especially the NFL? It isn't great.
Being obese is probably worse for you. NAFLD has long eclipsed alcohol related liver issues.
> Even simple unprotected sex can lead to massive medical problems
Even treated HIV is probably less of a risk to your long term health than obesity, but I'm not a doctor.
> Cocaine addiction. Meth
OK, yes, there are illegal drugs that are going to be worse for you than being fat.
I'll rephrase:
Being obese is basically the worst possible thing you can do to yourself that affects a huge portion of the population of the western world.
Very very few people are riding motorcycles without a helmet, even fewer are getting into planes flown by harrison ford, only a tiny tiny tiny fraction of the population even has the option of being a professional athlete.
You're getting downvoted here but I think there is precedent behind your statement. History is littered with weight loss drugs that had to be pulled because the shoe eventually dropped. Usually that was addiction or death which, admittedly, neither have been shown in the GLP-1's but, given the history of weight loss drugs, it's not unreasonable in my opinion to be cautious.
I'm not a chemist, biologist, or pharmacologist, but wouldn't it be more reasonable to be cautious based on how analogous the method of action is to other drugs, rather than the effect? GLP-1s don't work in the same manner that phen/fen did, for example.
DNP is an extremely effective drug for weight loss, but no one who knows anything about how it works would think that it would be reasonable to compare it to the GLP-1s, and anyone who knows how it works would also plainly see the dangers around its use.
GLP-1 type drugs have been on the market for decades now as well, and while they are not perfectly safe, we've got a good amount of data around the short to medium term side effects.
It'll never happen, as long as American culture views body weight as a moral failing. We can't make it easy for people to fix the things we want them to fix, after all.
It is such a fucking no-brainer. The costs of obesity, both monetary and in terms of human suffering, are staggering. Absolutely fucking staggering. We should be making this as available as humanly possible, NOW.
Yeah, what could go wrong with screwing with the neurochemical reward system of the entire population. Surely that will have no unintended side effects. It's literally a free lunch!
what could go wrong with screwing with the neurochemical reward system of the entire population
We already know what can go wrong.
We already did that decades and decades ago. Sugar, for example. Aside from so many foods being laced with it, you can now simply walk into a store and buy a kilogram of sugar and eat it. So many other examples. That ship sailed a long long time ago. All we can do now is nudge the dial the other way.
Hmm not quite. The bigger issue at hand is the large group of metabolic disorders linked to our unhealthy eating habits Alzheimer’s is now often referred to as Type 3 diabetes.
This drug in a nutshell partially paralyzes the stomach and upper intestine causing food to move through slowly. This has the effect of reducing food cravings as you literally stay full longer.
However slowing down the stomach muscles has many risks and many side effects.
Yes this drug is great for people who have struggled with weight loss and may not realistically be in a position to work on diet and exercise.
However this drug is not a substitute for the larger issue at hand. Many (possibly most) Americans are not living healthy lives in terms of mind, body (maybe spirit).
Improving physical activity leveled.. learning to eat less and to eat healthy should be a national priority. If anything the US government lack of addressing the elephant in the room and the underlying cause of many of these metabolic orders should outrage all Americans.
It doesn't appear that this is the issue. You can't explain a recent trend (obesity) using something that hasn't changed recently. And exercise is not very effective for weight loss compared to diet (it's something like 20%/80%).
* Blood sugar levels (or whatever this is a proxy for)
* Weight
* The changes the GLP-1 Agonists make to the body itself.
While it is simple to say if you reduce the weight, you reduce the blood sugar levels, and so the GLP-1 is unnecessary, you can look at many accounts of using Ozempic where it talks about reducing the "food noise."
That is, Ozempic makes it easier to eat the right things. I'm a "normal weight" through grit, but I don't think my life is better through said grit - in fact, I'd say it's significantly worse. In my earlier life, I was naturally thin, and I can say that my weight increase wasn't a significant change to my diet, nor was my weight loss: I just had to be hungry and irritable more.
So, fundamentally, the cause and effect doesn't matter, because the drug makes it easier to be a more healthy weight and to control the blood sugar.
I keep making the comparison to nicotine gum/patches, but for food. I'm hoping that such a simple analogy might help some people move past their innate biases, but not much traction so far.
In western societies with high levels of obesity, health is a signal of wealth and prestige. There's no "innate bias" here, just alarm over the debasement of the value of being thin and healthy. It's a cruel posturing, nothing more.
> nor was my weight loss: I just had to be hungry and irritable more
Yes! I keep trying to explain to folks that this is the benefit of these drugs, they let you keep a healthy relationship with food, maintain "intuitive eating" where you aren't constantly fighting and discarding your hunger signals, and aren't (as) miserable doing it.
I did it the hard way, I wouldn't wish it on anyone.
Another interesting point from the study (full paper linked in a other comment) was the comparison of semaglutide to other GLP-1 agonists taken by patients, with the impact being significantly higher vs. those.
Obviously we need some more double blind studies dedicated to this class of drugs and Alzheimer's, but this informs the direction researchers and drug companies will likely map out.
And how do you isolate being skinny because you are regularly active and eat well vs. being skinny because you are sedentary and eat garbage but then chase it down with a drug?
> nationwide database of electronic health records (EHRs) of 116 million US patients.
If you are expert in this space: Is such a dataset available publicly? If so, are there examples of other studies that have used this? Where does one go to read more about the mechanism of this study? Thanks!
