So has anyone managed to separate the effects of semaglutide from the effects of weight loss?
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 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.
Similar experience here on minimal dose of GLP-1. There is definitely something going on here other than "you are just losing weight and that's really why you are healthier".
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.
I really wish my insurance would cover GLP-1s, because I think reduction in fatty liver and other ancillary benefits, along with the weight loss, would be medically helpful for me.
> 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.
Jason Fung has preached against modern processed foods that destroy insulin sensitivity. Even artificial sweeteners can raise Insulin levels. His book "The Obesity Code" is a must read and discusses some of the pathways that link insulin and leptin (a hormone associated with eating)
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.
Speaking as someone who had the same kind of reservations, I think you sound exactly like me, and if I had any advice to my past self, it would be "get on it as early as it's available, start much lower than anyone thinks is sane, and never ever stop".
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.
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!!"
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.
I'm normal weight and am on a low dose (1mg every 10 days) of tirzepatide. I'm able to maintain my weight at this dose, and I've seen improvements in inflammation and other blood markers as well. It's not impossible, it's just difficult to do within the normal health system parameters (specific dosages tested for weight loss, etc.). I use a gray market supplier direct from China and reconstitute the dose myself.
> 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.
Nearly 75% of Americans are overweight. (over 30% 'overweight', over 40% 'obese').
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.
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.
Semaglutide was patented only in 2018. The previous medication was liraglutide.
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.
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.
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.
I'm not overweight but I've been thinking about getting a low does glp-1 for the supposed inflammation improvements which could be neuroprotective. The side-effects seem minor and if it doesn't agree with me, I can just stop since I'm not using it for weight control.
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.
> 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).
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.
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.
> 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
Good news: the readers of your post don't have to wait 100 years to have that thought.
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.
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.
I don't buy that. You can buy a steak and a potato for two for less than a bag of Doritos. A banana costs far less than a candy bar. A bag of mixed nuts will provide many meals.
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.
I'm a big semaglutide proponent after being on it for a year. I know research says it helps with inflammation, arthritis (separately from weight reduction), and all sorts of magical things.
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 had similar issues on Semaglutide, but I've found Tirzepatide much more tolerable. I've lost 165lbs, A1C has gone down to 5, I have more energy at 52 than I did at 32, and I am exercising like a maniac now. Maybe you could try it?
I have a very similar situation: on it for about a year, 220lbs to 180 at age ~40. Also very active: weight lifting / biking / swimming and - the sport that made me realize I needed to loose weight - rock climbing. I've always been very outdoorsy-adventurous, and climbing/mountaineering is the natural sort of "end game" for this lifestyle. My weight never really got in the way of anything else in my life (maybe my self esteem) but, this might offend some people, but climbing is a sport where you really cannot be even a little bit fat. It makes you painfully aware of your body weight. Most "good" climbers are built like bean-poles. I don't really need to be a "good" climber, just an "okay" and safe climber - I'm mostly interested in alpine trad below ~5.7. I still feel like I need to lose another 10lbs.
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.
Thanks for the details, really liked your posting this.
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.
If it makes you feel better I'm 50, and have developed those exact same symptoms over the half decade, without ever having to touching a GLP-1 agonist.
I do have some of it down to unwisely taking Ibuprofen semi-regularly, i.e. Kidneys, bladder.
Is it kind of the stuff where the benefits outweigh the side effects? I'm just scared of the unknowns with the drug with such overwhelming positive research. Maybe, I'm a paranoid person but I'm unable to believe that such a powerful drug isn't without any side effect, clinically proven.
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.
I'm on the pill version, which allows me to adjust the dosage on a more day-to-day level. It also doesn't need a fridge, so it allows me to travel more easily. There's a level that works best for me long-term, and it's quite a bit less than typical.
I thought the half-life was long enough that skipping a pill or taking a lower dose wouldn't make much of a difference?
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).
I’m also active and fat. And to me being active is more important than losing weight; I’d rather continue to do those long 2000kcal bike rides on weekends than having a healthier BMI. I’ve heard stories of my own friends bonking during a ride and I decided that I wanted to err on the side of overeating. So semaglutide doesn’t interest me. You aren’t the only one I’ve heard who started to have no energy after being on semaglutide.
That said the dementia benefit mentioned in the article still intrigues me.
I know people for whom GLP-1s made them lose weight, have a better relationship with food, and reduce their intrusive thoughts, and left them far more able to be active.
