Semaglutide linked to lower predicted dementia risk
alz-journals.onlinelibrary.wiley.com
alz-journals.onlinelibrary.wiley.com
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.
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.
With my labs at my current weight you can not tell that I am a type 2 diabetic. Previously, when I was at this very same weight in the past - all my labs indicated I was prediabetic.
Semaglutide and glp1s resensitize it which is why they have these effects.
My opinion
I've been wary of using online pharmacies due to concerns with knowing what's legitimate and what's not, so maybe a recommendation would help.
If you don't want to share publicly, can you put you contact info in your profile and I'll reach out to you?
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.
If the benefits are as big as some estimate, the added longevity and productivity will lead to more than that much economic benefit to the nation.
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.
TLDR; I'm a Fungster: https://www.youtube.com/channel/UCoyL4iGArWn5Hu0V_sAhK2w
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.
I got a concierge doctor who absolutely evaluates what I ask for skeptically, and pay for my GLP medications out of pocket, so I feel ethically totally comfortable with this position. The downsides are real and significant, it's not a "fun" medication, but just the change in how I feel is worth every penny, let alone the massive reduction in heart attack risk, liver enzyme numbers, and so on.
Quit the Wegovy and added a low dose of bupropion, and all of that reversed in a month.
I am overweight, not obese, have an A1C of 4.7, and run regularly. I've never had food noise. YMMV.
That said, I'm extremely prone to side effects, most people I know who have tried them started at maybe half the standard dose and had zero side effects at all. I'm the best possible guinea pig for these things, because if I can tolerate it, almost anyone who isn't frankly allergic or something can.
The other downside, obviously, is injections - you will need to learn how to use sterile technique to inject yourself or pay the incredibly high costs for the pens. The pills are also an option but I have no personal experience and their bioavailability is so low I don't know that I fully trust them.
They will completely change your relationship with food and alcohol, too. Your tastes will probably shift, nearly everybody I know who is on them has essentially given up booze (maybe a couple drinks a year, more or less)
I'd say the only unethical doctors here would be the ones not prescribing it for you based on your description of your life and needs.
Guidelines are guidelines, not strict rules for a reason. BMI is not the end-all measurement to decide if you are a candidate for these drugs.
Find a competent doctor who understands GLP-1s and you might be surprised.
But I've been thinking about this for a while and I'll talk to him anyway about the prospect of going on a low-dose GLP-1. If he's unreceptive then I'll ask about how to find a trustworthy out-of-network physician who isn't bound by the same incentives.
If you feel unable to fix your diet without it, and you think it's safer to get on it, why not make it happen?
FWIW, BMI as low as 27.0 is on-label ish, so if you went to an ordinary doctor with some rocks in your pocket you might be able to get a prescription relatively easily. I got a prescription from my GP with a nominal BMI right around there (I didn't take my shoes off or empty my pockets for the scale).
At most I was 24 BMI and I felt like a fat bastard during COVID. Work from home in sweatpants and I got up to 24 BMI. 77-78kg, 182cm. I just did not weigh myself so I actually did not notice I had gained! But I did and decided to do something about it.
But I lost the weight pretty quickly.
I grew up at 60-65kg and that is where I feel at home in my body. I feel like myself basically.
I should add I am 35, so certainly no spring chicken.
"omg how did you lose it"
Very easy.
1. Weight loss is done through diet, not exercise. Exercise is great for the body, but not a primary weight loss.
2. If you work an office job you do not need 3 full meals a day. Eat a light breakfast, a full lunch and a light meal for dinner.
3. On the weekends, fast. If you are committed, this weekend, buy like 4-5 litre of sugar free/diet soda, flavoured water zero calories, and caffeine pills. To distract yourself, play a high dopamine grind game like Diablo IV, PoE, Borderlands, WoW/FFXIV, CS, Valorant etc.
Just drink, do not eat. Hunger is temporary and will last like 1h for me, then the body "gives up". Do a 24h or 48h water fast, you will drop 5kg easy and feel way less bloated. Repeat next weekend...
Set an alarm every 2-3h to get up and walk. Get your 10k steps in everyday by walking outside.
"omg that's unhealthy"
Yes, ofc but it is more healthy than being overweight or close to overweight, agreed?
"you can only do this because ur a Swedish chad and you have walkable cities!!"
I'm a degenerate gamer.
Bad sleep also worsens my diet and makes me more hungry.
For me to have a healthy lifestyle I need to treat my ADHD first and quit multiplayer games.
What issues do u have with it.
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.
They seem to also act on some reward mechanism - making some stuff (not just food. Alcohol, gambling, porn, smoking, other drugs have anecdotally been reported to feel less attractive / addictive) have a reduced pull on one's will. They also measurably delay gastric emptying - to the point that some medicines, meant to be taken on an empty stomach, are not safe to take within up to 3 hours from the last meal, compared to one hour or so for other people.
Which are vastly overblown. I diet every year as part of bodybuilding, at a range of intensities and durations, and have never had issues with sudden metabolic changes that make it harder to lose weight.
Edit: although, there are well-known links between overweight and a lot of negative outcomes, and yet people are still too fat.
Obviously, 75% of Americans do not develop dementia. Do more who are overweight develop dementia than those who are not? Well...it's hard to say when 3/4ths of the population is overweight.
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."
