Semaglutide and Muscle
post by 5hout · 2023-07-28T18:36:22.036Z · LW · GW · 14 commentsContents
14 comments
tl;dr Semaglutide seems to have muscle loss effects that may entirely wash out the benefits of Beetus (Type 2) prevention and leave you at a lower bodyweight (but possibly worse off for longevity) than you were before.
There are very few things the rationalist community likes more than a new science answer to one of life's problems. If this new answer is a drug, “research chemical” or supplement so much that better. People have been super excited about Semaglutide (Wegovy/Ozempic) since it was approved for weight loss in 2021. One problem that has been discussed, but seems to be pushed under the rug (in a rush to let a drug rewire your brain to make you skinnier) is that it has a negative effect on lean body mass. Lean body mass (LBM) is (basically) all the non-fat in your body. Your bones, your muscles, connective tissue and what not.
A key problem to loss of LBM is that you're either losing bone density (a terrible thing) or muscle (a pretty damn bad thing). In the context of middle aged weight loss losing substantial muscle mass is incredibly worrying. Muscle mass is crucial to preventing metabolic disease, it is vital to letting your body regulate itself correctly. If you struggled to maintain weight, control blood sugar and avoid the beetus and were per-diabetic before Semaglutide, trying to go off and do this after losing a bunch of muscle mass is going to be difficult (at best).
Stealing #s from pdf page 130 (https://www.ema.europa.eu/en/documents/assessment-report/wegovy-epar-public-assessment-report_en.pdf). Two groups. 68 week intervention. Half lifestyle + placebo, half lifestyle + Semaglutide. Sub-groups of the total group (140 people in the US).
The good: 8.4 kg of fat loss for drug vs 1.4 kg for placebo. The bad: .4 kg visceral (i.e. super bad core fat) lost for drug vs .1 kg for placebo (68 weeks on a mindaltering/lifealtering drug with substantial side effects for many people to lose 1 pound of core fat?). The ugly: 5.3 kg of LBM lost for drug vs 1.8 kg for placebo.
Side note: DEXA scans are... not super reliable for small numbers. They struggle with stuff like “your weigh-in scan was you after eating a bunch of sugar and a cheeseburger and your weigh-out scan was after you fasted for 2 days b/c you remembered you were going in for a DEXA scan” (for example, if you (in a panic b/c of an upcoming scan) glycogen deplete your muscles and go in a bit dehydrated (or you were dieting and so were naturally like this) you may very well lose 1-2 kg LBM on a DEXA scan). The linked article does not discuss the DEXA scan procedures, which rarely control for stuff like this (partially b/c of compliance issues).
So assuming both groups were “actively dieting” for their 2nd scan, and not actively dieting (and likely instructed to not diet) before the first scan you can essentially discount the first 1 kg of LBM decrease.
So adjusted #s:
Drug: 8.4 kg fat loss, .4kg visceral fat loss, 4.3 kg LBM loss. Placebo: 1.4 kg fat loss, .1 kg visceral fat loss, .8 kg LBM loss.
So the drug group took Semaglutide for 68 weeks to cut 8.4 kg of fat and lose 4.3 kg of LBM. The placebo group lost 1.4 kg of fat and .8 kg of LBM. Meaning Semaglutide is, over 68 weeks of treatment, helped people lose 7 kgs of fat at the cost of 2.9 kg of muscle (over placebo).
Side note: If you cut a substantial amount of body weight you're probably losing some LBM, but the amount of actual physical muscle lost can be greatly reduced via appropriate resistance training. The linked study asserts standard clinical lifestyle intervention for both groups, and then measures this in part by minutes of activity making it very likely they gave people completely shit advice to do a bunch of cardio/LISS stuff which is known to increase LBM losses (but both groups got same advice).
The dose-response on how much muscle mass prevents how much beetus is unsettled, but I've often seen ~1:1 as the purported rate. 10% muscle mass increase decrease chances of beetus (Type 2) 10%. PDF page 127 shows a 14.75% drop in bodyweight. PDF page 62 discloses mean bodyweight of 103 kg. So back of the envelop math suggests people went from 103 kg to 88 kg, losing 8% of LBM they would have had at 88 kg with better planning and without Semaglutide, increasing (in a very stupid analysis) their odds of type 2 diabetes 8% (assuming they go off Semaglutide and don't gain weight).