I feel like we’ll eventually find out that how well GLPs work is going to depend on the “why” someone has extra weight.
People bonk because they're not eating enough DURING the ride. I'll eat (actually mostly drink) like 120-200g carbs on longer rides. Record is 700g during a 200km ride. I've seen big guys bonk too. It has very little to do with your BF% (although this is nuanced based on power zones and training 'durability' etc, etc).
There are so many active overweight or obese guys, whether it's cycling, swimming or hiking .This myth that inactivity = obesity or that activity fixes obesity or being overweight, need to die. It's not that simple. Hunger signals and how the body partitions/uses food is only orthogonal to activity.
For a lot of people, the alternative to GLP-1's is dying of a heart attack in their 50s, or taking decades off their lives by developing type 2 diabetes, or any number of complications from weight-related diseases.
My point is that it's not all roses. Overall I'm glad I took it and will continue to do so. It's not without downsides, despite the endless stream of favorable studies on it.
I'm younger than you and only loss a about 25 lbs. I've now gone to a maintenance dose and seen my energy recover substantially, I do still think (anecdotally) that when I got off for a week I got even more energy but it's hard to judge.
I also had low energy but that was really mostly when I was losing weight, which made sense. As I slowed weight loss and reduced dose, energy improved.
If you're overweight or especially if you're T2D I highly encourage you to discuss GLP-1 with your doctor. If you're T2D then get research retatrutide which looks to be an actual cure for T2D by clearing liver fat. It should be released early next year but research-use is available and what everybody is taking. Companies like finnrick do public testing of research peptides and a good place to gather names.
I’m on tirzepatide right now from Eli lily, and I’ve been very interested in Reta, but I can’t say that I jump at the chance to inject something into myself that hasn’t been tested directly on the actual thing I’m about to put into my body. I know there are testing companies that will test certain sources but it’s not like they’ve tested the vial you get. If there’s some kind of pathogen or bacteria or whatever in the vial you get, well, there’s no recourse: it was “for research use only”. That seems like an unacceptable risk, but I see so many people on the internet claiming miraculous results. Maybe if I knew someone in real life, but I know those biohacking subreddits and such are astroturfed to no end by companies looking to sell sketchy peptides.
> I know there are testing companies that will test certain sources but it’s not like they’ve tested the vial you get.
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.
That's a common and very acceptable concern and there's not great answers for it. Mostly a place will do multi-vail testing for purity, sterility, endotoxin and heavy metals. The idea is that the sample is sufficient to show safety. Many are rightfully dubious of this but still thousand and thousands of people taking it.
I hope Retatrutide pans out but encouraging people to hop on research chemicals when we already have drugs that can get lots of T2D people into remission is a stretch too far. Let's wait for the actual medicines to be produced by legitimate manufacturers instead of ordering grey market peptides from some nameless whoever with zero liability. This is absolutely not on the right side of the risk-reward equation. Mounjaro is more than good enough.
Retatrutide has a specific mechanism for clearing liver fat (glucagon) which makes it one of the most effective ways to treat T2D. This is the 3rd agonist not found in semaglutide or tirzepatide.
Diabates can harm the brain either indirectly, through vascular damage, or directly through nerve cell degeneration. The latter is a less studied mechanism and can explain the benefit from GLPs. But I agree, it's not different than a low calorie diet. In the modern times of abundance and sedentary lifestyle, fasting makes wonders. So, if you have even one vascular risk factor, just cut your calories in half, just stop eating. Your body will thank you.
Let's not be absolute. There are some people craving for food (esp. endomorphs), some binge eaters (eg under depression) or low metabolizers (hypothyroid) but for many it's easy to cut calories.
This is just flat out untrue. Going a day or two without eating anything feels freeing and wonderful. You simply have some coffee and go through your day, drink water. By not eating anything at all it’s much easier. Even having a couple bites of food gets the body revved up to eat more. Fasting is a choice to simply not. To abstain. To stop and pause. This idea is so un American that I believe people are simply unaware and unable to process the notion.
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.
tdlr: This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases. Novo Nordisk's actual dedicated clinical trials for Alzheimer's completely failed to show that semaglutide stops cognitive decline.
"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.
> This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases
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.
It wasn't even funded in the way funding a study usually means. That an entity handed over money to a research group. The study was done by employers in their work time for their salary. Its a Novo Nordisk study, and as you say its right there in the open. Pointing an llm against the paper to (wrongly) realize this is a real tragedy of literacy.
