We Know Where New Weight Loss Drugs Came From, but Not Why They Work
The empty auditoriums, Gila monsters, resistant pharmaceutical executives and enigmas that led to Ozempic and other drugs that may change how society thinks about obesity.
Credit…Ryan David Brown for The New York Times
Gina Kolata
For more than 25 years, Gina Kolata has been reporting on obesity research that until recently had found that drugs and changes in diet or exercise produced little lasting effect on weight.
Aug. 17, 2023Updated 9:47 a.m. ET
Every so often a drug comes along that has the potential to change the world. Medical specialists say the latest to offer that possibility are the new drugs that treat obesity — Ozempic, Wegovy, Mounjaro and more that may soon be coming onto the market.
It’s early, but nothing like these drugs has existed before.
“Game changers,” said Jonathan Engel, a historian of medicine and health care policy at Baruch College in New York.
Obesity affects nearly 42 percent of American adults, and yet, Dr. Engel said, “we have been powerless.” Research into potential medical treatments for the condition led to failures. Drug companies lost interest, with many executives thinking — like most doctors and members of the public — that obesity was a moral failing and not a chronic disease.
While other drugs discovered in recent decades for diseases like cancer, heart disease and Alzheimer’s were found through a logical process that led to clear targets for drug designers, the path that led to the obesity drugs was not like that. In fact, much about the drugs remains shrouded in mystery. Researchers discovered by accident that exposing the brain to a natural hormone at levels never seen in nature elicited weight loss. They really don’t know why.
“Everyone would like to say there must be some logical explanation or order in this that would allow predictions about what will work,” said Dr. David D’Alessio, chief of endocrinology at Duke, who consults for Eli Lilly among others. “So far there is not.”
Although the drugs seem safe, obesity medicine specialists call for caution because — like drugs for high cholesterol levels or high blood pressure — the obesity drugs must be taken indefinitely or patients will regain the weight they lost.
Dr. Susan Yanovski, a co-director of the office of obesity research at the National Institute of Diabetes and Digestive and Kidney Diseases, warned that patients would have to be monitored for rare but serious side effects, especially as scientists still don’t know why the drugs work.
But, she added, obesity itself is associated with a long list of grave medical problems, including diabetes, liver disease, heart disease, cancers, sleep apnea and joint pain.
“You have to keep in mind the serious diseases and increased mortality that people with obesity suffer from,” she said.
The drugs can cause transient nausea and diarrhea in some. But their main effect is what matters. Patients say they lose constant cravings for food. They find themselves satisfied with much smaller portions. They lose weight because they naturally eat less — not because they burn more calories.
And results from a clinical trial reported last week indicate that Wegovy can do more than help people lose weight — it also can protect against cardiac complications, like heart attacks and strokes.
But why that happens remains poorly understood.
“Companies don’t like the term trial and error,” said Dr. Daniel Drucker, who studies diabetes and obesity at the Lunenfeld-Tanenbaum Research Institute in Toronto and who consults for Novo Nordisk and other companies. “They like to say, ‘We were extremely clever in the way we designed the molecule,” Dr. Drucker said.
But, he said, “They did get lucky.” A Lonely Origin Story
Image Dr. Joel Habener stands in a lab in a white coat holding a glass slide. Dr. Joel Habener in 2007.Credit…Ruby Arguilla-Tull/Bloomberg News
In the 1970s, obesity treatments were the last thing on Dr. Joel Habener’s mind. He was an academic endocrinologist starting his own lab at Harvard Medical School and looking for a challenging, but doable, research project.
He chose diabetes. The disease is caused by high blood sugar levels and is typically treated with injections of insulin, a hormone secreted by the pancreas that helps cells store sugar. But an insulin injection makes blood sugar plummet, even if levels are already low. Patients have to carefully plan injections because very low blood sugar levels can result in confusion, shakiness and even a loss of consciousness.
Two other hormones also play a role in regulating blood sugar — somatostatin and glucagon — and little was known then about how they are produced. Dr. Habener decided to study the genes that direct cells to make glucagon.
That led him to a real surprise. In the early 1980s, he discovered a hormone, GLP-1, that exquisitely regulates blood sugar. It acts only on insulin-producing cells of the pancreas, and only when blood sugar rises too high.
It was perfect, in theory, as a targeted treatment to replace sledgehammer-like insulin injections.
Another researcher, Dr. Jens Juul Holst at the University of Copenhagen, independently stumbled on the same discovery.
But there was a problem: When GLP-1 was injected, it vanished before reaching the pancreas. It needed to last longer.
Dr. Drucker, who led the GLP-1 discovery efforts on Dr. Habener’s team, labored for years on the challenge. It was, he said, “a pretty lonely field.”
