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.