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I'm not commenting specifically on the heart-muscle aspect of the study, but it shouldn't be a surprise that the weight loss from this drug is significantly attributable to muscle loss; it almost always is when dieting. It's the same with keto/low-carb or any other kind of caloric-restrictive dieting (which Ozempic facilitates).

The modern weight-loss programs I'm seeing now (at least those aimed mostly at middle-aged men) emphasize consuming significant amounts of protein (2g for every 1kg of body weight each day) and engaging in regular resistance training, in order to maintain muscle mass.

The article addresses this:

To keep muscle strong while losing weight, Prado says it is essential to focus on two main things: nutrition and exercise. Proper nutrition means getting enough high-quality protein, essential vitamins and minerals, and other “muscle-building” nutrients. Sometimes, this can include protein supplements to make sure the body has what it needs.

Perhaps there needs to be more formal research into this, and a strong recommendation made to everyone using these drugs that this kind of diet and exercise plan is vital.

For the people who lift weights while on this/these drugs, how much lean muscle do they lose?

The point is is that most people lose muscle because they’re not lifting. You will lose muscle if you lose weight no matter the cause, if you are not lifting weights.

Not sure how much I lost during, but a substantial amount. I have been working out since about 20lbs from my goal weight and now roughly a year later - and have gained strength (based on the numbers I can lift) from before I lost 100lbs.

I don’t think it would have been possible to not lose substantial muscle mass while rapidly losing 100lbs over 9mo, even with extreme resistance training added to the mix. While DEXA scans are not super accurate, I’ve put on about 17lbs of muscle since my first scan 10mo ago, while maintaining a 12% or less bodyfat ratio.

That said, I’ve been eating extremely healthy both before and after being on the drug which helps a lot. The drug simply gave me the mental space to avoid the binges which were my particular problem. That and it controls portion sizes to European dinner vs. American restaurant sized meals for me.

> For the people who lift weights while on this/these drugs, how much lean muscle do they lose?

I was 92kg when I started on liraglutide (I was doing GLP-1 agonists before it was cool!) and 67% of muscle mass (61kg). I'm now at 69kg and 82% of muscle mass (56kg). I'm doing weight and resistance training twice a week, in addition to aerobic training.

One nice thing, while muscles don't become more massive, they for sure become more pronounced and visible with weight loss.

There are a lot of people here citing loss of muscle mass as a side effect of GLP-1s, when the reality is that weight loss almost always comes with muscle loss.

For me, that hasn't even been the case. I'm down 40lbs on a relatively low dose of Semaglutide and my muscle mass has moderately increased over the last 6 months. The hysteria over this is totally unfounded.

Anecdotes don't equal data. "Always" and "never" don't exist in medicine. I'm sure that your experience is accurate to yourself, but these studies have to cast a wider net since there is always variability in results.

Studies show strength training while losing weight can retain almost 100% of muscle.

https://pmc.ncbi.nlm.nih.gov/articles/PMC5946208/

Yep. I started resistance training 5x a week about a month in on tirzepatide and even with a severely restricted caloric intake (I just can't eat enough), I've gained LBM.

How did you measure the increase in LBM? This requires very advanced technical equipment. My suspicion is that you have noticed an increase in muscle volume and assumed it to be an increase in muscle mass. Those are largely due to water retention and increased blood flow. They revert quite quickly after you stop exercising for about a week.

Does ability to lift weight also decrease in about a week? I was recently out of town for over two weeks and came back with the ability to lift roughly the same amount I was able to prior to leaving.

My DEXA scans seem roughly correlated with the amount of weight I can do in my regular sets, which has increased about 50-70% depending on which muscle group you are talking about.

This is with heavy resistance training 3 times a week and Pilates once a week.

A good portion of the strength related to any specific lift is CNS adaptation up until a certain point (and most new lifters won't hit that threshold for quite some time), so strength on a lift you've been doing regularly isn't necessarily a good indicator. Building muscle will of course increase your strength too, but I've doubled my squat since getting back into lifting while certainly not doubling the muscle mass of the respective muscles.

Fair enough. I didn’t mean a 1:1 correlation in 50% on a Dexa means 50% more strength, just would expect my lifting ability to go down if I lost muscle mass (or if it were water weight to begin with). Neither have decreased much if at all during breaks, so I’m fairly convinced it’s “real” so to speak.

Looking through my weightlifting app my best tracked exercise (leg press) increased about 250% from start with a 60% (roughly, speaking from memory) increase in lean muscle mass as measured by a DEXA scan. If I remember when back from dog walks tonight I’ll update that with a real number off the actual data.

I was a total newb at lifting though, so those early gains came quite quickly.

I am curious as this is a concern I have for long term health.

DEXA scans are accurate and readily available in most cities for about $100. Just do it quarterly or whatever.

I am getting regular DEXA scans

Likewise, I did (and continue to do) keto for the last 6 months and lost 50lbs. 3 Weeks ago I started Semaglutide while continuing to do keto and it's just made everything easier. I've lost another 10lbs in the 3 weeks, am logging all my meals and taking macro goals into account. What's better is that because I was already "fat-adapted" as they say in /r/keto, my body isn't starving in a caloric deficit. It's just burning more fat as ketones.

Yes, I am trying to hit 100-150g+ of protein per day, yes I am in a caloric deficit. No, I don't feel like I have lost any muscle mass, but I do feel a lot more active at 60lbs lighter.

It predicts long term consequences on health. Not immediate ones. You wouldn't have noticed at all. Unless you measured your heart muscle weight.

It's good to work out. Perhaps it offsets any loss.

I get that it's upsetting and might contradict what you think.

At this stage we don't know for sure. It's something you might want to keep in mind. Especially if you take this drug without working out.

If someone is taking this medication for the right reasons, the risks of taking it are far lower than those associated with obesity and diabetes.

Also, concern of losing muscle mass on GLP-1 agonists (and diets in general) is well known and typically explained by the responsible MD to the patient.

You did not lose 40 pounds of fat while building lean muscle tissue unless you're BOTH relatively new to weightlifting and use PEDs, in which case, the "hysteria" is justified for an average person.

Just the former is likely enough over a 6 month span, even without great genetics. That's only a 1.6lb/week loss. Noob gains can be huge.

A caloric deficit that allows a continuous weight loss of 1.6 lbs a week for 6 months is significant enough to completely wreck your hormonal profile and put you in constant catabolic state, I doubt you would be able to put on any noticeable amount of muscle mass even during your noob gains phase in that context.

I've seen it happen with people even prior to the GLP-1s - prior to an injury derailing my last attempt to lose weight, I lost 30lb at an even faster rate and had 3 DEXA scans showing consistent increases in LBM.

This conversation does make me wonder about whether or not it would make sense to make the option available for people to go on exogenous testosterone (and yes potentially even women) while on these to help prevent muscle loss.

Yeah I've always found that complaint confusing. Of course you lose muscle when you eat less food. It'd be weird if that didn't happen. (Assuming you don't train hard or take hormones)

It also decreases gut motility, which helps with the intended effect of appetite suppression. Young healthy people tend to shrug at that. As an old person that takes it right off the menu even before I read about accelerated sarcopenea. Maybe it's the same effect on the peristaltic muscles.

A bare glp-1 agonist doesn’t, I think, but the weight loss versions are double-acting and do also slow digestion.

Tirzepatide (Zepbound) is double-acting but semaglutide (Ozempic) isn't. Both are prescribed for weight loss.

Some of the side effects of semaglutide are just a result of eating less calories.

Without a control group who also ate the same amount of calories but without the drug, it's hard to know if the side effect were directly caused by semaglutide or just a result of being in a calorie deficit.

Not a solid paper—-more like an abstract. I could not find any information on the strain or type of mice they studied. Data from one strain often fails to generalize to others. Trying to leap to human implications is beyond risky.

If you're trying to prove a positive benefit, then leaping from mice to humans is risky. If you're concerned about possible negative effects of something, then mice is a good place to start.

I wish discussions would focus on all source mortality instead of single stat x. If the all source mortality data comes back favorably you could read the interpretation of this data 100% opposite: regular calorie restricting diets fail to reduce heart size... Point being, without all source mortality data to back up that this is a bad thing it is a very hard stat to care about.