When he applied to the Endocrine Society to give talks, he found himself scheduled at the very end of the last day of the annual meetings.
“Everyone had left for the airport — people were taking down the exhibits,” he said.
From the late 1980s to the early 1990s, he spoke to nearly empty auditoriums. Dr. Eng’s Monster
Image Credit…Peter DaSilva for The New York Times
Success came from a chance discovery that was not appreciated at the time.
In 1990, John Eng, a researcher at the Veterans Affairs medical center in the Bronx, was looking for interesting new hormones in nature that might be useful for medications in people.
He was drawn to the venomous Gila monster when he learned that it somehow kept its blood sugar levels stable when it did not have much to eat, according to a report from the National Institutes of Health, which funded his work. So Dr. Eng decided to search for chemicals in the lizards’ saliva. He found a variant of GLP-1 that lasted longer.
Dr. Eng told The New York Times in 2002 that the V.A. had declined to patent the hormone. So Dr. Eng patented it himself and licensed it to Amylin Pharmaceuticals, which began testing it as a diabetes drug. The drug, exenatide or Byetta, went on sale in the United States in 2005.
But Byetta had to be injected twice a day, a real disincentive to its use. Drug company chemists sought even longer-lasting versions of GLP-1.
At Novo Nordisk, chemists began by using a well-known trick. They loosely attached GLP-1 to a blood protein that kept it stable enough to remain in circulation for at least 24 hours. But when GLP-1 slips off the protein, enzymes in the blood quickly degrade it. So chemists had to alter the hormone’s building blocks — a chain of amino acids — to find a more durable variant.
After tedious trial and error, Novo Nordisk produced liraglutide, a GLP-1 drug that lasted long enough for daily injections. They named it Victoza, and the F.D.A. approved it as a treatment for diabetes in 2010.
It had an unexpected side effect: slight weight loss. A Dismal History
Image Dr. Jeffrey Friedman, who discovered the hormone that tells the brain how much fat is on the body, in 1995.Credit…Remi Benali/Gamma-Rapho, via Getty Images
Obesity had become a dead end in the pharmaceutical industry. No drug that was tried worked very well, and every one that led to even modest weight loss had serious side effects.
For a flickering moment in the late 1990s, there was hope when Dr. Jeffrey Friedman at Rockefeller University in New York found a hormone that told the brain how much fat was on the body. Lab mice genetically modified to have none of the hormone ate voraciously and grew enormously fat. Researchers could fine-tune an animal’s weight by altering how much of the hormone it got.
Dr. Friedman named the hormone leptin. Amgen bought the rights to leptin and, in 1996, began testing it in people. They did not lose weight.
Dr. Matthias Tschöp at Helmholtz Munich in Germany tells of the frustration. He left academia three decades ago to work at Eli Lilly in Indianapolis, excited by leptin and determined to use science to find a drug for weight loss.
“I was so inspired,” Dr. Tschöp said.
When leptin failed, he tried a different gut hormone, ghrelin, whose effects were the opposite of leptin’s. The more ghrelin an animal had, the more it would eat. Perhaps a drug that blocked ghrelin would make people lose weight.
“Again, it wasn’t that simple,” said Dr. Tschöp, who left Lilly in 2002.
The body has so many redundant circuits of interacting nerve impulses and hormones to control weight that tweaking one simply did not make a difference.
And there was another obstacle, noted Dr. Tschöp’s former colleague at Lilly, Dr. Richard Di Marchi, who also was an executive at Novo Nordisk.
“There was very little interest in the industry in doing this,” said Dr. Di Marchi, now at Indiana University. “Obesity was not thought to be a disease. It was looked at as a behavioral problem.”
Image Dr. Friedman studied mice that had been genetically modified to have none of a hormone that told their brains how much fat was on their bodies. Researchers could fine-tune an animal’s weight by altering its hormones, but the study failed in humans.Credit…Remi Benali/Gamma-Rapho, via Getty Images Starving Rats
Novo Nordisk, which today has 45.7 percent of the global insulin market, thought of itself as a diabetes company. Period.
But one company scientist, Lotte Bjerre Knudsen, could not stop thinking about tantalizing results from studies with liraglutide, the GLP-1 drug that lasted long enough to be injected just once a day.
In the early 1990s, Novo researchers, studying rats implanted with tumors of pancreas cells that produced copious amounts of glucagon and GLP-1, noticed that the animals had nearly stopped eating.
“These rats, they starved themselves,” Dr. Knudsen said in a video series released by the Novo Nordisk Foundation. “So we kind of knew there was something in some of these peptides that was really important for appetite regulation.”
