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As another person commented, we currently believe the primary mechanism behind the pleitropic effects of GLP-1's to be a reduction in systemic inflammation and direct improvements in vascular/endothelial function.

The best paper I've seen on this was the recently published and very aptly named:

"Pleiotropic effects of GLP-1 receptor agonists — a narrative review of extra-metabolic outcomes in adults" (2026)

https://journals.viamedica.pl/medical_research_journal/artic...

Pleio-, many; -tropic, having effects; pleitropic effects, many effects effects.

I felt the impulsive need to write "many pleitropic effects".

Fat is inflammatory, especially visceral fat, so reducing that fat naturally reduces inflammation.

There’s a feedback loop with inflammation and fat. We’ve been telling people for decades to break the cycle by losing weight, but we also have studies that say you can only sustain about 7.5% weight loss per year. Anything more tends to rebound.

Then GLP-1 comes along and we stop fat negativity/positivity overnight.

Yeah entirely possible that GLP-1s are the closest thing to exercise in a pill.

Exercise does not result in loss of lean mass unless done at a severe deficit. If someone has a low baseline of lean mass, exercise usually boosts it even when a person is in a deficit, but if they are in a surplus, the lean mass boost is more significant.

GLP-1s don't.

1. Yes, for many of the benefits of GLP-1s, it's plausible the mechanism is weight loss. But actually achieving significant weight loss with other therapies is incredibly hard, so I think GLP-1s get some credit here.

2. Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone. E.g. the blood sugar regulation that makes them very effective for diabetes is not purely about weight management.

Stress eating is also a thing, so if we’ve misunderstood a chemical pathway that we created an agonist for it can be a little of column A and a lot of column B.

We have failed blood pressure drugs that turned into boner pills. We have failed blood pressure drugs that reduce social anxiety. In the field of medicine we have a lot of people acting like we understand the body but we don’t know shit. It’s a bit like how physics was “nearly done” before relativistic and quantum physics were discovered. We still don’t know shit. And we are going to kill or fail a lot of people between now and when we can find our asses with both hands.

you're not necessarily wrong, but science is likely also to continue saving a lot of lives while the endless search for our collective ass continues

As long as your illness is not inflammation or pain related.

We are good at making people live longer, not at making them live better.

>But actually achieving significant weight loss with other therapies is incredibly hard, so I think GLP-1s get some credit here.

Citation needed! it's not actually difficult, all you need is calorie deficit and it has been routinely done by bodybuilders, athletes, MMA fighters and movie stars/models and thousands of ordinary members on r/caloriedeficit subreddit or other fitness subs!

> Hunger signalling isn't the only thing GLP-1s do, so no, we should not just assume every effect stems from weight loss alone

Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.

> Citation needed! it's not actually difficult, all you need is calorie deficit and it has been routinely done by bodybuilders, athletes, MMA fighters and movie stars/models and thousands of ordinary members on r/caloriedeficit subreddit or other fitness subs!

Bruh, we're not doing this anymore. If weight loss was easy, we wouldn't have an adult obesity rate of 40%. Yes, yes, a handful of extraordinarily motivated individuals can successfully restrict calories to lose weight. But very clearly most people can't.

> Ofc, they also result in an increased risk of gallbladder stones, bile issues, hair loss, and severe loss of lean mass, and we've got actual studies on this.

You're conflating association and causality. They're used by the obese and diabetics, so they're associated with all kinds of things associated with obesity and diabetes. (But the plausible cause is that the 3rd variable is obesity/diabetes.) Loss of lean mass is basically identical to any other similar level of caloric restriction without corresponding resistance training -- if you don't eat enough to maintain muscle mass, and particularly if you aren't resistance training, no shit, you'll lose muscle. (And guess what? It's still better not to be obese.)

>Bruh, we're not doing this anymore. If weight loss was easy, we wouldn't have an adult obesity rate of 40%. Yes, yes, a handful of extraordinarily motivated individuals can successfully restrict calories to lose weight. But very clearly most people can't.