The problem with appetite suppression drugs is that they simply make you not feel hungry, but do nothing to fix your lack of discipline and self-control, I'm sure most people who lose weight on these drugs, and then come off, will just go back to their bad habits.

K. But getting to a healthy weight by means of discipline and self control has a ~1% success rate[1]. That's dismal.

I wouldn't blame anyone for choosing the drugs over dying early.

[1] https://www.healthline.com/health-news/obese-people-have-sli...

If you find it hard to control your eating when you always feel hungry, taking a drug to reduce your feelings of hunger is self-control. It's exactly looking at your body as a system and controlling it.

Maybe you can titrate off the drug and in a perfect world, the hunger signal doesn't come back on all the time; that'd be great. Maybe, while on the drug, you've developed eating habits that you can continue while off the drug, even though you feel hungry all the time, again. Maybe, it's just too hard to ignore the hunger signal, and you need the drug for a lifetime.

That's not to say these drugs are necessarily wonderful. Previous generations of weight loss drugs came with nasty side effects that weren't immediately apparent. Fen-Phen was a wonder drug until it ruined people's heart valves. Stimulant appetite supressants have issues because they're stimulants. Cigarrettes have appetite supressant properties (not surprising, nicotine is a stimulant), but they're cigarettes.

Personally, I don't have an overactive hunger signal; so when I eat poorly and gain weight, it's on me. But other people I know have a totally different experience with hunger. If your body is telling you all the time that you need to eat, it's hard to say no. Just like it's hard not to scratch when your skin is itchy. I can resist itchyness sometimes, but when it's constant, I'm going to scratch.

So why not just stay on the drugs?

You technically could but the idea here is to cut the excess bodyfat percent and get into the healthy range, rather than to keep losing weight, which itself is also unhealthy, but once you become dependent on the drugs to maintain your weight, without fixing your habits, you will just go between getting off the drug, binge eating, gaining the weight back, and hoping back on the drug and losing weight while barely eating, I can't imagine bouncing between such two extremities being good for your health.

Well, lots of people back off those dosages once they reach their goal weight and have minimal difficulty maintaining. As we know more about the long term effects of staying on the drug, it's totally possible it might make sense just to keep on it.

But as someone who spent a good chunk of their early adulthood having no problem with healthy habits and then slowly slipping into tons of bad ones, getting on tirzepatide has made it as easy for me to make those healthy choices that I made when I was in my 20s. Ones that I struggled with mightily after I got fat.

Hopefully more and more people will use them as a tool to help them get things back and order and then stay there, whether or not they keep taking it.

Can’t you just adjust the dosage to stabilize?

Yes, you can. Or most people can. It’s called a maintenance dose and is usually the minimum dose available for the particular drug you are on.

As these become more common and doctors more aware, the dosing guidelines will become much more nuanced and dialed in.

Most kill you. If I didn't misread articles on ozempic, they can cause digestive problems where food rots in your stomach. Bad depression was another side effect which blows my mind since you'd think looking better would make you feel great. And these were the minor things.

> digestive problems where food rots in your stomach

I assume you mean gastroparesis - this is an extremely rare side effect

> Bad depression

Again, pretty rare side effect.

If you think these are the minor things I'm confused as to what you think the major side effects are.

I don't think you realize the amount of people have taken Ozempic or similar drug. I'm lucky enough that I haven't had issues with body weight, but if I believe the stats (and my observations in real world confirm it), about 15% of adults are on it.

If it was "killing people", we would be seeing it literally everywhere. We're not talking about a small scale 50K+ observation... we're talking about literal millions.

This says 6% are currently on a GLP-1 drug and 15% have ever taken one in their life:

https://amp.cnn.com/cnn/2024/05/10/health/ozempic-glp-1-surv...

> Bad depression was another side effect

What? Ozempic has been noted for its mild _anti_ depression activity.

both can be true. it can reduce depression in 60% of people and increase it in 10%

It's my understanding that if you have hypertension, your heart muscle grows thicker as a consequence of working harder against your blood pressure, which reduces the flow capacity of your heart.

So if you have hypertension, this might actually be a "good" side-effect?

I was also thinking if in used with testestrone, which is dangerous because the heart is a muscle and unintended consequence of trt is heart muscle growth which decreases blood flow.

well that's a weight reduction too!

on a more serious note, could it be that the load on the muscle gets lower so they adjust?

8% reduction for 30% body weight reduction sounds reasonable to me at first glance

When Ozempic started making the rounds in the news with glowing reviews, my instincts told me there likely was some long term negative effective that wasn't immediately apparent yet.

If something sounds good too good to be true, it usually is.

You do have to factor in the (probable) cost of not using Ozempic, aka keeping the pounds on. It may be imprecise, but as an example, if a person was likely to die within 10 years at their current weight, any bad effects beyond the 10 year mark have to be heavily discounted.

I assume parent was talking about cosmetic and convenient weight loss not medically necessary weight loss.

I'm sure there are plenty of people taking it as a shortcut to dropping 10 or 20lb or whatever, but I imagine most people taking it are in the "I need to lose 70+ lb of fat" range.

On the other hand, being overweight takes years off your life:

"Specifically, we found that BMIs from 40 to 44 were associated with 6.5 years of life lost, but this increased to 8.9 for BMIs from 45 to 49, 9.8 for BMIs from 50 to 54, and 13.7 for BMIs from 55 to 59."

I think for some people the roi is measurable and reasonable.

https://irp.nih.gov/blog/post/2020/01/extreme-obesity-shaves...

At the very least, we should expect to see the same kinds of downsides you’d see for anyone who managed to eat way, way less and lose weight at a multiple-pounds-per-week rate for weeks and weeks on end without taking a drug to do it. They’d be truly miraculous if they achieved their results without even the same cost as doing the same thing without the drug.

> If something sounds good too good to be true, it usually is.

You mean like antibiotics? Or vaccines?

No one seems to remember Fen Phen or its stratospheric rise and fall https://en.m.wikipedia.org/wiki/Fenfluramine/phentermine

No one who brings up Fen Phen seems to grasp how long both that and GLP-1s have been on the market. We're up to 4x Fen Phen's run already (5-years Vs. 20-years). GLP-1 Agonists aren't new, they've just been approved for additional usages.

So why, after 20-years, and millions of people haven't fen-phen-like side effects appeared?

That was one of my first thoughts.

It’s perfectly possible for a new hot to have a severe side effect that won’t be noticed for quite a long time.

Semiglutide appears to have undergone final clinical trials in the US around 2017. Given it hasn’t been on the market terribly long and has only an exploded in popularity relatively recently it doesn’t seem like it would be that hard for it to have a serious side effect in a small portion of the population that hadn’t been detected before due to the limited number of people taking it, the amount of time it takes to manifest, or both.

Obviously it’s providing significant benefit that risk could easily be worth it. But as it gets marketed towards more and more people that won’t be true for all of them.

Semaglutide is a 3rd generation GLP-1 agonist, though. We're 20 years in on GLP-1s at this point.

This is most likely a good thing. It isn't killing cardiac myocytes, it's probably assisting with reverse remodeling. Fits with why we know it helps in heart failure.

The study found that heart muscle decreased in both lean and obese mice. So any observed muscle loss might not be just from losing body mass and not having to work as hard.

But if you're already lean and then go on a calorie deficit (as a result of decreased appetite from taking the drug), then muscle mass will be lost through metabolism of muscle and other tissue.

Then the study states further that the proportion of muscle loss is higher than expected from calorie restriction alone.

My gut feeling here is that where there's smoke there's fire, and I predict dramatic class action 40 years in the making, either like tobacco, or like baby powder, depending on the actual long term health outcomes.

And, this is great research! We need more like this ASAP!

So... could this be a treatment for enlarged hearts?

The research says

> Together these data indicate that the reduction in cardiac size induced by semaglutide occurs independent of weight loss.

Which does sound concerning. It's the drug, not the weight loss, that causes the muscle loss.

I guess the question is whether it's better than nothing. Is the loss in lean muscle a worse outcome than remaining obese?

I hope they re-run this study with retatrutide vs semaglutide. Apparently retatrutide does a better job at preserving muscle, and some bodybuilders will take small dosages (.5 - 1mg a week) of it in order to lose stubborn fat but keep muscle.

How are bodybuilders getting a phase 2 trial drug still in development by Lilly?