I really really really wish my records were kept tight, offline, air gapped, or otherwise not stored on a cloud system with Trust Me Bro™ HIPAA-compliant security.
(The Trust Me Bro™ security aspect is the "It's secure because people will go to jail" and "We so totes won't use this easily subpoenaed data against you" security, when it would be best if the data stayed on a RAID in my doctor's office and an offsite VPN-linked backup instead. This goes 20x for psychs.)
This would be amazing if true, but the lack of randomization makes me nervous. What if, like, patients who are about to get Alzheimer's are less aggressive about asking their doctor for semaglutide (which has been in shortage for a while), and that explains the trial results?
Alzheimer (the regular one, not the early onset) is a progressive condition usually not detected early. Moreover, keep in mind it is possible we understand less about Alzheimer than we thought, from the very start
According to this article, it's been (sorta) reproduced once, which is better than most studies. About 40-60% of scientific studies are not reproducible.
Given that, I'd want to see more reproductions.
Also, I'm very annoyed by our American culture which tries to fix problems with drugs, rather than preventing them from happening in the first place with good diet, exercise, sleep and stress management.
I think the food manufacturers are culpable here, and "manufacturer" is really the best word to use. They're more like chemists cobbling together edible compounds than farmers growing things that provide nutrition.
Absolutely. And every time I come on HN to point out processed foods are bad, I always get the feigned confusion "But are cooked carrots a processed food"
I agree with your sentiment, but frankly human nature just doesn’t work that way. We don’t have self control. We weren’t evolved for a world of abundance. This is no one’s fault, and it’s everywhere, china is getting fatter than most countries now.
Realistically, ozempic is a miracle and it seems to be a solution to numerous issues of our world.
It would be nice if it wasn’t so, but apart from the 10% of people who can control themselves (which also causes psychological issues btw), most people just can’t.
I reject your assumption that "This is no one’s fault, and it’s everywhere, china is getting fatter than most countries now."
It's the food industrial complex's fault, along with many others (politicians, individuals without self control, etc)
I lived in rural Colombia for 4 years. People had access to the junk food, but it wasn't consumed very much because the veggies and meat are all produced locally and super tasty and cheap. And the local dishes were extremely meat and veggie based.
Oh, and most people know how to cook there.
It's not a fact of human nature to be unhealthy. It's a fact of modern culture.
How long has Ozempic been around? I've never heard of it until very recently (maybe the last month or two) and suddenly I'm seeing it all the time. Maybe this is an instance of Baader-Meinhof phenomenon, but it doesn't feel like it.
Ozempic has been around about 10 years used mostly for diabetes, but it's use for weight loss management has exploded with the release similar drugs using the same core principles such as Wegovy and Mounjaro. There's also definitely a compounding effect of it being successful for people and them telling their friends.
TL;DR from the article:
The study found that patients prescribed semaglutide had a significantly lower risk for Alzheimer’s disease than those who had taken one of the seven other diabetes drugs. The results were consistent across gender, age and weight.
The biggest difference was seen when comparing patients who took semaglutide to those who took insulin: Semaglutide patients had a 70% lower risk of Alzheimer’s, the study found.
With the constant stream of positive news around GLP-1s, and ever-growing list of things they treat, we may all wind up on some dose with only the dose varying depending on what illness they're targeting.
> With the constant stream of positive news around GLP-1s, and ever-growing list of things they treat, we may all wind up on some dose with only the dose varying depending on what illness they're targeting.
So far, I haven't seen much evidence that GLP-1s have a positive effect on people who aren't overweight. And while I'll be the first to admit that the proportion of people who could benefit from these drugs is quite large, it's pretty far from everyone.
> So far, I haven't seen much evidence that GLP-1s have a positive effect on people who aren't overweight.
It is licensed, tested, and sold as a Type-2 Diabetes medication. Are you claiming it is ineffective for that purpose? Or if you're under the impression that no healthy weight T2 Diabetics exist, I have some news for you...
It is also being studied for: opioid addiction, alcoholism, Alzheimer's/Parkinson’s, Cardiovascular Disease, NASH, and PCOS.
"So far, I haven't seen evidence" may be more related to what you have read than what is available for you to read.
Don't dismiss the most important question -- does semaglutide really have any effects outside its current intended use for diabetes and weight loss?
In other words, would a thin, metabolically healthy person benefit from taking semaglutide?
So far, all of the wonderful benefits from taking the drug seem to be explainable by reduced caloric intake / weight loss / better glucose control in overweight and/or diabetic people.
> In other words, would a thin, metabolically healthy person benefit from taking semaglutide?
That's what this thread is about; and multiple other studies looking at different diseases/illnesses/addictions. Time will tell. It is currently approved for T2 Diabetes and Obesity.
GLP-1 have already been on the mass market longer than Fen-Phen (7-years for Fen-Phen Vs. 15+ years, even just Semaglutide has been available longer than Fen-Phen now, and Semaglutide is a third-gen GLP-1).
Honestly, this retort can be made about any/all new drugs entering the market. If you had a legitimate retort/critique I'm sure you would have presented it, but this is all we get.
This is what happens when you start out with "[thing] is bad" then work backwards to figure out a reason.
Ultimately the main reason it's bad right now is it's expensive. Far beyond the amount needed to recoup research investment and far far far far far far far far far beyond what it takes to synthesize.
