GLP-1 therapy increases visceral adipose tissue metabolic activity | Hacker News Reader

GLP-1 therapy increases visceral adipose tissue metabolic activity

onlinelibrary.wiley.com

105 pointsgumby118 comments

This is quite important news as visceral fat is actually the most dangerous kind of fat: even in lean adults, those with higher amounts of visceral fat are much more at risk for metabolic disorders and insulin resistance [1]. And you often can't tell if you have visceral fat by looking, since it's deep under your belly muscles, and a seemingly-skinny person can have unhealthy amounts of visceral fat. [2] If Ozempic is specifically increasing the metabolic rate of visceral fat beyond simply making caloric restriction easy (which it also does), that implies a pretty broad range of health improvements beyond just simple weight loss — especially since previous treatments were unable to target visceral fat preferentially to subcutaneous fat, despite visceral fat being more dangerous. [3]

1: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC419497/

2: https://www.webmd.com/diet/what-is-visceral-fat

3: https://pubmed.ncbi.nlm.nih.gov/28148928/

Is visceral fat causal of those other health issues? Or coincident?

Intermediate causal step. A bad diet (high glycemic diet) will increase insuline response, whose efficacy will be down regulated through several mechanisms, including accumulation of fat around our internal organs, which in turn further increase insuline resistance.

When mitochondria don't function properly, organs can't efficiently metabolize energy, which can contribute to fat accumulation, including around the organs.

Indeed.

Take a country like Singapore where obesity rates are low (11%) but type 2 diabetes rates are high (9%).

Compare that with the US with much higher obesity rates (40%+) but only slightly higher type 2 diabetes rates (11%).

Plenty of skinny fat older men in Singapore. Slightly overweight but it’s all visceral fat.

Genetic predisposition is likely also involved here? Why would Singaporeans develop same or higher levels of visceral fat than americans that are more obese than them?

https://www.healthhub.sg/live-healthy/the-skinny-on-trans-fa...

As a result, trans fats have been banned in Singapore not long ago: https://www.moh.gov.sg/news-highlights/details/ban-on-trans-...

Yup. Type 2 diabetes rates are far higher in East Asian populations than caucasians.

They start to show metabolic disorders at far lower levels of visceral fat. South Asians are similar.

Asking as a commoner without medical background. What is a effective method to measure visceral fat?

Measure waist circumference over time.

It can be reasonably accurately measured using dual-energy X-ray absorptiometry. A number of companies offer these scans at a reasonable cost.

For screening, waist-to-hip and waist-to-height ratios are reasonably reliable.

The colloquial term for this a DEXA scan for those seeking one.

first of all visceral fat isn't bad ... it serves a physiological purpose of padding organs and providing a close by source of energy. that's why it exists. it becomes a problem if excessive. now ozempic is "burning" it directly - where can i place my bet that this is just going to burn the candle from the other end?

i'm really curious, "burn the candle from the other end" sounds pretty negative, what are the downsides of burning excessive visceral fat? Non-excessive sounds irrelevant because it's really hard to imagine a healthy person paying for this.

to remove something excessive is by definition unlikely to cause harm. but how does ozempic know what is excessive and what is not? i'd expect it to disturb the physiological function of visceral fat after a certain unknown point. given that it is very difficult to measure visceral fat i'd assume that it would be even with involvement of medical specialists difficult to not overdo it.

The act of losing weight necessitates reduction of the mass of triglyceride stored in fat cells, so this sounds like a "duh", but whether it accelerates it through activating beneficial pathways is another matter. (E.g., how similar is a GLP-1 agonist to say diet alone or diet+exercise?)

There are many GLP-1 agonists approved now. Some are approved for type-2 diabetes as one trade name, and may also be approved under another trade name at a higher dosage. For example, Lixisenatide came off-patent for diabetes in 2020 but it doesn't have an obesity formulation in the US. The various GLP-1 agonists have slightly different risk profiles of causing pancreatitis and/or thyroid cancers.

I don't know though maybe the freezing method (cryolipolysis) could potentially be useful for some people, but it's probably still too soon to characterize its long-term risks and other benefits.

Also, CagriSema (cagrilintide (long-acting amylin analogue) & semaglutide) is promising for obesity.

I think cryolipolysis can only reduce subcutaneous fat, not visceral fat.

There's really no good mechanical way to preferentially kill adipose visceral cells to prevent them from storing excess energy in the first place. It's mostly a cosmetic procedure to reduce subcutaneous adipose population with fewer risks than mechanical surgery, but I bet it has very slight benefits but not enough to equal clinical management of obesity.

Maybe in the future there will be a temporary immunotherapy target to get the immune system to attack adipose cells but then terminate/unlearn before it gets too carried away.

>Maybe in the future there will be a temporary immunotherapy target to get the immune system to attack adipose cells but then terminate/unlearn before it gets too carried away.

Unlearning is usually not a thing for our immune system. I don't think this would even be the most promising target. Imagine being able to reverse autoimmune disorders.