China. It's trivial to purchase retatrutide, semaglutide, tirzepatide, and a wide variety of other peptides from Chinese labs, and for pennies on the dollar compared even to compounding pharmacy prices.

It's pretty clear that GLP-1 should be prescribed with protein powder. When your appetite is crushed you don't go for the chicken breast, you go for what is immediately appetizing (usually carbs+fats like pizza or fries). IMO this and a lack of resistance training (which should also be prescribed) probably makes up a large % of the muscle loss on these drugs. The problem is that the FDA only looks at dumb measures like weight lost, not body fat % when approving these drugs.

Tirzepatide let me stay away from the immediately appetizing junk food and almost exclusively eat a clean diet focused on protein.

My experience matches at least a dozen folks in my personal bubble. It’s sort of the point of the drug or it wouldn’t work very well.

Totally agreed on resistance training. The one thing I would change would have been starting that in a serious manner as soon I started the drug vs. waiting. Prescribing it is silly though - if that worked we wouldn’t need the drugs to begin with.

That may be your experience, it wasn't mine. I eat very healthy on Ozempic but yeah of the 60 lbs lost so far some of it is noticeably muscle because I don't exercise enough. The next 60 lbs of fat lost will hopefully be me swapping fat for muscle from weight lifting and swimming.

I find it significantly easier to eat healthy on tirzepatide, fwiw.

> When your appetite is crushed you don't go for the chicken breast, you go for what is immediately appetizing (usually carbs+fats like pizza or fries).

Um, when your appetite is "crushed", nothing is particularly appetizing. That is the entire point. It allows one to make better decisions or pass on eating.

folks, this is why I lean on skepticism in regards to “off label” usage (ie, weight loss).

Have only lived a few decades on this planet and the weight loss trends with pharmaceuticals is wild.

I like the way the title ends with "human cells" as if the main reason it was there was to cut off (?) all the people that respond with "In mice."

Well, in vitro.

So like, it's interesting that this happens in mice, but we did not see increased heart disease in human RCTs of these drugs.

Maybe the mouse dose is just absurdly high? "Mice were then administered semaglutide 120 μg/kg/d for 21 days." That could be vaguely reasonable -- human doses range from, idk, ~36 to ~200 μg/kg/d (2.5mg/week to 15mg/week at ~100kg).

> but we did not see increased heart disease in human RCTs of these drugs.

In fact, we've even seen the opposite - that it's cardioprotective.

They found the mice did not suffer from any heart problems, so it’s not surprising.

Keyword: "in mice"

Second gotcha: how much of the decrease is just attributed to the lower mass of the subject after the weigh-loss treatment

Though it's one good reminder that "catabolism" and "anabolism" are less selective than we wished to

This is going to be a non-result. It won't matter. The win from losing weight will easily outclass all of this. This drug should be in wide circulation. When the patents expire, we will enter a new era of American health.

If it causes cellular damage, it might be a big problem. "Some studies indicate that only about 1% of heart cells are renewed each year in younger people, dropping to about 0.5% by age 75. This means that a significant portion of heart cells remain from childhood into old age."

> emerging research showing that up to 40 per cent of the weight lost by people using weight-loss drugs is actually muscle

That's the sort of headlines that smells like bullshit to me.

My understand of those drugs is that they don't actually make you lose weight, they just cut your appetite so you can follow a diet to lose weight without hunger hammering at the door. So to start with, if that's the case, all they are observing is the effect of a diet. Not sure the diet drug has much to do with it.

Then I went from 133kg to 88kg with these diet drugs. Even though I exercised every day, I am sure I also lost some muscle mass as well, just because I don't have to carry 45kg every time I make a move anymore. Seems logical and would probably be concerned if it was any other way.

The next line of the article after that 40% quote:

> Carla Prado, a nutrition researcher in the Faculty of Agricultural, Life & Environmental Sciences and lead author on the commentary, explains this rate of muscle decline is significantly higher than what is typically observed with calorie-reduced diets or normal aging and could lead to a host of long-term health issues — including decreased immunity, increased risk of infections and poor wound healing.

The rather obvious problem is that these GLP1 agonists don't improve your diet. If you continue to eat a protein and nutrient deficient diet (which is probably a majority of Americans) with caloric restriction on top of that, that leads to excessive muscle loss that you wouldn't see in a weight loss diet. This normally doesn't happen without GLP1 agonists, because these diets are too difficult to stick to for most people. Those who stick to them usually turn to nutritious high satiety whole foods that help combat the negative effects of caloric restriction.

Losing weight without losing muscle mass is very hard. It requires extreme diets like a protein sparring modified fast where 80%+ of your calories are from lean protein while running a 50% caloric deficit. If this research is correct, then using GLP1 agonists shortcuts the feedback loops that make the diets hard to stick to, but they shift the tradeoffs from weight to overall nutrition.

"When a measure becomes a target, it ceases to be a good measure" and all that.

> The rather obvious problem is that these GLP1 agonists don't improve your diet

My understanding from initial anecdotes is this is actually literally wrong. Which was surprising to me, too. But people on GLPs tend to prefer more nutritious food (high protein and high fiber). I'm not sure if this has been studied directly in clinical trials yet but I know that food manufacturers have been reorienting their products toward healthier meal configurations in response to the GLPs.

I predicted the exact opposite of this, but so far I appear to have been wrong.

I’ve heard that anecdote from HN users many times but based on my meatspace social group of (mostly) California yuppies, that effect is vastly overstated. Even some of the diabetics I know on Ozempic have started using it as an excuse for a shittier diet. Now my sample size is barely ten people on Ozempic/Wegovy so take it with a grain of salt and what not, but I’m skeptical.

I bet there’s a large group of people - possibly over represented on HN and other online communities - that just need a little nudge to suppress their cravings and eat healthier, but that’s far from universal. For a lot of people, they wouldn’t even know where to start to eat healthier except choosing a salad over a burger at the takeout menu. Even with drugs masking cravings, many people just haven’t had good health or culinary education.

Odd Lots (Bloomberg finance podcast) had an episode back in June or something interviewing a food design consultant, and their focus groups came back very strongly in favor of healthier meal compositions. Agreed though, it's hard to know things :) Hopefully some real studies on this will be done soon.

Industry led focus group is not a legitimate source.

Depends on the focus group. Some are put together too establish that a product is wanted. Those are junk and useless. Others like this are designed to tease out trends and their accuracy is very valuable to the companies that commission them.

Uhhhh, in general this is true, but in this particular scenario they have a stronger incentive than almost anyone to understand true preference shifts created by these drugs.

It doesn't mean they end up with the correct findings, but they are absolutely incentivized to try to produce correct findings.

Lazy and inapplicable heuristics are not legitimate insights.

Did the consultant describe the change in focus group results or just the latest ones?

I was under the impression that consumers have been asking for healthier food compositions for decades, probably since the 70s or 80s when all the FUD around fat started. Maybe GLP1 agonists bring their buying choices more inline with the focus group results which would be an interesting phenomenon.

I forget the design of the experiment but I remember feeling that my prior assumptions (which were in line with GP) were potentially wrong, so it must've been moderately convincing. I work in clinical trials so I'm not a complete buffoon on experiment design, but accordingly I'm also aware a good experiment is obscenely difficult to conduct, and obviously this was nothing close to an actual RCT.

I take mirtazepene because it's the only antidepressant that works for me; unfortunately, it's also a massive orexigetic. And also unfortunately I have original Medicare that doesn't cover semaglutide until I develop additional heart problems or diabetes, so I'm forced to buy compounded semaglutide for 10% of the retail cost (but still higher than the rest of the world) out-of-pocket from a local large, retail, independent pharmacy that wouldn't risk bankruptcy selling fake medications.

And I don't eat meat for non-dietary reasons that include existential risks to all of humanity:

- Pandemics - Where did the "Spanish" flu (and influenza A, Asian flu, HK flu, and 2009 pandemics) and COVID come from?

- Antibiotic resistance - Most classes of antibiotics used in humans are also used to make industrially-farmed animals grow faster, leading to greater antibiotic resistance and more potential bacterial pandemics too

- Climate change - 17%, at least

- Air pollution - Not just the smell of pig crap in the air

- Water pollution - Ag runoff has been ruining river delta systems

- Soil pollution - (It's gross)

- Fewer available calories for total consumption

- More expensive foods by less supply and more demand

(Never bother with "meat is murder" dramatic preaching because most people who eat meat suffer from cognitive dissonance preventing them from admitting their lifestyle choice causes animal cruelty.)

