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.
The article title is fine. The title posted to HN (and other forums) should have outro or intro:
In a study funded by X, "Semaglutide linked to lower predicted dementia risk"
Or
"Semaglutide linked to lower predicted dementia risk", in a study funded by X.
This is a fair addendum that should be added when cross posting across websites. It need not be in the original link title. And this type of declaration should really follow most cross posted titles where a perceived bias/skepticism might otherwise be triggered without that knowledge being included. It's an explicit declaration upfront of potential conflicts.
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.
It's easy to say "just diet ez" and it's hard to "just diet".
If you can administer a treatment as a simple one and done thing, that's alright. If it's a pill you got to take every day, that's pretty bad. More than once a day? Horrible. Why? Because a lot of patients just don't have it in them to take a pill 3 times a day consistently.
If it's purely an "exercise willpower" thing or a "change your lifestyle" thing? You might as well give up.
The medical establishment wants to do things that work. Telling people "go diet" doesn't work. Semaglutide, evidently, does.
bro the problem is not eating burgers every time you see them. if eating a pill once a day will prevent somebody from having these urges people will easily make this a routine. fat people don't like being fat (body positive is the world biggest cope). if you give them something they gotta take once a day, takes 10 seconds, they will throw their money at you.
You say force a diet change on a patient. OP certainly meant forcing a diet change in the input of American factories. Sugar can be found in fruits. That's the right place. If you need some, use fruits, maybe alcohol. Everything else can be slashed. No sugar in prepared meals anymore. No sugar in pasta anymore. And most of all, no sugar in water. Sugar input makes more damage than cocaine today.
We can call it the Prohibition II. There will be underground bars with sick people binging on sugar. We can change the shape of sugar to prevent restaurants from adding it to food. We can make it bitter. Absolutely need sugar? Eat that lemon-tasting block. We can call it The War On Sugar.
I think it’s more because it’s kind of a strange rambling rant? He didn’t make any good points, he just made an analogy between it and alcohol prohibition like 7 times. He didn’t even bother to bring the idea home in the end, he just left it free-floating there. It’s just not a great comment.
The medical establishment that I have familiarity with (in the US) pretty much only ever treats symptoms, not causes.
Don't believe me? Next time you go to see your primary care physician, ask them what you should be doing to lower your risk of whatever malady tends to run in your family. (Diabetes, cancer, dementia, etc.) They're going to stare at you in blank confusion for a few seconds before making some vague suggestion about a better diet and more exercise. Guaranteed.
The reasons are many, and detailed enough to write MANY books about, but the low hanging fruit is: we don't have a culture of monitoring and improving our own individual health, physicians are trained almost exclusively to solve problems not prevent them, modern nutrition science is a joke, omnipresent health insurance distorts incentives for everyone, doctors are too overworked to get to know their patients, private equity has captured a large chunk of health care, drugs are positioned as the first line of treatment for almost everything, etc.
In my experience that’s wildly inaccurate. Dietary choices, weight loss, exercise, etc are often given as an effective means of avoiding and or controlling a wide range of conditions.
People are instead blowing off such advice because they don’t want to hear it.
I never knew Kaiser Permanente was so "anti-establishment" but I get pages of recommendations for healthy eating and exercise every time I go and also randomly as part of my "Personal Action Plan".
Everyone pretty much knows how to be healthy- good diet (leafy greens, abstain frand exercise. Diets, fads, etc are all just ways people sidestep being slightly uncomfortable rather than limit what they eat and do. Lots of societal things male it harder, eg hyper-palatable foods/ads/overworked/food availability, but that’s the long and short of the root cause.
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.
> 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.
There was a fringe that said being overweight was not unhealthy, but the more salient points were the following:
1. BMI was basically just pulled out of a hat, and it turns out that for many health concerns, the overweight class does better than the normal weight class, with the actual “clearly worse” outcomes really coming up as you trend into obesity.
2. Environmental and genetic factors are huge contributors to people being overweight. To some degree moralizing about weight loss is a bit like telling kids with asthma they should live in places with less pollution. Or telling someone with breast cancer to not have the BRCA gene.
3. Doctors would regularly miss health problems because they’d blame them on people being overweight / not exercising enough. Especially for difficult to diagnose issues, it’s easy to just point at the number you have that “looks bad”.
4. We still have no firm reason why people are gaining weight. The popular answer is sugar and processed foods but those very much already existed at scale in the 50s.
The tragedy is that it turned into a morality play where fat people were blamed for it, despite in many ways being as genetic as getting breast cancer.
The reality is people who actually study obesity know that basically GLP-1s are the only health intervention other than bariatric surgery that consistently works. At a population level no intervention has reversed fattening anywhere in the world.
To your point 4, we have lots of good reasons why people are gaining weight: they eat more. It's not exactly rocket science.
Obvious reasons include:
a) food is very cheap, especially processed food
b) portion sizes are comically large in the US
c) ubiquity of snacking and eating on the go, which is mostly high calorie
d) few people smoke now, and cigarettes are potent appetite suppressants
e) less social disapproval of being fat. To fair degree, being overweight is contagious
I agree completely with your last paragraph, at a society level. At an individual level, though, it's all on us to exercise self control for ourselves. Just most people don't want to.
Re point a, cheap calories have been around in abundance for 5 decades. The trend has actually been toward more fresh food being available, not more junk (most candies, sodas, and white bread brands are ancient).
lol at point e.
This is so not true. For a while there was a tiny blip where a corner of the internet was fat friendly.
I know a black lesbian from the south who was obese and managed to lose fat by weightlifting. She said by far being obese was worse socially than either of the other things. As part of getting in shape she started jogging and people mocked her for being fat while exercising.
> despite in many ways being as genetic as getting breast cancer.
This claim is utterly silly on its face. Look at pictures of folks in the US 60 years ago compared to today. The population did not randomly mutate a genetic condition towards the propensity of obesity. Folks who come from societies that are not all that overweight did not magically develop a genetic condition upon immigrating to the US. This claim is entirely non-credulous and most folks claiming such are doing so in bad faith.
Environmental is by far and away the largest factor. Meaning most everyone lives surrounded by highly palatable horrible-for-you food and lives extremely sedentary lifestyles entirely optimized for convenience.
It's really not something that needs ANY more examination than that. Fixing it is the hard bit. Everything else on top of this is a rounding error and not something that needs to even be discussed until the first order factor is fixed. Then we can start discussing nuance, outliers, and details. It's a waste of time otherwise.
GLP-1s are the only thing that has turned the tide even a little bit. Because people eat less. Any other benefit from that is again - secondary and perhaps interesting, but not the primary mode of action. GLP-1s proved it is the American diet that is the problem.
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.
It is also a large contributor to rising triglycerides levels and uric acid due to the way it is metabolized. Which in turn contributes to high blood pressure. It also makes Acetyl-CoA, which stimulates lipogenesis.
It is not even true that it is 'blood sugar invisible'. 30-50% of the fructose is converted in glucose and that's visible. The rest won't be available until you start burning fat.
> Yeah, a lot of people have bad diets, but infinitely more pressing is sedentary lifestyles.
No, that's only part of it. And a small part at that. The world didn't suddenly decide to get less active all of a sudden. You can blame some of the sedentary behaviors on societal changes (like suburbs and car dependency in the US), but other countries are getting just as unhealthy, metabolically speaking, and fat.
> The biological reality is that eating a big bowl of frosted flakes is perfectly fine if you follow it up with high amounts of activity.
It has to be really high. We are talking about hours to burn up that bowl of frosted flakes. Spend an hour at a treadmill, calculate the calories you spent. Now check the nearest cereal bar nutritional information. You'll be in for a surprise. You cannot outrun a bad diet.
Diet is most of what needs to be controlled for metabolic health. Resistance training will build muscles, and they are a good buffer since they will eat simple carbs even when you are inactive. Add cardio for cardiovascular health. But, unless you are an athlete or you are active the whole day, you should go easy on the frosted flakes.
>The world didn't suddenly decide to get less active all of a sudden
In many ways, yes it did. There is a shocking decline in active calories in every developed country, and it has been exported to the developing world as well. People are astonishingly lazy, on the average.
Like, Christ, it's so bad that the recommendation to take a brief, slow walk after meals is revolutionary now. Because the average person just waddles to their chair and then "digests". It is astonishing how lazy the average person is in many countries.