It behaved similarly but had a half-life of only a few hours. It required daily injections, and you could feel its effects wax and wane throughout the day.
Foods with both sugar and fat make you gain weight, e.g. ice cream is 50% sugar 50% fat. Eat ice cream every day and you'll only gain weight.
The only "social problem" we now have is that women are on a power-trip rebelling against the men who used to keep them honest about eating. Hence "body positivity" from feminists.
What does treat them like cigarettes mean? Tax them? Ban them within 15 feet of a building entrance? Put warning labels? Is giving or selling French fries to children a crime? Does this apply to food made at home?
A typical burger meal is definitely processed food because the meat is processed mechanically and mixed from different sources (usually with added fat); the bun is made from refined flour and refined oils; and the fries are thinly-cut potatoes blanched and fried in more refined oils. (Not to mention a whole bunch of chemical additives which are the norm rather than the exception; and "hyperpalatability" tweaks which means the food is formulated to taste unnaturally good.)
You could perhaps argue that a home-made burger meal made using whole cuts of meat, a lean wholemeal bread dough, and potatoes roasted in animal fat could count as a healthy/whole food meal, but it would taste different to the typical hamburger meal we all associate with fast food.
Fast food also has an enormous marketing industry behind it which pushes it in unhealthy volume, with maximum convenience, and at (until recently, at least) affordable prices.
Yes, this is all junk food. It's not that difficult.
Eaten in moderation these things are fine. But they are highly palatable calorie dense meals that are not great for you over time and in huge quantity. A burger is generally speaking a burger, regardless of how fancy. Deep fried stuff is deep fried, regardless of the cut of the vegetable or how organically it was grown.
Your latter question is far more interesting to me. I don't have a solution for that really. Society gets what society demands. I don't know how you'd fix those incentives without seriously horrible second and third order effects.
I think the former makes much more sense than the latter, since it is literally being funded by the govt. That's a reasonable first step, or possibly only step, especially considering that most people on food stamps are also on govt-funded/subsidized healthcare (meaning taxpayers will end up footing the bill when they require expensive treatments resulting in part from an unhealthy diet).
Even today, a Soda with 'real sugar', at least for me, is far more satiating for thirst or a 'quick sweet treat' than the same brand/'flavor' using corn syrup, that includes both the big chains as well as the local names.
If I drink a soda with sugar in it, I usually wind up wanting water after. If I drink something with corn syrup, I usually just want more of whatever I just had.
Seriously though, it's a dogshit thing to consume whether it is sweetened with HFCS or sucrose.
"Even today, a Soda with 'real sugar', at least for me, is far more satiating"
Did you know that in the acidic environment of a cola, sucrose quickly degrades into fructose and glucose (and if it didn't, your enzymes literally immediately crack sucrose into them). You know, exactly the same fructose and glucose that would be added by HFCS. The proportions differ a tiny amount, but this notion that one is satiating and the other isn't should really send you down a path of self-discovery, where you determine how you fell for nonsense.
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.
Proper sleep, eating less (including liquid calories), and exercising have been the mainstream medical advice for many decades.
Obviously, most people can’t accomplish that for whatever reason, so another solution was needed.
did western society engineer a junkfood-industrial-complex so addicting and so en-sickening that it ultimately required a sort of junk food methadone to wean itself off?
Lobbies and general government ineptitude have been a problem longer than obesity and that one needs to be solved first.
I've never really read much about people using it in this way though and I'm somewhat risk averse, so it's easy for me to keep procrastinating on getting the prescription.
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).
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.
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.
Where are you? In the US, women have had full voting rights for over 100 years.
Many many times in US history we've said something is true, but put some big asterisks after them. Slavery is over (except it's definitely still permitted in the US), it's illegal to discriminate based on race (except we allowed redlining for generations and arguably are still fighting it), rape is illegal (unless it's your spouse, then it was legal until '93. And a lesser crime still in much of the country).
Voting is no different. Heck, one might argue we still don't have universal suffrage. People who want to vote but because we've put barriers like underfunding stations, long lines, not giving time off to vote, etc. we're clearly preventing some types of people.
Good news: the readers of your post don't have to wait 100 years to have that thought.
When I grew up relatively poor we never ate out or ate junk food because it is ridiculously expensive in comparison. We made our food from cheap ingredients. To save money.
Yes it takes more time and is far more work and is less convenient. US society has valued convenience over everything else for a few generations now. Cheaper it is not.
And it holds true today with my own grocery shopping. Cooking meals and being smart about grocery shopping is far cheaper per meal than buying premade junk. The few times I do have a cart full of products from the middle aisles I am astounded at how expensive it is.
If people are working crazy hours, sometimes it's a struggle to even get time to properly shop for groceries, let alone cook. There's varying degrees of that too;
i.e. I remember the 3-4$ frozen pizzas that could be used as a dinner and leftovers; And yes, at least back then, We could instead buy some chicken, rice, and a can or two of soup or stock to do something way healthier, at the same overall cost per meal...
But it would take an hour or so to properly prepare instead of just tossing that 3-4$ frozen pizza into the oven and letting it do it's thing.
Then throw into the mix where both partners due to work and/or school aren't even home till 8PM, and one of them has to wake up by 7AM to get to work the next morning [0]
I've lived that situation, although thankfully that wasn't every night and we could balance between the healthy self cooked option and the junkish-food-pizza.