When I was on and could afford semaglutide, I improved my diet by consuming a high protein product with a low calorie breakfast nutrition supplement. I'm sure I probably could've accomplished similar with a multivitamin and a protein product. What I need to change is eating more low calorie, high fiber fruits and vegetables that don't taste like cardboard or a mowed lawn. My diet has gone to shit again because the insatiable, all-consuming (no pun intended) hunger has returned. I can't afford semaglutide right now so I must become unhealtier than simply obesity in a similar but lesser way than women who can't get surgeries until they're septic and dying from failed ectopic pregnancies before it will be covered... because somehow obesity is completely my lack of willpower when I wasn't obese before mirtazapine.

no wonder you're depressed

This observation is very interesting. I hope that it is studied more closely and we can read some peer reviewed research on the matter. One idea popped into my head: Could part of the cause be that people's mood and self-esteem improves during (GLP1 agonist-induced low hunger) weight loss? TL;DR: If you feel like shit about yourself (and body), then you are more likely to eat poorly, and vice versa.

That's an excellent hypothesis. Wouldn't be surprised at all if that was a component!

>My understanding from initial anecdotes is this is actually literally wrong. Which was surprising to me, too. But people on GLPs tend to prefer more nutritious food (high protein and high fiber).

Not only that but prescribers and patients have noticed that GLP-1 agonists also appear to significantly reduce people's consumption of drugs like alcohol, nicotine and opioids. At least in some populations.

Much more research is needed but right now it's extremely promising that they will have a place in addiction treatment in the future.

Yep! So far it looks like GLPs might just be a generic "craving-reducer." Pretty wild stuff if it holds (and we continue not to see significant adverse effects).

>Losing weight without losing muscle mass is very hard.

I was with you up to here. In my experience it's easy to maintain a huge proportion of your lean tissue during a weight loss diet: Do some resistance training, get some protein, and don't lose weight too quickly.

There's no need to go to the extreme of a PSMF - which will still have you lose a bunch of muscle on account of being too big a deficit. If you can keep your calories reasonable while on a GLP1 agonist, there doesn't seem to be any reason you'll lose an exaggerated amount of muscle.

It's notoriously hard to lose fat without also losing muscle. That's why bodybuilders bulk well past their target muscle mass before they cut for competition. I agree that you can do a lot to mitigate it through protein intake and resistance training, but you'll almost certainly still lose muscle when you're in caloric deficit, regardless.

Furthermore, this effect is dependent on genetics. What is no problem for one guy in the comment thread could be very challenging for another.

Also, "just do proper resistance training" is a bit of a stretch when we're talking about what is practical to expect of the masses taking Ozempic.

I'm not sure why this is so heavily downvoted. You raise some good points. I would add: The era of comical bulking is coming to an end. More and more scientific literature points to modest calorie surplus is the key to muscle gain (along with regular weight training).

Bodybuilders I know seem to have a a very difficult time keeping their muscle gains while on a cut, I don’t know why someone who is not in a gym 5+ days a week and on an extremely optimized heavy protein diet measured down to the gram would expect otherwise.

Is it possible to go very slow and keep most of your lean muscle mass? Sure. Is it practical? I have my doubts.

Part of the effectiveness of these drugs - for me at least - is that results are rapid and that is a self-reinforcing feedback loop. Diets that had me losing 1lb/week were simply too boring and unmotivating for me to keep up beyond a few months. A few days of vacation “cheating” and you wipe out a month or more of incredibly difficult to achieve loss. Restricting yourself mentally in what you eat every day adds up to exhaustion over time.

Some folks can manage to lose very slowly while also adhering to a strict calorie deficit of a few hundred per day, while also being consistent with resistance training. I’d say the evidence shows that these folks are in the small minority.

I will say more evidence is needed for this drug class - especially where the harm reduction principle may be a bit iffy outside of obese folks. However it was life changing to me in the way it let me change my eating habits to very healthy protein and veggies as my primary calorie intake, as well as made going to the gym on a strict schedule motivating enough to actually come out at the end with a better bodyfat to lean muscle ratio than where I started.

These gains have continued since I hit my goal weight - and now I’m starting to become one of those folks who the BMI no longer applies to in a good way. I do wish there was a good way to test heart muscle mass like there is lean body mass with a DEXA scan as I’m curious if my increased regular workout heartrates translates into building back any heart muscle mass like it did other lean muscle. Certainly a concern to keep an eye out for!

I’m curious as you are if folks who are slow responders and live active lifestyles see the same muscle loss the hyper responders do. For reference I lost over 100lbs in just under 9mo. I absolutely lost considerable muscle mass, but have since put it back on and then some.

It isn't hard to imagine that the last 10% of mass a bodybuilder has added was hard won and easily lost. That isn't representative of most people.

I feel like a cut is a very specific type of weight loss where the person gets down to an unusually low body fat %. It’s to the point where each bit of fat loss is a significant portion of your body’s fat reserves. It seems different from when there is an abundance of easily accessible fat to burn.

Well, bulking and cutting cycles are pretty common for anyone beyond the beginniner stage when wanting to add muscle mass, even if they're more recreational or a powerlifter or whatever. It's just way more efficient to be in a large enough surplus to make hitting your macros easier and then diet after than it is to try and be super careful about it. The powerlifters aren't worried about getting down to that show ready <10%, they're just trying to not be fat, and they still lose some muscle.

So, yes and no.

If you're doing resistance training for the first time in your life or the first time in years, noob gains will outpace loss if you train hard and get adequate protein. This is the case for a lot of people on these GLP-1s, at least at the start.

But if you have a massive quantity to lose, as in a multi-year process, you won't be able to keep up the noob gains for the entirety, and then yeah, you're going to basically just be training hard and shoving protein down your face just to keep the muscle loss minimal.

Intuitively, if you can lift a modest bench press (not novice, maybe beginner-intermediate) and you keep training and you consume a few fewer calories (not starve) why would you lose your strength.

Because the body does not make it easy to keep the same muscle with less fat.

For most people, it just doesn't really matter, because their strength is so far below their peak capability it won't be hard to cut some weight while maintaining strength. The closer you get to the edge of capabilities, though, the more it will matter.

If you are outside of your noob gains period and keep up your protein intake and resistance training you will minimize your muscle loss, but you'll still see some.

Bodybuilders will even take AAS that explicitly reduce catabolism of muscle mass like Anavar and still lose some muscle on cuts.

For the average overweight person? I disagree. The average obese person does little to no resistance training, eats very little protein, and wants to lose weight fast so they're not paying for expensive GLP1 drugs for a long period of time.

You're asking folks to make three separate changes: start exercising, change their diet to add protein, and use GLP1s to reduce food amount. And reducing food amount already goes against adding protein, so whatever protein they were getting is going to get cut even further.

I'm someone that used to be fit and lifted regularly. Got busy, got lazy, got fat. Tried multiple times to get not-fat after getting fat, and found it to be too difficult for me, despite it not being something I struggled with for many years earlier on in adulthood.

Getting on tirzepatide made it trivially easy for me to get back to a better diet, start exercising, etc. I do have to force myself to have an extra protein shake to hit my macros, though.

Increasing exercise also goes against reducing food amount, because it makes you hungrier.

I mean when I needed to lose weight (15kg, 85kg -> 70kg) I started with calorie restriction, and as a result of that actually looked at what I was eating and realized I was incredibly low on protein, and then from that added some daily light exercise partly just to avoid getting bored and wanting food.

So this isn't really 3 separate unrelated changes. Also at least in my experience, people tend to regard high protein things as the "energy dense" part of a meal - the problem with a lot of carbohydrates is they're not very filling.

The biggest problem with exercise is it's an awful way to lose weight - you don't burn that many calories, it makes you hungrier, and then your body optimizes to burn even less calories as you do it.

> In my experience it's easy

> Do some resistance training, get some protein

jeez, if people actually did that they wouldn't need the drug to begin with

I must disagree with your comment. Personally, I have witnessed so many people struggle for years with their weight. Being overweight and struggling to lose weight must be a 50 factor model: Multiple social, economic, and mental/physical health factors. These GLP1 drugs really are a game changer.