Low-end cost of $1000 a month is a lot. That's an expensive car lease, or half a cheap mortgage.
Suddenly USGov issues emergency production licenses and orders domestically to drop that down to effectively $0.10/kilodose on the market.
Suddenly when Denmark (or whoever) whines, USGov sends a cumulative NATO military defense bill, tells them they are the reserve currency, they have bigger nukes, and tough shit next time don't pork barrel the American people.
Lots of options for Americans; question is, can we be unprincipled enough to take the steps neccessary? :^)
I fully agree. Least of all because it is sold at between $60-200 abroad full-priced. Those countries just have price controls; the pharmacies are still making 80%+ profit margins in those places.
Ultimately, a lot of people will literally die because of this greed. That isn't hyperbole.
I just listened to an in-depth analysis of this last night. All of these great effects can be explained by reduced caloric intake / weight loss / better glucose control. In other words - it just means it works as intended.
So while it's an amazing drug / new class of drugs, it probably will not lower risk of Alzheimer's in metabolically healthy people.
You might think that these two (get skinny and lower Alzheimer's risk) are the only two benefits, but don't forget that this drug is also pretty much the end of the road for the "More People Should Be Fat!/HAES movement".
Because other interventions have the consequence of actually working.
If we compare the efficacy of "telling people to lose weight" vs taking ozempic, there is a stark contrast. Pooled results show that education and counselling[sic] did not significantly reduce weight (SMD –0.73, 95% CI –1.89 to 0.42, n = 3 studies; I 2 = 98%)[1]. The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo[2].
Telling people to just lose weight is not an evidence-backed intervention to affect weight loss. Continuing to practice it is equivalent to practicing folk medicine or alternative medicine. Despite us wanting it to work, it does not. Like all interventions, pharmaceutical interventions have the possibility of side effects, and it's up to the patient and doctor to weight risk vs reward. There is variation in both for each case, but we have to keep in mind that the mere existence of side effects is not typically a reason for categorically deciding against using a drug.
Do you think obese people have never tried just eating less? That doctors never tell them to do this and they never give it an attempt?
Yes, it is possible for every obese person on this planet to eat less and stop being fat. 100%.
But for some people, this is actually really difficult to do! And the more fat you put on, the more feedback loops there are in your body that push you towards eating more. Insulin and ghrelin response are big ones, but it wrecks your sex hormones, too - you're almost certain to see massive testosterone drops in men, which further stimulates your body to deposit more fat and build less muscle.
Being told to lose weight by diet and exercise is probably the most prescribed treatment on the planet, and one with one of the absolute lowest success rates.
So easy to invent imaginary diseases to cover for decadent lack of willpower and portray a decent life hygiene as something as heroic as firewalking or quitting crack.
The entire point of the ADHD diagnosis, in fact, is about the inability or reduced ability to "just focus more", and the medicine's purpose is to alleviate that imbalance
“Why” is a weird question. We don’t know why. We do know that people don’t just eat less. Haven’t in decades. No plan that relies on changing that is practical.
For the group, because I can never keep the terms straight:
Semaglutide is one specific drug within the class of GLP-1 agonists. Other examples include Liraglutide (Victoza, Saxenda), Dulaglutide (Trulicity), and Tirzepatide (Mounjaro, though this is technically a dual GIP/GLP-1 agonist).
Semaglutide is available under several brand names for different uses: Ozempic (type 2 diabetes), Wegovy (weight management), and Rybelsus (oral form for type 2 diabetes).
Of all things my taxes go to, I would love it the United States Government would buy the patent for this drug and make it freely available to anybody who wants it.
The number of things it apparently just cures is staggering.
I have been on compounded GLP-1 for a month, prior to this I was a highly functional alcoholic, basically starting drinking after work every night and going until I passed out. I've drunk well over 50 beers (probably more) a week for the last 20 years. I have not had a drink since going on it.
I have been reading obsessively about this drug since going on it. I have been fortunate enough not to suffer side effects on it, save for one -- frustration with the cynicism around it. A cynicism I shared prior to experiencing its effects.
I am convinced that, barring any life threatening long term side effects, this is the most important drug of our lifetime (from a first world perspective) or until a silver bullet cancer drug is found. The potential to be the tide that lifts so many boats and alleviates so much physical and emotional pain and suffering on a population level is almost overwhelming to think about.
> barring any life threatening long term side effects
There's the rub. We have not been prescribing semaglutide very long, and I won't trust it until we've had enough time to suss out long term side effects.
My father was on a long-term maintenance dose of immunosuppressant (I think prednisolone, but I could be misremembering) following his kidney transplant. When it was first prescribed to him, the long term side effects were either not known at all or not widely known. By the time these side effects were more widely known, it was too late, as he was already losing his vision (cataracts) and mobility (cartilage was being destroyed). He spent his last few years in pain.
I am very cautious about the potential for damaging long-term side effects.
> There's the rub. We have not been prescribing semaglutide very long, and I won't trust it until we've had enough time to suss out long term side effects.
We've been prescribing GLP-1s for almost 20 years now. Not to say they all should behave identically, but from a Bayesian inference perspective these things really do appear to be quite safe.
https://www.drugwatch.com/legal/ozempic-lawsuit/
Risk factors for NAION are basically all the things that you go on these drugs to treat - type 2 diabetes, sleep apnea, cardiovascular disease, blood pressure, etc. One observational study that shows some correlation isn't enough for me to be particularly concerned about it.