Not only that but high intakes of added sugars and fast-acting, high-glycemic carbohydrates are linked to an increased risk of cognitive decline and dementia. Excess simple sugars, particularly fructose and sucrose, promote insulin resistance, chronic inflammation, and vascular damage that impair brain function and accelerate neurodegeneration. So with other words, you diet is a major contributing factor here. The medical establishment and big pharma simple ignores the fact that the biggest health risk for a human being is the "modern" high sugar diet that Kellogs introduced in the US and spread to the western world (even to Asia at some extent).
I'm not sure how the medical establishment ignores this, from my understanding (and please correct me if I'm wrong as I'm not fact checking myself in this moment) - the association between the two is largely linked to vascular dementia (obesity, hypertension, yadda yadda).
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.
> The medical establishment and big pharma simple ignores the fact that the biggest health risk for a human being is the "modern" high sugar diet
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.
Diabetes is well known to be a massive risk factor for dementia - so no, people are not ignoring this!?
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.
They controlled for BMI at least, so they knew that was going to be a common question. BMI is a pretty good proxy for that, and they still said that the majority of the effect came from the compound and not BMI.
Fructose is blood sugar invisible, and plays no part in this conversation. Fructose can cause fatty liver and has been attributed with lots of voodoo, but the weird fructose focus of some is not evidence based. It's nonsense.
"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.
The fact that NN funded this study is very relevant but is not necessarily a negative as you make it out it to be. Perhaps that is not your intention but reading the comment made it look like that way.
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.
Regarding “actual tests”: My team and I built a battery of longitudinal cognitive assessments useful for testing memory and brain function. (http://getNeuroUX.com)
Factoring out the ad corpus yelping, the interesting counterpoint is that suppressing the risk signal isn't a good thing if it doesn't suppress the risk.
Didn't even bother looking into it because there's obviously not enough data yet to say anything substantial about GLP-1s and Alzheimers. But your comment should probably be the top.
I’m not an expert on this, but haven’t GLP-1’s been used for quite a while on more limited scopes? So maybe there’s a cohort of people that could approach statistical significance.
Which sort of affirms the mantra, "If you can't prove causation, try to prove correlation." This because you can market correlation to unsophisticated readers and imply causation.
> Which sort of affirms the mantra, "If you can't prove causation, try to prove correlation."
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.
This is one of the most distinguished peer reviewed journals on Alzheimer’s and dementia. Adults know not to make too much of a study of this scale and ambiguity. But considered as such, the paper is above suspicion.
So translated to human, does this basically mean then that semaglutide distorts dementia-predictions by altering the related biomarkers, rather than actually help with dementia?
I'm a strong proponent of GLP1. But a change in one marker is at best an okay signal. But the only thing one cares about is real changes in rates. Who cares about markers that don't translate to real clinical outcomes. That's the whole damn problem with everything from stupid "this makes you younger" claims and the tragedy that is the history of Alzheimer research.
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.
As is being sedentary - there are probably lots of interconnected factors in play, and GLP-1 receptor agonists seem to help with more than one (perhaps even many) of them.
Unpicking the exact chains of causation is likely going to be extremely complex, but the general picture continues to look good.
We should probably be studying people who wear smart watches and collecting the activity levels to control for that.
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.
Western disease and sugar heavy diets broadly speaking, which Semaglutide is a countermeasure against. Not yet a vaccine, but in due time (probably via gene therapy). Fructose also helps cancer metastases and spread.
First of all it’s a nice study. The dosages they always give are way too high and mice are rarely a reliable model.
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.
Sure, but there is nothing in the world of the last 30-40 years that can compare to GLP-1s in terms of helping people consume fewer calories. This is a very coarse statement, but I'm confident in making it: there is nothing healthier than being skinny, and GLP-1s make people skinny in a way that is unique in modernity. Our modern food systems are optimized to encourage people to consume as many calories as they can, and GLP-1s are bulwarks against this system, if you will.
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.
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.
Some researchers have (informally) taken to calling certain forms of dementia "type-3 diabetes", so I think this sounds at least plausible. It's far from a foregone conclusion or anything, but there's at least some evidence that dementia might be a metabolic issue, so it would make sense that something that improves metabolic health would also improve brain health.
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 used to be similarly judgemental and flippant when my BMI was 20~21 in my 20s and 30s.
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 should add I am 35 and male, so certainly no spring chicken!
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
Yes, the world is very aware of how to lose weight.
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.
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.