> If you continue to eat a protein and nutrient deficient diet (which is probably a majority of Americans)

Is it true the majority of Americans eat a protein deficient diet? I always thought there was too much protein in the western diet - nearly at every meals versus how we would have evolved with somewhat limited access.

So, lots of foraging for food that grows on plants and the occasional bison?

Would that we could convert the world to diets like that.

A lot of what Americans consume is really crappy carbs and sugar, unfortunately. Even fatty meats would be better than that.

I'm pretty skeptical of the "this rate of muscle decline is significantly higher than what is typically observed with calorie-reduced diets" claim. I suspect we're comparing apples to oranges rather than doing like-for-like comparisons at equivalent calories.

    > Losing weight without losing muscle mass is very hard.

Even pros on high doses of testosterone and multiple AAS lose some muscle mass when preparing for a show.

This is true. I just lost 30 pounds over 3 months and 17% was muscle. I thought I was eating a lot of protein, but I’ve upped it today.

I did an InBody scan the day I started (8/21) and just happened to have done my second one this morning.

I don’t think we can expect to retain 100% of muscle mass, and losing just 1/5th sounds like a good outcome.

I’ve understood that generalizing anything in today’s time is a losing game. I know many people with IBS/GI issues and I am also sure they have different underlying causes. Our gut biome and how digestion works in general needs to be researched much more.

I don’t know why progress has generally been so slowly on that front. For instance, GLP-1 was discovered in the 1970s. It took us another 40 years to commercialize it in the form of Semaglutide and another 10 years to get it ready for human consumption.

I'd like to see the diets in the study that are specified as the "calorie-reduced diets". (Can't seem to find the paper). If it's the same as the Standard American Diet, this muscle loss is quite explainable. I think the mitigation is relatively easy though, if you want to shift the p-ratio, recommending a daily high protein shake would do a lot to stave off muscle loss (and even more if resistance training is applied of course). The exercise addition is probably the hardest to adhere to.

I'd be surprised if either mice or human cells eat "the Standard American Diet"

Losing glycogen stored in muscle is not a huge issue IMO, as it should come back fast. Stuff that's easy to gain is usually easy to lose and vice versa.

Uh, GP is talking about losing muscle itself, not the glycogen in muscle.

Well, these studies look at FFM, which does include your water weight and glycogen stores, so they do make up a portion of it.

Nutrient deficient, sure, protein deficient? Probably not.

The claim that "a majority of Americans" eat a protein deficient diet is absurd on its face.

> Losing weight without losing muscle mass is very hard.

Yes it is.

> It requires extreme diets like a protein sparring modified fast where 80%+ of your calories are from lean protein while running a 50% caloric deficit.

I’m not any sort of expert but that sounds frankly, dangerous. I don’t see how you do something like that without damaging your liver.

It’s very possible to lose weight and gain muscle, but you have to be at just the right body composition (not lean and not obese) and then there’s a question of “over what period of time”?

Any duration under a month is probably pointless to measure unless you have some special equipment. Any duration over a month and it’s kind of obvious that it is possible. Eat a balanced diet without junk, work out regularly, and keep the calories to only what is necessary.

> I’m not any sort of expert but that sounds frankly, dangerous. I don’t see how you do something like that without damaging your liver.

I haven’t seen any credible research that a healthy person can damage their liver from excessive protein intake. Someone suffering from liver disease needs to be careful, sure, but evidence that it would harm a healthy liver is practically nonexistent.

That said, PSMF is explicitly not a sustainable diet and proponents generally don’t claim it to be. It’s a short term diet meant to preserve muscle mass under extreme caloric restriction (under 1.2k calories).

> Eat a balanced diet without junk, work out regularly, and keep the calories to only what is necessary.

If it were as simple as that, we wouldn’t be having this conversation.

> If it were as simple as that, we wouldn’t be having this conversation.

It pretty much is that simple. The problem is that simple is not easy.

    > nutrient deficient diet (which is probably a majority of Americans)

First hit is some blogspam trying to sell me "Nutrient Therapy". Second hit is CDC: https://www.cdc.gov/nutrition-report/media/2nd-nutrition-rep...

    > The Second Nutrition Report found less than 10% of the U.S. population had nutrition deficiencies for selected indicators.

Part of the problem is that the standards are incorrect. If you go by dietary standards, you are eating way too many carbohydrates and likely eating too many times a day, especially if you do not have an active job.

Most people should mainly be eating fat and protein with a decent amount of grains and fruit and vegetables. However, the standard advice is to eat a lot of grains, some fruit and vegetables, a modest amount of protein, and little fat. This is awful and leads to very high hunger. Especially if you eat multiple meals a day, as is also commonly recommended, this is a recipe for being ever hungrier day by day.

It wasn't until I eschewed all advice, started eating one big meal a day and maybe one snack and matching my carb intake with my fat intake that the hunger that I had known since childhood magically disappeared and I lost 25 lbs (and am losing more). Finally a 'normal' weight seems not only in sight, but extremely easy!

Yeah, my four donuts per day fill me up just fine or an extra large milkshake and a burger and I’m done for the day with food is definitely happening for some people. Let’s wait and see these drugs might prove to be very beneficial and more testing definitely needed.

Part of the problem is that doctors recommendunhealthy diets and will dismiss healthy diets.

Americans eat a shit ton of protein. No idea where you got idea that from.

See the actual research article:

https://www.sciencedirect.com/science/article/pii/S2452302X2...

This study on mice was suggested by a previous publication:

https://www.thelancet.com/journals/landia/article/PIIS2213-8...

where it had been noticed that in humans "the muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks", in comparison with muscle loss of only 10% to 30% when the weight is lost just by eating less, without semaglutide.

So with semaglutide, a larger fraction of the weight loss affects muscles than when the same weight is lost by traditional means.

While for other muscles the loss of mass may not be so important, the fact that at least in mice the loss also affects the heart is worrisome and it certainly warrants further studies.

> Studies suggest muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks. This substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested. By comparison, non-pharmacological caloric restriction studies with smaller magnitudes of weight loss result in 10–30% FFM losses

Emphasis my own. In short: no evidence this is anything other than due to rapid weight-loss.

The article does dissect the difference between weight loss drugs and dieting in general. Where they found that muscle mass loss was higher in those that took the drug as opposed to those who followed a calorie restricted diet.

To your point, the drug is absolutely to do with it if by taking the drug people need to be more mindful of the types of food they eat, if they have a smaller window to consume nutrients.

It is most certainly a contributor and for some who may not exercise like you, or consume an appropriate level of protein this research may show that those taking the drug need to focus on a more protein right diet.

I don't have it at hand [edit: [0]] but there are a number of studies showing exercice had more health impact than weight loss (you can combine both of course, but just losing weight has less benefits)

As you point out, losing muscle is common in a diet, and the researchers are well aware of it. Their point was that this aspect is not pushed enough and is drowned by the losing weight part.

From the paper:

> Dismissing the importance of muscle loss can create a disconnect between patients' increased awareness of muscle and the role it plays in health, and clinicians who downplay these concerns, affecting adherence to and the development of optimised treatment plans.

[0] https://journals.lww.com/acsm-csmr/Fulltext/2019/08000/Effec...

For the "Fitness Versus Fatness" part for instance

Interestingly, when I was part of a weight loss diet study at my local university I actually gained muscle whilst losing weight.

I had multiple full body dexascans during the programme.

I didn’t change my exercise routine at all. I wasn’t hitting the gym or doing weights, just my usual basic cardio.

And I gained muscle and lost ~10kilos in weight.

It wasn’t much muscle, but the amount of muscle was higher than before.

The latest research I’ve pulled suggests that DEXA scans are fairly inaccurate and aren’t a reliable way to measure body composition even for the same person across time.

MRI is the gold standard, everything else is pretty loosely goosey.

Sorry, no references but this comes up pretty often in the science based lifting communities on Reddit and YouTube if you want to learn more.

https://macrofactorapp.com/body-composition/

Estimates in level of inaccuracy on the high end ranges from ~5% to ~10%

If you see your lean mass going up in DEXA, your muscles are getting larger, and you're getting stronger, particularly across a wide variety of exercises where CNS adaptation can't explain the strength gains, they're likely broadly accurate.

Mine have all tracked quite closely with what I'm seeing in the mirror and what is happening when it comes to the amount of weight I'm moving.