> As of March 31, only 4 cases of gastroparesis were recorded for semaglutide—the active ingredient in Ozempic and Wegovy—in the FDA Adverse Event Reporting System (FAERS), a surveillance database updated by healthcare professionals, consumers, and manufacturers. For tirzepatide—the active ingredient in Mounjaro and Zepbound—there is just one case logged.
I don't have more recent numbers, but these seem pretty low.
I don't think anyone is saying that there is no chance of significant side effects in people, but when measured against the risks of being obese, they'd have to be very bad and impact a significant number of people taking the drug.
Wow, someone experienced an adverse effect from a drug and are suing?
This adds literally zero information.
Gastroparesis is a serious, life-threatening side effect.
It occurs in a small number of patients, sure, but maybe that just means I am more risk averse than you. My calculus is simple. I don't need wegovy. I can lose (and am losing) weight without it. Sure, it would be easier with wegovy, but it is not necessary. I am not going to take an unnecessary drug that has a nonzero chance of killing me.
>I can lose (and am losing) weight without it
Excellent! A huge chunk of people try and fail to do this for a wide variety of reasons.
If you can lose weight without the help of a GLP-1 drug, then yeah, that is likely the safest option. But most people aren't choosing between using a GLP-1 drug to lose weight or losing weight without it - they're choosing between staying fat and using the GLP-1.
> I am very cautious about the potential for damaging long-term side effects.
This is fair. But I'll ask you this: how long would it take for you to trust it? Assuming there are no side effects beyond what we know now, which are:
* gastroparesis is a small number of patients
* elevated thyroid cancer risk in mice
* nausea and general uncomfortableness when taking it (some percentage, not all)
* muscle and bone loss which seems to be roughly on par with any rapid weight loss approach
* a small percentage of people develop malaise, anhedonia and suicidal ideation
* a propensity to gain some percentage of weight back and/or relapse in addictive behavior when going off the drug
These are the side effects we know about with over a decade of prescribing GLP-1 agonists. Assuming these continue to be the primary side effects, how long would you wait until you are comfortable in trusting they are the only ones?
We've been prescribing semaglutide since 2017 and the predecessor since 2010.
Exenatide, a GLP-1, was approved in 2005.
Agreed. The constant cynicism about everything, framed by some stupid moral hazard nonsense, is exhausting.
It reminds me of the British reaction to the famine in Ireland - the good ministers were concerned about the moral health of the Irish. If they were provided with charity food, it would be a terrible tragedy if they became dependent. Just let them starve to death, with a clean soul.
2.5mg?
Still titrating up, will be there in a month.
Can you describe what happened that you don't want to drink (many people who are addicted to something don't actually enjoy it anymore)? Did you still enjoy drinking before? Do you have the desire to drink?
do you have adhd, and do you think your drinking is at all related to adhd/lack of executive function? just curious, not implying.
I do not have ADHD. I am not sure exactly why I drink so much -- there are a number of alcoholics on both sides of my family, but I also spent many years drinking in bars in a big city, living a very social life. During COVID I became much more of a solitary drinker and over the last five or so years I have drank out of a sense of malaise. Every morning became the day I was going to take a break and every night there was an excuse to start drinking again.
The strange thing about GLP-1s effect on my desire to drink is how it manifests: I just don't care about drinking. I actually _could_ drink and be fine I think, I haven't tested it. I don't go through life with the burden of the knowledge of my own addiction. I don't have to be vigilant about triggers and self-assess my actions. I just don't drink.
how long did you keep drinking after starting? thanks for response
No prob.
I noticed that I did not want to drink the day after my first shot. It was that fast. If anything the closest I came to drinking came from routine, not desire. That is to say, what is an afternoon watching football if not with a beer in hand? But I was able to move past that.
One thing I should make clear, no matter how heavy a drinker I have been at times in my life, including with liquor, I have never had a physical addiction. A person deep in the throws of physical addiction will need to approach this carefully.
If you are interested in this topic, I highly recommend reading this newsletter: https://recursiveadaptation.com/
There is a lot of great writing on this subject and some real world testimonies in there. Also happy to answer any more questions here.
Novo Nordisk's market cap is $500 B, mostly on the basis of GLP-1 drug profits, and the US' entire discretionary budget is $1,700 B. Even if Denmark would allow the sale, and even if somehow the US did not need to pay a premium to shareholders (typical in acquisitions), that would still be a very substantial expenditure.
The correct unit of measurement here is Iraq wars.
Purchasing NN Would cost roughly 0.2 Iraq wars.
That is a sensible unit.
This ignores the fact that the patents expire in 5-7 years, GLP1 is (relatively) trivial to produce and will be a $100 generic by 2032.
Voting majority is also controlled by the Novo Nordisk Foundation. It's already the wealthiest foundation on the planet so they're unlikely to give up their flagship enterprise.
That's not the way to go about it at all.
The EU loves to ransom US tech companies for budget money. It's very clear that this is an opportunity for the US to similarly damage a big EU company by threatening its patents in the US, or otherwise hitting Novo for tens of billions of dollars in ransom money. The US market is by a huge margin the most important drug market in the world, and especially for Novo.