But I've also lived the situation where both parties are working late, or the commute is so bad, you're glad you advanced enough you could afford the more expensive, but at least then managable 'taco bell' option.
But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm [1]
[0] - You don't want to eat too late for other health reasons of course...
[1] - And yes, that group really does tend to be less healthy overall from my personal experiences, even if their dining tastes are 'expensive'.
The average American spends 4-5 hours a day on personal screen time, and this skews higher the poorer you get based on a few studies. I've found from talking with folks on the subject many of them are the ones glued to social media and/or the TV.
I agree it's much more convenient to toss a couple pizzas in the oven. I do not agree it's less expensive. I don't know where you're buying your rice or chicken, but even at $4/pizza I can't pencil that out. Chicken comes with free chicken stock if you're buying $5 rotisserie chickens (or whole chickens) and keeping the bones and vegetable ends/etc. around for stock making. This is the level of poor I was talking about. Even at $2.69/lb (the price I paid ~3 weeks ago) for chicken breast, it's going to be cheaper to feed two people than split a whole pizza. Rice is less than 30 cents a serving bought in bulk 50lb bags from a local ethnic store. $1 of rice and a $5 chicken is going to feed around 3-5 people, or give 1 person a lot of leftovers.
I agree one cannot live on just chicken and rice, but one cannot live on just the cheapest frozen pizzas either. I've kinda done both during my life. I lived probably a decade on junk food because I was either too busy or too lazy to do my own cooking like I did growing up. But this was after I started making IT money and could afford it.
> But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm
I definitely agree with this one. Habits and skills are passed down generationally. Someone may not even know where to start looking at youtube for how-to videos to make their own chicken stock for close to free with a $5 crock-pot from the local thrift store these days. And that's probably intermediate level cooking skills, much less beginner level. My wife and I joke about our "depression era cooking" hobby.
I agree there are exceptions, nuance, etc. to this topic. But I get so tired of folks pretending eating home cooked meals is somehow more expensive than an equivalent quality prepared meal. Yes, you can spend as much as you want cooking at home. But the same is true eating out or buying pre-made stuff.
The time factor is certainly very true though. You get much better at it as you practice over the years, but it's always going to be easier and faster to just toss some chicken nuggets into the microwave and be done with it.
This is not moralizing or anything like that. I have lived well over half of my adult life eating junk, and only since getting married to a partner who loves cooking have I turned this back around to my childhood experiences. And we certainly do not optimize very hard for cost - just smart choices by buying stuff on sale, in-season, and in bulk when it makes sense to. I just really cannot square the claim to reality that it's cheaper to eat junk food than it is to eat moderately healthy at home. It's one of those Internet social media memes that just becomes truth by repeating it so much.
Price out a bag of rice, a bag of beans, etc.
> food companies' only interest is in maximizing profit
Pleasing your customers is how profit is maximized.
Besides, I bet if you were faced with two stores, one that charges $x for A, and another that charges $(x-1) for A, you'd patronize the latter store.
A Hershey's chocolate bar is $3.99-$4.99. A banana is maybe 50 cents.
At least 10 to 15-ish years ago, I would actually be closer to agreeing;
You could get Cube or Chuck steak for 3-5$ a pound and potatoes were cheap as hell too. Toss some diced onion in and You'll have a good dinner.
How do I know? Well I grew up in a family where for... reasons[0] we were not that well off for quite a while.
Cube Steak was one of the big things we did for a family meal that Dad cooked. (Chili was his other favorite to make, which was also cheap to do for how much food came out of it...)
However the current prices of beef, I feel like you'd need to have a long standing personal relationship with a local butcher or rancher to make this true.
[0] - My mother's over-propensity for being truly Christ-like in her charity to family and others, also sending myself and my three siblings to Catholic school to avoid the then-absolutely-failed Detroit Public school system were major factors.
While we're at it, on the $5 Hershey's bar - Walmart has a 7.56 oz (214g) one for $4.52 [1] which claims to be eight servings so again obviously just like a single banana.
[0] https://www.walmart.com/ip/Doritos-Nacho-Cheese-Tortilla-Sna...
[1] https://www.walmart.com/ip/Hershey-s-Special-Dark-Mildly-Swe...
If you ignore everything like, including but not limited to, market capture, addictive products, lock-in, information asymmetry, planned obsolescence, dark patterns, captive markets, artificial scarcity, seldom-lucrative-yet-important services and any externality, very true!
Only question is do you want to spend 1 hour making it and cleaning up.
I lost 40 pounds in a year(230 to 190) at age 50. Great! I also went from being active and fat(weightlifting with some cardio) to basically having no energy. In the last year I've had arthritis appear in several joints. I'm awake several times a night to pee(yeah, prostate is acting up but I still void completely. The semaglutide is like a diuretic for me at night.). I get waves of hypoglycemia like feelings where I feel weak and spaced out. I'm afraid to get off of it because now my joints can't handle the extra weight. My doc recommended going to every other week now that my BMI is normal but as far as I can tell that advice isn't backed up by any research. Anyway, it's a powerful drug that works well but is not without side effects.
I do have some of it down to unwisely taking Ibuprofen semi-regularly, i.e. Kidneys, bladder.
That said the dementia benefit mentioned in the article still intrigues me.