Biology is super complicated with lots of surprising dependencies between different biological pathways. So it is possible. That said, I am skeptical as well. For example, if the body sheds 15% of its weight, does the heart naturally shrink by 15% as well? With so many people taking these drugs, there is enough data to begin to profile the rare risks of these drugs in humans (the clinical trials would have found any of the obvious risks)

Just curious, does your appetite come back whence you cut off the meds?

The only reason I want to lose weight is to eat more freely, won't be useful if I lose my appetite too.

You don't lose taste, you lose your appetite, which means you can resist the temptation to eat easily, and you feel full very quickly. That doesn't prevent you from eating what you like, but it does help you to not eat too much of it, which I hope is not what you mean by "more freely".

The appetite comes back when you cut the meds, but it's an appetite based on your new weight. But if you then go on a some suggar rampage, you will regain weight and your appetite will grow too.

Those drugs are merely a guard rail to complete a diet successfully, but if people do not change their eating habbits, the same causes will produce the same effects after they cut the meds.

What I’ve found is foods I could usually binge on like pizza I’m quite full on GLP-1 inhibitors and can quite happily stop at half or 2/3 of a pizza. Usually I’d have eaten the whole thing (12” think napoleon style pizza Americans) and want more, refined carbs I never feel full from.

Thanks, that's good enough. I have been going to weight loss for over 6 months but I'm stuck between 79 and 80kg. It's a bit difficult to add more weight lifting because I tended to hurt myself, so eat less is better.

    > It's a bit difficult to add more weight lifting because I tended to hurt myself

Add walking for 2h per day is the recommended I’ve seen.

Thanks, 2h is a bit too much for me, so what I do is about 3-4 10-12 mins walk-sprint walk reps. Basically half walk (3.5m/h) and half sprint-walk (4.4m/h). I wish I could do more but my joints are not really good.

Just walking is better. You get a steady burn. If you do high intensity you burn calories for a good while afterwards. Mild intensity doesnt do much.

I saw someone mention that they craved heroin less on ozympic.

Experiences vary but I worried I’d, like, not enjoy food on it.

Nope, not a problem. I just get full much faster and am even more prone to simply not eating when I’m busy, than I already was. Not as food-focused when idle, but I still snack a little or whatever.

Appetite comes back yes

It does.

god... 133kg down to 88kg, that's like a dream to me. Years of trying to get under 100 by 'traditional' calorie restriction diet & exercise.

One of my friends has tried many fad diets, etc. and he finally just went and paid cash for a GLP-1 and he's lost a lot of weight and is feeling much better. If I were in that situation, I would just do the same.

bringing it down is not even half the battle, it's what happens next is the more interesting part

You keep taking the GLP1 agonist, otherwise you gain the weight you lost.

These drugs are like psychedelics. There are lots of non users talking about them like they know them but all they did is read stuff in popular media.

My friend cut usage after he lost weight and finds maintenance easy.

some fun study sort of concluded that the ratio carbs vs fat and protine is the entire mechanic. fat people who eat almost nothing eat only carbs thin people who can eat huge amounts every day eat a lot of fat and protein. Both eat other things just not as much.

I really eat a lot. When my gf cooked more and the potato meat ratio changed from 1:3 to 3:1 I immediately started to grow fat. I had her adjust it to 1:1 and started eating lots of sausages and chicken legs between meals. 500g to a kg per day worth of extra food. My body fat declined rapidly.

So it smells like bullshit because of your personal anecdote? Or because some scientific evidence or experience you have?

Yeah, folks don't like thinking that obese people have a lot of muscle needed to move around. And losing weight is losing all weight.

Seems like some of the comments need to learn that a big hypertrophic heart is much worse for you than a normal sized heart. Folks: GLP-1s have demonstrated benefit from heart failure, and this heart muscle change is probably mechanistic in that.

If you’re 20% smaller, it would make sense that your heart could pump 20% less.

Uh, I think most highly in/shape people have normal sized, very healthy hearts and their bpm is like 45.

Their hearts are not physically smaller, nor did they shrink during their build-up to current physique.

Saying things like this is harmful at best. Please don’t.

It seems the article isn't just saying it's heart muscle that's being lost but regular muscle in general. Even more so than in a low calorie diet.

From the commentary,

>Studies suggest muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks. This substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested. By comparison, non-pharmacological caloric restriction studies with smaller magnitudes of weight loss result in 10–30% FFM losses.

Comparing weight loss of different magnitudes is kind of comparing apples to oranges. Of course, it's not really possible to get persistent, large magnitude weight loss any other way than by using these drugs, so I understand why the comparison was made.

There's a linked article saying that 40% of the weight loss is muscle.

Outside of cardiac muscle, which is a bit worrisome, 40% of weight loss being from muscles is incredibly typical for any diet that sheds pounds.

There are very complex dietary regimes that can be followed to minimize this, but most studies have shown that they don't save any time compared to losing weight and then working to get the muscle back afterwards.

> Dyck’s study comes on the heels of a commentary published in the November issue of The Lancet by an international team of researchers from the U of A, McMaster and Louisiana State University who examined emerging research showing that up to 40 per cent of the weight lost by people using weight-loss drugs is actually muscle.

This is, again 100% typical of what happens with caloric restriction.

Literally the next line after the 40% quote:

> Carla Prado, a nutrition researcher in the Faculty of Agricultural, Life & Environmental Sciences and lead author on the commentary, explains this rate of muscle decline is significantly higher than what is typically observed with calorie-reduced diets or normal aging and could lead to a host of long-term health issues — including decreased immunity, increased risk of infections and poor wound healing.

Do you have a source that 40% muscle loss is typical for a caloric restriction diet without GLP1 agonists?

> Do you have a source that 40% muscle loss is typical for a caloric restriction diet without GLP1 agonists?

OK I actually checked up on this, and it is more like 30%, but that number gets worse as you get older. For young healthy men it can be 20%, but as you get older that number gets worse and worse.

I'd want to see a comparison of a similar cohort of people going on a calorie restricted diet of the same magnitude, with a similar (lack of) activity levels.

The study at https://www.thelancet.com/journals/landia/article/PIIS2213-8... compares people who had less overall weight loss on a pure calorie restricting diet, which, well, by definition isn't the same thing.

> There are very complex dietary regimes that can be followed to minimize this

The dietary regime isn't complex -- just consume a LOT of protein. Something like 1-2 g/kg/d. And non-dietary: do strength training.

This works until it doesn't.

Professional body builders do bulk/cut/bulk/cut because after awhile you can't lose weight and put on muscle at the same time, especially if you want to get to the point of being shredded.

(well you can do it, but there is no benefit over bulking and cutting)

Yep, I can anecdotally confirm as I’m on such a routine right now.

I started losing weight from severe obesity with a caloric deficit but noticed I was also feeling weaker in general (aside from the tiredness that comes with eating under your TDEE).

I started going to a trainer and he had me change my macros so that I was consuming about 200g of protein per day in addition to 4 days per week of full body workouts on top of my cardio.

Since then I’ve lost an additional 150% of my initial weight loss, and have gained moderate muscle mass on top of that.

“Dyck, who is the Canada Research Chair in Molecular Medicine and heads up the Cardiovascular Research Centre, says his team did not observe any detrimental functional effects in hearts of mice with smaller hearts and thus would not expect any overt health effects in humans.”

This makes sense. If fasting hurt your heart many of your ancestors would have died early. There is strong selection pressure to survive extended fasts.

Sounds like a perfect counter to using steroids in bodybuilding which can cause an enlarged heart. I wonder if we will start seeing GLP-1 in bulk cut cycles more moving forward.

>My understand of those drugs is that they don't actually make you lose weight, they just cut your appetite so you can follow a diet to lose weight without hunger hammering at the door.

While acknowledging that the mechanism is different, this was the same effect of Ephedrine, which went through a similar craze as Ozempic before the full complications were known. My bet is that this will be similar, where the risks end up being outweighed by the benefit for extreme obesity and diabetics, but that the cosmetic weight loss aspect of it will become outlawed or highly regulated.

Don’t care. I’m down 30lbs.

There is no way magic weight loss pill with no side effects could possibly go wrong!!!

The marketing is astounding.

"Weight-loss drug."

Oh, would that be Semaglutide?

<click>

Hey, would you look at that!