I do not agree with this. Those studies being used to push the idea that "diet and exercise failed obese people" are flawed, and I posted a comment on this post explaining all the flaws. You can choose to respond to them instead; I won't copy paste it here.

Weight loss requires a calorie deficit, and the average person has no training or education for this. Why would you expect them to be good at something they've had no education or training in? 40% obesity rate is not surprising when no education/training exists for average person.

We've already achieved guaranteed results within 2–3 weeks for free (we make no money from this) for all of our users for weight loss or gain, with validation from 17,000+ users for free.

If we are just "scammers," how do we make money by pushing this idea?

You can read reviews and testimonials from people.

The method we use is "slight deficit", see this: https://macrocodex.app/knowledge/rethink/adaptive-tdee/ (you can find all citation/research being used to achieve this)

Our solution is available for free to use!

A deficit so small that most users won't even know that they are at deficit!

You know that if i remove 150kcal from your diet, your wouldn't notice? that's like 2 slices of bread. So the hunger suppression will never be a question for vast majority of fat people

150kcal deficit over a year = 7.1kg or 15.6 lbs lost! and 300kcal = 31.2lbs or 14.2kg!! all this without any injection or drug without any exercise or severe loss of lean masss

>You're conflating association and causality.

Same is true when you talk about positives of GLP-1s, most of the benefits actually come from "calorie restriction" and it's very hard to seperate which part comes from where.

How much training or education is needed? I mean, frankly, a person can just go watch a 20 min YouTube video and learn all they need about how to restrict calories to lose any amount of weight they like.

You don't think people are capable of this?

>I mean, frankly, a person can just go watch a 20 min YouTube video and learn all they need about how to restrict calories to lose any amount of weight they like.

Feeling like you understand something and actually understanding it are two very different things.

Let's take something as simple as "calorie deficit."

Being at a calorie deficit itself requires knowing two things:

1. How much you burn in a day (total daily energy expenditure or TDEE)

2. How much your intake is for the day

Deficit = TDEE - Intake

You can do calorie counting for #2. But what can you do for #1?

The average guy does not know how to calculate these properly, let alone judge weight movement, which can move a lot in the opposite direction due to water weight fluctuations that can exceed 1 kg+ of movement a day.

If you calculate your maintenance calories using a TDEE calculator and get 3,000 kcal, then apply a 400 kcal deficit, your target intake becomes 2,600 kcal/day.

But what if your actual maintenance drops by 300 kcal the following week?

Your effective deficit is now just 100 kcal/day, assuming your intake stays the same.

Eventually you might find yourself barely losing weight, or not seeing any noticeable change for a while. You'll start wondering, "I'm eating in a deficit, so why am I not losing weight? Is there something genetically wrong with me?"

You might even blame your metabolism.

The problem is that your original calorie target was based on a static estimate of maintenance, not a continuously updated one. Your energy expenditure changes as your body weight, activity, and other factors change. A TDEE calculator can't account for those changes in real time.

The average guy does not understand expenditure, weight movement, the calorie-to-fat equation, water-weight fluctuations, and many other gotchas, and no, 20 minutes may not be enough to understand all this for an average Joe.

We use neural network for #1 problem, we've 17,000+ members and 2,000+ members in our telegram community group seeing great results!

if interested, you can checkout our completely free solution to this problem, https://macrocodex.app/

Guaranteed results within 2-3 weeks, no paywall, or ads.

> Citation needed! it's not actually difficult

It's simple, and people think simple = easy. It's simple, yet very difficult. Walking up 1,000 stairs is also simple, you just put one foot in front of the other until you're up. But it's hard. We know weight loss is hard because of how many people are obese. Most obese people have tried to lose weight many, many times and have failed. If it was easy, they wouldn't fail. Evidently it is difficult, and no other perspective is reasonable.