>It has to be really high. We are talking about hours to burn up that bowl of frosted flakes.
I love that you declare that I'll be "in for a surprise", as if you're educating me. Hilarious stuff.
In any case, really high is...a bit of an exaggeration. I cycled 30km this morning, at the crack of dawn. A fairly casual, 20km/h or so ride down to the lake and back. That's an estimated 900 calories, or about three bowls of frosted flakes with milk. And the fun thing is that I didn't even eat this morning and did it purely on glucose reserves. This wasn't some athletic thing and was very much a casual "catch the end of summer" thing. Actual athletes absolutely destroy those numbers. People engaged in basic recreational sports destroy those numbers.
And that bike ride is something people would do just getting to and from places in the not to distant past. Where people were constantly moving and doing. Now most of the readers of this comment will have done nothing today beyond moving from seat to seat in various transporters and digestion chambers.
We've all been around someone who is spectacularly lazy who'll tell you about their "metabolism", and who'll jealously jeer when a peer eats without concern and somehow stays healthy. In the vast majority of cases, the latter person is active in their life, and the former person is one of those seat-to-seat people. Being active impacts every facet of your life, and endless choices throughout the day, and it yields an enormous impact on your health.
edit: meant to address the fructose. The fructose converted to glucose does so slowly enough that there is a marginal impact on blood sugar. And the average person consumes multiples more glucose than fructose. Should people consume less fructose (ergo sugar, even if the current admin is trying to healthwash sucrose)? Absolutely. But glucose and simple carbs are the biggest vehicle towards blood sugar and overwhelming glucose reserves.
Exercise and basic activity absolutely, unequivocally "works" for removing glucose from blood, which was the foundation of this argument. I'm not giving people diet advice. Indeed, we were talking about frosted flakes, and there are cyclists that have glucose energy drinks -- massive dumps of glucose -- that they consume while riding, and the impact on their blood sugar is utterly negligible. Because activity is an incredible modulator, given that your muscles literally run on glucose, and of course your leg muscles are your largest consumers.
Further, the Hadza study in no universe declared that it requires activity "in the extremes"[1] to alter energy consumption. Not only was their activity not particularly large, they were 112lb men consuming 2,650 calories a day (which is huge for that small of a man. The caloric recommendation for a 112lb active man is 2,000 calories...). The human body is not a magic energy machine that harvest energy from the air, and while it can modulate some things such as "fidgeting" and some other basic processes, the idea that the activity you do doesn't reflect your energy consumption has zero scientific backing.
The exercise paradox is that someone consuming enormous amounts of food but then adding a little exercise routine probably isn't going to achieve much. Which...of course. Control the calories going in is infinitely more effective. But anyone trying to assuage themselves by declaring the exercise paradox for why they're sedentary is cosmically misinformed. The fact that active Hadza men stayed lean on what would normally be considered a massive caloric excess is not the evidence for this belief.
[1] - Paradoxically the study actually entirely contradicts the way you are using it, and I think you might have heard a poor summary of it. The study wasn't that activity doesn't use more calories -- of course it does as the human body isn't a perpetual motion machine -- but rather that going from a lot of activity to an extreme amount of activity starts to plateau and doesn't just linearly move up forever, as the body will start conserving elsewhere. So no, it doesn't require "extreme" exercise, and that is not at all what the study says. And if a 112lb American sedentary man was consuming 2,650 calories a day, they quickly would be significantly more than 112lbs.
You say they did little exercise ("their activity not particularly large", "little exercise routine") and yet they stayed lean, QED. But also you say they didn't achieve much. I don't know what you're saying. I suppose this flailing around is a kind of exercise, and you like exercise.
I know the study said nothing about "extreme exercise", I put that part in to appease you by providing a way in which you might be right.
OK, reading again, you mention "basic activity" at the start, which is reasonable, in contrast with your massively strenuous starvation bike rides. If the thesis is "move around a little in order to accomplish the basic energy expenditure which is as good as it gets," then fair enough.
LOL, no, I didn't. You seem to have read my comment like your understanding of that study.
Moderately active hunter/gatherers consuming a massive number of calories a day for their size saw plateauing energy consumption, where increasing the activity saw a reduced climb. Again, humans are not perpetual motion machines, and anyone seriously arguing that doing more activity is magically free suffers from self-delusion.
I referred to "little exercise" relative to gluttonous people with a gross calorie excess who then add a little exercise routine and thinks they'll lose weight. They'd be massively more successful cutting calories.
Regarding “actual tests”: My team and I built a battery of longitudinal cognitive assessments useful for testing memory and brain function. (http://getNeuroUX.com)
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.
They've been used for over 20 years but until they became a weight loss drug recently, almost all of the research was on diabetics which introduces two confounding factors: diabetes and the diets diabetics already have to follow to manage the disease. It's hard to draw any conclusions when the results are muddied by those two factors.
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.
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?
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.
Not that dramatically. Things like fatty liver take a long time to reverse. It’s not like you stop eating junk food and then suddenly your body is chilling. No, the damage is done and takes a long time to repair. It’s like smoking. You can benefits from quitting smoking within 20 minutes. But to reach the full benefit and reversal, you need 15 years.
A lot of metabolic stuff is due to insulin and insulin sensitivity. This drives pretty much everything. Insulin sensitization is pretty terrible and it gets more important as you age.
Unfortunately natural selection doesn't need to fix this as it doesn't cause issues until after reproduction and often until after your grandkids are born.
Semaglutide and glp1s resensitize it which is why they have these effects.
> 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.
As someone who has experienced so many different sides of this, you have zero clue the degree to which your appetite and ability to suppress it is hormonal until you get hormonally compromised (and then fix it, in my case, happily)
Blaming individuals for a public health crisis affecting 40% of the population is absolutely silly. There are a lot of individuals like me, who overeat behaviorally, but that doesn't explain the scale of the issue. maybe 8-10% of the population has some sort of eating disorder, the other 30% are just regular people eating an american diet.
I think this is easy to say as a healthy eater (I am one too, always have been). However, unlearning a lifetime of bad habits is hard. But yeah, it's costing nations billions that could be better spent.
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 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.
They also clearly have some impacts on metabolism. It’s well known that a challenge with dieting isn’t just eating less, it’s metabolic changes that make weight loss harder. GLP-1’s avoid that.
They seem to also act on some reward mechanism - making some stuff (not just food. Alcohol, gambling, porn, smoking, other drugs have anecdotally been reported to feel less attractive / addictive) have a reduced pull on one's will. They also measurably delay gastric emptying - to the point that some medicines, meant to be taken on an empty stomach, are not safe to take within up to 3 hours from the last meal, compared to one hour or so for other people.
It’s not clear to me that they slow down metabolism consistently, although that does seem to be the effect in some people.
I rather think the opposite is true, that by increasing signals that the body is satiated in many cases it is avoiding a metabolism slowdown caused by hunger.
Which are vastly overblown. I diet every year as part of bodybuilding, at a range of intensities and durations, and have never had issues with sudden metabolic changes that make it harder to lose weight.
Your body naturally tries to maintain homeostasis. When you cut your food supply below what your average is, and probably has been for years, your body will fight you in every way it can.
For example, I eat too much and started eating less. I now eat normal portions instead of portions fit for 2 people. I have more than enough food and energy, and yet, I am hungry. The hunger is fake, I certainly don’t need more calories. But my body thinks it does based off of its knowledge.
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.
> 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."
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.
Gastrointestinal - nausea, extreme fullness, paradoxically both rapid and slow transit (I recommend lots of fiber, but that will make you too full too), bloating, all kinds of negative stuff, and obviously if you're on a calorie deficit because you get full off a single bite of food you're going to have low energy and feel pretty garbage on that front (thus ramp slowly), but also some jitteryness, all manner of things. I would call the first week on a tiny dose something like a very mild GI bug or flu, in terms of everything I experienced.
That said, I'm extremely prone to side effects, most people I know who have tried them started at maybe half the standard dose and had zero side effects at all. I'm the best possible guinea pig for these things, because if I can tolerate it, almost anyone who isn't frankly allergic or something can.
The other downside, obviously, is injections - you will need to learn how to use sterile technique to inject yourself or pay the incredibly high costs for the pens. The pills are also an option but I have no personal experience and their bioavailability is so low I don't know that I fully trust them.