Some will say “well lose the weight, and then train hard to get the LBM back”. To this I say, my friend, have you tried to add muscle mass? Have you tried since you turned 30? An untrained individual might put on 5 kg in year 1, and maybe 2.5 kg in years 2 and 3 of training. If you're already trained, oops that's means you're not getting that 5 kg in a year, also these numbers include younger people so if you're middle aged reading this... adjust down. Finally, putting that on requires consistently gaining weight. Most commonly suggested for an “optimal” LBM vs fat perspective 2450 calories a week (350 a day) surplus. In a period of training (where you stupidly bulk until gaining the muscle back) that's putting on 9 kg to gain back that 2.9 kg of newbie muscle.
That's (more or less) how much you lost in the first damn place! Now you've gotta cut, again, only you're older.
Others will chime in saying “but you can do good training, take Semaglutide and maybe dodge the muscle loss side effects”. This seems reasonable, however I would note that Peter Attia (a Canadian longevity doctor/researcher) claims he seems much higher LBM in his clients (and he steadfastly advises people to engage in muscle gaining/muscle loss reducing strength training). If he's seeing a higher than predicted LBM loss (in a population that is almost far more likely to be engaging in appropriate resistance training) than I suggest there is something else going on here with LBM that should make people very wary of Semaglutide.
2nd to final note: A key target demographic for Semaglutide is the 55-75 prediabetic overweight group. This is a group that CANNOT and SHOULD not be risking LBM losses. They simply are wildly unlikely to be able to put substantial LBM back on, and falls (as they age out of this group) are very dangerous. They should be prepping everyday to be 76-85, and that includes doing everything they can to prevent osteoporosis and muscle loss.
Now, as to the longevity question, certainly cutting 14.75% of your bodyweight seems like a damn good start to living longer (if you are substantially overweight). It'd be great if they reported changes in waist size (although the tiny visceral fat loss numbers are indicative that it would look just ok on this front). But, it's a new drug for this use, studies are very limited and it's not exactly known as a low side effect adventure. Maybe (stealing an idea from Derek at More Plates More Dates (best citation https://www.youtube.com/watch?v=pNCx9fu-enk)) better dosing (2-4 times per week vs 1 time per week) can mitigate this. If I was betting on it, I'd bet that in 15 years doing a few years of Semaglutide is seen as a total wash for "normally overweight" people, and it's set aside for only the most severely overweight.
Actual final note: The key counterclaim is people just don't lose weight and keep it off. Surely something that cuts 14.75% of bodyweight and then lets them figure out how to be healthy is probably worth it. I have lost weight, kept it off for years, gained weight, lost it, blah blah blah.
I understand this struggle. I know how hard it is. Maybe one day there will be a shortcut. Maybe one day the fix won't be 4 days of eating right, sleeping right and training for every single day of over eating. But, based on what I've read, today is not that day.
14 comments
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comment by Elizabeth (pktechgirl) · 2023-07-29T06:06:37.241Z · LW(p) · GW(p)
Do you have comparable numbers for weight lost the old fashion way? Crudely, it looks like the treatment and placebo group had the same ratio of fat:lean mass loss, so treatment doesn't look obviously worse.
Replies from: 5hout↑ comment by 5hout · 2023-07-29T11:08:40.775Z · LW(p) · GW(p)
That's a very good question. Unfortunately the answer is nearly undefined/very high variance depending on the person undergoing the weight loss. There's a huge range of expected outcomes depending on history and weight loss plan.
Ideal case might be Neutral LBM: Fairly obese youngish person. No training history (say someone that was super active, but not athletic, in HS). Goes to college, walks a ton stays pretty skinny. Gets first desk job around 25-26 and gains a ton of weight. Holds onto the weight, without much activity for 2-3 years. Diets in the most careful sense (.5% of bodyweight per week for 3-5 weeks then a maintenance week, macros on point, heavy resistance training, limited intense cardio). This person might stay LBM neutral, actually gain muscle and come out with massively improved body composition both on a naive DEXA scan and in reality.