I thought this was known about older GLP-1 antagonists like semaglutide, which is why there's some excitement around the newer dual-action types like tirzepatide? My understanding is the newer drugs cause substantially less muscle mass loss.

As a coder, I'm realising more and more that the human body isn't so different from a computer. When you try to fix something without having complete understanding of all the relevant parts of the system, you will invariably introduce new issues. With a machine as complex as the human body, it seems inevitable that the field of medicine would be a game of whac-a-mole. Finding solutions which don't create new problems is hard and should not be taken for granted.

Add on that there is no complete understanding of this system with all the Unknown Unknowns etc and you can see why we should test this stuff better before letting hims.com just disperse it across the american populace

Perhaps--though worth keeping in mind that the overwhelming alternative is just lifelong obesity, along with all the negative impacts from that.

At least at a societal level, some increased rates of pancreatitis and a little suboptimal muscle loss are peanuts compared to what high obesity rates do to people at scale.

Yes 100%. That's why I never understood the rollout of MRNA vaccines during COVID. It's like pushing a massive code change straight to production during peak traffic and without the normal phased rollout. I totally understand where conspiracy theorists are coming from. That didn't seem right.

yeah, it's too bad the tech didn't have a better way to gain peoples trust (through some other breakthrough with the normal set of clinical trials). I think the solve was impressive (tell cells to produce a protein that looks exactly the same as the viruses and place it outside the cell to piss off antibodies) but protein-protein interaction data is hard to come by. Maybe these guys can figure it out https://www.aalphabio.com

Yea, except without error checking, and fully analog technology.

Although, "single cosmic ray upset events," are just as devastating.

There's tons and tons of error checking- we have at least 5 different error correction and repair systems in DNA, cell cycle checkpoints, and extreme redundancy and feedback homeostasis at nearly every level. Every individual cell has it's own 4 copies of almost every critical gene- two of each chromosome made up of two strands of DNA each. Human bodies can function 70+ years, sometimes with no medical care- something no computer or man made complex machine comes close to.

Beyond specific diseases we understand, it's still mostly a total mystery why we aren't immortal- we have not yet identified what is the basic mechanism of aging, or why it happens at different rates in different species, and mostly our systems are fundamentally capable of repairing and regenerating almost anything, but for some reason get worse and worse at doing so over time. Moreover, this doesn't seem to happen in all organisms- there are many animals that live ~4x human lifespans, and at least one species of jellyfish that is biologically immortal.

Redundancy is not error checking. The "error correction" mechanisms are actually just "proofreading" mechanisms and are almost entirely local and centered around transcription. Common mode errors are harder to induce due to the plain redundancy of DNA pairs but also not impossible, and once induced, are impossible to locally notice or correct. In some cases the "error correction" machinery is the cause of these induced errors. The result is genetic disease and/or cancer and is a case of missing error _checking_. Perhaps my definition was exceptionally parsimonious.

> with no medical care [...] something no computer or man made complex machine comes close to.

That's because we get far more units of "work" out of our machines than the person living for 70 years with "no medical care." Some people live just 30 years with no medical care too. And the machine does not need to sleep. We eat food they eat lubrication oil. I don't think this was a good analogy.

> it's still mostly a total mystery why we aren't immortal

While we haven't pinpointed the mechanism, we have a pretty good idea of why, and where in the system we should be looking for the answers.

> but for some reason get worse and worse at doing so over time.

You are a living Ship of Theseus and these "error correction" mechanisms are not perfect. Aside from this there are known genetic disorders which alter the rate at which people age. This is not nearly as mysterious as you're making it out to be.

> there are many animals that live ~4x human lifespans

And what are their resting respiration rates?

> and at least one species of jellyfish that is biologically immortal.

In theory. We haven't found an immortal one yet. They all die. They're also nowhere near our level of biological complexity or capability.

A computer is much more likely than your body to have small, self contained parts that just function. Your body is the result of millions of years of accidental evolution - See the canonical example of the laryngeal nerve in a giraffe. Computer programs are often designed to be small and modular. They might have to worry about memory layout shifting because some other program grew - That's nothing like your spleen trying to occupy the same physical space as your stomach and causing digestion issues.

For all of medical science's experience and history with debugging the human body, there's still so much more to understand.

It concerns me how discussions, such as this one go on HN. This is an important topic. With the epidemic of obesity we now find a drug that appeals to a large number of people. This is an important topic as well.

What is the current comment receiving most of the comment?

"That's the sort of headlines that smells like bullshit to me"

That's the sort of comment that smells like bullshit to me. What kind of place is this?

Many times I find the posts on HN interesting, but increasingly these kind of comments make me wonder about Y Combinator. Is this really the best they can do?

And for us readers who are supposed to be so called hackers, is this the best we can do?

It is my own perception that HN has gotten worse in the six months but these sort of "meta" discussions can be as much part of the problem as part of the solution or possibly a bad smell.

My take it this.

The median scientific paper is wrong. I wrote a wrong paper. The average biomedical paper doesn't fit the standards of the Cochrane Library mostly because N=5 when you need more like N=500 to have a significant result. Since inflationary cosmology fundamental physics has been obsessed with ideas that might not even be wrong.

It's well known that if you lose a lot of weight through diet (and even exercise) you are likely to lose muscle mass. With heavy resistance exercise you might at best reduce your muscle loss if you don't use anabolic steroids and similar drugs. That you could have changes in heart muscle with using these weight loss drugs isn't surprising for me at all and it's the sort of thing that people should be doing research both in the lab and based on the patient experience.

(Funny you can get in trouble if you do too much exercise, spend 20 years training for Marathons and you might get A-Fib because you grew too much heart muscle instead of too little.)

A lot of the cultural problem now is that people are expecting science to play a role similar to religion. When it came to the pandemic I'd say scientists were doing they best they could to understand the situation but they frequently came to conclusions that later got revised because... That's how science works. People would like some emotionally satisfying answer (to them) that makes their enemies shut up. But science doesn't work that way.

The one thing I am sure of is that you'll read something else in 10 years. That is how science works.

The HN you are yearning for disappeared about 8-10 years ago when it was largely taken over by normies and people way outside the hard-core-tech fold. It's not very different from Reddit front-page now if the topic is even remotely political.

For purely technical topics you expect good quality discussion, but those threads barely get comments in the two digits.

If you think HN users are normies, I think you might be in a bubble. Normies ain’t this literate.

I’m sure complaining about HN is as old as HN.

Specifically comparing HN to reddit is old as well. It's mentioned in the guidelines to not say HN is turning into reddit. The examples of this shared in the guidelines go back to 2007

Yes sometimes the loudest voice definitely rises to the top and it’s annoying, but I also think it’s a condition that too many new members don’t know how to use the upvote button.

I also think it’s a symptom that HN does not allow enough people to use the down vote button. you could be a commenting member for years and not be able to downvote or you could be somebody who posts a few click bate links you copied from another aggregator and all of a sudden you have the ability to downvote. It’s pretty dumb.

From my observation it is hard to get to 501 karma points by the karma gained from submissions than through comments. So for comments every 1 upvote equals 1 karma. But for submissions, god only know what is the conversion rate /s. I think there are many factor. But I think this mechanism is to limit people creating accounts and mass down voting anything they don't like. So it is trying to solve another problem. However upvote power should be limited for new accounts (I don't know if this already the case)

I might be biased in my perspective because I tend to focus on links that make it to the front page. It's true that many links end up languishing in obscurity.

I just think the level of effort involved is different. For instance, the person who posted the link to the study we're now discussing earned 199 points with far less effort than you put into replying to my comment. Many of the links posted are copied from Reddit, Twitter, Slashdot, etc.

I am sure what he actually got is much less than that number. If you got 200 up votes to a comment then that's 200 karma, but with submissions it is different, maybe dang can shed some light on that. Also what gets traction depends on a lot of things that you will find that most people will have the vast majority of their submissions have little to zero activity. So it is not that easy, some will manage to do it but the purpose is to limit that to something manageable. Then I think dang is managing both up voting ans down voting rings. With up voting being harder (everyone can do that)

Yeah, normies suck. I totally only want to hear from people obsessed with the latest computer Science minutia!

I agree with your desire for what HN should be, and disagree with your assessment that the top voted comment doesn’t support it.