They will completely change your relationship with food and alcohol, too. Your tastes will probably shift, nearly everybody I know who is on them has essentially given up booze (maybe a couple drinks a year, more or less)
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.
What is junk food? For example — are cheeseburgers and French fries junk food? What about when you make them at home, or at a fancy restaurant without artificial ingredients? Is it certain additives? If McDonalds makes a happy meal without additives, is it no longer junk food?
What does treat them like cigarettes mean? Tax them? Ban them within 15 feet of a building entrance? Put warning labels? Is giving or selling French fries to children a crime? Does this apply to food made at home?
Most of the time when people try to define healthy food vs. junk food in a fair and unbiased way, the line gets drawn at "whole foods" vs "processed foods".
A typical burger meal is definitely processed food because the meat is processed mechanically and mixed from different sources (usually with added fat); the bun is made from refined flour and refined oils; and the fries are thinly-cut potatoes blanched and fried in more refined oils. (Not to mention a whole bunch of chemical additives which are the norm rather than the exception; and "hyperpalatability" tweaks which means the food is formulated to taste unnaturally good.)
You could perhaps argue that a home-made burger meal made using whole cuts of meat, a lean wholemeal bread dough, and potatoes roasted in animal fat could count as a healthy/whole food meal, but it would taste different to the typical hamburger meal we all associate with fast food.
Fast food also has an enormous marketing industry behind it which pushes it in unhealthy volume, with maximum convenience, and at (until recently, at least) affordable prices.
Why does grinding the meat at home make a huge difference vs grinding it in a factory? Depending on the cut you choose, the condiments you add, and the portion size, a hamburger at home could be Lot less healthy than a McDonald’s burger. McDonald’s patties don’t have any fillers afaict.
The point is that “junk food” is a pretty amorphous and vague category. If you want to enforce portion or calorie restrictions you can do that, but it would have to be way more encompassing of a regulation than targeting “junk food”
Even today, a Soda with 'real sugar', at least for me, is far more satiating for thirst or a 'quick sweet treat' than the same brand/'flavor' using corn syrup, that includes both the big chains as well as the local names.
If I drink a soda with sugar in it, I usually wind up wanting water after. If I drink something with corn syrup, I usually just want more of whatever I just had.
No, the evidence is that there is no significant difference in satiety. HFCS is 55% fructose / 45% glucose, while sucrose is 50% fructose / 50% glucose.
Not saying Sugar itself is much better, however, yes, there is research indicating that the two are metabolized differently, so that difference in composition should be considered.
Real sugar in your soda pop? What are you, a health nut? Must be a real my body is a temple sort.
Seriously though, it's a dogshit thing to consume whether it is sweetened with HFCS or sucrose.
"Even today, a Soda with 'real sugar', at least for me, is far more satiating"
Did you know that in the acidic environment of a cola, sucrose quickly degrades into fructose and glucose (and if it didn't, your enzymes literally immediately crack sucrose into them). You know, exactly the same fructose and glucose that would be added by HFCS. The proportions differ a tiny amount, but this notion that one is satiating and the other isn't should really send you down a path of self-discovery, where you determine how you fell for nonsense.
People have tried. Any time the government tries to do anything a substantial portion of the electorate throws a childish hissy fit and tries to make out that the Bolsheviks are coming to make their fries less tasty for no good reason.
What's interesting is that it's different parts of the electorate that get upset. When Republicans wanted to make junk food/soda ineligible for food stamps, Dems got upset. And when Dems wanted to tax large sodas, Republicans/libertarians got upset.
I think the former makes much more sense than the latter, since it is literally being funded by the govt. That's a reasonable first step, or possibly only step, especially considering that most people on food stamps are also on govt-funded/subsidized healthcare (meaning taxpayers will end up footing the bill when they require expensive treatments resulting in part from an unhealthy diet).
Feel free to elaborate on my alleged insincerity. Was I insincere in noticing that there are partisan patterns at play, or insincere when pointing out that the govt should have more control over govt-run/taxpayer funded programs, as opposed to transactions between private parties?
A "sin tax" on unhealthy products impacts everyone equally. The Republican plan has absolutely nothing to do with health (and they've thankfully barely even tried to pretend it is, instead just going with a "well why should they get treats?" punitive angle), and everything to do with punching down. It's amazing that there are tens of millions of terrible people in the US who will vote for staggering levels of corruption, self-dealing, stupidity, and incompetence so long as those people will punch down on the right people.
As LBJ correctly observed - "If you can convince the lowest white man he's better than the best colored man, he won't notice you're picking his pocket. Hell, give him somebody to look down on, and he'll empty his pockets for you." It's amazing how punching down can get votes.
EDIT: insincere guy, who seriously tried to pretend that it's "partisan" to find a difference between those initiatives -- one predicated on health concerns, the other on punching down -- is now crying for moderation assistance because I quoted a US president, in a situation that is perfectly applicable to exactly this policy that they are laughably trying to equivocate.
Amazing that you again allege insincerity, with zero evidence. You then go on to make false claims about what I said and avoid the obvious point that my problem is not with the historical figure that you quoted, but the fact that you injected race into a conversation that was about food.
As for whether you violate the HN guidelines, the number of your recent comments that are greyed out tends to indicate that I'm not the only one who thinks you're out of step here.
Unfortunately in most countries the blocker is politics, not the desire of public health officials to do anything. See the current US admin going after vaccines while declaring open season for peptides.
this is exactly right. We've got this society that readily accepts unpleasantness as what you need to do to get ahead(I'll question that but it's beside the point). People regularly accept suffering of all sorts. However, ask someone to eat a boring meal. that's a hard no. So, you've got large parts of society that won't accept that perhaps they shouldn't eat like children.
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.
did western society engineer a junkfood-industrial-complex so addicting and so en-sickening that it ultimately required a sort of junk food methadone to wean itself off?
Even more so. Not absolute weight loss but the effect of loss of the systemic inflammation due to a surplus of visceral fat which has significantly more systemic effect than subcutaneous fat or other types of loss of mass.
> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker
Public health has been trying to get obese people to lose weight forever, what are you talking about. We've known it's bad in enough other ways. It was just really, really hard (at a population level).
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.
>> 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 think you need to read up on why the civil rights act was necessary and the things it fought for. Woman's suffrage was fought for a long time ago, but that does not mean it was universally applied.
Many many times in US history we've said something is true, but put some big asterisks after them. Slavery is over (except it's definitely still permitted in the US), it's illegal to discriminate based on race (except we allowed redlining for generations and arguably are still fighting it), rape is illegal (unless it's your spouse, then it was legal until '93. And a lesser crime still in much of the country).
Voting is no different. Heck, one might argue we still don't have universal suffrage. People who want to vote but because we've put barriers like underfunding stations, long lines, not giving time off to vote, etc. we're clearly preventing some types of people.
Then teach us.. when did they got actual voting rights? (i'm not trying to be snarky but sometimes it' not easy seeing the level of history ignorance in society)
> 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.
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.
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.
... It can cut both ways, and depends a lot on the 'level' of poverty and specific circumstances, although the calculus has shifted over time.
If people are working crazy hours, sometimes it's a struggle to even get time to properly shop for groceries, let alone cook. There's varying degrees of that too;
i.e. I remember the 3-4$ frozen pizzas that could be used as a dinner and leftovers; And yes, at least back then, We could instead buy some chicken, rice, and a can or two of soup or stock to do something way healthier, at the same overall cost per meal...
But it would take an hour or so to properly prepare instead of just tossing that 3-4$ frozen pizza into the oven and letting it do it's thing.
Then throw into the mix where both partners due to work and/or school aren't even home till 8PM, and one of them has to wake up by 7AM to get to work the next morning [0]
I've lived that situation, although thankfully that wasn't every night and we could balance between the healthy self cooked option and the junkish-food-pizza.
But I've also lived the situation where both parties are working late, or the commute is so bad, you're glad you advanced enough you could afford the more expensive, but at least then managable 'taco bell' option.
But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm [1]
[0] - You don't want to eat too late for other health reasons of course...
[1] - And yes, that group really does tend to be less healthy overall from my personal experiences, even if their dining tastes are 'expensive'.
You are describing time, not cost. I can assure you my family worked pretty demanding jobs with long hours. And spent hours preparing food on top of it.
The average American spends 4-5 hours a day on personal screen time, and this skews higher the poorer you get based on a few studies.