Middling case might be Low LBM loss: Person has a decent training/life history, so they are carrying some "extra" muscle vs baseline. Been overweight for a while. Weight loss is limited to .5% bodyweight per week, with 2-3 cheat days per month (but no maintenance weeks). Resistance training is decent, limited cardio. They're going to lose some, LBM, might lose some muscle, but not too much. Exact numbers are hard, but would be reasonable to expect naive body composition to go way up (DEXA scan) and if you spent time carefully figuring out if they lost muscle/bone/other, it'd be mostly other (if not entirely other).
Pretty bad case might be High LBM loss: Average life/training history, person does intense cardio and aims for >1% bodyweight per week of weight loss. This person is going to get hit with a truck of LBM loss (absent pharmacological interventions or lucky genetics).
So the money question is where does Semaglutide stack up? We know from the paper that they didn't provide quality training advice, but we also know that the weight loss was spread (non-linearly) over 68 weeks (simple division meaning .22% per week, when .5% per week is seen as a very muscle/LBM preserving rec'd rate). I'm away from desktop so I don't have the study pulled up, but iirc the distribution of weight loss rates over time was very conservative/favorable to preserving muscle/LBM. We also know there was poor (if standard for diet research) compliance with the plans, b/c the weight loss average rate was much lower than expected for the diet advice that was provided.
This is why the results are concerning. If you told me someone was going to lose .5%-.7% per bodyweight per week for a month or two, then really slowly lose weight for the remainder of 68 weeks, and have professionally provided diet/training advice I would expect them to lose lower than average LBM. On the other hand, maybe it's an effect of being given a weight loss drug and seeing your weight drop? You think "heck this is awesome, I'm just going to chill and get skinny".
I don't know. But, the results combined with the reports of it making people "skinny fat" coming from multiple sources, notably largely consisting of doctors that have been giving it to people and then going sounding the alarm, adds another arrow to the bundle of "maybe we pump the breaks on this, or at least go into very very carefully with professional resistance training and a well craft diet" vs (what people seem to be doing (anecdotally) of pinning semaglutide once a week and chilling.
comment by [deleted] · 2023-07-28T19:52:23.756Z · LW(p) · GW(p)
Gears level wise, is there a theory why this would happen? GLP-1 agonists are thought to touch stomach emptying rates and your brains sense of food load.
Were you to follow your advice of "days of eating right, sleeping right and training for every single day of over eating" - which people who are obese have tried for decades and achieving normal BMI is rare - how is this mechanically different? Eating right means smaller meals and eating less kcals than daily metabolic needs.
Mechanically it's costing you an enormous amount of willpower, and the food spends less time in your stomach. You would expect to lose a mixture of lean and fat mass over time.
Mechanically you wouldn't expect that this in fact causes any difference in outcome than dieting the willpower way. Unless the slowing of digestion is changing the nutrient profile absorbed.
As for regaining lean body mass, there's always oxandrolone. That's an effective way to do it.
Polypharmacy starts to get complex but I mean real medicine has to be that way. What do you think a hypothetical ASI system validated on results is going to prescribe in 2050? It's not going to be 1 pill once a day. You will likely need an implant loaded with hundreds of drugs and the doses are varying in response to feedback from implanted sensors.
Here in the hand axe days of medicine I guess you get semaglutide, get your weight to safe numbers, and oxandrolone back up. (And yes, while oxandrolone is supposed to be one of the safest anabolic steroids, absolutely it creates new set of problems that you need additional medicine to counter. This is where you end up with "hundreds of drugs variable dosage" - each drug is causing new side effects but it's a diminishing series so it's possible to solve if you knew exactly mechanically what each substance is doing)
Replies from: 5hout↑ comment by 5hout · 2023-07-28T20:55:02.808Z · LW(p) · GW(p)
Breaking my thoughts to your comment into 4 parts.