Find an abusive excuse to invalidate their patents if all else fails. Let Europe learn a valuable lesson in trade wars.
At this point in time, you are in no position to be teaching any lessons to the rest of the world, other than cautionary tales of wasted potential and the self-inflicted wounds of a belligerent populace.
Not to be that guy but obesity is arguably kind-of a national security emergency thing...
First-gen GLP-1 goes off patent in 2031 (e.g. semaglutide). Seems far off, but is frighteningly close for Novo. Tirzepatide gets genericized in 2039 and has better efficacy, which is why Lilly is in such a strong position right now.
There is an enormous amount of biotech work to develop next-gen versions that have better half-lives, lower adverse events, and most importantly, have long patent lives. But it seems base GLP-1 are good enough that we should see massive societal change starting next decade.
Lilly is probably in an even stronger position if retatrutide continues to look as good as it has in the current trials. Better weight loss than tirzepatide, and recent results have shown it has excellent results on reducing fat deposits in the liver... and NAFLD is the leading cause of severe liver disease in the world.
They don't have to buy the patent, they can issue a compulsory licence for it https://en.wikipedia.org/wiki/Compulsory_license#United_Stat...
Gonna be fun discovering what side effects it causes in 20 years tho.
- Significantly increased mortality risk
- Higher rates of cardiovascular disease
- Type 2 diabetes
- Sleep apnea and breathing problems
- Osteoarthritis due to excess pressure on joints
- Multiple types of cancers (colon, breast, endometrial)
- Depression and anxiety from social stigma
- Reduced mobility and quality of life
- Higher medical costs (~$1,429 more annually per person)[1]
- Decreased workplace productivity
- Shorter life expectancy (can reduce by 5-10 years)
Oh no wait, sorry, those are the effects of obesity.
[1] https://pubmed.ncbi.nlm.nih.gov/19635784/
The real question is whether these side-effects are going to be worse than 20 years of not taking it.
This is the question and for people that are older the scales steadily tip towards just taking the damn drug because in 20 years they're likely to be dead anyways.
Take a look at exenatide, a GLP-1 that was FDA-approved in 2005.
https://www.perplexity.ai/search/does-exenatide-lower-or-ext...
You might be right, but it has been in testing/development for 20 years now.
Liraglutide, the predecessor to semaglutide, has been on the market for 15 years :)
It will likely save so many lives, it may still make sense to take it with those risks.
Seems like you need to increase the usage of it as your body starts adapting to it and the weight loss plateaus. IMO, I think the hype around this drug is a bit much and I expect a significant number of users won't be able to meet or maintain their weight loss goals with it.
it'd have to be pretty bad to outpace mortality for being obese
Exactly. I see all these breathless claims of new uses and how wonderful this drug is and wonder when the other shoe is going to drop.
I’ll make my usual response: we know that being obese is basically the worst possible thing you can do to yourself, and the longer you are, the worse it is. The side effects are going to be pretty awful just to negate that, much less all the other things they seem to be good for.
>> being obese is basically the worst possible thing you can do to yourself
Lol. I can think of dozens of worse things. Drinking. Cocaine addiction. Meth. Winding up in prison for some reason. Riding a motorcycle without a proper helmet. Getting into a plane flown by Harrison Ford. Even simple unprotected sex can lead to massive medical problems. Ever looked up the average life expectancy of professional athletes, especially the NFL? It isn't great.
> Drinking
Being obese is probably worse for you. NAFLD has long eclipsed alcohol related liver issues.
> Even simple unprotected sex can lead to massive medical problems
Even treated HIV is probably less of a risk to your long term health than obesity, but I'm not a doctor.
> Cocaine addiction. Meth
OK, yes, there are illegal drugs that are going to be worse for you than being fat.
I'll rephrase:
Being obese is basically the worst possible thing you can do to yourself that affects a huge portion of the population of the western world.
Very very few people are riding motorcycles without a helmet, even fewer are getting into planes flown by harrison ford, only a tiny tiny tiny fraction of the population even has the option of being a professional athlete.
> Drinking. Cocaine addiction. Meth.
Ozempic treats all of those too.
You're getting downvoted because you didn't even care to do a simple Google search as to when the first GLP-1 was released. 2005. Almost 20 years.
We have the data.
You're getting downvoted here but I think there is precedent behind your statement. History is littered with weight loss drugs that had to be pulled because the shoe eventually dropped. Usually that was addiction or death which, admittedly, neither have been shown in the GLP-1's but, given the history of weight loss drugs, it's not unreasonable in my opinion to be cautious.
I'm not a chemist, biologist, or pharmacologist, but wouldn't it be more reasonable to be cautious based on how analogous the method of action is to other drugs, rather than the effect? GLP-1s don't work in the same manner that phen/fen did, for example.
DNP is an extremely effective drug for weight loss, but no one who knows anything about how it works would think that it would be reasonable to compare it to the GLP-1s, and anyone who knows how it works would also plainly see the dangers around its use.
GLP-1 type drugs have been on the market for decades now as well, and while they are not perfectly safe, we've got a good amount of data around the short to medium term side effects.
GLP-1s are completely different from all those drugs. There's no reason to use them as evidence for it.
It'll never happen, as long as American culture views body weight as a moral failing. We can't make it easy for people to fix the things we want them to fix, after all.