I agree it's much more convenient to toss a couple pizzas in the oven. I do not agree it's less expensive. I don't know where you're buying your rice or chicken, but even at $4/pizza I can't pencil that out. Chicken comes with free chicken stock if you're buying rotisserie chickens and keeping the bones and vegetable ends/etc. around for stock making. This is the level of poor I was talking about.
> But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm
I definitely agree with this one. Habits and skills are passed down generationally. Someone may not even know where to start looking at youtube for how-to videos to make their own chicken stock for close to free with a $5 crock-pot from the local thrift store these days.
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 $(x-1) for A, you'd patronize the latter store.
> Pleasing your customers is how profit is maximized.
If you ignore everything like, including but not limited to, market capture, addictive products, lock-in, information asymmetry, planned obsolescence, dark patterns, captive markets, artificial scarcity, seldom-lucrative-yet-important services and any externality, very true!
At least 10 to 15-ish years ago, I would actually be closer to agreeing;
You could get Cube or Chuck steak for 3-5$ a pound and potatoes were cheap as hell too. Toss some diced onion in and You'll have a good dinner.
How do I know? Well I grew up in a family where for... reasons[0] we were not that well off for quite a while.
Cube Steak was one of the big things we did for a family meal that Dad cooked. (Chili was his other favorite to make, which was also cheap to do for how much food came out of it...)
However the current prices of beef, I feel like you'd need to have a long standing personal relationship with a local butcher or rancher to make this true.
[0] - My mother's over-propensity for being truly Christ-like in her charity to family and others, also sending myself and my three siblings to Catholic school to avoid the then-absolutely-failed Detroit Public school system were major factors.
I'm québécois, my grandma came from a big family (12 siblings IIRC). She used to cook with ground beef all the time cause that's what her mother cooked with too - it was THE cheap source of protein. Meat loaf, shepherds pie, meat pie, beef and cheese macaroni, the whole shebang. Nowadays, when I cook any of those meals, it's cause I feel like eating that specific thing, but it often turns out to be the most expensive meal of the week.
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.
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'm using reta myself, but honestly it's because sema/tirz isn't allowed for me either. If you have medical tirz available, you should have some serious reasons to jump into the unregulated shark tank.
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.
As a consequence I ate less. Weirdly, I think I eat more sugar now but my total calorie intake is lower. I eat more sugar because sometimes it's the only thing that seems palatable or I'm trying to counteract the hypoglycemia feelings.
Yes the medicine does it. It's attacking T2D via several pathways, but in the case of Reta the glucagon is doing the heavy lifting of clearing liver fat.
This extra receptor is why Reta is a triple agonist unlike semaglutide (single glp1) or tirzepatide (glp1+gip double agonist).
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.
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'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).
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.
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.
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 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).
Going back to my endurance days, I think people bonk because they aren't adapted. After a year or so of pushing through the bonk, and growing up with hypoglycemia if I didn't eat frequently, I got to where I could start out at 5am on an empty stomach and not eat until noon or later. If I did bonk, I'd sip V-8(yeah, really) and instantly recover.
Being a competitive athlete is probably why you have no idea what I'm talking about (and maybe you're not in your 50s). You have a reason to keep your momentum and you are likely more regularly active than I was. Sure I lifted weights, but it was only 2-3 days a week for maybe 6 hours total.
I'm trying but I've got a toddler and now it seems like every joint hurts. No time to get to a gym and no room for a decent home gym. I did start to do back day again at the Y when we go on the weekend for the pool. We'll see...
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.
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.
Also age plays a pretty significant role. I know older asians who regularly walk who still got T2D. You could argue that walking isn't physically active enough... but they'd argue otherwise. It's all relative.
At the risk of being argumentative I had a horrible diet for the past ~10 years and carried 50 extra pounds. However I also exercised a lot as a hobby and to my shock my glucose and other bloods always came out in the normal range.
This year I started Mounjaro and dropped the 50 pounds. Curious to see what my next checkup shows.
People kick around the idea of the "personal fat threshold". E.g. caucasians seem to be better at carrying fat than, say, Southeast Asians. White people seem to be able to better store fat without metabolic side effects; SEA seems to get T2D at a much lower bodyfat percentage.
Possibly maybe, but plenty of caucasian friends at my old bodyweight/fat percentage had/have horrible markers. I lean more towards the protective effect of exercise.
Look at Figure 2C in particular. The hazard ratio of smoking is 1.41. The hazard ratio between "Low" (<25th percentile) and "Below Average" (25th-49th percentile) cardiovascular health is 1.95.
In other words, it is better to be a smoker than in the lower 25% of non-exercisers. By far. It's not even close.
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.
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.
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.
Myelin and membranes aren’t triglyceride stores. There’s no lipolytic pathway that strips a neuron’s membrane the way a caloric deficit empties an adipocyte.
"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.
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.
It is well known that forcing a sudden drop in chronically high average blood glucose (like, from 200+ to a normal ish range) with insulin can cause vision loss. I wonder if it's the same mechanism?
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.
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.
I think it rubs plenty of laymen the wrong way to not make it a bit more explicitly known.
The world could use a bit less nuance in our headlines these days.
> [...] not make it a bit more explicitly known.
Honest question, how could it be made more explicitly known? It's literally under ACKNOWLEDGMENTS, in the most clear language possible.
The article title is fine. The title posted to HN (and other forums) should have outro or intro:
In a study funded by X, "Semaglutide linked to lower predicted dementia risk"
Or
"Semaglutide linked to lower predicted dementia risk", in a study funded by X.
This is a fair addendum that should be added when cross posting across websites. It need not be in the original link title. And this type of declaration should really follow most cross posted titles where a perceived bias/skepticism might otherwise be triggered without that knowledge being included. It's an explicit declaration upfront of potential conflicts.
It's never enough for purity tests.
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.
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.
It's easy to say "just diet ez" and it's hard to "just diet".
If you can administer a treatment as a simple one and done thing, that's alright. If it's a pill you got to take every day, that's pretty bad. More than once a day? Horrible. Why? Because a lot of patients just don't have it in them to take a pill 3 times a day consistently.
If it's purely an "exercise willpower" thing or a "change your lifestyle" thing? You might as well give up.
The medical establishment wants to do things that work. Telling people "go diet" doesn't work. Semaglutide, evidently, does.
bro the problem is not eating burgers every time you see them. if eating a pill once a day will prevent somebody from having these urges people will easily make this a routine. fat people don't like being fat (body positive is the world biggest cope). if you give them something they gotta take once a day, takes 10 seconds, they will throw their money at you.
You say force a diet change on a patient. OP certainly meant forcing a diet change in the input of American factories. Sugar can be found in fruits. That's the right place. If you need some, use fruits, maybe alcohol. Everything else can be slashed. No sugar in prepared meals anymore. No sugar in pasta anymore. And most of all, no sugar in water. Sugar input makes more damage than cocaine today.
We can call it the Prohibition II. There will be underground bars with sick people binging on sugar. We can change the shape of sugar to prevent restaurants from adding it to food. We can make it bitter. Absolutely need sugar? Eat that lemon-tasting block. We can call it The War On Sugar.
people are so addicted to sugar that you are getting downvoted and maybe even flagged.
I like "The War on Sugar" idea (even tho I went out 1 hour ago to buy lots of chocolates and candies, as I'm an addict).
I think it’s more because it’s kind of a strange rambling rant? He didn’t make any good points, he just made an analogy between it and alcohol prohibition like 7 times. He didn’t even bother to bring the idea home in the end, he just left it free-floating there. It’s just not a great comment.
The medical establishment that I have familiarity with (in the US) pretty much only ever treats symptoms, not causes.
Don't believe me? Next time you go to see your primary care physician, ask them what you should be doing to lower your risk of whatever malady tends to run in your family. (Diabetes, cancer, dementia, etc.) They're going to stare at you in blank confusion for a few seconds before making some vague suggestion about a better diet and more exercise. Guaranteed.
The reasons are many, and detailed enough to write MANY books about, but the low hanging fruit is: we don't have a culture of monitoring and improving our own individual health, physicians are trained almost exclusively to solve problems not prevent them, modern nutrition science is a joke, omnipresent health insurance distorts incentives for everyone, doctors are too overworked to get to know their patients, private equity has captured a large chunk of health care, drugs are positioned as the first line of treatment for almost everything, etc.