> Imagine being able to reverse autoimmune disorders

That would be awesome. Perhaps if it were possible dump the state of memory B cells (I'm wondering if flow cytometry can do this), classify and inventory immunoglobulins, filter them out via perfusion, and custom program naive B cells and add them back to the body. Memory T cell types seem way messier but some should be tunable with epigenetic levers. We will eventually learn how to hack the adaptive immune system, but it's going to take a lot of research time and effort to produce to a specific autoimmune therapy for a specific clinical problem likely customized to a single individual.

Can we talk about the elephant in the room for a second? tens of millions of people are taking this, and they'd need to keep taking this medication for the effects of the drug to remain.

If there is a legitimate hormonal imbalance or genetic defect, I get it. But short of that, are there not only two root causes left? Which in my opinion would be:

1) Poor diet, which includes poor quality in food supply

2) Poor choices being made, or made for people. This includes car-centric cities, sedentary lifestyle and similar well known ailments of modern life.

The root cause isn't being solved, only the adverse effects are temporarily inhibited so long as people continue to afford dependency on the pharmaceutical industry. How can any medical professional support this?

It is already so hard to trust American medicine; doctors having intimate financial relationships with pharma is already a public secret. This certainly doesn't help. They already ruined generations by blaming weight gain on fats instead of sugar because of these corrupt relationships with pharma and other corporate types. I don't doubt the efficacy of the medicine, but the disease is not fatness, it is the reason we get fat that needs to be solved. Rarely do shortcuts result in long term solutions. Why is this different? How do I know this won't expose us to higher cancer risks, new types of diseases like nutrition absorption disorders or becoming over dependent on these medicines and developing malnutrition?

I just don't get the lack of skepticism.

If an individual's environment causes them to self-harm by stabbing themselves with a knife, you take away the knife before (if) you look at the root cause.

The body wants to maintain whatever weight it usually has, if you can keep that weight lower using drugs, there is absolutely a way to stop using the drug and keep the weight loss. You need lifestyle changes, of course, and that is something these GLP-1 agonists do for you. They make you not want to eat.

This. We have however many millennia of natural selection influencing our genetic characteristics, and that's been shoehorned into a very different lifestyle over the past few hundred years.

Ideally, we could allow everyone enough time off enough exercise, rest, and so on, to emulate what has shaped us for the first however many millennia, but we haven't.

Using a medication to compensate for that seems reasonable, provided we've accurately estimated it's negatives, etc...

I am a doctor, so let me give you the perspective from the other side.

A friend of mine who works in primary care has a policy of not prescribing semaglutide unless a patient has tried at least three months of diet/exercise first. She now has a long list of patients who decide to screw that and self-refer to a specialist who'd write them the script. I don't work in primary care myself, but this more or less matches my own experience - 95% of people do not want to put in the effort of changing diet, exercise, and other lifestyle habits. They want a quick fix.

In the words of Ronnie Coleman, "Everybody wants to be a bodybuilder, but nobody wants to lift no heavy-ass weights."

So I really do think the popularity of semaglutide is a bottom up phenomenon. There is has been huge consumer demand for a weight loss drug for decades, and pharma is only now meeting that demand.

> doctors having intimate financial relationships with pharma is already a public secret

A small number of elite doctors have intimate relationships with pharma. The other 99% who are prescribing semaglutide do not profit from it. In fact, it's the other way around. You can't bill for the act of prescribing medications, but there are dedicated billing codes for counseling a patient on diet/lifestyle modification.

What most people don't know is that patients are terrible. I'm not a doctor but I know some doctors and patients.

Many are unlucky to have unforgiving disorders.

This is easily seen in T2D which is mostly diet related and fixable.

I agree with you, but people shouldn't really have to put in the effort to change diet or exercise or lifestyle habits. But the environment that produces those habits SHOULD change.

I lost a bunch of weight when I moved to Dublin and started walking everywhere. Then I moved to the Netherlands and lost even more, and got stronger. I didn't particularly try, I just lived somewhere where I used my own body to get around and the "normal" portion sizes were actually somewhat sane (a bag of Doritos here is maybe a third the size of one in the US).

I was 280 pounds when I lived in suburban California. I'm 180 pounds now.

Build bike lanes and public transport, put schools where kids can walk to them, and maybe don't sell a thousand calories of chips in a personal-sized and marketed bag, and it should get better.

As an added bonus you get a lot less air pollution (and noise pollution, etc.) and less people being run over!

>you get a lot less air pollution

I know what you meant, but according to a comment here once, European city streets actually have worse air pollution than US ones because Europe went hard for diesel engines (to reduce CO2 emissions) for its cars, and diesel produces a lot of very small carbon particles, which turned out to be more harmful than most people suspected back when the diesel decision was made.

Amsterdam has banned most diesel vehicles [1], so at least this is not universally true (anymore).

[1]: https://www.amsterdam.nl/en/traffic-transport/low-emission-z...

Indeed, and I’m worried about the same old mistakes being made with EV’s. They produce lots of tyre particulates thanks to being so heavy, which then get in to our brains.

Of course, Volkswagen lying about their diesels and killing people in the aggregate didn’t help.

What we need is car-free or low-car cities, not just different cars.

Due to it being a common anti-EV talking point, tire longevity has been a strong selling point for EV tires. Longer lasting tires produce less particulates, so this natural pressure should also produce fewer particulates.