It is such a fucking no-brainer. The costs of obesity, both monetary and in terms of human suffering, are staggering. Absolutely fucking staggering. We should be making this as available as humanly possible, NOW.
Yeah, what could go wrong with screwing with the neurochemical reward system of the entire population. Surely that will have no unintended side effects. It's literally a free lunch!
what could go wrong with screwing with the neurochemical reward system of the entire population
We already know what can go wrong.
We already did that decades and decades ago. Sugar, for example. Aside from so many foods being laced with it, you can now simply walk into a store and buy a kilogram of sugar and eat it. So many other examples. That ship sailed a long long time ago. All we can do now is nudge the dial the other way.
Because you can buy sugar from the store, having the US subsidize ozempic for for the entire population makes logical sense. Got it.
Perhaps you could take your childishness elsewhere. It does grow tiring.
You are not the arbiter of what is "childish".
This style of condescension does grow tiring.
oh, so i guess you live outside and hunt animals for food? how's your all-natural neurochemical reward system?
If I'm not completely natural, then the entire population should have access to subsidized ozempic. Got it.
ie subsidized ozempic means everyone will use it?
You aren't making compelling points by pretending the OPs are stating things they are not.
so you used the same logic that i made fun of in your post to make fun of the logic in your post... to say that my post was silly?
whoa that is a crazy, powerful idea. my favorite kind.
>> The number of things it apparently just cures is staggering.
It cures behavior, not directly disease. I see red flags. Firefly did a movie about a drug that interfered with people's motivations to do things.
What evidence would it take to change your no-free lunch heuristic?
Are you seriously suggesting that Ozempic might lead to the Reavers from Firefly?
I don't remember seeing any overweight or obese people on Miranda.
Thank you
Nothing is being healed, we are just helping people cope with excess
Hmm not quite. The bigger issue at hand is the large group of metabolic disorders linked to our unhealthy eating habits Alzheimer’s is now often referred to as Type 3 diabetes.
This drug in a nutshell partially paralyzes the stomach and upper intestine causing food to move through slowly. This has the effect of reducing food cravings as you literally stay full longer.
However slowing down the stomach muscles has many risks and many side effects.
Yes this drug is great for people who have struggled with weight loss and may not realistically be in a position to work on diet and exercise.
However this drug is not a substitute for the larger issue at hand. Many (possibly most) Americans are not living healthy lives in terms of mind, body (maybe spirit).
Improving physical activity leveled.. learning to eat less and to eat healthy should be a national priority. If anything the US government lack of addressing the elephant in the room and the underlying cause of many of these metabolic orders should outrage all Americans.
Just my two cents
> is now often referred to as Type 3 diabetes.
No it isn't. Stop trying to make fetch happen.
> Improving physical activity leveled
It doesn't appear that this is the issue. You can't explain a recent trend (obesity) using something that hasn't changed recently. And exercise is not very effective for weight loss compared to diet (it's something like 20%/80%).
How do you isolate this from the therapeutic benefits of simply losing weight and being skinny?
There are multiple confounding factors:
* Blood sugar levels (or whatever this is a proxy for)
* Weight
* The changes the GLP-1 Agonists make to the body itself.
While it is simple to say if you reduce the weight, you reduce the blood sugar levels, and so the GLP-1 is unnecessary, you can look at many accounts of using Ozempic where it talks about reducing the "food noise."
That is, Ozempic makes it easier to eat the right things. I'm a "normal weight" through grit, but I don't think my life is better through said grit - in fact, I'd say it's significantly worse. In my earlier life, I was naturally thin, and I can say that my weight increase wasn't a significant change to my diet, nor was my weight loss: I just had to be hungry and irritable more.
So, fundamentally, the cause and effect doesn't matter, because the drug makes it easier to be a more healthy weight and to control the blood sugar.
I keep making the comparison to nicotine gum/patches, but for food. I'm hoping that such a simple analogy might help some people move past their innate biases, but not much traction so far.
In western societies with high levels of obesity, health is a signal of wealth and prestige. There's no "innate bias" here, just alarm over the debasement of the value of being thin and healthy. It's a cruel posturing, nothing more.
> nor was my weight loss: I just had to be hungry and irritable more
Yes! I keep trying to explain to folks that this is the benefit of these drugs, they let you keep a healthy relationship with food, maintain "intuitive eating" where you aren't constantly fighting and discarding your hunger signals, and aren't (as) miserable doing it.
I did it the hard way, I wouldn't wish it on anyone.
Another interesting point from the study (full paper linked in a other comment) was the comparison of semaglutide to other GLP-1 agonists taken by patients, with the impact being significantly higher vs. those.
Obviously we need some more double blind studies dedicated to this class of drugs and Alzheimer's, but this informs the direction researchers and drug companies will likely map out.
Omg, you figured it out! Shit.
All we need to do is just tell a few million people to lose weight.
"That was Easy!"™
And how do you isolate being skinny because you are regularly active and eat well vs. being skinny because you are sedentary and eat garbage but then chase it down with a drug?
> nationwide database of electronic health records (EHRs) of 116 million US patients.
If you are expert in this space: Is such a dataset available publicly? If so, are there examples of other studies that have used this? Where does one go to read more about the mechanism of this study? Thanks!
Likely this is some aggregator in the Healthcare space that uses tools that effectively fingerprint patients in each EHR.
This deduplicates patients and lets them find specific details like which medications they are on without knowing any PII.