In my experience that’s wildly inaccurate. Dietary choices, weight loss, exercise, etc are often given as an effective means of avoiding and or controlling a wide range of conditions.
People are instead blowing off such advice because they don’t want to hear it.
I never knew Kaiser Permanente was so "anti-establishment" but I get pages of recommendations for healthy eating and exercise every time I go and also randomly as part of my "Personal Action Plan".
Everyone pretty much knows how to be healthy- good diet (leafy greens, abstain frand exercise. Diets, fads, etc are all just ways people sidestep being slightly uncomfortable rather than limit what they eat and do. Lots of societal things male it harder, eg hyper-palatable foods/ads/overworked/food availability, but that’s the long and short of the root cause.
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.
> 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.
There was a fringe that said being overweight was not unhealthy, but the more salient points were the following:
1. BMI was basically just pulled out of a hat, and it turns out that for many health concerns, the overweight class does better than the normal weight class, with the actual “clearly worse” outcomes really coming up as you trend into obesity.
2. Environmental and genetic factors are huge contributors to people being overweight. To some degree moralizing about weight loss is a bit like telling kids with asthma they should live in places with less pollution. Or telling someone with breast cancer to not have the BRCA gene.
3. Doctors would regularly miss health problems because they’d blame them on people being overweight / not exercising enough. Especially for difficult to diagnose issues, it’s easy to just point at the number you have that “looks bad”.
4. We still have no firm reason why people are gaining weight. The popular answer is sugar and processed foods but those very much already existed at scale in the 50s.
The tragedy is that it turned into a morality play where fat people were blamed for it, despite in many ways being as genetic as getting breast cancer.
The reality is people who actually study obesity know that basically GLP-1s are the only health intervention other than bariatric surgery that consistently works. At a population level no intervention has reversed fattening anywhere in the world.
To your point 4, we have lots of good reasons why people are gaining weight: they eat more. It's not exactly rocket science.
Obvious reasons include:
a) food is very cheap, especially processed food
b) portion sizes are comically large in the US
c) ubiquity of snacking and eating on the go, which is mostly high calorie
d) few people smoke now, and cigarettes are potent appetite suppressants
e) less social disapproval of being fat. To fair degree, being overweight is contagious
I agree completely with your last paragraph, at a society level. At an individual level, though, it's all on us to exercise self control for ourselves. Just most people don't want to.
Re point a, cheap calories have been around in abundance for 5 decades. The trend has actually been toward more fresh food being available, not more junk (most candies, sodas, and white bread brands are ancient).
lol at point e.
This is so not true. For a while there was a tiny blip where a corner of the internet was fat friendly.
I know a black lesbian from the south who was obese and managed to lose fat by weightlifting. She said by far being obese was worse socially than either of the other things. As part of getting in shape she started jogging and people mocked her for being fat while exercising.
> despite in many ways being as genetic as getting breast cancer.
This claim is utterly silly on its face. Look at pictures of folks in the US 60 years ago compared to today. The population did not randomly mutate a genetic condition towards the propensity of obesity. Folks who come from societies that are not all that overweight did not magically develop a genetic condition upon immigrating to the US. This claim is entirely non-credulous and most folks claiming such are doing so in bad faith.
Environmental is by far and away the largest factor. Meaning most everyone lives surrounded by highly palatable horrible-for-you food and lives extremely sedentary lifestyles entirely optimized for convenience.
It's really not something that needs ANY more examination than that. Fixing it is the hard bit. Everything else on top of this is a rounding error and not something that needs to even be discussed until the first order factor is fixed. Then we can start discussing nuance, outliers, and details. It's a waste of time otherwise.
GLP-1s are the only thing that has turned the tide even a little bit. Because people eat less. Any other benefit from that is again - secondary and perhaps interesting, but not the primary mode of action. GLP-1s proved it is the American diet that is the problem.
> Everyone knows that eating high sugar diets and being overweight is unhealthy.
There is a lack of evidence that the public understands what healthy and healthy effectively mean to their day to day lives,
aside from “looking better”.
Guess what category of drug reduces the intake of large amounts of sugar?
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.
> Fructose can cause fatty liver
It is also a large contributor to rising triglycerides levels and uric acid due to the way it is metabolized. Which in turn contributes to high blood pressure. It also makes Acetyl-CoA, which stimulates lipogenesis.
It is not even true that it is 'blood sugar invisible'. 30-50% of the fructose is converted in glucose and that's visible. The rest won't be available until you start burning fat.
> Yeah, a lot of people have bad diets, but infinitely more pressing is sedentary lifestyles.
No, that's only part of it. And a small part at that. The world didn't suddenly decide to get less active all of a sudden. You can blame some of the sedentary behaviors on societal changes (like suburbs and car dependency in the US), but other countries are getting just as unhealthy, metabolically speaking, and fat.
> The biological reality is that eating a big bowl of frosted flakes is perfectly fine if you follow it up with high amounts of activity.
It has to be really high. We are talking about hours to burn up that bowl of frosted flakes. Spend an hour at a treadmill, calculate the calories you spent. Now check the nearest cereal bar nutritional information. You'll be in for a surprise. You cannot outrun a bad diet.
Diet is most of what needs to be controlled for metabolic health. Resistance training will build muscles, and they are a good buffer since they will eat simple carbs even when you are inactive. Add cardio for cardiovascular health. But, unless you are an athlete or you are active the whole day, you should go easy on the frosted flakes.
>The world didn't suddenly decide to get less active all of a sudden
In many ways, yes it did. There is a shocking decline in active calories in every developed country, and it has been exported to the developing world as well. People are astonishingly lazy, on the average.
Like, Christ, it's so bad that the recommendation to take a brief, slow walk after meals is revolutionary now. Because the average person just waddles to their chair and then "digests". It is astonishing how lazy the average person is in many countries.
>It has to be really high. We are talking about hours to burn up that bowl of frosted flakes.
I love that you declare that I'll be "in for a surprise", as if you're educating me. Hilarious stuff.
In any case, really high is...a bit of an exaggeration. I cycled 30km this morning, at the crack of dawn. A fairly casual, 20km/h or so ride down to the lake and back. That's an estimated 900 calories, or about three bowls of frosted flakes with milk. And the fun thing is that I didn't even eat this morning and did it purely on glucose reserves. This wasn't some athletic thing and was very much a casual "catch the end of summer" thing. Actual athletes absolutely destroy those numbers. People engaged in basic recreational sports destroy those numbers.
And that bike ride is something people would do just getting to and from places in the not to distant past. Where people were constantly moving and doing. Now most of the readers of this comment will have done nothing today beyond moving from seat to seat in various transporters and digestion chambers.
We've all been around someone who is spectacularly lazy who'll tell you about their "metabolism", and who'll jealously jeer when a peer eats without concern and somehow stays healthy. In the vast majority of cases, the latter person is active in their life, and the former person is one of those seat-to-seat people. Being active impacts every facet of your life, and endless choices throughout the day, and it yields an enormous impact on your health.
edit: meant to address the fructose. The fructose converted to glucose does so slowly enough that there is a marginal impact on blood sugar. And the average person consumes multiples more glucose than fructose. Should people consume less fructose (ergo sugar, even if the current admin is trying to healthwash sucrose)? Absolutely. But glucose and simple carbs are the biggest vehicle towards blood sugar and overwhelming glucose reserves.
But there's the exercise paradox, which is that it doesn't work.
https://en.wikipedia.org/wiki/Exercise_paradox
Possibly it works in the extremes, but if so, it's modern and unnatural.
Exercise and basic activity absolutely, unequivocally "works" for removing glucose from blood, which was the foundation of this argument. I'm not giving people diet advice. Indeed, we were talking about frosted flakes, and there are cyclists that have glucose energy drinks -- massive dumps of glucose -- that they consume while riding, and the impact on their blood sugar is utterly negligible. Because activity is an incredible modulator, given that your muscles literally run on glucose, and of course your leg muscles are your largest consumers.
Further, the Hadza study in no universe declared that it requires activity "in the extremes"[1] to alter energy consumption. Not only was their activity not particularly large, they were 112lb men consuming 2,650 calories a day (which is huge for that small of a man. The caloric recommendation for a 112lb active man is 2,000 calories...). The human body is not a magic energy machine that harvest energy from the air, and while it can modulate some things such as "fidgeting" and some other basic processes, the idea that the activity you do doesn't reflect your energy consumption has zero scientific backing.