Popular EV's aren't significantly heavier than ICE vehicles. A Tesla model 3 and a BMW model 3 are both about 3500 pounds. Range is a huge selling feature for EV's and weight has a significant impact on range, so there is strong evolutionary pressure to lighten EV's. Crappy EV's like the Hummer are heavy; but popular EV's like Tesla's and Hyundai's have weight comparable to normal cars so that they can have impressive ranges without too many expensive and heavy batteries.

EV's increased tire wire is due to their massive torque at low range. If you want your tires to last, just don't drive like a hooligan. We got 70,000 km out of our first set of EV tires.

Tire particulates are an "all cars a bad" issue. EV's are not significantly worse than petrol vehicles vis a vis tire particulates. Their lack of exhaust particulates means that an EV produces about ~half the total number of particulates.

Well this was interesting to me, thanks for sharing. Looking at https://www.emissionsanalytics.com/news/do-no-harm it looks dependent on what you're optimizing for (and not driving like a hooligan helps, hard acceleration and braking wears tires more).

Even so, I still find that the fewer cars there are, the easier it is for me (and my kids) to walk and bike places safely, helping us be healthier (and not reliant on drugs like Ozempic) which was the real point of my comment.

That is a very strange article. The Model 3 and Niro are not comparable cars, the Model 3 is much larger and much more powerful.

Sure, but if I'm overweight and unhealthy now, taking medication is a better bet for weight loss than lobbying for rezoning my entire city.

why not do both. But yes, after taking a pill it's very easy to forget about the need to improve environment. Until you need to take another pill again, and again...

I think the cost of the pill is a pretty strong incentive to want to stop taking it. If the pill is cheap and harmless, then that's just great, there's no need to spend effort improving your environment at all, you've solved the problem already.

It's literally the point of Brave New World. The whole populace is hooked on beneficial drugs so they don't want to improve themselves and their society.

Would you feel differently if instead of being hooked on drugs, we deployed gene therapy at scale to patch the dysfunctional pathways Western society and economies have taken advantage of? What if patching the genome is helping people so that they have capacity to contribute more to improving society? Consider not only the metabolic changes a GLP-1 agonist encourages (a vaccine against Western diet, if you will), but also inhibits addiction.

GLP-1 pharma intervention is breadboarding the human, next step is a permanent fix. Adversarial bioengineering, if you will.

Then you get into Iain Banks' The Culture where every citizen is basically an artificial creation. I have no problem with any specific solution to our societal problems, I take issue with their externalities.

Regarding your proposed gene therapy, would this gene therapy be available to anyone? Could it be refused? Is it reversible? Who would pay for it? The beauty of The Culture is that it is not monolithic, has no border, has godlike AI that takes care of all the problems, and can be abandoned or joined by anyone.

I think we are quite a bit away from that future, but I can understand the concern and moral hazard, the future is hard to predict. In the near term, if we can fix this specific reward and metabolic pathway with gene therapy, the therapy is safe, and can be made broadly available, I think it should be done.

The logic of public health and product design applied to urban/spatial planning basically. And, unsurprisingly, it works wonders.

And it’s a happier, less lonely life!

> but people shouldn't really have to put in the effort to change diet or exercise or lifestyle habits

Everyone is directly responsible for their own health and nobody else is. The insanity of this statement is baffling.

> put in the effort of changing diet

If the genetic / hormonal explanation is right, it would mean the "effort" is not the same for everyone. So expecting people on the wrong side of the equation to not go for a solution to right the scales demonstrate a lack of empathy.

Would you call cochlear implants a quick fix for people who have problem hearing?

It's not a "lack of empathy". GP is just stating the fact that most people are physically capable of losing weight, but since it is uncomfortable and hard they don't. It's not analogous to being unable to hear.

There's nothing with wanting a quick fix to make it easier and less unpleasant. I'd happily use a provably safe one. The only issue is that currently that fix carries unknown risks.

The whole discussion here is about the environment though.

In absolute, changing diet is not inherently hard : it's pretty easy to eat a balanced diet and get pleasure from it.

But it's not enough to just say "eat better", "do more sports" : people can't change the way the lived their whole life if you don't educate and help them to make the change. The education on this topic is so poor that we are still confusing balanced diet and low-calorie diet.

And then there is the elephant in the room which is the refined sugar : for some dubious reason, most scientists agree that refined sugar acts like a hard drug but nobody officially wants to call it a drug. Recent research are saying that the addictive effects of refined sugar are akin to heroin. That's a serious issue then. What it means is that a doctor asking his patient to eat less sugar / eat a balanced diet without further guidance or help is just like saying to an heroin addict that he should stop.

I'm relatively overweight and pretty self educated on the topic but I still decided to work with a nutritionist to change my diet and we are talking about months if not years of follow-up. Eating habits are largely automated by our biology : willpower and education are nothing against an hypoglycemia induced sugar craving.

Like drugs, most people need help and guidance on the long term to change those habits. But what's even worse is that unlike drugs, unhealthy products are basically everywhere in your supermarket, your TV ads, your billboards, your friends lifestyle, and even worse, profoundly ingrained in the culture. You have to fight the "drug" but also the whole capitalist world around you.