Although it's encouraging, they do mention that the reduction in the BMI also have an effect (they take it into the consideration by lowering the β −0.092 to β −0.066 (P < 0.001)).
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.
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.
GLP-1 does a lot more than just stomach signaling. It shrinks visceral fat, it's been shown to clear liver fat, and it actually increases mitochondrial efficiency similar to if you were to do endurance work/cardio. There's a lot going on with it. That's kind of what the parent is talking about, all these second-order effects that were not obvious. There is also evidence of down-regulated mTOR signaling and epigenetic protection. And these aren't all just bullshit, big pharma funded studies either.
Calling it now, the downside is the effects are most apparent on higher dosages, but you cant take higher dosages forever. Eventually you run out of body fat, have go reduce the dose, and the benefits dither.
"Semaglutide attenuates a proteomics-based dementia risk signature "
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
Their operating profit was up 11% on a margin of 44% according to their recent quarterly release, and they beat EPS by 23%. They were in a little trouble in the stock market a few years ago as competitors came online, but they are doing pretty well right now.
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.
Read a interesting piece recently that Semaglutide reduces inflammation, and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
> and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
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.
> The question now is if GLP-1s have additional anti-inflammatory influence.
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.
Even at the max dose you will hit a spot where you stop losing weight before you get anywhere near running out of body fat. Some people even go off label stacking two or more or cranking the dose past officially supported levels because they still are overweight.
People honest with themselves will understand that it’s a chronic treatment, you don’t stop.
For sure we still need to find out many related outcomes.
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.
To save others the click: It increased the likelihood to 1 in 10,000 in adults with type 2 diabetes.
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.
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.
So has anyone managed to separate the effects of semaglutide from the effects of weight loss?
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 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.
Similar experience here on minimal dose of GLP-1. There is definitely something going on here other than "you are just losing weight and that's really why you are healthier".
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.
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I really wish my insurance would cover GLP-1s, because I think reduction in fatty liver and other ancillary benefits, along with the weight loss, would be medically helpful for me.
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> 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.
We're too soft on companies, but equally too hard on people who have a food addiction.
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Perhaps they need a bigger drum. Maybe they make a set of health guidelines, and for those who choose to follow them you get a $1000 tax rebate.
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.
Capitalist systems and dysfunctional healthcare in the US thrive on people with chronic unhealthy issues and habits
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.
TLDR: Being fat is very very unhealthy, and all the culture around fat acceptance is a disgrace and an insult to our intelligence.
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Jason Fung has preached against modern processed foods that destroy insulin sensitivity. Even artificial sweeteners can raise Insulin levels. His book "The Obesity Code" is a must read and discusses some of the pathways that link insulin and leptin (a hormone associated with eating)
TLDR; I'm a Fungster: https://www.youtube.com/channel/UCoyL4iGArWn5Hu0V_sAhK2w
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.
That's awesome!
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.
Speaking as someone who had the same kind of reservations, I think you sound exactly like me, and if I had any advice to my past self, it would be "get on it as early as it's available, start much lower than anyone thinks is sane, and never ever stop".
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.
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> I'm sure I could find an unethical doctor to prescribe it if I looked hard enough
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.
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Why wait?
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?
Very american thread and comments.
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.
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You can probably get a prescription for a low dose, but you'll be self pay.
You should start Metformin now and thank me later.
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.
I'm normal weight and am on a low dose (1mg every 10 days) of tirzepatide. I'm able to maintain my weight at this dose, and I've seen improvements in inflammation and other blood markers as well. It's not impossible, it's just difficult to do within the normal health system parameters (specific dosages tested for weight loss, etc.). I use a gray market supplier direct from China and reconstitute the dose myself.
My assumption was that GLP-1's don't suppress appetite so much as suppress the compulsion to eat when not necessary/more than necessary?
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> 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.
Nearly 75% of Americans are overweight. (over 30% 'overweight', over 40% 'obese').
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.
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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.
Semaglutide was patented only in 2018. The previous medication was liraglutide.
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.
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.
It’s been no secret that being fat is terrible for us. It’s getting people to actually eat less is the hard part.
What should public health have done differently?
Treat junk food like cigarettes
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Tax fat people. No, I'm not joking. Especially in countries with some sort of socialist health system.
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.
What is interesting about it?
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.
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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.
I'm not overweight but I've been thinking about getting a low does glp-1 for the supposed inflammation improvements which could be neuroprotective. The side-effects seem minor and if it doesn't agree with me, I can just stop since I'm not using it for weight control.
