At a risk of being ignorant: Isn’t obesity a function of calories intake and calories burn rate? If so, why do we even need a drug for that? What should a possible drug target here? Assuming no changes in behaviour and thus a continued steady daily caloric surplus, would it even work?
At a really fundamental level, yes, it boils down to calories in versus calories out. However, in practice it's more complicated than that, partially for psychological reasons.
Anyone will lose significant weight on a strict enough diet. Unfortunately, severe calorie restriction does things to your metabolism -- basically, your body notices there's not enough food, and tries to slow everything down so that your existing stores will last as long as possible. This (a) isn't good for you, since major organs are having to limp along, and (b) means your diet gets less effective, as "calories out" aggressively shrinks. There's evidence that this lasts for a fair while after a diet stops, making it really easy to regain weight.
Then, psychologically, most people have a hard time sticking with any sort of long term diet. Unless you have an abnormally low hunger response, ignoring feeling hungry all the time (even just a little bit) is very hard. Cheating on your diet is very alluring, and your body gives you all the rewards for doing things that feel like they're avoiding you slowly starving to death.
The latter point is where these drugs come in. By suppressing hunger signals, dieting suddenly becomes easy, removing the escalating willpower requirement. (Honestly, I'd worry about whether you'd still suffer the metabolic effects of calorie restriction even if you're not noticing the hunger, but hopefully that's being studied and they're only prescribed along with a solid nutritional plan...)
> Anyone will lose significant weight on a strict enough diet. Unfortunately, severe calorie restriction does things to your metabolism
Who said anything about "strict" or "severe calorie restriction" ?
To loose weight a person need only regularly eat 100 or 200 calories less than their daily requirement. For many who are obese, we're talking about having one less can of coke per day, or one less slice of a whole pizza or less ice cream every day.
A severely obese person can perfectly well eat McDonald's every single day, and eat more calories than a regular gym junkie and STILL lose weight!
Yes, your instinct is correct, you have vastly oversimplified it in an unhelpful way. The body is not an energy equation to be balanced.
The desire to eat is driven by our hormones and these are not easily overridden by willpower. In fact, study after study shows that willpower is insufficient for most people. Hunger is produced by a complex set of factors that we do not fully understand. What we eat and how we live plays a big part in how hungry we feel.
Calories should not be counted like some fungible currency. Each food is a complex and poorly understood cocktail of organic chemistry. Food is not processed by the body in the same way or at the same speed. In the most simple sense, unprocessed whole foods digest the slowest and provide the most even energy to the body, while highly processed food is digested quickly and leaves you hungry again soon. And above all else, fiber is the most amazing thing that can be in your food to regulate your digestion and make you feel more full.
And the consumption of energy is also not a matter of willpower to go to the gym. The body regulates is caloric burn to suit its environment, again, based on a complex and poorly understood web of signals. But in simple terms, trying to eat less can also caus your body to go into a "low power mode" where you burn less energy, ultimately being counterproductive.
The magic of this drug is that is hijacks one of the important hormone pathways involved in hunger and causes you to eat less calories without a single conscious thought. If proven out as safe and effective, it could be the silver bullet in an obesity epidemic that has never had any easy solutions before.
It's very important to consider "metabolic rate" in these considerations. I have been nearly under-weight my entire life (I'm in my 60s) and I've eaten as much high-calorie food I've felt similarly, usually a large amount (generally consuming the most any gathering I'm at, etc, eating three meal a day, etc).
The one thing I've always done is avoid foods with added sugar and in general processed food. There's good evidence that the consumption of "ultra-processed" food is associated with the obesity epidemic and that these food are what people weight-maintenance processes out of balance.
Given this, adding a drug to solve that problem might not be a panacea. What other bad effects could result from a strong drug plus a crap diet? We'll start another mass experiment to find, I suppose.
I am very much not talking about willpower. I am saying it is NOT about willpower.
And sure, there is an energy equation here thermodynamically, but it is unhelpful. It would be something like:
Calories in * X = Calories consumed * Y + Fat stored * Z
Where X, Y and Z are unknown and barely controllable factors related to hunger, type of food, digestion, microbiome, hormones, genetics, metabolism, environment, society and so on.
Evolution had no care about the understanding of applied physics when we came up the evolutionary tree. Understanding physics here almost has no effect on our behavior.
Instead look at the evolutionary incentives. If you starve you are going to die and it is going to fucking hurt the entire time you are dying.