> In absolute, changing diet is not inherently hard : it's pretty easy to eat a balanced diet and get pleasure from it.

But even a balanced diet can let you put weight if you eat too much.

We know genetics disorder like Prader-Willis can cause insatiable appetite. Even with a "balanced diet" those affected by it will end-up obese.

Now the current research on GLP-1 hint at many people having a harder time feeling satiated, not to the Prader-Willis point but still worse than what is considered normal. For people who don't have the problem it is easy to think they just have more discipline / willpower and that's why they're thin. I'd like them to imagine what would happen if after eating 2 or 3 pizza slices they'd still feel like their stomach is empty. What if it's not a one time occurrence but all day every day from the moment they develop a conscience to their death bed. A little like drug addiction but you need some drug to live so it is legal and you can buy it everywhere. Still think you'd have the discipline to not go for the whole pizza?

I totally agree with you but "being obese" is just a data point. Being obese is defined by your ICM, which means nothing else than being heavier than the norm.

Being obese with a balanced diet is absolutely not the same thing than being obese because you eat too much "bad" calories. Obese or not, a balanced diet gives you everything your body needs to function properly, be able to move and for your mind to be clear.

The thing is, obesity is a really, really recent trend in humanity history, so recent that a lot of countries are still not concerned by the phenomena (but it's changing). It's pretty certain that _something_ in the environment changed recently and made the humans obese.

People who blames other people willpower just don't understand that if obesity is in an uptrend, it means that people who were previously healthy are becoming obese for some reason. Something new pressurizes humans to become obese and the only question is not if you are concerned but when will the pressure be high enough.

I think it's refined sugar. Plus a bonus of sedentary lifestyles.

> I'd like them to imagine what would happen if after eating 2 or 3 pizza slices they'd still feel like their stomach is empty

Even that is the generous interpretation. Imagine instead of just their regular (or lack of) hunger signals, people had an alarm constantly ringing in the head telling them to eat all the time, that was only ever silenced if they over ate. The persistence of it pushes it in the direction of mental torture.

Yes, technically it can be overcome, but it is a huge tax on your life.

The truth is we can never really know what someone else's inner experience is.

Percent of adults age 20 and older with overweight, including obesity: 73.6%

this is a crisis.

at this point this is like going to a 3rd world country and telling them if you dont want all the problems that come with not having money to just get rich.

like its possible, my brother did it, most my family did it, we all have the capability to do it. it maybe harder for some due to physical limitations or mental ones. so why dont you? dont hate being poor and not getting all the women and luxuries?

74% is sick and its infectious. it curates mental problems that make it even harder to overcome. 74% means there are too many factors that are contributing to this epidemic. if modern technology is able to help get society on the right track i dont know why anyone should be.. for lack of a better word fat shamed haha.

of course we need to be careful and thoughtful. im not even sure though if it will be available for most people anytime soon. i hope so though, iv never been fat per say. maybe a bit more lbs then id like but i do understand how much it helps every part of your life being at a satisfying weight. this could be the greatest cure for depression through medicine ever imo.

i live in one of the fattest cities in america. when i go outside i swear to you sometimes i can go a day without seeing a single person of normal weight. besides the few homeless in my area.

Most are capable of losing it, very few are capable of maintaining their achievement for many years.

Rephrasing the famous quote, it's easy to lose weight — I've done it four times already, ranging from 95 kg to 60 kg over the course of the last 15 years. It's much more difficult to maintain healthy weight over the long term — the longest period I managed that was only three years. Even if you have all the information and know which problems obesity leads to, it's difficult to keep yourself from getting back into unhealthy territory unless you're willing to spend your entire life counting calories and tracking weight religiously.

It's something with the brain, it's insatiable and won't leave you alone until you stuff yourself to the point that you physically can't eat any longer. The last time I gained weight (from 68 kg to around 88 kg) I did it eating only healthy food in unhealthy amounts.

If I can get magic fix (like semaglutide) that would allow me not to think about food any longer and maintain healthy weight over the rest of my life, that would be great.

> it's difficult to keep yourself from getting back into unhealthy territory unless you're willing to spend your entire life counting calories and tracking weight religiously.

It depends on your habits. My habits are generally good enough that I don't need to count calories. Which is mostly luck, not an achievement of mine, btw.

> The last time I gained weight (from 68 kg to around 88 kg) I did it eating only healthy food in unhealthy amounts.

First, there isn't even clear consensus what's healthy and what isn't. But even if there was, I doubt you only ate healthy food. It is very hard to gain much fat eating a lot of vegetables and some fish and eggs.

Of course it's possible your diet is great. My experience with fat people has been that their diet was a whole lot worse than they claimed...

I'm glad you mentioned bodybuilding, since its known to even laymen that taking anabolic steroids gives you an edge that is impossible to replicate just with diet and exercise.

This ozempic study seems to suggest something similar.

Self-discipline is a noble concept, and probably important in the grand scheme of things, but sometimes medicine and technology outpaces what is naturally possible, which inevitably results in a moral backlash.

> 95% of people do not want to put in the effort of changing diet, exercise, and other lifestyle habits. They want a quick fix.

Well yes obviously that is difficult to do. Our society (American society, that is) is about “me” and convenience.