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.
> 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.
>50 years ago women didn't have voting rights
Where are you? In the US, women have had full voting rights for over 100 years.
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> 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
Good news: the readers of your post don't have to wait 100 years to have that thought.
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.
I don’t consider that since it’s simply not true.
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.
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I don't buy that. You can buy a steak and a potato for two for less than a bag of Doritos. A banana costs far less than a candy bar. A bag of mixed nuts will provide many meals.
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.
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This is not true. Legumes/dairy/spices/vegetables are cheaper than boxed foods.
Only question is do you want to spend 1 hour making it and cleaning up.
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I'm a big semaglutide proponent after being on it for a year. I know research says it helps with inflammation, arthritis (separately from weight reduction), and all sorts of magical things.
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 had similar issues on Semaglutide, but I've found Tirzepatide much more tolerable. I've lost 165lbs, A1C has gone down to 5, I have more energy at 52 than I did at 32, and I am exercising like a maniac now. Maybe you could try it?
I have a very similar situation: on it for about a year, 220lbs to 180 at age ~40. Also very active: weight lifting / biking / swimming and - the sport that made me realize I needed to loose weight - rock climbing. I've always been very outdoorsy-adventurous, and climbing/mountaineering is the natural sort of "end game" for this lifestyle. My weight never really got in the way of anything else in my life (maybe my self esteem) but, this might offend some people, but climbing is a sport where you really cannot be even a little bit fat. It makes you painfully aware of your body weight. Most "good" climbers are built like bean-poles. I don't really need to be a "good" climber, just an "okay" and safe climber - I'm mostly interested in alpine trad below ~5.7. I still feel like I need to lose another 10lbs.
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.
Thanks for the details, really liked your posting this.
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?
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If it makes you feel better I'm 50, and have developed those exact same symptoms over the half decade, without ever having to touching a GLP-1 agonist.
I do have some of it down to unwisely taking Ibuprofen semi-regularly, i.e. Kidneys, bladder.
Is it kind of the stuff where the benefits outweigh the side effects? I'm just scared of the unknowns with the drug with such overwhelming positive research. Maybe, I'm a paranoid person but I'm unable to believe that such a powerful drug isn't without any side effect, clinically proven.
The principal side effect is that you eat less.
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.
The drug has been in use for 20 years. The only side effect I've had is nausea and it passes after a few minutes.
I'm on the pill version, which allows me to adjust the dosage on a more day-to-day level. It also doesn't need a fridge, so it allows me to travel more easily. There's a level that works best for me long-term, and it's quite a bit less than typical.
I thought the half-life was long enough that skipping a pill or taking a lower dose wouldn't make much of a difference?
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).
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I’m also active and fat. And to me being active is more important than losing weight; I’d rather continue to do those long 2000kcal bike rides on weekends than having a healthier BMI. I’ve heard stories of my own friends bonking during a ride and I decided that I wanted to err on the side of overeating. So semaglutide doesn’t interest me. You aren’t the only one I’ve heard who started to have no energy after being on semaglutide.
That said the dementia benefit mentioned in the article still intrigues me.
I know people for whom GLP-1s made them lose weight, have a better relationship with food, and reduce their intrusive thoughts, and left them far more able to be active.
I feel like we’ll eventually find out that how well GLPs work is going to depend on the “why” someone has extra weight.
People bonk because they're not eating enough DURING the ride. I'll eat (actually mostly drink) like 120-200g carbs on longer rides. Record is 700g during a 200km ride. I've seen big guys bonk too. It has very little to do with your BF% (although this is nuanced based on power zones and training 'durability' etc, etc).
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Being active is great but fat is still dangerous. Let's not lie to ourselves.
> 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
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I'm on tirzepatide, a competitive athlete, and have no idea what GP is talking about.
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There are so many active overweight or obese guys, whether it's cycling, swimming or hiking .This myth that inactivity = obesity or that activity fixes obesity or being overweight, need to die. It's not that simple. Hunger signals and how the body partitions/uses food is only orthogonal to activity.
You are a proponent, but your outcomes seem worse?
Losing 40 pounds where sometimes it feels like this weight is impossible to lose. That's what makes it worth it.
For a lot of people, the alternative to GLP-1's is dying of a heart attack in their 50s, or taking decades off their lives by developing type 2 diabetes, or any number of complications from weight-related diseases.
My point is that it's not all roses. Overall I'm glad I took it and will continue to do so. It's not without downsides, despite the endless stream of favorable studies on it.