It's very common for researchers within health systems to want to collaborate and combine populations to perform retroactive data analysis.
There is no public dataset of EHRs of this size.
I really really really wish my records were kept tight, offline, air gapped, or otherwise not stored on a cloud system with Trust Me Bro™ HIPAA-compliant security.
(The Trust Me Bro™ security aspect is the "It's secure because people will go to jail" and "We so totes won't use this easily subpoenaed data against you" security, when it would be best if the data stayed on a RAID in my doctor's office and an offsite VPN-linked backup instead. This goes 20x for psychs.)
Almost all health datasets are not public
This would be amazing if true, but the lack of randomization makes me nervous. What if, like, patients who are about to get Alzheimer's are less aggressive about asking their doctor for semaglutide (which has been in shortage for a while), and that explains the trial results?
Alzheimer (the regular one, not the early onset) is a progressive condition usually not detected early. Moreover, keep in mind it is possible we understand less about Alzheimer than we thought, from the very start
https://www.nbcnews.com/science/science-news/alzheimers-theo...
This publication is bogus. It is too soon to know if there is any benefit at all from Semaglutide.
According to this article, it's been (sorta) reproduced once, which is better than most studies. About 40-60% of scientific studies are not reproducible.
Given that, I'd want to see more reproductions.
Also, I'm very annoyed by our American culture which tries to fix problems with drugs, rather than preventing them from happening in the first place with good diet, exercise, sleep and stress management.
A drug that reduces appetite is kinda tackling good diet, at least.
Keyword is "kinda"
I think the food manufacturers are culpable here, and "manufacturer" is really the best word to use. They're more like chemists cobbling together edible compounds than farmers growing things that provide nutrition.
Absolutely. And every time I come on HN to point out processed foods are bad, I always get the feigned confusion "But are cooked carrots a processed food"
These aren't preventative drugs, they are to treat people who are already fat.
Looks like this is not exactly true given they reduce cravings.
Where did I say it was a preventative drug?
I agree with your sentiment, but frankly human nature just doesn’t work that way. We don’t have self control. We weren’t evolved for a world of abundance. This is no one’s fault, and it’s everywhere, china is getting fatter than most countries now.
Realistically, ozempic is a miracle and it seems to be a solution to numerous issues of our world.
It would be nice if it wasn’t so, but apart from the 10% of people who can control themselves (which also causes psychological issues btw), most people just can’t.
I reject your assumption that "This is no one’s fault, and it’s everywhere, china is getting fatter than most countries now."
It's the food industrial complex's fault, along with many others (politicians, individuals without self control, etc)
I lived in rural Colombia for 4 years. People had access to the junk food, but it wasn't consumed very much because the veggies and meat are all produced locally and super tasty and cheap. And the local dishes were extremely meat and veggie based.
Oh, and most people know how to cook there.
It's not a fact of human nature to be unhealthy. It's a fact of modern culture.
It makes your poop sit in your tummy and rot
How long has Ozempic been around? I've never heard of it until very recently (maybe the last month or two) and suddenly I'm seeing it all the time. Maybe this is an instance of Baader-Meinhof phenomenon, but it doesn't feel like it.
Ozempic has been around about 10 years used mostly for diabetes, but it's use for weight loss management has exploded with the release similar drugs using the same core principles such as Wegovy and Mounjaro. There's also definitely a compounding effect of it being successful for people and them telling their friends.
Trials started in 2008 AFAICT: https://en.wikipedia.org/wiki/Semaglutide#History
https://www.sciencedirect.com/science/article/pii/S258953702...
TL;DR from the article: The study found that patients prescribed semaglutide had a significantly lower risk for Alzheimer’s disease than those who had taken one of the seven other diabetes drugs. The results were consistent across gender, age and weight.
The biggest difference was seen when comparing patients who took semaglutide to those who took insulin: Semaglutide patients had a 70% lower risk of Alzheimer’s, the study found.
Full link to the study itself: https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz...
With the constant stream of positive news around GLP-1s, and ever-growing list of things they treat, we may all wind up on some dose with only the dose varying depending on what illness they're targeting.
> With the constant stream of positive news around GLP-1s, and ever-growing list of things they treat, we may all wind up on some dose with only the dose varying depending on what illness they're targeting.
So far, I haven't seen much evidence that GLP-1s have a positive effect on people who aren't overweight. And while I'll be the first to admit that the proportion of people who could benefit from these drugs is quite large, it's pretty far from everyone.
> So far, I haven't seen much evidence that GLP-1s have a positive effect on people who aren't overweight.
It is licensed, tested, and sold as a Type-2 Diabetes medication. Are you claiming it is ineffective for that purpose? Or if you're under the impression that no healthy weight T2 Diabetics exist, I have some news for you...
It is also being studied for: opioid addiction, alcoholism, Alzheimer's/Parkinson’s, Cardiovascular Disease, NASH, and PCOS.
"So far, I haven't seen evidence" may be more related to what you have read than what is available for you to read.
Don't dismiss the most important question -- does semaglutide really have any effects outside its current intended use for diabetes and weight loss?
In other words, would a thin, metabolically healthy person benefit from taking semaglutide?
So far, all of the wonderful benefits from taking the drug seem to be explainable by reduced caloric intake / weight loss / better glucose control in overweight and/or diabetic people.