Nobody seems to want to say what is obvious to me: ban junk food. Sugary white bread, Cheez Its, Oreos, candy, ice cream, highly processed frozen burritos, frozen pizza, Little Debbie’s, potato chips , all of it.

It is crazy to me the C levels of poison food companies do not rot in jail for the rest of their lives for knowingly selling poison and lying about it. It is crazy to me how a group of people can conspire to harm the citizens of a nation in the name of profit and not receive any consequences. It’s crazy to me the governments of that nation actually enjoy it and don’t care.

The data however shows that diet and exercise fails for most people though. I don't see it as entirely irrational to go strait to the more effective drugs.

Getting weight off temporarily is generally helpful for getting weight off permanently.

For someone who is 100+ pounds overweight, losing a big chunk of that has a whole set of knock on effects (lower appetite, ability to actually exercise without pain, more general energy, fewer depressive episodes, etc.), that help make permanent weight loss a lot more achievable. In addition, semaglutide can be tried before a doctor would normally do a gastric bypass (and probably makes that operation a lot easier even if it doesn't completely work).

And, before you go blaming everyone that their dietary choices are their own fault, do be aware that the total number of fat cells is highly conserved in the human body. In addition, fat cells "remember" the weight when they were created and only turn over at about 20-25% per year. If you were obese in adolescence and teenage years due to the habits your parents taught you, that can be really difficult to correct as an adult.

Sure, these kinds of drugs are wrong for losing those 20 pounds that you should remove via diet, some extra exercise and some lifestyle changes. Yeah, a lot of people are stupidly using these drugs from dumb reasons instead of what they should be using them for.

That doesn't make the drugs useless.

> The root cause isn't being solved, only the adverse effects are temporarily inhibited so long as people continue to afford dependency on the pharmaceutical industry. How can any medical professional support this?

> I just don't get the lack of skepticism.

Simple answer is people like to eat, lack discipline, and want to look good. None of these will ever change, and so the economic pressure is immense and unstoppable. Until it's proven that these drugs have serious side effects (and that's a real possibility), people will gamble on the risk/reward.

I wouldn't touch them yet myself, but I can see it's a fait accompli. As for solving the root cause, doctors and policy makers have tried everything, to little or no avail. And so we're back to those 3 variables that won't change.

> Simple answer is people like to eat, lack discipline, and want to look good.

This is indeed a simple answer, and way over simplified. You can walk into any grocery store in the US and most of the floor space is dedicated to packaged poison and chemicals masquerading as food.

That's part of it, for sure. But even fixing that, I am confident you'd still have an obesity epidemic in the US (and many other places). The causal tendrils of the problem go so deep. And fixing grocery choices won't happen. It would require a level of government intervention and control that wouldn't be tolerated. You could argue it was done successfully with cigarettes, but food would be a thousand times harder legally, culturally, and practically.

> Simple answer is people like to eat, lack discipline, and want to look good

this is not the answer to the question they asked, just a useless triviality. They are not asking _why_ people would like this, it's obvious, they are asking how is this possible to continue eating garbage and living a bad lifestyle, and keep losing weight, and is it then still a health positive or not?

People on semaglutides may not actually continue to eat garbage - with a smaller total caloric intake it becomes a lot more important to use it on nutritious food, since your body still needs all the same vitamins and minerals. And without the same cravings doing that becomes easier.

> continue eating garbage and living a bad lifestyle, and keep losing weight

Easy, you don't. Just like someone on Nicorette isn't as unhealthy as a smoker. These drugs curb addiction, so you eat less.

These people lose weight because they have taken all the steps to lose weight. Less food less weight, it's that simple.

It was approved for medical use in the US in 2017

In June 2008, a phase II clinical trial began studying semaglutide, a once-weekly diabetes therapy as a longer-acting alternative to liraglutide

Medical Professional don't have a finance or business background, therefore they and their thoughts matter very little to how corporate wonderland decides anything. Unless some kid of a billionaire dies...

AFAIK semis solve your 1st point precisely - people don’t like junk food anymore and they prefer smaller portions.

imo, you wont get a complete model that explains whats happening unless you include the mental health aspect and how it all ties into this. the gut-brain connection is real. but its like just because it is harder to measure, we act as though it does not exist.

1. As individuals we're already completely dependent on the inventions of modern civilization, so putting yet another thing onto the list won't actually change much.

2. Your argument boils down to "if there exists a traditional way to solve a problem then we should keep doing things the old way, even if the old way costs more time, energy, and money; for example it's better to use a sickle instead of combine harvester because combine harvesters are evil because they make people lazy" which is exactly how you avoid civilizational progress.

> Rarely do shortcuts result in long term solutions.

This sentence is so ridiculous it deserves a witty insult but the etiquette of this website stops me.

The very point of this study is that ozempic's effects go beyond what one would experience if they went on a very strict diet. It's literally better than self-discipline.

> The root cause isn't being solved [...] they'd need to keep taking this medication for the effects of the drug to remain.

Hold up, how is impermanence such a black-mark when it's also true of everything else? Exercising must be continued indefinitely, or else the benefits fade, and the same is true of dieting.