I'm younger than you and only loss a about 25 lbs. I've now gone to a maintenance dose and seen my energy recover substantially, I do still think (anecdotally) that when I got off for a week I got even more energy but it's hard to judge.
I also had low energy but that was really mostly when I was losing weight, which made sense. As I slowed weight loss and reduced dose, energy improved.
Try Tirzepatide or one of the other drugs. They each have their own side effect profile.
What dose? Have you considered lowering it?
2.4mg for over 6 months. I'm considering dropping back a level(1.7mg?).
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Good that someone speaks up on the side effects.
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.
If you're overweight or especially if you're T2D I highly encourage you to discuss GLP-1 with your doctor. If you're T2D then get research retatrutide which looks to be an actual cure for T2D by clearing liver fat. It should be released early next year but research-use is available and what everybody is taking. Companies like finnrick do public testing of research peptides and a good place to gather names.
I’m on tirzepatide right now from Eli lily, and I’ve been very interested in Reta, but I can’t say that I jump at the chance to inject something into myself that hasn’t been tested directly on the actual thing I’m about to put into my body. I know there are testing companies that will test certain sources but it’s not like they’ve tested the vial you get. If there’s some kind of pathogen or bacteria or whatever in the vial you get, well, there’s no recourse: it was “for research use only”. That seems like an unacceptable risk, but I see so many people on the internet claiming miraculous results. Maybe if I knew someone in real life, but I know those biohacking subreddits and such are astroturfed to no end by companies looking to sell sketchy peptides.
> I know there are testing companies that will test certain sources but it’s not like they’ve tested the vial you get.
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.
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That's a common and very acceptable concern and there's not great answers for it. Mostly a place will do multi-vail testing for purity, sterility, endotoxin and heavy metals. The idea is that the sample is sufficient to show safety. Many are rightfully dubious of this but still thousand and thousands of people taking it.
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I hope Retatrutide pans out but encouraging people to hop on research chemicals when we already have drugs that can get lots of T2D people into remission is a stretch too far. Let's wait for the actual medicines to be produced by legitimate manufacturers instead of ordering grey market peptides from some nameless whoever with zero liability. This is absolutely not on the right side of the risk-reward equation. Mounjaro is more than good enough.
Semaglutide cleared my liver fat and fixed my moderate NAFLD in a matter of months. Why is retatrutide necessary?
Retatrutide has a specific mechanism for clearing liver fat (glucagon) which makes it one of the most effective ways to treat T2D. This is the 3rd agonist not found in semaglutide or tirzepatide.
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Semaglutide clears liver fat? I had no idea. I’m curious to know more about your protocol
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Are you implying the medicine did it or does the medicine just make you eat less which cleared it? Like is there an MOA of the drug itself?
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Diabates can harm the brain either indirectly, through vascular damage, or directly through nerve cell degeneration. The latter is a less studied mechanism and can explain the benefit from GLPs. But I agree, it's not different than a low calorie diet. In the modern times of abundance and sedentary lifestyle, fasting makes wonders. So, if you have even one vascular risk factor, just cut your calories in half, just stop eating. Your body will thank you.
GLP-1 provides the only plausible way to do so.
Let's not be absolute. There are some people craving for food (esp. endomorphs), some binge eaters (eg under depression) or low metabolizers (hypothyroid) but for many it's easy to cut calories.
This is just flat out untrue. Going a day or two without eating anything feels freeing and wonderful. You simply have some coffee and go through your day, drink water. By not eating anything at all it’s much easier. Even having a couple bites of food gets the body revved up to eat more. Fasting is a choice to simply not. To abstain. To stop and pause. This idea is so un American that I believe people are simply unaware and unable to process the notion.
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.
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tdlr: This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases. Novo Nordisk's actual dedicated clinical trials for Alzheimer's completely failed to show that semaglutide stops cognitive decline.
"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.
> This is a Novo Nordisk-funded study focusing on predictive biomarkers rather than real-world dementia cases
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.
You seem to be arguing that people shouldn't be skeptical, by default, of studies of products that are funded by the companies that make the products.
They funded this study as a prospective way of increasing the adoption and market share of their trademarked medication. It deserves skepticism.
It wasn't even funded in the way funding a study usually means. That an entity handed over money to a research group. The study was done by employers in their work time for their salary. Its a Novo Nordisk study, and as you say its right there in the open. Pointing an llm against the paper to (wrongly) realize this is a real tragedy of literacy.