With that one line of information you now understand not only humans but the vast majority of animal life on this planet and why almost all animals get fat if you leave a full food dish around. We are optimized to avoid starving at all costs. When winter comes you could die. When the summer drought comes you could die. Your animal brain is yelling at you to pack on the pounds now that the eating is good because the lean times are coming. Our animal brain has no understanding or concept that times are good, we need to slow down. It has never been a primary evolutionary driver.
Notably, this is (presumably) why our bodies often think it's a very good trade-off to turn everything down instead of burning fat. Fat is important long-term storage that might be what gets us through the winter starvation, and storing/burning it is a lossy process -- turning down the tap on our energy usage for a little while, however, might be all we need to get through a lean few weeks.
you can tell these people have never tried to bulk and cut cycle, if you guys start lifting weights or even taking stimulants it becomes beyond obvious that it is a simple input/output sort of thing. The psychological, I saw someone mention the hypothalamus part, that must be the real difficult thing.
in a banal sense this is true but the reality is less clear than the CICO folks would have you think. there are regulatory functions in the method for energy consumption (basal metabolic rate is not constant) and microbiota have a substantial effect both through their own metabolism and endocrine effects
It's the other way round: the point of the drug is to change behavior. By changing the hunger response.
The hunger response is not quite as low-level as, say, the breathing response, but you'll notice that it's very difficult to choose to stop or reduce your breathing below a level that your body will accept, and after a very short while your conscious will will simply be overridden.
Modern nutrition science has found that each person, at any given time, has a "metabolic setpoint". This is basically a target weight that their endocrine system is trying to keep them at. There's a feedback loop, where below this weight hunger hormones will nudge them to eat more and metabolic hormones will lower caloric expenditure (lowering body temperature, sleeping longer, fidgeting more). And vice versa above this weight.
Most people will have a +/- 25 lbs window, where the feedback loop is minimal. But once they step outside this window the nudges become increasingly strong. This is why it's generally easy to lose 15 lbs, but really hard to lose 50 lbs. Also why many can lose weight under very targeted lifestyle interventions, but rapidly snap back as soon as they relax even a little bit. Finally it's why the vast majority of normal weight people don't need to count calories, their metabolic setpoint intuitively matches their appetite to their caloric needs.
"Eat fewer calories" is technically a solution, in the same way that "stop drinking alcohol" is a solution for an alcoholic. The problem is someone who has an obese-level metabolic setpoint will literally be ravenous 24/7 once they get down to healthy weight. If you haven't experienced this yourself, try fasting for 48 hours, putting out a bowl of chips on the table in front of you, and resist the urge to eat even one while you try to do something else. That is what it's like to be an obese person trying to lose a large amount of weight.
GLP-1 agonists work by short circuiting the hormones that regulate hunger. It's basically the equivalent of moving your metabolic setpoint 100 pounds lower. The need to explicitly count calories no longer exists, because your appetite will naturally limit itself well below the point of caloric expenditure.
> Modern nutrition science has found that each person, at any given time, has a "metabolic setpoint". This is basically a target weight that their endocrine system is trying to keep them at.
Citation? This goes against everything I've heard from credentialed experts and against my own experience as well. For one thing, it's unclear how you'd explain the weight gain of the median person in the western world over the last 30 years. For another, it's very strange that people like me (previously) gained 5-10 pounds a year, if our bodies were supposedly trying to keep us at a particular set point.
Metabolic set points can and will drift over time. So if somebody starts out with a setpoint at 22 BMI, they might naturally be anywhere from 21-24 BMI at any given time. As food in the environment becomes more hyper-palatable and calorically dense, people are more likely to "settle" at the upper end of this range. Over time spending more time at the upper end of one's range will "nudge" up the setpoint gradually and continuously.
But the point is this is a slow and continuous process that occurs over years or even decades. Discontinuously making a big shift in weight, up or down, is basically impossible. Which is why despite very high rates of obesity, it's basically unheard of for someone to gain 50 lbs in a short period of time. Almost all weight gain takes the form of 5 lbs one year, 5 lbs another year, and so on.
I would look for studies on ghrelin (the hunger hormone) - lose weight it goes up, gain weight it goes down - that's the set point behaviour.
The phenomena of an ever increasing set point I believe is down to periods of willful over-indulgence that overruns the power of our hormonal homeostasis to recover from so it settles higher than it started when pushed too hard.