Your post suggests that there is some kind of superior one-and-done weight-loss fix that is being overlooked or neglected, but I don't think we even have consensus on what this "root cause" is, and it's not clear why we should expect a perma-fix to be just around the corner.

Is the root problem "humans aren't calibrated for abundant food"? Is the single-event fix a form of gastric-restriction surgery? Genetic editing?

I have to offer a hard disagree here for a number of reasons.

First of all this is just blatantly disregarding the first order quality of life benefits, which is beyond inexcusable. The second chance at an elevated quality of life counts as legitimate rationale in and of itself. Even a 'season' of improved quality of life needs to matter to those of us who value health and life.

But secondly, as a consequence of the above, it can dramatically shift the odds of maintaining good habits in a positive direction. It's easier to initiate and sustain momentum from a position of strength, of enjoying a benefit that's already in hand, than it is to try and summon the extraordinary willpower necessary to initiate and power through a long-term health journey. I don't see any reason to force people to take path that except for a confused desire to impose pull-yourself-up-by-your-bootstraps moralizing.

Third, it appears to come with the benefit of moderating cravings for alcohol, which in and of itself is such a critical health benefit is that it could compensate for even quite serious side effects, if it had them.

Fourth, it does address significant root causes. Unlike a bariatric surgery or gastric sleeve, it is an intervention that impacts cravings and metabolic processes at their source. Different people are born with different exposures to the risks given our reward and addiction systems. Our relationships to those risks is not more or less healthy, more or less attestament to our self-control, many of us are getting those benefits for free and aren't truly challenged. Nor should we be. Whatever our initial state we didn't "earn" that and once again I think it's confused moralizing true require people to essentially rewire their reward systems out of a subjective belief that that's more pure path to self regulation.

Fifth, it is a medicine and medicines involve tradeoffs. Being qualified to prescribe medicines involves being trained to think coherently about a trade-offs. If you're not trained, then ignoring benefits and focusing on negatives might feel like it's some form of enlightened skepticism. But it's just as much malpractice to ignore the benefits of medicine as it would be to ignore negative side effects. Even it's necessary to maintain a lifelong relationship with the specific form of medicated intervention, that can be a net positive trade-off for long-term quality of life.

The comment author has zero moralizing and zero denial of quality of life benefits, or any of this. They simply seem to say that if a person doesn't eliminate the root cause of their obesity, they will still continue to suffer from health damage (or maybe even more, tbd) despite the actual benefits of this pill - and this is not discussed, unlike the hyped-up benefits, which btw may mislead people to think that they shouldn't change now that their appetite+weight is magically reducing, and all-positive publicity also encourages people who have little need for this pill to hoard it and drive the price(profits) up.

A number of other things you mention are pretty subjective. It's just as hard for me to diet and exercise when I'm BMI 19 or BMI 25. In fact, that's true for 90+% of people, because everyone almost universally rebounds to bad habits, in all studies. This "power through a long-term health journey" is your whole life, always, there is no start or stop to this until we die or give up, even with this pill. The pill may help with the BMI part, but it obscures the fact that there is still very real health damage from bad diet and bad lifestyle no matter what your BMI or even visceral fat is.

Excellent question! This is the picture I'm getting so far:

* the observable weight loss seems real based on reports - that's easy to measure, and harder to fabricate like "blaming fats" conspiracies of the past. Unless there is truly massive numbers falsification in all these studies, which i doubt. So that's kind of exciting.

* stuff like this article about visceral fat might also be true, so that's also easy to get excited about, and might even be true.

Major downsides are transparent and predictable - this is not magic, or willpower replacement for health, because:

* if you keep eating garbage, you will still suffer health damage despite losing weight. If I eat nothing but twinkies for a year, and this pill makes me feel full after two twinkies a day, I will lose weight, I will also kill my liver and suffer severe malnutrition - you are right! A less extreme, average American food will also produce health damage while losing weight on this pill.

* if you live a bad lifestyle while on this pill, you will still lose weight, but will damage your health exposing yourself to things like diabetes, CVD, etc.

* the big unknown for me - curious about that - do people develop tolerance for this pill? and another big one, do they rebound violently (much worse than usual) once they stop taking it after a while? or not. This is easier to cover up and harder to measure.

* other more subtle things like is there a link to higher cancer risks over time, etc, but the first two "cons" points are big enough for me already.

TLDR: this is a way to look better and soften some effects of obesity, but does not help with continuing health damage that still needs to be addressed in a more traditional way unfortunately. Lack of skepticism is not because the massive downsides are unknown or absent, but because apparently they are less of a concern to users+marketers.

> But short of that, are there not only two root causes left?

No.

Let me paraphrase the conversation I had with the head of obestity at one of Europe's leading research hospitals (top 5 in EU):

Once you get a certain amount of overweight, regardless of the cause, there are so many regulation systems in your body (at least 20 that we know of) which kick in to keep you overweight that it is not possible to diet and exercise your way back to a healthy weight without picking up a new disease (eating disorder, exercise additiction, etc.). The people who manage it spend the rest of their lives obsessively weighing everything they eat, exercizing every day, and even then if they slip up or lose mobility or something, inevitably they will become overweight again.

The only known medical treatment is operating on the stomach. This changes enough of the regulation systems (including the hormonal ones) that it has a reasonable chance of sticking. GLP-1 seems to offer a second option.