The exercise paradox is that someone consuming enormous amounts of food but then adding a little exercise routine probably isn't going to achieve much. Which...of course. Control the calories going in is infinitely more effective. But anyone trying to assuage themselves by declaring the exercise paradox for why they're sedentary is cosmically misinformed. The fact that active Hadza men stayed lean on what would normally be considered a massive caloric excess is not the evidence for this belief.
[1] - Paradoxically the study actually entirely contradicts the way you are using it, and I think you might have heard a poor summary of it. The study wasn't that activity doesn't use more calories -- of course it does as the human body isn't a perpetual motion machine -- but rather that going from a lot of activity to an extreme amount of activity starts to plateau and doesn't just linearly move up forever, as the body will start conserving elsewhere. So no, it doesn't require "extreme" exercise, and that is not at all what the study says. And if a 112lb American sedentary man was consuming 2,650 calories a day, they quickly would be significantly more than 112lbs.
You say they did little exercise ("their activity not particularly large", "little exercise routine") and yet they stayed lean, QED. But also you say they didn't achieve much. I don't know what you're saying. I suppose this flailing around is a kind of exercise, and you like exercise.
I know the study said nothing about "extreme exercise", I put that part in to appease you by providing a way in which you might be right.
OK, reading again, you mention "basic activity" at the start, which is reasonable, in contrast with your massively strenuous starvation bike rides. If the thesis is "move around a little in order to accomplish the basic energy expenditure which is as good as it gets," then fair enough.
>You say they did little exercise
LOL, no, I didn't. You seem to have read my comment like your understanding of that study.
Moderately active hunter/gatherers consuming a massive number of calories a day for their size saw plateauing energy consumption, where increasing the activity saw a reduced climb. Again, humans are not perpetual motion machines, and anyone seriously arguing that doing more activity is magically free suffers from self-delusion.
I referred to "little exercise" relative to gluttonous people with a gross calorie excess who then add a little exercise routine and thinks they'll lose weight. They'd be massively more successful cutting calories.
This really isn't difficult to understand.
I edited a conclusion in, maybe we can agree on it.
Regarding “actual tests”: My team and I built a battery of longitudinal cognitive assessments useful for testing memory and brain function. (http://getNeuroUX.com)
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.
They've been used for over 20 years but until they became a weight loss drug recently, almost all of the research was on diabetics which introduces two confounding factors: diabetes and the diets diabetics already have to follow to manage the disease. It's hard to draw any conclusions when the results are muddied by those two factors.
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.
IIRC, mostly used to help with type 2 diabetes... But effects on that cohort may not generalize to the general population.
This particular study was done on people without diabetes, at least.
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.
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?
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.
Could be just because you stopped eating bad food. Things improve dramatically once you limit your intake of industrialized food.
Not that dramatically. Things like fatty liver take a long time to reverse. It’s not like you stop eating junk food and then suddenly your body is chilling. No, the damage is done and takes a long time to repair. It’s like smoking. You can benefits from quitting smoking within 20 minutes. But to reach the full benefit and reversal, you need 15 years.
A lot of metabolic stuff is due to insulin and insulin sensitivity. This drives pretty much everything. Insulin sensitization is pretty terrible and it gets more important as you age. Unfortunately natural selection doesn't need to fix this as it doesn't cause issues until after reproduction and often until after your grandkids are born.
Semaglutide and glp1s resensitize it which is why they have these effects.
My opinion
> 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.
Nah, we’re still too soft on people. It’s really not hard to eat a healthy diet.
As someone who has experienced so many different sides of this, you have zero clue the degree to which your appetite and ability to suppress it is hormonal until you get hormonally compromised (and then fix it, in my case, happily)
Blaming individuals for a public health crisis affecting 40% of the population is absolutely silly. There are a lot of individuals like me, who overeat behaviorally, but that doesn't explain the scale of the issue. maybe 8-10% of the population has some sort of eating disorder, the other 30% are just regular people eating an american diet.
I think this is easy to say as a healthy eater (I am one too, always have been). However, unlearning a lifetime of bad habits is hard. But yeah, it's costing nations billions that could be better spent.
If it’s not too hard why are people not doing it?
It's really not hard to not drink. It's really not hard to not do heroin. It's really not hard to...
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 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.
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?
They also clearly have some impacts on metabolism. It’s well known that a challenge with dieting isn’t just eating less, it’s metabolic changes that make weight loss harder. GLP-1’s avoid that.
They do slow down the metabolism, yes.
They seem to also act on some reward mechanism - making some stuff (not just food. Alcohol, gambling, porn, smoking, other drugs have anecdotally been reported to feel less attractive / addictive) have a reduced pull on one's will. They also measurably delay gastric emptying - to the point that some medicines, meant to be taken on an empty stomach, are not safe to take within up to 3 hours from the last meal, compared to one hour or so for other people.
It’s not clear to me that they slow down metabolism consistently, although that does seem to be the effect in some people.
I rather think the opposite is true, that by increasing signals that the body is satiated in many cases it is avoiding a metabolism slowdown caused by hunger.
> metabolic changes that make weight loss harder
Which are vastly overblown. I diet every year as part of bodybuilding, at a range of intensities and durations, and have never had issues with sudden metabolic changes that make it harder to lose weight.
That’s very nice for you, but it is a phenomenon that is well documented by research: https://pmc.ncbi.nlm.nih.gov/articles/PMC4989512/
Your body naturally tries to maintain homeostasis. When you cut your food supply below what your average is, and probably has been for years, your body will fight you in every way it can.
For example, I eat too much and started eating less. I now eat normal portions instead of portions fit for 2 people. I have more than enough food and energy, and yet, I am hungry. The hunger is fake, I certainly don’t need more calories. But my body thinks it does based off of its knowledge.
It’s both. That’s why it’s so effective.
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.
> 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."
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.
What downsides have you experienced?
Gastrointestinal - nausea, extreme fullness, paradoxically both rapid and slow transit (I recommend lots of fiber, but that will make you too full too), bloating, all kinds of negative stuff, and obviously if you're on a calorie deficit because you get full off a single bite of food you're going to have low energy and feel pretty garbage on that front (thus ramp slowly), but also some jitteryness, all manner of things. I would call the first week on a tiny dose something like a very mild GI bug or flu, in terms of everything I experienced.
That said, I'm extremely prone to side effects, most people I know who have tried them started at maybe half the standard dose and had zero side effects at all. I'm the best possible guinea pig for these things, because if I can tolerate it, almost anyone who isn't frankly allergic or something can.
The other downside, obviously, is injections - you will need to learn how to use sterile technique to inject yourself or pay the incredibly high costs for the pens. The pills are also an option but I have no personal experience and their bioavailability is so low I don't know that I fully trust them.
They will completely change your relationship with food and alcohol, too. Your tastes will probably shift, nearly everybody I know who is on them has essentially given up booze (maybe a couple drinks a year, more or less)
In my experience, basically all downsides can be solved by lowering the dose, and not escalating dosages as fast as the doctors tell you.
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.
What should public health have done differently?
Treat junk food like cigarettes
What is junk food? For example — are cheeseburgers and French fries junk food? What about when you make them at home, or at a fancy restaurant without artificial ingredients? Is it certain additives? If McDonalds makes a happy meal without additives, is it no longer junk food?
What does treat them like cigarettes mean? Tax them? Ban them within 15 feet of a building entrance? Put warning labels? Is giving or selling French fries to children a crime? Does this apply to food made at home?
Most of the time when people try to define healthy food vs. junk food in a fair and unbiased way, the line gets drawn at "whole foods" vs "processed foods".
A typical burger meal is definitely processed food because the meat is processed mechanically and mixed from different sources (usually with added fat); the bun is made from refined flour and refined oils; and the fries are thinly-cut potatoes blanched and fried in more refined oils. (Not to mention a whole bunch of chemical additives which are the norm rather than the exception; and "hyperpalatability" tweaks which means the food is formulated to taste unnaturally good.)
You could perhaps argue that a home-made burger meal made using whole cuts of meat, a lean wholemeal bread dough, and potatoes roasted in animal fat could count as a healthy/whole food meal, but it would taste different to the typical hamburger meal we all associate with fast food.
Fast food also has an enormous marketing industry behind it which pushes it in unhealthy volume, with maximum convenience, and at (until recently, at least) affordable prices.