I feel like we’ll eventually find out that how well GLPs work is going to depend on the “why” someone has extra weight.
> decided that I wanted to err on the side of overeating
The reason you bonk is because you've run out of sugar in your muscles not fat
It’s definitely one of, if not the most, currently focused on aspects of endurance sports outside of the actual training.
I was a fat kid growing up. I've had a BMI of 30±1 since age 12. I also have a family history of heart disease. Literally every male on my father's side for three generations has had a heart attack in their late 50s. We all have roughly the same body type. I already had hypertension in my mid 30s. Semaglutide has made me feel like there's hope.
Unfortunately, I can relate to the lower energy levels. While I'm no longer lugging an extra 40lbs around (a full pack!), I still bonk way faster. My gym sessions are way shorter. Luckily, I haven't lost much muscle mass, so I look great and it's been the "cut" I've never been able to achieve, but I'm sure if I ever wanted to "bulk" I'd have to go off it. I've found if I have a big trip or climb coming up, I have to take a way smaller dose the week, or even weeks, prior. I found this out the hard way when I puked on a climb in North Cascades. I just couldn't eat, and felt like shit the whole time.
The trick has been self managing my dose. I'm on compounded generic, so I can dose myself with my own needles. If I have a big trip coming up, I'll take like 25% of my maintenance dose for a week or two prior. This has been almost a superpower, because I'll get this massive burst of energy from the calorie intake. Im still not really sure if this is healthy, not the "taking 25%" part, but the fact that I feel like superman when I'm off it or on a low dose for a bit. Not sure what this says for someone who is basically taking semaglutide because their weight was holding them back from the activities semaglutide makes them too bonked to do anyways.
As a former Climber, moved to an area that doesn’t have a decent rock Gym and bought a house, this is inspiring. I have a chance to climb again and it will require losing some weight loss. I’m just a hair into the overweight category at the doctor.
One question: how tall are you?
However, I started a new position at a startup which is very heavily invested in agentic development, to the point where I basically just drive claude and codex all day long, and haven't written a single line of code for work in 9 months, and that may be causing some cognitive decline...
Eating less can have positive effects (losing weight), but can also make you feel like shit (in a wide variety of ways), as your body is running on less energy intake than it has been accustomed to.
Depending on your activity level and the makeup of your diet, eating less can also lead to muscle loss and nutrient deficiencies.
Also, do you cut pills? I had looked into this and only found info saying that it ruins the delivery mechanism. I was skeptical of this because it would benefit the pill makers to convince people that these special pills cannot be cut, even though they do not require extended delivery (quite the opposite).
Lower the dose (with your doctor, of course). For me, the “middle” dose was the sweet spot of positive effects with minimal side effects.
You are likely a “hyper-responder” to GLP-1s.
Also, tirzepatide had far fewer side effects for me, fwiw.
YMMV, of course.
As a slim person naturally, I see these drugs as cheating and I hope they are all not good.
We need some markers for separation, clothes are another good one. I am "dressed up" for wearing chinos and an OCBD lol.
It's why you order a decent amount of it (e.g. 2 years supply, it lasts forever in a freezer) and pay for your own randomized testing of the batch you got. You go direct to the source, not via the middle men selling it for 10x markup on a per-vial basis.
Certainly not perfect, and it adds significant cost - but still way cheaper than the regular sources via pharmacy for Zepbound.
I'm not convinced reta really shows that greater of results than tirz though. YMMV significantly here. Tirz is already so effective you are chasing marginal gains for the most part.
The problem is I'm too skinny now to get it!
Getting the person to a caloric deficit is already 90% of the work. And that will make glucagon rise
As a consequence I ate less. Weirdly, I think I eat more sugar now but my total calorie intake is lower. I eat more sugar because sometimes it's the only thing that seems palatable or I'm trying to counteract the hypoglycemia feelings.
This extra receptor is why Reta is a triple agonist unlike semaglutide (single glp1) or tirzepatide (glp1+gip double agonist).
"A predictive biomarker is like a "check engine" light on your dashboard. It warns you that there is a risk of a future problem. In this study, the researchers only checked if the drug turned off the "check engine" light (by measuring blood proteins), rather than testing if the car was actually driving properly (by testing the patients' actual memory and brain function)."
Always do FIRST analysis on studies. Or have AI do it for you. I used Gemini to dig into this:
"Novo Nordisk funded this study, and several of the researchers are employees or minor shareholders. While corporate funding doesn't automatically mean the data is fabricated, it does mean the company is highly motivated to find and publish data that makes their blockbuster drug (semaglutide, marketed as Wegovy, Ozempic, and Rybelsus) look like a preventative treatment for a wider range of conditions, expanding its market and driving up profits."
"Funding: The study was funded by Novo Nordisk A/S.
Investigation: Researchers conducted a post hoc analysis using data from the randomized, placebo-controlled SELECT trial. They applied the Dementia SomaSignal Test (dSST)—a 25-protein risk score—to non-fasted serum samples collected at baseline and at week 104 to estimate 5-year and 20-year all-cause dementia risk in patients receiving semaglutide (2.4 mg) versus a placebo.
Results: Semaglutide significantly attenuated the progression of the dementia risk signature. Compared to the placebo group, the 5-year predicted risk increased 2.5-fold less (a 26.0% lower predicted event rate) and the 20-year risk increased 1.67-fold less (an 8.8% lower rate). Semaglutide also lowered the odds of patients moving into a higher dementia risk category by 36%.