1: "Were you to follow your advice of "days of eating right, sleeping right and training for every single day of over eating" - which people who are obese have tried for decades and achieving normal BMI is rare - how is this mechanically different? Eating right means smaller meals and eating less kcals than daily metabolic needs"
All these using Freedom Units:
I've cut from >230 (I think peak around 245/250) to under 190 2 times with a 3rd 30 pound cut snuck in there. Going off Friday afternoon memory:
2013: >230 (Graduated law school, moved back to home state)
2014:<190 (insane caloric restriction combined with dumb resistance training and lots of cardio).
2015end:>230 (in 2015ish I started a new job with horrible commute, ~3 hours of driving a day).
2016end/2017/2019/part2020: <190 (keto/IF/less dumb lifting/working from home)
2020-2023: Long slow accumulation from 190 to >230 then down to just over 200, then back to 230 now down again. 505 squat(wraps)/405 deadlift/260 bench/190 ohp (all between 200-220 BW).
In 2020 I had 2 major life changes. My first (of now 2) kids was born and I decided to bulk, not realizing how much harder I would find it to lose weight when I had child induced sleep deprivation + ~5% of the free time I used to have (WFH 40-45 hours per week + and no kids = very high free time). The combination of intentional weight gain + sleep deprivation was/is brutal, and I'm still dealing with the aftermath.
Now I'm considering things and trying to cut (while maintaining muscle). So, I would say I have followed it and am back to following it. This is not the exhortation of some skinny s**t that's run a 5k a day for 20 years and never had any trouble with weight. This is from someone who has been to the (bottom? top?) of the mountain (stayed there) and is trying to get back.
Current systems seem crap. I've seen 3% able to to keep a significant bodyweight loss off for a year said in many places. I don't have an answer, other than I don't think the answer is Semaglutide.
2: To the proposed Semaglutide/AADs stack (or sequential usage), I think that's a very intriguing idea if someone is in their 20s, has disposable income, goes into it both eyes open with blood testing, good sleep/diet/lifting/coaching and generally takes it seriously. Personally, I think it would be somewhat successful, if only because it would function as an very powerful compliance filter (i.e. if someone complies with all the blood testing to go on blast, and diet/sleep/lift/coaching they are going to see very good results regardless, but having the drugs will very plausibly help with compliance). I would note that going straight to Anavar seems a mite excessive, and well monitored "sports TRT" would seem a good first step if someone is thinking of this route (although I have heard in many places it is easier to get a bottle of Anavar than monitored "TRT" (I could more easily get a script for Deca + Test than reliably sourceAnavar based on my understanding)). Disclosure: Purely hypothetical for me, I've never experienced a lifting plateau that simple compliance with programming/sleep/diet didn't fix, so never felt it was reasonable to pursue assistance even before other concerns (i.e. 2 kids and a wife and just terrible genetics for drug interactions).
3: Mechanical stuff: No clue here at all. My honest shot in the dark is 3 guesses.
3a: Semaglutide (based on personal reports online) absolutely messes with your brain/general thought patterns. This could be downstream of hormone changes from dieting, or some unknown interaction or something else. If you go and read people's stories this is a very common theme. It's doing more things in your brain than messing with perceptions of fullness/hunger/slowing your stomach down.
3b: Hand wavey "the body is complicated" and who knows on nutrient abosoption/mechanisms.
3c:I think we are so far from understanding willpower (even as it relates to food) that our advice on this front is closer to mysticism than anything else. More honestly, I think we'd be better off simply telling people to do a modified 12 steps with food, or intentionally obsessing about clean eating (i.e. if you hit 30 and have been overweight for >5 years you're probably better off being an obsessed nutter that can't shut the f**k up about keto/vegan/carnivore and weighing a healthy BW + doing cardio than you are staying overweight)
4: "What do you think a hypothetical ASI system validated on results is going to prescribe in 2050? It's not going to be 1 pill once a day. You will likely need an implant loaded with hundreds of drugs and the doses are varying in response to feedback from implanted sensors."