Why does grinding the meat at home make a huge difference vs grinding it in a factory? Depending on the cut you choose, the condiments you add, and the portion size, a hamburger at home could be Lot less healthy than a McDonald’s burger. McDonald’s patties don’t have any fillers afaict.
The point is that “junk food” is a pretty amorphous and vague category. If you want to enforce portion or calorie restrictions you can do that, but it would have to be way more encompassing of a regulation than targeting “junk food”
(to all the boolean questions): yes, yes, yes, yes, yes, yes, yes, yes, yes.
And have a real conversation around Corn syrup.
Even today, a Soda with 'real sugar', at least for me, is far more satiating for thirst or a 'quick sweet treat' than the same brand/'flavor' using corn syrup, that includes both the big chains as well as the local names.
If I drink a soda with sugar in it, I usually wind up wanting water after. If I drink something with corn syrup, I usually just want more of whatever I just had.
Is there evidence supporting the idea that sugar is more satiating? My understanding was that they were equally unhealthy
No, the evidence is that there is no significant difference in satiety. HFCS is 55% fructose / 45% glucose, while sucrose is 50% fructose / 50% glucose.
Well, There's at least this as a start... https://nutrition.org/sugars-created-equal-lets-talk-fructos...
Not saying Sugar itself is much better, however, yes, there is research indicating that the two are metabolized differently, so that difference in composition should be considered.
yeah that was my understanding. for some reason corn syrup is vilified. the real problem there (as I understand it) is corn subsidies.
Real sugar in your soda pop? What are you, a health nut? Must be a real my body is a temple sort.
Seriously though, it's a dogshit thing to consume whether it is sweetened with HFCS or sucrose.
"Even today, a Soda with 'real sugar', at least for me, is far more satiating"
Did you know that in the acidic environment of a cola, sucrose quickly degrades into fructose and glucose (and if it didn't, your enzymes literally immediately crack sucrose into them). You know, exactly the same fructose and glucose that would be added by HFCS. The proportions differ a tiny amount, but this notion that one is satiating and the other isn't should really send you down a path of self-discovery, where you determine how you fell for nonsense.
The idea that there’s some magic ingredient that makes soda a healthy choice is why discussion of “Junk food” Is so weird
People have tried. Any time the government tries to do anything a substantial portion of the electorate throws a childish hissy fit and tries to make out that the Bolsheviks are coming to make their fries less tasty for no good reason.
What's interesting is that it's different parts of the electorate that get upset. When Republicans wanted to make junk food/soda ineligible for food stamps, Dems got upset. And when Dems wanted to tax large sodas, Republicans/libertarians got upset.
I think the former makes much more sense than the latter, since it is literally being funded by the govt. That's a reasonable first step, or possibly only step, especially considering that most people on food stamps are also on govt-funded/subsidized healthcare (meaning taxpayers will end up footing the bill when they require expensive treatments resulting in part from an unhealthy diet).
This is a pretty insincere take.
Feel free to elaborate on my alleged insincerity. Was I insincere in noticing that there are partisan patterns at play, or insincere when pointing out that the govt should have more control over govt-run/taxpayer funded programs, as opposed to transactions between private parties?
I am sincerely curious to know your opinion.
A "sin tax" on unhealthy products impacts everyone equally. The Republican plan has absolutely nothing to do with health (and they've thankfully barely even tried to pretend it is, instead just going with a "well why should they get treats?" punitive angle), and everything to do with punching down. It's amazing that there are tens of millions of terrible people in the US who will vote for staggering levels of corruption, self-dealing, stupidity, and incompetence so long as those people will punch down on the right people.
As LBJ correctly observed - "If you can convince the lowest white man he's better than the best colored man, he won't notice you're picking his pocket. Hell, give him somebody to look down on, and he'll empty his pockets for you." It's amazing how punching down can get votes.
EDIT: insincere guy, who seriously tried to pretend that it's "partisan" to find a difference between those initiatives -- one predicated on health concerns, the other on punching down -- is now crying for moderation assistance because I quoted a US president, in a situation that is perfectly applicable to exactly this policy that they are laughably trying to equivocate.
Howler troll behaviour.
Replying to your edit:
Amazing that you again allege insincerity, with zero evidence. You then go on to make false claims about what I said and avoid the obvious point that my problem is not with the historical figure that you quoted, but the fact that you injected race into a conversation that was about food.
As for whether you violate the HN guidelines, the number of your recent comments that are greyed out tends to indicate that I'm not the only one who thinks you're out of step here.
You obviously do not know what the word "sincere" means. Please look it up before posting further.
How does any of this make my comment insincere? Even if I agreed with it, I wouldn't understand how it proves your original accusation.
I also don't love your injection of flame-bait racial comments, which probably violate HN guidelines.
Unfortunately in most countries the blocker is politics, not the desire of public health officials to do anything. See the current US admin going after vaccines while declaring open season for peptides.
this is exactly right. We've got this society that readily accepts unpleasantness as what you need to do to get ahead(I'll question that but it's beside the point). People regularly accept suffering of all sorts. However, ask someone to eat a boring meal. that's a hard no. So, you've got large parts of society that won't accept that perhaps they shouldn't eat like children.
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.
> What is interesting about it?
did western society engineer a junkfood-industrial-complex so addicting and so en-sickening that it ultimately required a sort of junk food methadone to wean itself off?
I mean kinda yeah
Even more so. Not absolute weight loss but the effect of loss of the systemic inflammation due to a surplus of visceral fat which has significantly more systemic effect than subcutaneous fat or other types of loss of mass.
> If this is caused by the weight loss, it is a little disappointing that public health didn't act quicker
Public health has been trying to get obese people to lose weight forever, what are you talking about. We've known it's bad in enough other ways. It was just really, really hard (at a population level).
Alzheimers dementia is sometimes called type 3 diabetes, so it may be both.
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!
>> 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.
I think you need to read up on why the civil rights act was necessary and the things it fought for. Woman's suffrage was fought for a long time ago, but that does not mean it was universally applied.
Many many times in US history we've said something is true, but put some big asterisks after them. Slavery is over (except it's definitely still permitted in the US), it's illegal to discriminate based on race (except we allowed redlining for generations and arguably are still fighting it), rape is illegal (unless it's your spouse, then it was legal until '93. And a lesser crime still in much of the country).
Voting is no different. Heck, one might argue we still don't have universal suffrage. People who want to vote but because we've put barriers like underfunding stations, long lines, not giving time off to vote, etc. we're clearly preventing some types of people.
No, black woman (among many other minorities) certainly didn't. I guess that part isn't taught in american schools as thoroughly as it should be.
If you're seriously claiming black women didn't have the right to vote in 1976, you should probably provide some evidence rather than snide remarks.
Then teach us.. when did they got actual voting rights? (i'm not trying to be snarky but sometimes it' not easy seeing the level of history ignorance in society)
Federally? 1920.
When did all the voter suppression become illegal? 1965.
I can't help but notice that you're still providing absolutely no evidence for an extraordinary claim.
> 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.
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.
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.
... It can cut both ways, and depends a lot on the 'level' of poverty and specific circumstances, although the calculus has shifted over time.
If people are working crazy hours, sometimes it's a struggle to even get time to properly shop for groceries, let alone cook. There's varying degrees of that too;
i.e. I remember the 3-4$ frozen pizzas that could be used as a dinner and leftovers; And yes, at least back then, We could instead buy some chicken, rice, and a can or two of soup or stock to do something way healthier, at the same overall cost per meal...
But it would take an hour or so to properly prepare instead of just tossing that 3-4$ frozen pizza into the oven and letting it do it's thing.
Then throw into the mix where both partners due to work and/or school aren't even home till 8PM, and one of them has to wake up by 7AM to get to work the next morning [0]
I've lived that situation, although thankfully that wasn't every night and we could balance between the healthy self cooked option and the junkish-food-pizza.
But I've also lived the situation where both parties are working late, or the commute is so bad, you're glad you advanced enough you could afford the more expensive, but at least then managable 'taco bell' option.
But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm [1]
[0] - You don't want to eat too late for other health reasons of course...
[1] - And yes, that group really does tend to be less healthy overall from my personal experiences, even if their dining tastes are 'expensive'.
You are describing time, not cost. I can assure you my family worked pretty demanding jobs with long hours. And spent hours preparing food on top of it.