Subjects: The analysis included 2,970 older adults aged 65 and older (mean age of ~69.7 years) who had overweight or obesity and cardiovascular disease, but no history of diabetes. The cohort consisted of 814 women (27.4%) and 2,156 men (72.6%).
Time: The study evaluated data over a 104-week (2-year) follow-up period. The analysis was published on August 8, 2026."
And then map the weakness to each respective letter if you want to dig deeper.
You act like all this is hidden, but the title of the article and the list of authors makes this self-evident.
> Novo Nordisk's actual dedicated clinical trials for Alzheimer's completely failed to show that semaglutide stops cognitive decline
Sure, but the EVOKE studies were focused on something that could be sold as a product covered by insurance: semaglutide to those who had already developed Alzheimer’s. It is widely agreed the trial failed because it was a population already diagnosed with dementia. There’s lots of studies not funded by Novo that show semiglutatide has reduced the incidence of dementia in the diabetes population. Novo knows that running a general study on whether semaglutide reduces dementia in a non-diagnosed population is useless to their bottom line because insurance will never pay for everyone to take the drug.
The world could use a bit less nuance in our headlines these days.
Honest question, how could it be made more explicitly known? It's literally under ACKNOWLEDGMENTS, in the most clear language possible.
They funded this study as a prospective way of increasing the adoption and market share of their trademarked medication. It deserves skepticism.
I think it's hard to argue "The medical establishment" ignores diet as an important factor.
I think the reality a lot of the time is doctors prescribe something to help. They can't force a diet change on a patient, and they're not mutually exclusive interventions.
If you can administer a treatment as a simple one and done thing, that's alright. If it's a pill you got to take every day, that's pretty bad. More than once a day? Horrible. Why? Because a lot of patients just don't have it in them to take a pill 3 times a day consistently.
If it's purely an "exercise willpower" thing or a "change your lifestyle" thing? You might as well give up.
The medical establishment wants to do things that work. Telling people "go diet" doesn't work. Semaglutide, evidently, does.
We can call it the Prohibition II. There will be underground bars with sick people binging on sugar. We can change the shape of sugar to prevent restaurants from adding it to food. We can make it bitter. Absolutely need sugar? Eat that lemon-tasting block. We can call it The War On Sugar.
Don't believe me? Next time you go to see your primary care physician, ask them what you should be doing to lower your risk of whatever malady tends to run in your family. (Diabetes, cancer, dementia, etc.) They're going to stare at you in blank confusion for a few seconds before making some vague suggestion about a better diet and more exercise. Guaranteed.
The reasons are many, and detailed enough to write MANY books about, but the low hanging fruit is: we don't have a culture of monitoring and improving our own individual health, physicians are trained almost exclusively to solve problems not prevent them, modern nutrition science is a joke, omnipresent health insurance distorts incentives for everyone, doctors are too overworked to get to know their patients, private equity has captured a large chunk of health care, drugs are positioned as the first line of treatment for almost everything, etc.
The medical establishment isn’t ignoring this at all. They’ve been pushing for healthier diets forever. Primary doctors have always been pushing for healthy eating.
That doesn’t mean patients welcome the advice or follow it. Everyone knows that eating high sugar diets and being overweight is unhealthy.
There was some short-live resistance to the idea that being overweight was unhealthy, but that wasn’t coming from the medical establishment. That was an anti-science, anti-medicine movement that went mainstream under a misplaced desire to not make anyone feel bad in any way. That movement has lost steam quickly as an easier option has appeared for reducing appetite and inducing weight loss.
I don’t understand how you’re trying to twist this into a claim that big pharma is ignoring the impact of unhealthy eating. GLP-1 drugs work by reducing unhealthy overeating and cravings for unhealthy foods.
1. BMI was basically just pulled out of a hat, and it turns out that for many health concerns, the overweight class does better than the normal weight class, with the actual “clearly worse” outcomes really coming up as you trend into obesity.
2. Environmental and genetic factors are huge contributors to people being overweight. To some degree moralizing about weight loss is a bit like telling kids with asthma they should live in places with less pollution. Or telling someone with breast cancer to not have the BRCA gene.
3. Doctors would regularly miss health problems because they’d blame them on people being overweight / not exercising enough. Especially for difficult to diagnose issues, it’s easy to just point at the number you have that “looks bad”.
4. We still have no firm reason why people are gaining weight. The popular answer is sugar and processed foods but those very much already existed at scale in the 50s.
The tragedy is that it turned into a morality play where fat people were blamed for it, despite in many ways being as genetic as getting breast cancer.
The reality is people who actually study obesity know that basically GLP-1s are the only health intervention other than bariatric surgery that consistently works. At a population level no intervention has reversed fattening anywhere in the world.
There is a lack of evidence that the public understands what healthy and healthy effectively mean to their day to day lives,
aside from “looking better”.
"The medical establishment and big pharma simple ignores the fact "
Do you really think the "medical establishment" hasn't been *screaming* about poor diets for decades? The fact that people ignored them doesn't give you an opening to suddenly spout horseshit. And big pharma has had an enormous focus on blood sugar for decades, and you're here yipping like they just want to sell you boner pills. What bizarre world is this?