> In other words, would a thin, metabolically healthy person benefit from taking semaglutide?
That's what this thread is about; and multiple other studies looking at different diseases/illnesses/addictions. Time will tell. It is currently approved for T2 Diabetes and Obesity.
My PCP agrees that the great results I'm getting on Fen-Phen mean I won't need to switch!
GLP-1 have already been on the mass market longer than Fen-Phen (7-years for Fen-Phen Vs. 15+ years, even just Semaglutide has been available longer than Fen-Phen now, and Semaglutide is a third-gen GLP-1).
Honestly, this retort can be made about any/all new drugs entering the market. If you had a legitimate retort/critique I'm sure you would have presented it, but this is all we get.
This is what happens when you start out with "[thing] is bad" then work backwards to figure out a reason.
Ultimately the main reason it's bad right now is it's expensive. Far beyond the amount needed to recoup research investment and far far far far far far far far far beyond what it takes to synthesize.
Low-end cost of $1000 a month is a lot. That's an expensive car lease, or half a cheap mortgage.
Suddenly it's a national security issue.
Suddenly USGov issues emergency production licenses and orders domestically to drop that down to effectively $0.10/kilodose on the market.
Suddenly when Denmark (or whoever) whines, USGov sends a cumulative NATO military defense bill, tells them they are the reserve currency, they have bigger nukes, and tough shit next time don't pork barrel the American people.
Lots of options for Americans; question is, can we be unprincipled enough to take the steps neccessary? :^)
These things are priced against their alternatives, and so are almost definitionally less expensive than the status quo ante.
I fully agree. Least of all because it is sold at between $60-200 abroad full-priced. Those countries just have price controls; the pharmacies are still making 80%+ profit margins in those places.
Ultimately, a lot of people will literally die because of this greed. That isn't hyperbole.
Hasn't there been speculation/study along the lines of Alzheimer's being a form of diabetes?
Yes. For example: "Is Alzheimer's disease a Type 3 Diabetes? A critical appraisal" https://www.sciencedirect.com/science/article/pii/S092544391...
Is it the ozempic or just the healthier weight / lower calorie intake?
I just listened to an in-depth analysis of this last night. All of these great effects can be explained by reduced caloric intake / weight loss / better glucose control. In other words - it just means it works as intended.
So while it's an amazing drug / new class of drugs, it probably will not lower risk of Alzheimer's in metabolically healthy people.
"Just"?
Get skinny and keep my brain? No thanks. At some point this roller coaster ride needs to end.
You might think that these two (get skinny and lower Alzheimer's risk) are the only two benefits, but don't forget that this drug is also pretty much the end of the road for the "More People Should Be Fat!/HAES movement".
https://en.wikipedia.org/wiki/Health_at_Every_Size
And good riddance I say!
Finally, pharma is paying for studies showing the advantages of not being obese.
[dead]
Oh Oh Oh Ozem...I forgot the rest
Why not just lose weight by eating less? I know that sounds like a dumb question.
But genuinely, aren’t you just paying money to… not spend the money on food instead?
Because other interventions have the consequence of actually working.
If we compare the efficacy of "telling people to lose weight" vs taking ozempic, there is a stark contrast. Pooled results show that education and counselling[sic] did not significantly reduce weight (SMD –0.73, 95% CI –1.89 to 0.42, n = 3 studies; I 2 = 98%)[1]. The mean change in body weight from baseline to week 68 was −14.9% in the semaglutide group as compared with −2.4% with placebo[2].
Telling people to just lose weight is not an evidence-backed intervention to affect weight loss. Continuing to practice it is equivalent to practicing folk medicine or alternative medicine. Despite us wanting it to work, it does not. Like all interventions, pharmaceutical interventions have the possibility of side effects, and it's up to the patient and doctor to weight risk vs reward. There is variation in both for each case, but we have to keep in mind that the mere existence of side effects is not typically a reason for categorically deciding against using a drug.
1. https://pmc.ncbi.nlm.nih.gov/articles/PMC7154644/
2. https://www.nejm.org/doi/full/10.1056/NEJMoa2032183
Do you think obese people have never tried just eating less? That doctors never tell them to do this and they never give it an attempt?
Yes, it is possible for every obese person on this planet to eat less and stop being fat. 100%.
But for some people, this is actually really difficult to do! And the more fat you put on, the more feedback loops there are in your body that push you towards eating more. Insulin and ghrelin response are big ones, but it wrecks your sex hormones, too - you're almost certain to see massive testosterone drops in men, which further stimulates your body to deposit more fat and build less muscle.
Being told to lose weight by diet and exercise is probably the most prescribed treatment on the planet, and one with one of the absolute lowest success rates.
This is like asking why ADHD patients don’t just get over it by focusing more.
So easy to invent imaginary diseases to cover for decadent lack of willpower and portray a decent life hygiene as something as heroic as firewalking or quitting crack.
I would state it in a kinder way maybe, but at the end of the day that's basically what you have to do? ¯\_(ツ)_/¯
The entire point of the ADHD diagnosis, in fact, is about the inability or reduced ability to "just focus more", and the medicine's purpose is to alleviate that imbalance
“Why” is a weird question. We don’t know why. We do know that people don’t just eat less. Haven’t in decades. No plan that relies on changing that is practical.
The problem is the damage to the body's metabolism and hormonal balance. The drugs help fix that damage.