Christmas, holidays, times of stress, home-baking passions (my downfall), liquid calories and ultra calorie dense eating-for-leisure that don't stimulate our sense of fullness early enough to stop.
The cruelty is that it's a hell of a lot easier to eat when not hungry than to push a plate away when jonesing for it, so it keeps going up.
People have trouble dealing with hunger because we frame it all wrong in the western convention. I'm hungry, I should eat a little something, is what most people think. An ascetic from the east who fasts is not immune to the pain of hunger, they just understand that hunger is a sensation that is neither good nor bad, and what they choose to do with that sensation is up to them, and they are not bound to it and do not have to satiate it right then.
I imagine if a prescribed diet from a doctor also came with mental health counseling, that overcoming the satiation issue could be a lot easier for more people. It really is a frame of mind issue that prevents most peoples weight loss from being more successful.
It really is not a frame of mine. We know this because GWAR genome studies find that the SNPs most correlated with obesity are expressed in the hypothalamus, which has nothing to do with higher thought.
Its not like you black out and the chips are in your mouth though, to act on hunger requires conscious effort. That is what the ascetics are practicing, resisting these primal urges because they can be resisted by the higher thinking brain.
And if ascetics were even a significant portion of the human population I would say that would be a useful measure. Instead their numbers are low enough that they are a statistical outlier along with those people that seem to eat as much as they want and not gain weight.
The fact is you can choose to starve yourself to death if you put your mind to it. I would counter that with 'why the hell would you want to'. Wasting a huge portion of my brain time to tell myself (oh yea, don't eat) seems like a massive waste of time and energy.
>to act on hunger requires conscious effort
Does it? I'd like to develop a test where I starve a large people for a little while. Then while I distract them with something I put some easy to eat like chips in their peripheral view and see how many of them realize they started consuming the chips. My ethicist says I can't do this unfortunately, but I imagine that a significant fraction of the group will not realize when they started eating them.
>Wasting a huge portion of my brain time to tell myself (oh yea, don't eat) seems like a massive waste of time and energy.
That's not what the ascetics come to learn. They aren't even thinking about the hunger at all when they are fasting. The sensation is barely registered in their thought. Plus even with your example for those people who do not realize what they are doing with the chips, if you are serious about dieting you wouldn't set yourself up for such temptation like having a bag of tempting candy perhaps in plain view. You'd do what people who quit smoking do and throw away the junk food or otherwise get it out of easy access. Then you've given yourself another layer of friction that requires even more conscious effort to overcome: if you want to act on your craving for chips, you now have to go to the store and buy them.
>if you are serious about dieting you wouldn't set yourself up for such temptation
But that's the point. You live in a world full of this stuff and a huge portion of people do not have the option to setup the world in such a manner they can avoid temptations being around them.
People that fail to quit smoking have the biggest problem when other smokers offer them cigs. And smokers are a 'small' portion of the population, we all eat. That's why we came up with things like bupropion and varenicline so people can quit smoking. Most people tried and failed to quit smoking multiple times.
As someone from an Eastern country with a strong ascetic tradition, I find this framing unhelpful. Yes, our culture places a strong emphasis on fasting, but is simultaneously also experiencing its own obesity epidemic - and it's not because we're adopting a western framework around hunger. More and more people can now afford high calorie ingredients in our native cuisines that were a luxury a few decades ago. When I was a kid, things like ghee were prohibitively expensive, and I grew up seeing it as a special treat consumed sparingly. I never had to develop self-control around expensive, high satiety food because access was self limiting. If all we could afford to eat daily was rice and lentils, it was hard to be morbidly obese. My generation has faced an obesity epidemic, partly due to easy access to rich foods my ancestors didn't have but my culture and cuisine valorizes. Industrialization of food production has made access much more egalitarian, but we have yet to develop the collective restraint needed.
These drugs modulate your hormones to reduce appetite and cravings for unhealthy foods. When people lose weight the normal way, their endocrine system sends out a “you are starving, eat” hormone response that is extremely difficult to overcome and success requires 100% compliance for the rest of your life.
Success in adjusting diet does not require '100% compliance for the rest of your life'. It requires serious changes yes, but even frequent slips as part of a largely altered diet won't discount it. This perspective - as well as being factually inaccurate - feeds into shame spirals and negative self efficacy. It's also true that virtuous circles can be built on diet and exercise, replacing the endorphin lift provided by sugar / carbohydrate load; and in the longer term homeostasis can be achieved at a healthier weight. It is difficult, but it's absolutely not as impossible as this comment implies.
