Comment by londons_explore

I have some individual anecdotal evidence. I spent a long time, basically a year, relatively heavy but on a very small dose of GLP drugs due to tolerability issues, and my labs improved dramatically, to a degree we redid them out of disbelief, even without weight loss. I believe one of the suspected underlying causes is reduction in fatty liver despite constant body weight and composition, and also inflammation reduction directly through GLP influence in other areas of the body.

I'm not great evidence because N=1 and all the confounders, but I found that it absolutely made me much healthier without weight loss. I then went on to increase the dose slowly and have lost a bunch of weight and my labs improved even more, which I attribute mostly to the body mass reduction.

> So has anyone managed to separate the effects of semaglutide from the effects of weight loss?

In general? Yes. For this specific thing? We haven't even really shown the effects matter for humans.

> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker - lots of people have been overweight for a century now, so literally 10's of millions of people could have been saved from dementia had action been taken 100 years ago.

Public health has been banging the drum on obesity for decades now. But humans on the whole aren't built to be able to resist hyper palatable calorie dense cheap foods.

It’s in broad terms weight loss related. More specifically blood glucose and insulin regulation which can be out of whack even if you’re not diabetic on paper. This is why you’ll see people claiming they’re not diabetic but still saw improvement from Ozempic and friends. Their insulin and glucose regulation was spoke. in casual terms “fucked”.

GLP-1 receptor agonists such as semaglutide act partly through the brain to reduce hunger, increase satiety, and lower spontaneous energy intake. Sustained caloric reduction produces weight loss, including loss of visceral fat around the abdominal organs and ectopic fat stored in tissues such as the liver. These fat depots are metabolically active and contribute to insulin resistance through excess fatty-acid delivery, inflammatory signalling, and disruption of normal insulin action.

As they shrink, muscle and liver tissues become more responsive to insulin, so the pancreas no longer needs to secrete as much insulin to maintain normal glucose levels.

This reduces the compensatory hyperinsulinaemic state that can exist for years before diabetes develops and decreases the probability that impaired glucose regulation will progress toward overt type 2 diabetes.

Those changes propagate into the cardiovascular system.

Better insulin sensitivity and lower visceral and liver fat are commonly accompanied by lower triglycerides, improved blood pressure, reduced systemic inflammation, and better endothelial and vascular function, thereby reducing several mechanisms that contribute to atherosclerosis and cerebrovascular injury.

GLP-1 receptor agonists also have a direct metabolic action independent of weight loss: when glucose is elevated, they enhance pancreatic insulin secretion and suppress inappropriate glucagon secretion, improving glucose control without forcing insulin secretion when glucose is low.

The overall effect is therefore a combination of an immediate GLP-1-mediated improvement in appetite and glucose regulation followed by progressively larger downstream effects from weight and fat loss, which together reduce the metabolic and vascular abnormalities associated with cardiovascular disease and, over much longer periods, potentially with dementia risk.

My wife has hardly lost any weight from Zepbound but she went from having such intense back spasms she could maybe walk a few hundred feet at a time to being able to easily handle a week at the Disney World parks on foot. Before she had to rent a motorized scooter. Absolutely life changing for her.

All my immediate family members are obese. I'm not (BMI 24.5, borderline overweight at the high end of normal, highest lifetime BMI was 29.5), but that's through strenuous, exhausting effort over decades. I also exercise regularly, though I've learned over time how disconnected exercise is from weight management.

At my weight, I'm not a candidate for going on a GLP-1. I'm sure I could find an unethical doctor to prescribe it if I looked hard enough, but I don't want to have the downsides hidden from me.

My weight has been steadily ratcheting up over the years, since I don't have as much room in my life as I used to for living with the discomfort of caloric deficit. If that continues, I will probably become a candidate for GLP-1s, like my immediate family members, just after a decade or so of possibly unneeded striving.