The average American spends 4-5 hours a day on personal screen time, and this skews higher the poorer you get based on a few studies.
I agree it's much more convenient to toss a couple pizzas in the oven. I do not agree it's less expensive. I don't know where you're buying your rice or chicken, but even at $4/pizza I can't pencil that out. Chicken comes with free chicken stock if you're buying rotisserie chickens and keeping the bones and vegetable ends/etc. around for stock making. This is the level of poor I was talking about.
> But then there's the sort of 'generational passing on' where we now have multiple generations raised on carry out, fast food, or microwaved meals. Sometimes where they were never given the teaching or responsibility of cooking because (for reasons similar to above, including more affluent cases) the general concept of 'a home cooked meal' becomes the exception case rather than the norm
I definitely agree with this one. Habits and skills are passed down generationally. Someone may not even know where to start looking at youtube for how-to videos to make their own chicken stock for close to free with a $5 crock-pot from the local thrift store these days.
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.
> Pleasing your customers is how profit is maximized.
If you ignore everything like, including but not limited to, market capture, addictive products, lock-in, information asymmetry, planned obsolescence, dark patterns, captive markets, artificial scarcity, seldom-lucrative-yet-important services and any externality, very true!
Where are you getting a steak and potato for 2 for less than a bag of Doritos? Is it a 50 lb bag of Doritos?
Maybe it's 4oz of very lean tough steak and a single small russet potato with no fat, and the two mentioned are five year olds.
I can buy the day old steaks for $5-6, and a potato is maybe 50 cents. Doritos are $6.49.
A Hershey's chocolate bar is $3.99-$4.99. A banana is maybe 50 cents.
....
At least 10 to 15-ish years ago, I would actually be closer to agreeing;
You could get Cube or Chuck steak for 3-5$ a pound and potatoes were cheap as hell too. Toss some diced onion in and You'll have a good dinner.
How do I know? Well I grew up in a family where for... reasons[0] we were not that well off for quite a while.
Cube Steak was one of the big things we did for a family meal that Dad cooked. (Chili was his other favorite to make, which was also cheap to do for how much food came out of it...)
However the current prices of beef, I feel like you'd need to have a long standing personal relationship with a local butcher or rancher to make this true.
[0] - My mother's over-propensity for being truly Christ-like in her charity to family and others, also sending myself and my three siblings to Catholic school to avoid the then-absolutely-failed Detroit Public school system were major factors.
I'm québécois, my grandma came from a big family (12 siblings IIRC). She used to cook with ground beef all the time cause that's what her mother cooked with too - it was THE cheap source of protein. Meat loaf, shepherds pie, meat pie, beef and cheese macaroni, the whole shebang. Nowadays, when I cook any of those meals, it's cause I feel like eating that specific thing, but it often turns out to be the most expensive meal of the week.
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.
You are missing the protein.
Eggs and legumes and yogurt and milk and tofu have protein. And chicken isn’t that expensive.
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.
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'm using reta myself, but honestly it's because sema/tirz isn't allowed for me either. If you have medical tirz available, you should have some serious reasons to jump into the unregulated shark tank.
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.
Semaglutide clears liver fat? I had no idea. I’m curious to know more about your protocol
My protocol was to take semaglutide
As a consequence I ate less. Weirdly, I think I eat more sugar now but my total calorie intake is lower. I eat more sugar because sometimes it's the only thing that seems palatable or I'm trying to counteract the hypoglycemia feelings.
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?
Yes the medicine does it. It's attacking T2D via several pathways, but in the case of Reta the glucagon is doing the heavy lifting of clearing liver fat.
This extra receptor is why Reta is a triple agonist unlike semaglutide (single glp1) or tirzepatide (glp1+gip double agonist).
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.
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'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).
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.
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.
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 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).
Going back to my endurance days, I think people bonk because they aren't adapted. After a year or so of pushing through the bonk, and growing up with hypoglycemia if I didn't eat frequently, I got to where I could start out at 5am on an empty stomach and not eat until noon or later. If I did bonk, I'd sip V-8(yeah, really) and instantly recover.
I'm on tirzepatide, a competitive athlete, and have no idea what GP is talking about.
Being a competitive athlete is probably why you have no idea what I'm talking about (and maybe you're not in your 50s). You have a reason to keep your momentum and you are likely more regularly active than I was. Sure I lifted weights, but it was only 2-3 days a week for maybe 6 hours total.
Maybe start lifting weights again? 50 isn't a death sentence; I know a lot of competitive 50s-year-olds.
I'm trying but I've got a toddler and now it seems like every joint hurts. No time to get to a gym and no room for a decent home gym. I did start to do back day again at the Y when we go on the weekend for the pool. We'll see...
People who eat well below their maintenance calories tend to have lower energy levels. That's the most likely explanation.
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
True, but sugar can be converted to fat in the body. If you eat too much sugar before/during a ride, the extra sugar becomes fat.
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.
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?).
You’re on too high a dose. The highest dose made me a vegetable, with no energy, and so on. That is not the way.
Lower the dose (with your doctor, of course). For me, the “middle” dose was the sweet spot of positive effects with minimal side effects.
You are likely a “hyper-responder” to GLP-1s.
Also, tirzepatide had far fewer side effects for me, fwiw.
YMMV, of course.
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.
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.
Isn't lower calorie consumption in general correlated to longevity? (Assuming no major malnutrition)
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.
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.
To "actshully" you (because there are no absolutes in biology) pro-triathlete Lionel Sanders got his hba1c up to prediabetic range (5.9)
https://www.tri247.com/triathlon-news/elite/lionel-sanders-t...
Also age plays a pretty significant role. I know older asians who regularly walk who still got T2D. You could argue that walking isn't physically active enough... but they'd argue otherwise. It's all relative.
Doubt you can eat just pure fructose for 30 years and ”move” and avoid diabetes.
At the risk of being argumentative I had a horrible diet for the past ~10 years and carried 50 extra pounds. However I also exercised a lot as a hobby and to my shock my glucose and other bloods always came out in the normal range.
This year I started Mounjaro and dropped the 50 pounds. Curious to see what my next checkup shows.
People kick around the idea of the "personal fat threshold". E.g. caucasians seem to be better at carrying fat than, say, Southeast Asians. White people seem to be able to better store fat without metabolic side effects; SEA seems to get T2D at a much lower bodyfat percentage.
Possibly maybe, but plenty of caucasian friends at my old bodyweight/fat percentage had/have horrible markers. I lean more towards the protective effect of exercise.
Agree 100%. To quote myself:
---
Which do you think is worse: smoking, or not exercising?
https://jamanetwork.com/journals/jamanetworkopen/fullarticle...
Look at Figure 2C in particular. The hazard ratio of smoking is 1.41. The hazard ratio between "Low" (<25th percentile) and "Below Average" (25th-49th percentile) cardiovascular health is 1.95.
In other words, it is better to be a smoker than in the lower 25% of non-exercisers. By far. It's not even close.
https://news.ycombinator.com/item?id=40080849
Let me emphasize: that exercise hazard ratio is between LOW and BELOW-AVERAGE.
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
That's a big percent for something that is completely devastating. This is objectively good news.
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.
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.
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.
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.
> It shrinks visceral fat, it's been shown to clear liver fat
The brain is 60% fat, so I'm not running to the pharmacy yet.
Myelin and membranes aren’t triglyceride stores. There’s no lipolytic pathway that strips a neuron’s membrane the way a caloric deficit empties an adipocyte.
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
"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.
And a doubling in the rate of waking up blind.
Doubling doesn’t mean much without knowing the base rate.
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.
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.
It is well known that forcing a sudden drop in chronically high average blood glucose (like, from 200+ to a normal ish range) with insulin can cause vision loss. I wonder if it's the same mechanism?
It tends to happen when:
1) You must have a crowded optical disc as a precursor (low cup to disc ratio). Genetic and can be tested
2) You have stiff veins/arteries due to poor metabolic/cardio health
3) when blood pressure drops too much, blood flow can get cut off to the optical nerve temporarily due to reliance on high blood pressure due to 2
4) Due to loss of blood flow, optic nerve swells and closes blood flow into the eye due to 1
It's also true that having a crowded optical disc is pretty much a required precursor condition to suffering NAION.
Which you can get checked for via a $50 optical scan.
No crowded disc, very little risk.
(Cup to Disc ratio of 0.2ish or less starts to present risk)
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.
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.