I think people who think it's "just that simple" have never seriously tried to starve their body. It's truly incredible how far the human brain will go to get food into your mouth when it thinks you're trying to starve it.
> Isn’t obesity a function of calories intake and calories burn rate? If so, why do we even need a drug for that?
Because calorie intake is substantially impacted by things like satiety. As the article's subtitle heavily hints at, "A class of drugs that quash hunger" is beneficial in moving that bit of the equation.
I understand, but appetite/hunger seems to be just a part of the issue. The second part being people (myself included) using food to comfort ourselves. I feel bad -> I seek tasty food to comfort myself, even if I am not hungry. The whole candy-market is built around. How are drugs to address this?
Indeed, we need an economic policy, not an economic drug. I’m totally for behavioural policies for obesity, such as don’t buy sweets, go for a walk each day, or make sure to eat vegetables each time you are hungry, etc.
> I’m totally for behavioural policies for obesity, such as don’t buy sweets, go for a walk each day, or make sure to eat vegetables each time you are hungry, etc.
So are physicians, and most patients. It's just a lot harder than it sounds to sustain. There's the old adage that "the definition of insanity is trying the same thing over and over expecting different results"; attempting to cure obesity by telling patients "exercise more, eat less" is precisely that.
This is too absolutist. People aren't immutable, unable to control themselves at all without drugs. Anyone who gives up smoking without a patch has to decide to never pick up a cigarette again. They may have "given up" a few times before, and the last time they succeeded. By your logic they shouldn't have tried more than once.
> But if we check back after five or 10 years, there's a good chance they will have put the weight back on. Only about five per cent of people who try to lose weight ultimately succeed, according to the research. Those people are the outliers, but we cling to their stories as proof that losing weight is possible.
> In a meta-analysis of 29 long-term weight loss studies, more than half of the lost weight was regained within two years, and by five years more than 80% of lost weight was regained.
"Just eat right and exercise more" may work for a small number of people, but for most it's setting folks up to fail. It's good that we're starting to get medication options that can help folks achieve those changes; bariatric surgery works, but it's a big deal for the body.
Bariatric surgery also tends to require a period of weight loss beforehand as well as extensive behavior modification afterward. These new drugs should make that process much easier.
Well, to be clearer, the first is just an article, but it talks about obese people, not all people. That's what I mean. Obese people are not all people, and studies of weight loss in obesity are on a few obese people.
Take a 'large enough' population of animals and give them an all you can eat buffet for months. What percentage of them becomes overweight? It won't be 100%, but the numbers should be pretty high. I have a very strong feeling (sadly no evidence, they won't let me trap random people in cages for months at a time to test this) that the human numbers and the animal numbers will look very much alike.
My what? I was countering an absolutist position; I wasn't presenting my own.
And yes, animals can be made to starve to death as well, if you give them a bar to push that gives a dopamine hit. That doesn't mean we should shrug and say, "Well, it's inevitable that I'm going to die now, because I failed once" the first time we fail to refrain from getting such a hit.
There is some evidence to show that obesity has been rising independently of behavioral changes (even though they do contribute), due to deterioration in the food quality. Look at obesity rates amongst animals for example, especially wild animals that feed off of human food.
Because many people just aren't able to get that ratio to a point that they're at a healthy weight (for numerous reasons - behavioral, medical, etc.).
"Assuming no changes in behavior" doesn't make sense, because the drug makes people feel full after a smaller amount of calories and thus changes behavior.
Don’t you ever eat sweets despite of not being hungry? I don’t think the issue is people overdosing rice or legumes because they are so hungry. The issue seems to me like quick comfort foods that we eat not to get full but because they just feel so good in our mouths. I don’t think I’ve ever eaten ice cream out of hunger:)
Yeah, I agree with all of that, but I would differentiate slightly between not being hungry and being full. I snack when I'm not necessarily hungry, but I don't snack right after I've eaten a full meal and am actively full.
Anyway, semantics of hunger/fullness aside, the effect of the drug is behavioral - people taking it do end up eating significantly less, which leads to substantial weight loss.
Also it is much easier to pass those snacks and other stuff when you are full or not hungry. If this is consistent state, it can also effect how accessible at other times snacks and such are.