Lots of people are in situations far worse than mine, so I don't feel unlucky — but it would be nice if there were a clearer path forward. While lowering risk for Alzheimer's is not a priority for me, other effects of GLP-1s sound extremely enticing — especially reports of reduced food craving.

That is the question now. Some studies have some early evidence that GLP-1s might reduce inflammation markers a little more than weight loss alone.

Giving GLP-1s to normal weight people doesn’t work well because they can have to work harder to maintain their weight. That can be a real problem as people get older where maintaining muscle mass is important for quality of life and longevity. I remember how hard it was to keep some of my grandparents at a healthy weight, so adding a GLP-1 to a non-obese elderly group is a no-go for study purposes. Going to be hard to separate these effects out.

> So has anyone managed to separate the effects of semaglutide from the effects of weight loss?

I was looking for that in particular. The study does say:

"To assess whether the observed effect was mediated by weight reduction, we performed a sensitivity analysis adjusting for change in BMI from baseline to week 104. In this adjusted model, the treatment effect coefficient was attenuated from β −0.092 to β −0.066 (P < 0.001), corresponding to a reduction of 28% in the estimated effect size. This attenuation indicates that 72% of the treatment-associated difference in 20-year dementia risk persisted after accounting for BMI change, suggesting that mechanisms beyond weight loss contribute to the observed proteomic signature modification."

With all the research into dementia and its causes, if there was a simple strong link to overweight I can't imagine that would not stand out in the data and be well known by now.

Edit: although, there are well-known links between overweight and a lot of negative outcomes, and yet people are still too fat.

Semaglutide was invented in the early 2000s. Weight loss is an extremely complicated and societally mediated problem that we didn't have a 'cheat code' like this for until recently.

GLP-1s seem like a night and day difference in intervention adherence though. For various obvious and non-obvious reasons, it’s very hard to produce an intervention that people will adhere to to make the test group lose weight.

What should public health have done differently?

It’s been no secret that being fat is terrible for us. It’s getting people to actually eat less is the hard part.

that is the interesting question. also the effects of weight loss vs. the effects of disengagement with the engineered to be addictive "food products" side of the western diet.

Even more so. Not absolute weight loss but the effect of loss of the systemic inflammation due to a surplus of visceral fat which has significantly more systemic effect than subcutaneous fat or other types of loss of mass.

> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker

Public health has been trying to get obese people to lose weight forever, what are you talking about. We've known it's bad in enough other ways. It was just really, really hard (at a population level).

Alzheimers dementia is sometimes called type 3 diabetes, so it may be both.

There are some effects of GLP-1s which definitely cannot be explained by weight loss. For example, some patients report that they lost their compulsive habits - gambling, shopping etc. In some, the effect is so extreme that it flips into outright anhedonia, an inability to enjoy anything.

GLP-1s are ultimately treatments that act on our neurohumoral regulation, and hormones tend to have a lot of functions all around the body. Claude would say that the expected "blast radius" of fiddling with hormones is much bigger than that of just losing weight.

Dementia aside, there are plenty of very obvious reasons we should have been discouraging obesity and encouraging healthier eating and lifestyle habits.

Lobbies and general government ineptitude have been a problem longer than obesity and that one needs to be solved first.

But... the profits!

it is a little disappointing that public health didn't act quicker - lots of people have been overweight for a century now, so literally 10's of millions of people could have been saved from dementia had action been taken 100 years ago

Given that the drug did not exist until only recently and it took decades to develop with the latest of technology, I don't see how this could have been possible. Stomach surgery has been around for 50 years though, but it's a bigger undertaking than an injectable drug.

>> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker

I imagine people hundred years in the future will think of our current society rightfully as dumbfucks. But should we be surprised? 50 years ago women didn't have voting rights; homosexuals were incarcerated in western societes; all because of moral and power implications of some powerful men. Not much different with Semaglutide.

Well, if you consider that is much cheaper to eat trash than healthy, and that food companies' only interest is in maximizing profit, you have what we have.