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Not only that but high intakes of added sugars and fast-acting, high-glycemic carbohydrates are linked to an increased risk of cognitive decline and dementia. Excess simple sugars, particularly fructose and sucrose, promote insulin resistance, chronic inflammation, and vascular damage that impair brain function and accelerate neurodegeneration. So with other words, you diet is a major contributing factor here. The medical establishment and big pharma simple ignores the fact that the biggest health risk for a human being is the "modern" high sugar diet that Kellogs introduced in the US and spread to the western world (even to Asia at some extent).
I'm not sure how the medical establishment ignores this, from my understanding (and please correct me if I'm wrong as I'm not fact checking myself in this moment) - the association between the two is largely linked to vascular dementia (obesity, hypertension, yadda yadda).
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.
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> The medical establishment and big pharma simple ignores the fact that the biggest health risk for a human being is the "modern" high sugar diet
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.
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Diabetes is well known to be a massive risk factor for dementia - so no, people are not ignoring this!?
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.
They controlled for BMI at least, so they knew that was going to be a common question. BMI is a pretty good proxy for that, and they still said that the majority of the effect came from the compound and not BMI.
Guess what category of drug reduces the intake of large amounts of sugar?
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Fructose is blood sugar invisible, and plays no part in this conversation. Fructose can cause fatty liver and has been attributed with lots of voodoo, but the weird fructose focus of some is not evidence based. It's nonsense.
"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.
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The fact that NN funded this study is very relevant but is not necessarily a negative as you make it out it to be. Perhaps that is not your intention but reading the comment made it look like that way.
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.
Regarding “actual tests”: My team and I built a battery of longitudinal cognitive assessments useful for testing memory and brain function. (http://getNeuroUX.com)
Factoring out the ad corpus yelping, the interesting counterpoint is that suppressing the risk signal isn't a good thing if it doesn't suppress the risk.
Didn't even bother looking into it because there's obviously not enough data yet to say anything substantial about GLP-1s and Alzheimers. But your comment should probably be the top.
GLP-1s have been used for over 20 years. There likely is enough data to say something, even if it's not water tight.
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I’m not an expert on this, but haven’t GLP-1’s been used for quite a while on more limited scopes? So maybe there’s a cohort of people that could approach statistical significance.
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Cognitive Decline != Alzheimer's. There are other forms of cognitive decline in aging.
Much appreciated post, but can you keep the AI slop separate from the rest of it?
Which sort of affirms the mantra, "If you can't prove causation, try to prove correlation." This because you can market correlation to unsophisticated readers and imply causation.
> Which sort of affirms the mantra, "If you can't prove causation, try to prove correlation."
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.
Or, less conspiratorially, if correlation can be proven and causation is plausible but unproven, there may be benefits.
Proving correlation but not causation does NOT rule out causation.
This is one of the most distinguished peer reviewed journals on Alzheimer’s and dementia. Adults know not to make too much of a study of this scale and ambiguity. But considered as such, the paper is above suspicion.
So translated to human, does this basically mean then that semaglutide distorts dementia-predictions by altering the related biomarkers, rather than actually help with dementia?
Doesn’t socialized medicine mean that big brother already knows the answer to these questions? Why isn’t NHS or whomever more useful on these issues?
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I'm a strong proponent of GLP1. But a change in one marker is at best an okay signal. But the only thing one cares about is real changes in rates. Who cares about markers that don't translate to real clinical outcomes. That's the whole damn problem with everything from stupid "this makes you younger" claims and the tragedy that is the history of Alzheimer research.
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.
This is interesting. Diabetes is a well-known risk factor for dementia.
As is being sedentary - there are probably lots of interconnected factors in play, and GLP-1 receptor agonists seem to help with more than one (perhaps even many) of them.
Unpicking the exact chains of causation is likely going to be extremely complex, but the general picture continues to look good.
We should probably be studying people who wear smart watches and collecting the activity levels to control for that.
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.
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Western disease and sugar heavy diets broadly speaking, which Semaglutide is a countermeasure against. Not yet a vaccine, but in due time (probably via gene therapy). Fructose also helps cancer metastases and spread.
https://www.sciencealert.com/common-sugar-appears-to-loosen-...
First of all it’s a nice study. The dosages they always give are way too high and mice are rarely a reliable model.
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.
> Western disease and sugar heavy diets broadly speaking
No, just being sedentary. There's no such thing as acquired diabetes in physically active people.