We evolved as hunter gatherers and have been hunter gatherers for most of our history. Continuously moving while collecting resources, even into old age. Today, most people don't continuously move. They go from bed, to work, to the couch at home, then to bed, with as little physical movement as they can possibly do in between.
Maybe if more people at least simulated how much a hunter gatherer moved a day, we'd see a much healthier population versus continuing this sedentary behavior that we have not evolved to do while remaining healthy. Agriculture which enabled a sedentary lifestyle for many people did not happen long enough ago for our species to be well adapted to this behavior; it was only 10,000 years ago, while our ancestors had been hunting and gathering for at least 2 million years, likely foraging even longer still.
It's like treating an addiction by telling the addict "it's ok to have some, just pinkie swear you won't overdo it."
People who are obese or grossly obese often aren't just eating a "little extra" here and there. Imagine more like "extra pizza a day" or "eat a cake once a week because that seems like a good idea".
1Kg of human fat is around 8000kcals give or take.
50lbs is 22Kg. 176000kcal. It's 586x "extra slices of pizza", almost two years of overeating every day.
That's exactly what I said. 300 cals indefinitely. I obviously didn't mean you eat one slice of pizza and gain 50lbs.
It's easy to say "put down the pizza," but pizza is just an example.
300 calories is also 1/4 a cup of rice (50 cals), 1/3 service of chicken (100 cals) an egg (78 cals), a teaspoon of olive oil (40 cals), and a toast (75 cals).
There are lot of reasons its hard to cut weight. Measuring calorie intake to 300 calories is hard enough. But also, its easy to eat a bit more at each meal if you are hungry (and it adds up).
When you are so fat your metabolic maintenance rate hovers around 4000 kcal per day you lose all sense of what to eat and after years of over eating old habits die hard.
On paper dieting is the easiest thing. You literally need to watch one hole and it is right under your nose, but in practice it isnt that easy.
Appetite is great way to control obesity - if you dont want to eat you wont
I had an opinion that this all sounded silly but then watched the 60 Minutes segment on the drugs and what the doc talked about is, in my layman's recollection, the body remembers its weight and wants to get back to that which is why a lot of people end up losing and then gaining most of it back. Genetics play a role in this, I forget how but something to do with what these drugs help change.
I wonder if rather than a placebo they had a control group also try to lose with caloric restriction and defined plateaus where they maintain a weight for some period of time. For example instead of lose 1lb/week for 52 weeks, lose 1lb/week for 12 weeks, maintain weight for 8 weeks, repeat. Maybe the element of the body "remembering" a weight happens when you plateau at a weight for a while? Kinda like giving the body some time to adjust as you lose.
Other than this is mostly useless in itself.... Calorie restriction really only works well under medical supervision (multiple studies show people suck at calorie counting and avoiding calorie intake). Once the supervision is over, most people gain the weight back.
I have a feeling it may happen with this shot too, and if so I foresee it will have primary treatment to lose weight then a secondary to maintain status.
There already are quite effective weight-loss drugs but they're not across-the-board medically-approved for that effect (with some exceptions) because they're also drugs of abuse, namely the cocaine and amphetamine drug families. However, many obese people get around this by getting an ADHD diagnosis (any quick search will reveal that 'obesity and ADHD are highly correlated' due to this phenomenon). The WebMD blurb is fairly accurate:
> "Sometimes the medicines most often used to treat ADHD can cause weight loss. Stimulant drugs like methylphenidate (Ritalin) and amphetamine/dextroamphetamine (Adderall) make you less hungry and make your body burn calories faster than usual. Some of them are even used to help people lose weight or treat binge eating.Oct 26, 2021"
"The effects of amphetamine on body weight and energy expenditure" (1992) Jones et. al
However, in many cases if people stop taking such drugs they can regain the weight, and the drugs can be addictive if dose regimens are not carefully managed (which doesn't seem to be a problem with ADHD). Note also these drugs are much cheaper than this new class, likely by a factor of 10.
In the long run, new behaviors (quitting alcohol and sugary foods, increasing exercise, reducing overall calorie intake, etc.) are probably needed for persistant long-term effects on reducing obesity.
I believe you are correct, but that leaves several possibilities for the drugs to be effective. They could work by either causing you to lose interest in food/improving impulse control so that you eat less, or by increasing your calorie burn rate, or by causing your body to absorb less calories from the same amount of food.