> the "modern" high sugar diet that Kellogs introduced in the US and spread to the western world (even to Asia at some extent).
Kellogg? Did you know that white rice has a glycemic index significantly higher than table sugar (because, as previously mentioned, fructose is not a blood sugar)?
Yeah, a lot of people have bad diets, but infinitely more pressing is sedentary lifestyles. The reason Asia gets away with a rice-heavy diet (which is almost pure glucose, in a very simple form), though this is turning the wrong way, was busy, active lifestyles. The biological reality is that eating a big bowl of frosted flakes is perfectly fine if you follow it up with high amounts of activity.
Glucose is quite literally fuel for your body. And it's fine if you're actually using that fuel, but becomes a problem when often the overweight (and insulin resistant) and sedentary flood their blood with glucose, with nowhere for it to go.
It is also a large contributor to rising triglycerides levels and uric acid due to the way it is metabolized. Which in turn contributes to high blood pressure. It also makes Acetyl-CoA, which stimulates lipogenesis.
It is not even true that it is 'blood sugar invisible'. 30-50% of the fructose is converted in glucose and that's visible. The rest won't be available until you start burning fat.
> Yeah, a lot of people have bad diets, but infinitely more pressing is sedentary lifestyles.
No, that's only part of it. And a small part at that. The world didn't suddenly decide to get less active all of a sudden. You can blame some of the sedentary behaviors on societal changes (like suburbs and car dependency in the US), but other countries are getting just as unhealthy, metabolically speaking, and fat.
> The biological reality is that eating a big bowl of frosted flakes is perfectly fine if you follow it up with high amounts of activity.
It has to be really high. We are talking about hours to burn up that bowl of frosted flakes. Spend an hour at a treadmill, calculate the calories you spent. Now check the nearest cereal bar nutritional information. You'll be in for a surprise. You cannot outrun a bad diet.
Diet is most of what needs to be controlled for metabolic health. Resistance training will build muscles, and they are a good buffer since they will eat simple carbs even when you are inactive. Add cardio for cardiovascular health. But, unless you are an athlete or you are active the whole day, you should go easy on the frosted flakes.
In many ways, yes it did. There is a shocking decline in active calories in every developed country, and it has been exported to the developing world as well. People are astonishingly lazy, on the average.
Like, Christ, it's so bad that the recommendation to take a brief, slow walk after meals is revolutionary now. Because the average person just waddles to their chair and then "digests". It is astonishing how lazy the average person is in many countries.
>It has to be really high. We are talking about hours to burn up that bowl of frosted flakes.
I love that you declare that I'll be "in for a surprise", as if you're educating me. Hilarious stuff.
In any case, really high is...a bit of an exaggeration. I cycled 30km this morning, at the crack of dawn. A fairly casual, 20km/h or so ride down to the lake and back. That's an estimated 900 calories, or about three bowls of frosted flakes with milk. And the fun thing is that I didn't even eat this morning and did it purely on glucose reserves. This wasn't some athletic thing and was very much a casual "catch the end of summer" thing. Actual athletes absolutely destroy those numbers. People engaged in basic recreational sports destroy those numbers.
And that bike ride is something people would do just getting to and from places in the not to distant past. Where people were constantly moving and doing. Now most of the readers of this comment will have done nothing today beyond moving from seat to seat in various transporters and digestion chambers.
We've all been around someone who is spectacularly lazy who'll tell you about their "metabolism", and who'll jealously jeer when a peer eats without concern and somehow stays healthy. In the vast majority of cases, the latter person is active in their life, and the former person is one of those seat-to-seat people. Being active impacts every facet of your life, and endless choices throughout the day, and it yields an enormous impact on your health.
edit: meant to address the fructose. The fructose converted to glucose does so slowly enough that there is a marginal impact on blood sugar. And the average person consumes multiples more glucose than fructose. Should people consume less fructose (ergo sugar, even if the current admin is trying to healthwash sucrose)? Absolutely. But glucose and simple carbs are the biggest vehicle towards blood sugar and overwhelming glucose reserves.
More broadly, diet is a frustrating modifiable risk factor - there are lots of studies suggesting the (somewhat nebulous) "Mediterranean" diet is protective, and beyond that, omega 3s.
But human diet is uncontrolled, highly varied, and reporting is difficult to obtain and unreliable (people don't want to admit what they ate), so a lot of these data are seen as interesting, promising but unconfirmed.
1. It makes sense for companies that profit from their drugs to use their profits to also commission such studies.
2. Faking data or causing harm exposes these companies to total black swan events for which they will pay dearly so they often have incentives to release anything that might harm their patients.
There’s already tons of correlation published for semaglutide lowering rates of dementia. This study is an effort at helping find the mechanism beyond the generally also known correlation that losing weight lowers rates of dementia.
Proving correlation but not causation does NOT rule out causation.
I wish they compared straight-up weight loss without disease. In this specific population, the bias has a known direction: unintentional weight loss in older adults is a well-documented dementia prodrome = weight starts dropping years before diagnosis. So placebo-arm weight losers are enriched for people already on the downward trajectory, and any comparison matched or adjusted on BMI change-diff inherits that, making the drug look better than it should in this study design.
And the 5-year OR 0.74, and no BMI-adjusted coefficient is given for it. The 5-year calibration is dominated by near-term inflammatory/metabolic pathways — exactly what weight loss moves, so it plausibly attenuates much more than 28%.