>But it's hard. We know weight loss is hard because of how many people are obese. Most obese people have tried to lose weight many, many times and have failed

Weight loss requires a calorie deficit, and the average person has no training or education for this. Why would you expect them to be good at something they've had no education or training in? 40% obesity rate is not surprising when no education/training exists for average person.

>Evidently it is difficult, and no other perspective is reasonable.

We already have group of 2000+ people, app with 17,000+ users losing weight on demand! All for free and anyone can verify this.

GLP-1 probably reduces systemic inflammation, with far-reaching consequences. That is a much bigger effect than just losing weight, though weight loss contributes to that.

Then there are the mental effects, such as people reporting that they lost various addictive habits (gambling, compulsive shopping etc.)

I mean sure sure, I get that, but take this article I found from a simple Google search.

https://www.health.harvard.edu/heart-health/weight-loss-drug...

I get that science has to be thorough, but how is it at all worth writing about that losing weight makes your risk of heart attacks lower? That GLP-1s are involved suddenly makes this news?

Again, not trying to be snide. I'm on the side of science here, but there's gotta be something the scientists are looking at that I'm not.

It is my impression that the topic is being constantly rehashed precisely because the effects of GLP-1s are observed to be significantly more pronounced than what can be attributed to the weight loss alone.

I see. So, instead of

"GLP-1s cause an improvement in cardiovascular health"

if you said

"GLP-1s cause an improvement in cardiovascular health more than as would be expected by equivalent weight loss"

would that be more specific? Is this right?

People have been claiming similar effects for astrology, alchemy, and other things as well.

You really have put a lot of effort into negative contributions throughout this thread, seemingly because you have a personal incentive for some service you offer. It's a bad look.

>“GLP-1 receptor agonists are being shown to benefit many chronic diseases over and above their effect on weight,” John Deanfield, FRCP, FESC, professor of cardiology at the Institute of Cardiovascular Sciences at University College London, told Medical News Today. “These include liver diseaseTrusted Source, kidney diseaseTrusted Source, diabetes, and neurological diseasesTrusted Source such as Parkinson’s diseaseTrusted Source. They should therefore not be labeled merely as ‘weight loss’ drugs, but as drugs that can have a direct effect to improve patients’ health.”

>Building off this research, Deanfield is the lead author of a new study recently published in the journal The LancetTrusted Source that provides further evidence of semaglutide and lowered major cardiac event risk, regardless of how much weight a person loses while taking the GLP-1 medication.

>“Semaglutide has previously been shown in the SELECT trial to significantly reduce major adverse cardiovascular events in overweight/obese patients with known heart disease but without diabetes,” Chen explained. “This study analyzed the information from the SELECT study, and found that this benefit to cardiovascular health did not depend on how overweight patients were or how much weight they lost.”

>“This interesting finding suggests that the cardiovascular benefits of semaglutide act through a biochemical mechanism not dependent simply on changing the body weight of an individual,” he continued. “This may open up other avenues of research and therapies that could improve heart health.”

https://www.medicalnewstoday.com/articles/weight-loss-drug-h...

There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.

GLP-1 then addresses factor X, and the problems it causes, including weight gain.

Not that obesity doesn't independently cause problems but very plausible causality runs more than one way.

I would use the word "possible", not "plausible". GP's scenario is plausible since it doesn't need positing an as of yet unknown factor X.

>There is another plausible causal mechanism: weight gain flowing from hunger/metabolic dysregulation. This dysregulation being caused by some "factor X" which also causes other problems.

GLP-1s are being promoted to and used by the general public, who aren't even obese, because GLP boosters push the magical properties of GLP-1s.

Even most obese people do not actually need GLP-1s.

These studies control for such variables, confounding effects are easy to think of, but 9/10 times here on HN, the authors DID control and adjust for that confounder, the commenters just didn't read the methods.