HN is the only forum I know of that has broadly grasped that most so-called “science” outside of the hard sciences and mathematics is complete garbage and driven by funding needs. The world is awash in non-knowledge. This is an extremely serious issue.

Building the skill to rapidly come to a preliminarily judgement of a headline is crucial.

There is plenty of garbage in hard science too. Start with

https://arxiv.org/archive/hep-th

The most reliable source of knowledge we have are in the science. This is further reinforced by technological development that validated the sciences, although at time the technology may precede the science.

> disagree with your assessment that the top voted comment doesn’t support it.

Did you read the paper or skim its abstract, figures, and conclusion? I'm not so sure that commenter did, or they may have cited this,

> Because we report smaller cardiomyocytes in cultured cells and in mice treated with semaglutide, it is tempting to speculate that semaglutide may induce cardiac atrophy. However, we do not observe any changes in recognized markers of atrophy such as Murf1 and Atrogin-1. Thus, we cannot be certain that semaglutide induces atrophy per se or if it does, it may occur via molecular pathways that have not been identified herein.

> Building the skill to rapidly come to a preliminarily judgement of a headline is crucial.

You can't judge this paper based on the popsci headline.

> most so-called “science” outside of the hard sciences and mathematics is complete garbage and driven by funding needs

Based on my reading of the figures and conclusion, I don't think you should call this paper garbage.

I agree 100%. Those kinds of comments have no place, and add little to nothing to the discussion. Many HN discussions outside of pure tech invite all kinds of crazy and uninformed comments -- health/diet, finance/economy, etc.

The developers of these new peptide-based hormone-acting drugs like semaglutide(ozempic) could be called biohackers, but the system they're hacking on - the human endocrine system - is a delicate system. Introducing semi-synthetic mimics of native hormones can go wrong in all kinds of ways, and hormone-analogue drugs have a poor track record (anabolic steroids, DES, etc.) so extra caution makes sense.

Semaglutide is based on a 31-amino acid polypeptide that mimics the human GLP-1 hormone. At position 26, the lysine side chain is conjugated with a fatty diacid chain, to slow degradation and prolongs half-life, and there are some other modifications. However, the target - the GLP receptor - is not just expressed in the intestinal tract but all through the body, in muscle, central nervous system, immune system, kidneys and others. So some unexpected effects beyond the desired ones are likely.

Semaglutide was recently shown to have potent effects on the heart, and possibly beneficial to certain heart disease conditions associated with obesity. Makes me suspect this drug should be restricted to clinically obese cases where strong intervention with close medical supervision is needed. However for healthy people who just want to lose a relatively small amount of weight it really doesn't seem wise.

"Semaglutide ameliorates cardiac remodeling in male mice by optimizing energy substrate utilization..." (June 2024)

https://www.nature.com/articles/s41467-024-48970-2

For that reason HN should just remove the down/up votes, because it will turn this place to an echo chamber like reddit, these brownie points are useless.

Disagree. The “hacker ethos”, to me, is laypeople taking a crack at things without pretension.

Your comment lacks any substantive argument about the comment you complain about.

Apparently the topic is “important”. To me an appeal to importance when policing style spells like bullshit.

After I saw yesterday’s thread about politics in science was flooded with new sockpuppet accounts named after slurs spreading filth and downing everything they don’t agree with I no longer expect anything meaningful from comments here.

HN only works when you have a working assumption that people commenting here are smarter than you. It encourages respect and good faith engagement of content, instead of ad hom, concern trolling, and cargo culting.

It's been years since I've had that mindset when entering any thread above a certain number of comments.

What exactly do you think this forum is if you think this forum is above such sentiments?

I have noticed this too. The site guidelines say 'no low effort comments', but low effort comments that fit the general zeitgeist are often allowed, while well-thought-out ones that disagree are downvoted. If anyone has a suggestion for an alternative forum focused on technology and science, I really would love suggestions.

To be fair, that comment was about the claim:

> emerging research showing that up to 40 per cent of the weight lost by people using weight-loss drugs is actually muscle

Which is… obviously bullshit.

You lose muscle when you lose weight, especially if weight loss is rapid. This is why it's important to be physically active when you're losing weight. It doesn't matter if you're on drug or not.

they might have confused muscle and lean mass/FFM

The source article links to a reference for the 40 percent claim, which itself links to a couple articles that aren't available without a JAMA account.

I can't read the original sources there, but what makes you say its obviously bullshit?

From the abstract:

"Studies suggest muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks. This substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested. By comparison, non-pharmacological caloric restriction studies with smaller magnitudes of weight loss result in 10–30% FFM losses."

The "surprising" part is kinda bullshit, and implies there's something special about glp-1s. It is the opposite of surprising that weight loss includes a lean mass loss.

That said, being skinnyfat is probably bad for you and the idea that you should work to preserve/build muscle and not only lose weight is a good one.

FFM isn’t entirely muscle, but what other weight would be shed when losing FFM other than muscle?

> FFM isn’t entirely muscle, but what other weight would be shed when losing FFM other than muscle?

I'm not an expert, but I have to imagine that most of it is muscle.

After dramatic weight loss, a person will probably lose some bone - particularly in the lower body - due to decreased loading.

I know body builders sometimes eat extremely high protein diets (more than 1 g/lbs of body weight) and lift quite hard to try to hang on to as much muscle mass as possible. And they still lose some when cutting.

Water weight is a big one, and is part of your FFM. I lost 10lb of water weight in my first 24 hours on tirzepatide.

Some of it is likely bone density as well. You can prevent the bone density and muscle loss with proper diet and exercise, though.

[dead]

The cure for obesity isn't a pill.

Remember in the 80's and 90's when exercising and being healthy was considered a cool thing? Remember there was a gym on every corner and people were all about looking good and being healthy, eating healthy and living longer?

Then somewhere. . .

- We started normalizing obesity.

- We started this whole "body positivity" trend that celebrating morbidly obese people like Lizzo as positive role models was a good thing?

- We started introducing fat mannequin models in retail stores because being obese shouldn't have a stigma?

Obesity is a problem because we, as a culture have completely normalized obesity. Instead of promoting healthy diets and exercises and saying being obese has consequences like shortening your life and will make you susceptible to various diseases like diabetes and heart disease? All we've done is told people its ok to be obese and eat sugary drinks and over processed foods, because you can just have surgery and that will fix it. Or you can take a pill and that will fix it.

IT WON'T.

IT NEVER WILL.

We've gone down a road that is staggeringly dangerous because we've accepted being morbidly obese as something that's completely normal.

This is nonsense. The majority of the population don't want to be fat, ugly, and unhealthy and want to persists in maintaining good healthy habits in which they don't eat junk food.

People who promotes fat positivity are ridiculed.

Blaming it on culture overly simplify the issue, which is going to be a complex mix of interacting causes.

No, some chemical or chemicals got added to the environment around 1980.

All I can say is try losing 20 pounds and keeping it off for two years and how easy it is. Fat shaming might make a difference but I suspect it would be like knocking off 5 lbs from the average where you really need to knock off 50 lbs.

You only started seeing Victoria's Secret getting fat models in the last few years, the obesity epidemic on the other hand started in the Regan years. Maybe it's like taking your belt off when you get heartburn (though I know if I go that route pretty soon I'm going to need suspenders) Try

https://arxiv.org/abs/q-bio/0312011

for a theory that may be wrong but fits the chronology.

I like how they aren't saying Semaglutide in the title in an attempt to perhaps keep it from immediate scrutiny.

The first link goes to the study and it does mention the ingredient: https://www.sciencedirect.com/science/article/pii/S2452302X2...

I am talking about UAlberta's title specifically.

"Semaglutide Reduces Cardiomyocyte Size and Cardiac Mass in Lean and Obese Mice" was also written by UoA researchers. I don't see anything nefarious in the choice of the title for the news blurb.

More likely because the average reader won't know what that is versus the current title which succinctly summarizes it.

https://www.fda.gov/drugs/postmarket-drug-safety-information... Same thing??

No. That’s talking about the compounded versions (NOT in an auto pen) that were temporarily allowed due to shortages, but whose authorization has since been revoked.

> Unapproved GLP-1 Drugs Used for Weight Loss Yeah that would be perfect. But editorializing it to the point of calling it `weight loss drug`, just feels like it is begging for the reaction of "oh yet another weight loss drug".