It continues to astonish me that eating disorders which result in weight loss are (correctly) accepted by society as diseases with complex causes which can include lifestyle and self-control but also mental health and innumerable other things, but if you're overweight clearly you are a sad sack of shit that just can't open their mouth without shoving food in it.

> Can we talk about the elephant in the room for a second? tens of millions of people are taking this, and they'd need to keep taking this medication for the effects of the drug to remain.

This is untrue, you can stop taking the drug and the effects will persist, most people keep weight off after coming off the drugs.

I've assembled some stuff on this here:

https://glp1.guide/content/do-people-regain-all-the-weight-l...

There are anecdotal reports of astounding levels of hunger returning (more than before perhaps) but this can be solved by a more gradual wean-off (like the ramp up).

> I just don't get the lack of skepticism.

There has never been such a con-free, researched solution to weight loss (and originally these drugs were meant to treat type 2 diabetes, so it's more like we have a viagra situation on our hands).

Don't read what the media puts out, go back and read the research papers. It's not magic -- it's well researched, and while it's not clear exactly every effect, there is a growing body of evidence.

> If there is a legitimate hormonal imbalance or genetic defect, I get it.

'No Way to Prevent This,' Says Only Nation Where This Regularly Happens.

> Poor diet > Poor choices > legitimate hormonal imbalance or genetic defect

The legitimate hormonal imbalance and genetic defect is being human. Our brains and bodies were never intended to operate in a setting with a surplus of extremely nutritious food.

To me, it is clear that food can be extremely addictive, maybe even more so than traditional avenues of addiction like nicotine or alcohol. It's obvious that modern day foods are constructed in such a way to ensure this addiction.

They have appropriate amounts of fat, sodium, and sugar to give an immediate good feeling to people, as well as increase their dopamine for a while.

The reality is that the obesity epidemic is the primary killer in the first world. We have moved past the point where we can close our ears and yell "bootstraps! bootstraps!!!"

Clearly this is bigger, more complex, and more sinister than online armchair doctors will have you believe. Look around you. I see a society of sickness. Did everyone magically, at the same time, become lazy? Is everyone just stupid? I don't think so.

So basically some drugs encourage the metabolism of people who need a CPAP to lose weight, possibly tied to brown adipose tissue.

It works in mice and probably works in humans but was not the main focus of the study so they didn't have a good control group to be able to prove it.

A potential human study control problem is obesity most often exacerbates OSA.

Is this why folks on ozempic often have a specific "look" in their face? Or is that just a side effect of semaglutide?

It's just weight loss.

As someone on Ozempic, and who has been through a few periods of weightless before - I'm not convinced it is just weightless. The three other people whom I know that are either on, or have used it, have all had experience with dry head and facial skin. It's not a long bow to draw to wonder if the drying is related to skin moisture and elasticity.

I've found a good vitamin a boosting skoncare regime and general face moisturiser application goes some way to noticeably reducing the flakiness and dryness.

Seems like it. When I was skinny(not a rapid weight loss, it took years), I looked very different. I look a lot more friendly when I'm fatter. My skinny face was a bit.. harsh.

I'm not sure if it's true or not, but read an article just last week that Ozempic seemed to remove most/all elasticity from skin in their face. That's a bit concerning, but unfortunately, I didn't research further to see how true that is. If it is, it would certainly explain a 'look.'

I think it’s because you lose your buccal fat. I only notice it on people who are already fairly thin and taking Ozempic.

I was under the impression that “ozempic face” was just an inaccurate shorthand for the buccal fat removal surgery that seems to be all the rage currently among the starlets

Ozempic face isn't real -- it'd happen for any other effective form of drastic whole-body weight loss.

There's just been nothing so effective (and relatively side-effect free and cheap, believe it or not) up until now.

Note that the wider class of drugs are called GLP1 Receptor Agonists.

Successful weight loss is so uncommon that it's alarming the effects when it occurs

If you stop taking it, and the weight returns, does it return as visceral fat?

If weight return, yes. Usually, at least with men, visceral fat storage is 'filled' first, then it goes to the closest storage available (abdominal, thighs, boobs, then face. If it reach your face, you're at least medically obese).

So cryolypolisis after the weight is lost?

Nevermind. Just saw another comment pointing out that this is unrelated. My mistake.

TIL, thanks for this insight -- where did you find this rule of thumb?

I don't remember. I was obese and started having some joint issues and visage fat, so i bought a scale, calculated my BMI, found roughly 34, then tried and failed my first attempt at calories limitations. Then I really prepared for a true diet, spend months informing myself, got used to hunger by fasting for 5 days, and got my weight under control. It's during that time that I learned about that. It might have been on a HAES forum before they went crazy (circa 2017 it was mostly support (and a dating site tbh), and a view of 'if you don't have health issues, do not hurt yourself trying to loose weight'. Now, from a more external POV, it seems it changed toward 'it's okay even if your health struggle')

many people of Asian or Indian ancestry store a lot of face in the face though

What does the body do with all the extra energy?