I think the conclusion is not warranted at all: that semaglutide does more than its weight loss explains, not the same or less. Which is also the commercially valuable claim. And note that Novo funded the study, AND two authors are Novo employees/shareholders.
In short, I like GLP1s, but I'm not convinced by this study that GLP1 treatment reduces dementia incident rates meaningfully compared to normal health weight loss.
Putting this idea in people’s mind, that they will be OK if they don’t eat for a day, would be revolutionary. However, companies want to sell things rather than simply give people a basic idea and open their world to possibilities.
Unpicking the exact chains of causation is likely going to be extremely complex, but the general picture continues to look good.
But if GLP-1 makes you more active, who am I to complain. There's the reason they approve stomach stapling surgeries on morbidly obese people. They are so compromised that anything that gives them a chance to be more active offsets some of the risks of surgery, and the risks of inaction.
https://www.sciencealert.com/common-sugar-appears-to-loosen-...
But you’re also ignoring the fact that the same study shows that glucose inhibits the behavior.
So your claim that the study indicates its sugar is incorrect. The study indicates a possible impact from fructose which is countered by glucose, so the real issue is the fructose to glucose ratio.
Table sugar providing equal fructose and glucose molecules is acquitted by this study.
Babies born under sugar rationing grew into adults with lower cancer risk - https://news.ycombinator.com/item?id=49345843 - August 2026
No, just being sedentary. There's no such thing as acquired diabetes in physically active people.
https://www.tri247.com/triathlon-news/elite/lionel-sanders-t...
Also age plays a pretty significant role. I know older asians who regularly walk who still got T2D. You could argue that walking isn't physically active enough... but they'd argue otherwise. It's all relative.
This year I started Mounjaro and dropped the 50 pounds. Curious to see what my next checkup shows.
Note I am not Western
Being fit is healthier. Studies support the idea that being overweight but physically active is cardiovascularly healthier than being skinny(GLP-1 or not) and sedentary.
It's something we found and started using to one specific problem, but it later turned out that it has lots of other, extremely wide-ranging consequences. Except that in this case, these consequences are positive.
Maybe we should try consuming less in general and see what the effects are. Is there a semaglutide for my shopping habits? Maybe ban ads?
The brain is 60% fat, so I'm not running to the pharmacy yet.
The less appetite you have the less you eat crap. The less crap you eat the healthier you are.
There's a little more to it than that obviously but this is the reason that they're finding all these "unexpected" things improving when people take semaglutide. Most food eaten by most people with access to semaglutide is crap, that makes you unhealthy. Eating less crap improves lots of factors.
But the good news is, eating less crap makes you less unhealthy independent of other factors too.
Two years of semaglutide treatment appears to substantially slow the worsening of a blood protein signature associated with future dementia risk
Just skimming through it, it's possible there are direct benefits, but it could also be other environmental factor. This study will most likely generate others that give us more insight in the future.
At most I was 24 BMI and I felt like a fat bastard during COVID. Work from home in sweatpants and I got up to 24 BMI. 77-78kg, 182cm. I just did not weigh myself so I actually did not notice I had gained! But I did and decided to do something about it.
But I lost the weight pretty quickly.
I grew up at 60-65kg and that is where I feel at home in my body. I feel like myself basically. I should add I am 35, so certainly no spring chicken.
"omg how did you lose it"
Very easy.
1. Weight loss is done through diet, not exercise. Exercise is great for the body, but not a primary weight loss.
2. If you work an office job you do not need 3 full meals a day. Eat a light breakfast, a full lunch and a light meal for dinner.
3. On the weekends, fast. If you are committed, this weekend, buy like 4-5 litre of sugar free/diet soda, flavoured water zero calories, and caffeine pills. To distract yourself, play a high dopamine grind game like Diablo IV, PoE, Borderlands, WoW/FFXIV, CS, Valorant etc.
Just drink, do not eat. Hunger is temporary and will last like 1h for me, then the body "gives up". Do a 24h or 48h water fast, you will drop 5kg easy and feel way less bloated. Repeat next weekend...
Set an alarm every 2-3h to get up and walk. Get your 10k steps in everyday by walking outside.
"omg that's unhealthy"
Yes, ofc but it is more healthy than being overweight or close to overweight, agreed?
"you can only do this because ur a Swedish chad and you have walkable cities!!"
I'm a degenerate gamer. lol
My health took a few wrong turns and I now have a BMI of 30. My diet is just as good, if not better, than back when I was slim. But now my sleep is worse, I tire much more easily, recover much worse from exercise, and, crucially, I am much hungrier.
I no longer preach how simple it is to maintain a healthy weight. I should have known better back then and kept my mouth shut.
I haven't slept a full night in years due to having to get up and pee or waking up for some reason. Maybe sleep apnea but I haven't bothered to get it checked.
My diet is like crap, I eat junk food, sandwiches and chips and zero calorie soda.
Still 19-21BMI now as I weigh myself daily to keep in check. And having been 24BMI back down to 19-20BMI, I know it can be done and how to do it.
Maybe if I am 55 it will get harder sure.
But I just dont get as much dopamine from eating as others I guess. As the thinspo girls on TikTok, Youtube say "Eating is not the main event."
Thank you for commenting as I notice a lot of people just downvote or think I am trolling, but I am honest here but I dont express myself very well.