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Sugar heavy diets is everywhere IF people can afford to have them if you look at the data. There is no such thing as Western vs Eastern in this sense.
Note I am not Western
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Isn't lower calorie consumption in general correlated to longevity? (Assuming no major malnutrition)
Sure, but there is nothing in the world of the last 30-40 years that can compare to GLP-1s in terms of helping people consume fewer calories. This is a very coarse statement, but I'm confident in making it: there is nothing healthier than being skinny, and GLP-1s make people skinny in a way that is unique in modernity. Our modern food systems are optimized to encourage people to consume as many calories as they can, and GLP-1s are bulwarks against this system, if you will.
>there is nothing healthier than being skinny
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.
That's a big percent for something that is completely devastating. This is objectively good news.
Semaglutide reduces appetite.
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.
Some researchers have (informally) taken to calling certain forms of dementia "type-3 diabetes", so I think this sounds at least plausible. It's far from a foregone conclusion or anything, but there's at least some evidence that dementia might be a metabolic issue, so it would make sense that something that improves metabolic health would also improve brain health.
Very american thread and comments.
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
I used to be similarly judgemental and flippant when my BMI was 20~21 in my 20s and 30s.
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 should add I am 35 and male, so certainly no spring chicken!
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
Yes, the world is very aware of how to lose weight.
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.
I like to compare weight to smoking.
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!
Although it's encouraging, they do mention that the reduction in the BMI also have an effect (they take it into the consideration by lowering the β −0.092 to β −0.066 (P < 0.001)).
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.
Better summary:
Two years of semaglutide treatment appears to substantially slow the worsening of a blood protein signature associated with future dementia risk
I swear, Semaglutide is reverse Asbestos.
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.
Semaglutide reduces appetite. Who could have known that eating less will have positive effects?
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?
GLP-1 does a lot more than just stomach signaling. It shrinks visceral fat, it's been shown to clear liver fat, and it actually increases mitochondrial efficiency similar to if you were to do endurance work/cardio. There's a lot going on with it. That's kind of what the parent is talking about, all these second-order effects that were not obvious. There is also evidence of down-regulated mTOR signaling and epigenetic protection. And these aren't all just bullshit, big pharma funded studies either.
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Calling it now, the downside is the effects are most apparent on higher dosages, but you cant take higher dosages forever. Eventually you run out of body fat, have go reduce the dose, and the benefits dither.
I hope that people will study the emotional impacts of these drugs.
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.
"Semaglutide attenuates a proteomics-based dementia risk signature "
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
Their operating profit was up 11% on a margin of 44% according to their recent quarterly release, and they beat EPS by 23%. They were in a little trouble in the stock market a few years ago as competitors came online, but they are doing pretty well right now.
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.
Can you elaborate on your claims? As it currently stands, I’m only reading meaningless drivel from you.
Read a interesting piece recently that Semaglutide reduces inflammation, and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
> and very likely the weight-loss and a lot of the other emerging benefits are likely the effects of reduced inflammation.
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.
> The question now is if GLP-1s have additional anti-inflammatory influence.
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.
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Reading about GLP-1 medications reminds me of the movie Limitless. Being on them sounds great, getting off of them not so much.
not really. these drugs only merely make you not overweight or obese, which was normal until around 1980 or so.
The study implies it also does other stuff though. That's the thing
in older adults *with obesity *and cardiovascular disease without diabetes
Absolutely magical drug ! It makes you thinner, younger and now smarter !
Alzheimer's disease is not a reduction in intelligence, don't be crass.
For as long as you're on it, but eventually you run out of body fat.
Even at the max dose you will hit a spot where you stop losing weight before you get anywhere near running out of body fat. Some people even go off label stacking two or more or cranking the dose past officially supported levels because they still are overweight.
People honest with themselves will understand that it’s a chronic treatment, you don’t stop.
We are very early in the semaglutide world, exciting times ahead!
For sure we still need to find out many related outcomes.
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...
To save others the click: It increased the likelihood to 1 in 10,000 in adults with type 2 diabetes.
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.
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In addition to being closely associated with the conditions semaglutide treats, NAION is quite rare.
If it reduces inflammation and causes weight loss, I find it impossible to believe you can just stop and not get rebound on both.
Which to me just sounds like every other addictive drug. Paradise while you’re high, and eventually you pay for it.
Or continue to take it.
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This is one of those fake stats, where
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.
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And a doubling in the rate of waking up blind.
Doubling doesn’t mean much without knowing the base rate.