It gets burnt off as normal? Ozempic and co make the users feel less hungry so they eat less. A kilo of fat is about 7000 kcal, humans at rest use about 2000-2500 kcal a day, if there is a deficit of 500 kcal a day they lose two kilos of fat a month (on paper); total weight loss may be higher due to reduced fluid contents.

(disclaimer: armchair logic)

So do you start sweating because of excess heat? Do you suddenly feel more energetic?

The average Western man burns less than 2000 kcal/day, I would say optimistically 1500 kcal/day for the people around me, most of them don't exercise much.

The problem with your computation is that the body is not stupid, when you stop eating, it stops burning. I don't know the exact numbers, but it is absolutely not linear like that.

GLP-1 agonists seem to slightly increase resting heart rate, which might indicate a similar increase in basal metabolic rate.

I don't think the title of the post is accurate, at least not based on the link.

> Here, we present data from a proof-of-concept study on 30 individuals with obstructive sleep apnea and obesity who were randomized to a GLP-1 therapy-based weight loss regimen, continuous positive airway pressure, or a combination of both for 24 weeks.

They compared weight loss medication to a sleep apnea treatment and the weight loss medication group lost fat... which happens when your appetite is suppressed and you eat less - you lose some muscle and some fat, some of the fat you lose is visceral, some isn't.

They note that their discovery relating VAT activity increase to weight loss wasn't the original focus of their study, so they hadn't prepared an additional weight loss control group - I think they leave open both appetite suppression and metabolism increase as possible factors - "individuals with lower VAT metabolic activity may benefit most from the dual impact of GLP-1 on reduction of energy intake and increased metabolic activity"

Another bullet point in the list of benefits for GLP1 RAs -- it's amazing all the areas that it seems to touch.

I've been on the lookout personally for more negative side effects (it's almost suspicious how little there are, though it varies by person to person), but also excited to hear of benefits.

Some of the benefits recently led 23andMe to get into GLP1s:

https://glp1.guide/content/23andme-gets-into-glp1/

They even a paper on some possible benefits with Alzheimers, though I think the research is in it's infancy. I think the plastic story is a bit more compelling though.

>I've been on the lookout personally for more negative side effects

I've got a rare one for you. "Realistic dreams"

It wouldn't matter the content of the dreams, (they weren't all bad); but every night my dreams were so vivid that I wouldn't be rested in the morning.

I'm able to get dreams by just take melatonin, like vivid ones.

A bit late here, but vivid dreaming... that's absolutely a new thing I haven't seen before.

Interesting, this reminds me of the effects of coming off of THC, I wonder if there's some relation.

It's great if GPT-1 meds increase the burn of visceral fat. But can we really say that from that study? It could very well be just the effect of the caloric deficit per se (that follows the hunger supression and delayed gastric emptying due to GLP-1).

A caloric deficit leads to a loss of visceral fat. It wouldn't suprise me, if we see the same VAT activity if we had a control group with the same caloric deficit. Only then we could calculate the direct effect of GLP-1 to the VAT acitivity.

Generally speaking, is Ozempic safe?

For the reasons the FDA and EMA approved it, for diabetes, yes.

I mean the question is rather what's the alternative. Diabetes - even well managed - already shortens your expected lifespan considerably by more than ten years.

So the safety profile has a different baseline risk.

If you're morbidly obese, and don't yet have diabetes, it's still so likely that you will develop it, and a host of other issues, that it's probably still better to lose weight with ozempic. Morbidly obese people also have an extremely shortened lifespan.

If you're only a little overweight and you're trying to get a lean physique. That's where you should really think if taking a risk is worth it.

The FDA has approved this class of drugs for weight loss as well. Wegovy is the version that was FDA approved for weight loss, it's the same drug as Ozempic but at a different dose.

Source: https://www.fda.gov/news-events/press-announcements/fda-appr...

For what it's worth, it's also one of the only classes of weight loss drugs the FAA has felt was safe enough to approve for pilots to use. (The only other one being metformin, which has a much more modest effect.) They tend to be very picky about the safety profile of drugs that are used by aviators.

This is a big deal for folks in aviation, because until now there has been no other options available other than lifestyle modification - which is always preferable when it works, but statistically has an abysmal success rate.

> it's the same drug as Ozempic but at a different dose.

Yea.. it's just a 5x higher dose.

The maximum Ozempic dose is 2.0 mg. The maximum Wegovy dose is 2.4 mg.

The difference is not as dramatic as you're making it sound. And again, both are FDA approved within this dosing schedule.

0.5mg is the standard maintenance dose of Ozempic. You _can_ get higher doses _if_ your provider decides you need temporary additional blood sugar control.

2.4mg is the standard maintenance dose of Wegovy.

It actually is that dramatic. The brands are approved for different purposes and control different diseases. The doses are designed as such. This is the _entire_ point of Wegovy even existing.

Rybelsus: "Am I a joke to you?"

This class of drugs has been around for 20 years. It’s a very typical overnight success story.

Whether it is safe for you is not answerable by randoms on the internet, but the class of drugs (GLP1 Receptor Agonists) are VERY well researched (like other commenters have pointed out).

If the wealth of anecdotal experience isn't enough for you, read the published research and trials.

This will definitely give us one of the largest sample sizes in medical history.

Fat and happy.

And unhealthy.

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