I am cought between two worlds, I am not smart enough to be here really, but not dumb enough to start commenting on TikTok. I belong on 2009 Reddit but that Reddit is long gone... thanks for letting me ramble. Hope the mods dont come and get me again.. u.u
Turns out knowledge doesn't work very well, or rather loses efficacy in certain environments. Individuals can vary in their ability to regulate the hunger response signal they feel, which is stronger with higher weight (as your body now needs more calories to maintain its larger size).
GLP-1s don't appear to have such an efficacy loss and do work well. Sometimes with minimal to no side effects.
Your arrogance shows you don't understand population level weight gain, or the biology of weight loss difficulty. Obviously calorie deficits lead to weight loss. But that isn't the hard part. It never was.
Here in Sweden only 5% smoke now.
40-50% used to smoke in the 60s.
It's like we have forgotten how to change peoples behaviours? Even when the answer is right in front of us in the past.
Growing up in the 90s and 00s "never smoke" campaigns were relentless and it has born fruit. Thankfully, also my parents never smoked and instilled how bad it is. But the public campaigns, the smoke packet images, the price increases.
So yes a lot of it is global incentives.
But you can still be an individual.
Same with clothes, growing up everyone wanted to be black in 2005 or emo. I had to re-discover good menswear like OCBDs and chinos. It does take some effort.
So, I like to see it as a differentiatory. Yes most is environment. I grew up with a skinny and active family. In a Swedish city. Truly obese people are rare and something IS wrong with them. Mentally and/or physically. You cannot just give up and blame everything else.
Summary from you feels like: "aaah help the food is teleporting into my mouth heeelp!!"
I would honestly love to have a discord or phonecall with all disagreeers with my points.
Cheers!
ie : clinically meaningless.
The company behind this, Novo Nordisk is increasingly desperate, as tirzepatide destroys the semaglutide revenue stream and the consequent job losses decimate the company
They have launched new semaglutide oral products which are growing faster than previous products, and they have multiple drugs in the research pipeline in late phases.
I wonder if that may be the root of a lot of these changes we are seeing and might provide more clues into what might be possible with them.
That’s not correct. GLP-1s interact with satiety (fullness) circuits and reduce appetite. They also have minor effects delaying gastric emptying, meaning the stomach stays full longer.
There is some early data suggesting that they might reduce some inflammation markers slightly more than weigh loss alone, but losing weight and controlling food intake without GLP-1s reduces the same inflammatory markers. The question now is if GLP-1s have additional anti-inflammatory influence.
I don’t know why someone would claim all of their effects are downstream of inflammation. Some people get stuck in modes where they think inflammation is the cause of everything and can’t comprehend causal effects going in the other direction.
This is well established, not at all a question.
> they might reduce some inflammation markers slightly more than weigh loss alone
There's no "slightly," It's going to be a news story for years to come. It's a broad spectrum anti-inflammatory drug of a breadth and efficacy never seen before.
People honest with themselves will understand that it’s a chronic treatment, you don’t stop.
Last year it become known that it increases (high relative risk, low absolute risk) non-arteritic anterior ischemic optic neuropathy (NAION), ie sudden, sometimes permanent vision loss.
https://www.ema.europa.eu/en/news/prac-concludes-eye-conditi...
Diabetics are already more prone NAION. This studies contribution was to show that diabetics on GLP-1's are MORE prone. It does not show that the general population is more prone when taking GLP-1's.
I didn't check to see if other studies prove that.
1) You must have a crowded optical disc as a precursor (low cup to disc ratio). Genetic and can be tested
2) You have stiff veins/arteries due to poor metabolic/cardio health
3) when blood pressure drops too much, blood flow can get cut off to the optical nerve temporarily due to reliance on high blood pressure due to 2
4) Due to loss of blood flow, optic nerve swells and closes blood flow into the eye due to 1
Which you can get checked for via a $50 optical scan.
No crowded disc, very little risk.
(Cup to Disc ratio of 0.2ish or less starts to present risk)
Which to me just sounds like every other addictive drug. Paradise while you’re high, and eventually you pay for it.
Sure, they hit a fucking surrogate, that's sometimes interesting for additional research.
But we have incredibly strong clinical evidece oral semaglutide did not significantly reduce clinical progression in patients with early symptomatic Alzheimer's disease.
if among people not taking it you would see 4 out of 100 get dementia within 5 years of when you started measuring,
if they were taking it you'd instead see 3 out of 100 get dementia within 5 years,
and the number is either a projection ("predicted risk") because they didn't actually study it for 5 years,
or the number is a p-hack because they checked every possible thing they could with the 5-year data they had and this was the only interesting thing that they found ("post hoc analysis"),
or both (the projection of a p-hack), which I suspect because they also tell you about the 20-year risk,
and it is a study sponsored by the manufacturers of the drug,
being suggested to cure a disease diagnosed by checklist (rather than any physical test.)
Will that keep it out of the headlines? No, it was written to become a "free" ad that will be published by the people they send enormous amounts of money to, but by their "news" departments.
The best thing we can do for the progress of medicine in the US is to make direct-to-consumer advertising of prescription drugs illegal again. There would be no use for this if the media hadn't been bribed to become cheerleaders for any old shit. It's illegal everywhere in the world other than the US and New Zealand.