Lean mass loss on GLP-1 receptor agonists: a downside of the “miracle drugs”

#1

Interesting article about the risks of using semaglutide for weight loss in healthy people.

from the information we can scrape together based on sub-cohort data, these “miracle drugs” start to look a bit less miraculous. In 2021’s STEP 1 trial – the first and only trial demonstrating the efficacy of semaglutide as a treatment for adult obesity – a subset of 140 patients underwent DEXA scans for body composition analysis. Among these patients, lean mass accounted for approximately 39% of total weight loss – substantially higher than ideal. In a substudy of 178 patients from the SUSTAIN 8 trial on semaglutide as a diabetes treatment, the average proportion of lean mass loss was nearly identical at 40%, despite lower doses and less total weight loss than in the STEP 1 trial.

While those with obesity stand to reap considerable health benefits from fat loss, the potential benefits of fat loss among healthy-weight individuals are minimal and are unlikely to offset the sizable health risks associated with reduced lean mass. Further, because the only large-scale trials of GLP-1 agonists have been conducted in obese or overweight study populations, we don’t yet know if these drugs affect body composition in normal-weight individuals in an equivalent manner.

Has anyone using those compounds noticed any muscle loss?

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#2

Hmm

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#3

Basically, when we take these drugs we become less hungry, we don’t do resistance training and/or eat enough protein, so the lean mass loss is higher. From Peter’s article:

Increasing weight-bearing exercise and strength training can help to counteract losses in muscle and bone mass while taking these drugs, and patients should be careful that they’re consuming sufficient protein in spite of the overall reductions in appetite and calorie intake.

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#4

Yeah this really seems like a nothing-burger to me. Obviously you’ll lose substantial muscle mass if you cut calories while not resistance training or eating enough protein.

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#5

It’s definitely not nothing. Healthy people taking it for weight loss should know that resistance training is still required if they don’t want to lose lean mass.

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#6

But significant loss of lean mass is going to happen with all weight loss programs that involve successful caloric restriction unless resistance training and adequate protein intake are maintained. It’s not unique to this new class of drugs. It’s a warning all people should get before being put on weight loss meds, weight loss surgery or any kind of calorie restricted diet IMO.

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#7

I think the concern is that the percent of muscle loss is considerably higher when using this drug.

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#8

I guess we’ll see if there’s some other physiological mechanism that specifically causes lean mass loss with these drugs, but my understanding was that the final weight loss mechanism is simply decreased appetite and hence decreased caloric intake. As Attia mentioned, there’s a paucity of data so far.

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#9

Not that surprised. It is definitely NOT a nothingburger. The referenced study was done on obese patients with specific exercise and diet interventions.

This is why I’m extremely careful, it’s way too easy for uninformed people to talk about something they know nothing about on this forum.

I always read the paper, look at the methodology, and understand what’s actually going on before commenting.

I also don’t care to believe what Peter Attia says - regardless of him being right or wrong on the topic. Funny thing is a few articles from Attia I read were miscited or had the opposite reference of what was stated. Could be a string of “honest mistakes” or perhaps more likely - the cheap folks he hires to write for him that aren’t physicians/medical researchers/etc are just doing a lousy job. It becomes difficult in some articles where he speculates on certain claims which seem entirely unsupported. At least that’s what I found after subscribing for one month and diving in some of the content that was on his website and breaking down the references.

There is a real concern about sarcopenia for GLP-1RAs if you look at the small portion of participants who underwent DXA:

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In this subset, total mass loss was ~14 kg. While nearly 8.5 kg (~60%) was fat loss, the lean mass loss reported was ~40%. This is clearly the high end of expected - ~20% is expected via lifestyle intervention alone.

Any endocrinologist and obesity medicine physician can tell you this. A sizable amount may speculate that it might negate a large amount of the positive CV outcomes seen in GLP-1RAs with sarcopenic obesity.

I’d like to see studies on increasing protein intake to avoid sarcopenic obesity when on GLP-1RAs but not easy. FDA doesn’t use DEXA for these (they’d use it for bone density tho), despite it also being the “gold standard” for body composition.

If you look at the actual trials for approval on weight loss - it is always paired with specific diet/exercise interventions. However, there are people on the internet (particularly social media/TikTok/Instagram) that heavily promote/hype it up and get it either through black market or unscrupulous places with no such interventions in conjunction with the GLP-1RA and clearly do not have any indication for GLP-1RAs.

In this scenario, you get people who inadvertently buy into the hype without reading a single study and parrot all kinds of nonsense - as with many weight loss/cosmetics. There are many potential long term risks when messing with hormones, hence I’m extra careful to think of the tradeoffs in patients when even considering offlabel use.

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#10

In this subset, total mass loss was ~14 kg. While nearly 8.5 kg (~60%) was fat loss, the lean mass loss reported was ~40%. This is clearly the high end of expected - ~20% is expected via lifestyle intervention alone.

Do you have a source for that claim?

Any endocrinologist and obesity medicine physician can tell you this. A sizable amount may speculate that it might negate a large amount of the positive CV outcomes seen in GLP-1RAs with sarcopenic obesity.

I don’t believe those drugs were specifically designed for people at risk for sacropenia.

However, there are people on the internet (particularly social media/TikTok/Instagram) that heavily promote/hype it up and get it either through black market or unscrupulous places with no such interventions in conjunction with the GLP-1RA and clearly do not have any indication for GLP-1RAs.

If people are falling for BS they find on social media, it’s not the fault of ozempic or the pharma industry.

I disagree on that. Many things in life “mess with hormones” and yet have no impact on health or lifespan. Other things, like fat, do have a huge impact on hormones and do negatively impact your health but here it’s “natural”?

#11

Hi @tongMD , great to see your thoughtful and rich entry

Do you have any perspective on how the increase in insulin from these GLP-1 drugs might impact an optimal longevity phenotype?

That is one of my main worries with these drugs.

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#12

Ok, but are these just instructions given to the participants, or are they being prescribed resistance training specifically and actually being monitored to see if they’re doing it? I hope someone is doing a study like this – GLP1-RA along with protein supplement and verified resistance training because I’d hypothesize a similar amount of “weight loss” but nearly double the fat loss with little if any muscle loss. Unless, of course, there is some kind of additional pro-sarcopenia mechanism at play.

#13

Can you be more specific? This comes across as an attempt to smear/discredit Attia without providing any actual evidence.

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#14

I came across this thread searching for GLP-1 impacts on mTOR (a curiosity), and can describe my experience. I lost 63 lbs over the past year, 51 of that on Tirzepatide. After losing the first 12 lbs I got a DEXA scan. 24 weeks later I got another. During that time I had lost another 37 lbs.

The DEXA scans showed -39 lbs of fat, +2 lbs lean mass. Bodyfat dropped from 31.5% to 21%.

There is a catch, though. I started TRT right before that first DEXA, and I’m sure that helped a lot. I also ate at least 1.6 g/kg body weight animal protein (I wanted the leucine) and did heavy barbell training 3-4x per week.

Since the last DEXA I’ve lost another 14 lbs and retained my strength, so I assume I have not lost muscle, or at least not much. I have since increased calories back to a maintenance level.

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#15

You could also take enough to cut calories SOME (and completely cure binge eating/excess calories + save some $$ on food) without losing any weight, and you would still get most of the health benefits. In that sense, still having some appetite/not losing weight on them is a good thing