Weight-loss drug found to shrink muscle in mice, human cells

> 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.

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.

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.

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.

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.

> Do some resistance training, get some protein

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

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.

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.

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.

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.

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

    > 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.

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.

    > Losing weight without losing muscle mass is very hard.

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.

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.

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.

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

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.

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.

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.

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!

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

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.

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.

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

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.