Yes, strong agree (with the caveat I think you need to add at least another 50 years).
↑ comment by [deleted] · 2023-07-28T21:46:37.964Z · LW(p) · GW(p)
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Your anecdote isn't helpful here. People usually fail this way while semaglutide works.
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People take small doses of anavar by itself. If your goal is to add a few lean kilograms back as a 50+ year old, this would be how.
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Generally in human physiology if you have no mechanism, no way for A to cause B, it's correlation and not causation. You certainly would need much more data to prove your "lean loss" hypothesis. The studies I have seen show immediately mortality benefits because lower body mass means less load on the heart and blood vessels. You are claiming long term harm that hasn't been established to happen.
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The Singularity hypothesis says this is possible. Were it to take 50 more years, the hypothesis is false. It's like saying a nuclear bomb that is detonating slowly and doubling in power level every year is not going to hit megatons of yield for 75 years.
The route to success I see is the singularity will allow for the necessary tools to solve biology (through mass robotic self replication followed by replication of all bioscience experiments to date followed by the systematic building of ever more complex human mockups). A company could do this, getting trillions in investment from self interested (AI company founder) trillionaires, in a friendly jurisdiction. The medical results from a machine with this amount of intelligence, knowledge, and tools would not be deniable. (As in low hanging wise, elderly patients would lose their frailty from bone marrow replacement with deaged hemopoietic stem cells, stage 4 patients would have a 100 percent survival rate, heart disease patients would get regenerated hearts with performance like a marathon runner, and so on. Dementia patients would recover. These things are all possible if you can manipulate the genes in adults and know what you are doing)
The current economic machine will create those trillionaires within 10-15 years if they do succeed in creating AGI.
comment by johnlawrenceaspden · 2023-07-28T22:10:39.856Z · LW(p) · GW(p)
I wouldn't touch this stuff with someone else's bargepole. It looks like it takes the willpower out of starvation, and as the saying goes, you can starve yourself thin, but you can't starve yourself healthy.
I could be convinced, by many years of safety data and a well understood causal mechanism for both obesity and the action of these drugs, that that's wrong and that they really are a panacea. But I am certainly not currently convinced!
The question that needs answering about obesity is 'why on earth are people with enormous excess fat reserves feeling hungry?'. It's like having a car with the boot full of petrol in jerry cans but the 'fuel low' light is blinking.
Replies from: 5houtcomment by Three-Monkey Mind · 2023-07-28T20:54:59.969Z · LW(p) · GW(p)
A key problem to loss of LBM is that you’re either losing bone density (a terrible thing) or muscle (a pretty damn bad thing).
Could also be skin. Losing skin if you're losing fat is a good thing, I'd think, since you don't want to weigh 200 pounds yet still have all the skin you had when you were 300 pounds.
Has any work been done to see where the LBM has been coming from?
Replies from: 5hout↑ comment by 5hout · 2023-07-28T21:01:30.042Z · LW(p) · GW(p)
Not to my knowledge. There's a handful of studies that are pretty superficial (i.e. people come in for some DEXA (body composition) scans and that's it. I think it's going to take some time, because anyone involved in seeking approval of the drug has a huge negative incentive to look in this box, given the at least plausibly neutral results from the first supportive studies.
I think the place to look for citizen science on this is going to be in the longevity community and similar areas where you have people semi-openly experimenting with what is sometimes colloquially called "sports TRT" (i.e. running a testosterone only steroid cycle with modest amounts compared to other uses). Certainly a lot of people that hoped on the TRT optimization bandwagon in the last few years (telemedicine changes may have spurred this on as far as I can tell) are overweight, and I can't imagine they won't try another (sometimes insurance eligible) injectable to fix the overweight part. The data will be messy, but I think there will be hints in a few years.
comment by YimbyGeorge (mardukofbabylon) · 2023-07-28T21:52:21.207Z · LW(p) · GW(p)
That was a serious request tldr?
Replies from: 5houtcomment by YimbyGeorge (mardukofbabylon) · 2023-07-28T21:51:45.675Z · LW(p) · GW(p)
Tldr?