Eh, no, the vast majority of splashy headline studies that make it to HN show some associative result where causality is not established. They can not control for all possible confounding. The money sentence from the study is "semaglutide was associated with significantly reduced epigenetic aging relative to placebo across multiple generations of epigenetic clocks."

https://www.nature.com/articles/s41467-026-72861-3

It kinda seems like a bunch of markers moved randomly and some of them happened to move together: "In contrast, causality-enriched epigenetic clocks28 AdaptAge, CausAge, and DamAge exhibited directionally heterogeneous and statistically non-significant changes." That gets you a publication but I don't know that I'd bet money on follow-up study results.

I've been around research enough to be allowed to comment: "oh you sweet summer child".

GLP-1 receptors are G-protein coupled receptors (GPCR). There have been multiple nobel prizes given for work done to understand their function and we still barely understand them. It's a highly nonlinear interconnected signaling pathway. Imagine the worst spaghetti code you've ever seen times 10 - nothing is idempotent, high hysteresis, position state and time dependencies everywhere, every function works exclusively through side effects that mutate global variables, the same molecule can both drive and suppress signalling and that signalling can both cause some effect and stop that same effect.

Basically with glp 1 it seems to be broadly related to the mess of nonsense that has to do with inflammation/immune/cardio stuff - maybe a set of adaptations that made more sense in a world with more infectious disease/food scarcity but less so now, maybe just a grab bag because evolution is stochastic and is not actually survival of the fittest (it's just survival of the things that survive - there could be 10 organisms that are highly adapted to a particular environment and 2 that are not and would be outcompeted and then a rock falls on the 10 and now the gene pool is what it is - evolution doesn't care). So not really surprising that a thing that works via a mechanism we don't super understand against a condition we done super understand has a bunch of impact on other stuff we don't super understand

When you see reporting like this it means there was some study that had some evidence of some effect that somewhat matches the description in the headline, but nothing more than that. How good of a study it was, how large the effect, how in alignment or not it is with a body of evidence, how reproduceable it is, how exaggerated the press release is. Are all left out and are all critical to how much anyone should care about the statement. What it definitely does not mean is "all scientists are asserting this truth in the headline"

Glp1s aren't just appetite suppressants. Two identical people doing and eating identical things -one on glp1 and one not - the one on willose more weight and have better biomarkers like insulin sensitivity

True, GLP-1 user will have higher loss of lean mass than one who is dieting on calorie deficit and exercise so they'll look more "shrunken raisin" than other.

> the one on [GLP1s] will lose more weight

This isn't true. Identical people on identical diets will lose the same weight, GLP1 or not.

> and have better biomarkers like insulin sensitivity

(That part is true.)

>This isn't true. Identical people on identical diets will lose the same weight, GLP1 or not.

No, this isn't true.

Even when two people are identical twins eating the same amount of food and doing the same amount of exercise and activities, weight loss will differ because:

Rate of loss of BodyWeight rate is directly proportional to amount of deficit applied!

Deficit = TDEE (total calorie burn of the day) - Intake

If TDEE is not the same, weight loss will differ, regardless of whether the underlying activity level, genetics, or amount of food or everything else is the same.

For more details u can check my post on this: https://macrocodex.app/knowledge/macrocodex/smart-calorie-bu...

>(That part is true.)

Improved insulin sensitivity is associated with lower excess body fat THE MOST and better skeletal muscle metabolic function. Greater lean mass may contribute.

Therefore, if a person on GLP-1 loses more lean mass than one without, they may not actually have better insulin sensitivity.

The two explicitly identical people have the same TDEE.

No, they don't. It's very difficult to have the SAME TDEE even in identical twins, eating the same food and having same activity level.

Yeah!

These scientists, whose job it is to think about this really hard, why didn't they just think of the most obviously obviously thing? I'm sure they didn't!

...

Dude. Come on.

Do you admire science for its explanations? Do you like explanations generally?

I was abundantly clear about this exact thing in my comment.

I even asked, explicitly, “what do the scientists know that I don’t?”

I asked despite the question sounding dumb, because that’s what you do when you genuinely want to know more!

Many people don't do their jobs properly. Why should scientists get the benefit of the doubt?

If something is true it will survive the scrutiny, requires no appeal to authority.