Other studies by academic researchers found that rats lost their appetites if GLP-1 was injected into their brains. Human subjects who got an intravenous drip of GLP-1 ate 12 percent less at a lunch buffet than those who got a placebo.
So why not study liraglutide as both a diabetes drug and an obesity drug, Dr. Knudsen asked.
She faced resistance in part because some company executives were convinced that obesity resulted from a lack of willpower. One of the champions of investigating GLP-1 for weight loss, Mads Krogsgaard Thomsen, the current chief executive of the Novo Nordisk Foundation and former chief scientific officer of the company, said in the video posted by the foundation that he “had to spend half a year convincing my C.E.O. that obesity is not just a lifestyle condition.”
Dr. Knudsen also noted that the company’s business division had struggled with the idea of promoting liraglutide for two distinct purposes.
“It’s either diabetes, or it’s a weight loss,” she recalled in the foundation video series.
Finally, after liraglutide was approved in 2010 for diabetes, Dr. Knudsen’s proposal to study the drug for weight loss moved forward. After clinical trials, the F.D.A. approved it as Saxenda for obesity in 2014. The dose was about twice the diabetes dose. Patients lost about 5 percent of their weight, a modest amount.
But Dr. Martin Holst Lange, executive vice president of development at Novo Nordisk, said in a telephone interview that it was at least as good as other weight-loss drugs, and without side effects like heart attacks, strokes and death.
“We were super excited,” he said. Beyond Diabetes
Image A Novo Nordisk site outside Copenhagen.Credit…Scanpix Denmark/Reuters
Despite the progress on weight loss, Novo Nordisk continued to focus on diabetes, trying to find ways to make a longer-lasting GLP-1 so patients would not have to inject themselves every day.
The result was a different GLP-1 drug, semaglutide, that lasted long enough that patients had to inject themselves only once a week. It was approved in 2017 and is now marketed as Ozempic.
It also caused weight loss — 15 percent, which is three times the loss with Saxenda, the once-a-day drug, although there was no obvious reason for that. Suddenly, the company had what looked like a revolutionary treatment for obesity.
But Novo Nordisk could not market Ozempic for weight loss without F.D.A. approval for that specific use.
In 2018, a year after Ozempic’s approval for diabetes, the company started a clinical trial. In 2021, Novo Nordisk got approval from the F.D.A. to market the same drug for obesity with a weekly injection at a higher maximum dose. It named the drug Wegovy.
But even before Wegovy was approved, people had begun taking Ozempic for obesity. Novo Nordisk, in its Ozempic commercials, mentioned that many taking it lost weight.
Hinting turned out to be more than enough. Soon, said Dr. Jeffrey Mechanick, an endocrinologist at Mount Sinai’s Icahn School of Medicine, patients latched onto Ozempic. Doctors prescribed it off label for those who did not have diabetes.
“There was a little bit of gaming going on,” Dr. Mechanick said, with some doctors coding patients as having pre-diabetes to help them get insurance coverage.
By 2021, fed by social media, a general frenzy for weight loss and aggressive marketing by Novo Nordisk, the news that Ozempic made people lose weight had reached a tipping point, said Dr. Caroline Apovian, a co-director of the Center for Weight Management and Wellness at Brigham and Women’s Hospital and a consultant for Novo Nordisk and other companies. Ozempic was on everyone’s lips, even though Wegovy was the drug approved that year for obesity.
But Wegovy caught up.
In July, doctors in the U.S. wrote about 94,000 prescriptions a week for Wegovy compared with about 62,000 a week for Ozempic. Wegovy is in such demand, though, that the company is unable to make enough, its spokeswoman Ambre James-Brown said. So for now, while it ramps up production, the company sells the drug only in Norway, Denmark, Germany and the United States. And at pharmacies in those countries, shortages are frequent.
And Dr. Apovian, like many other obesity medicine specialists, is now booked with patients a year in advance.
Image Credit…Cydni Elledge for The New York Times More Medicines, More Mysteries
The reason Ozempic and Wegovy are so much more effective than Saxenda remains a mystery. Why should a once-a-week injection produce much more weight loss than a once-a-day injection?
The drugs, said Randy Seeley, an obesity researcher at the University of Michigan, are not correcting for a lack of GLP-1 in the body — people with obesity make plenty of GLP-1. Instead, the drugs are exposing the brain to hormone levels never seen in nature. Patients taking Wegovy are getting five times the amount of GLP-1 that they would produce in response to a Thanksgiving dinner, Dr. Seeley said.
And, he added, in the brain, “the drugs go to unusual places.” They are not just going to areas thought to control overeating.
“If you were designing a drug, you would say that’s a bad idea,” said Dr. Seeley, who has consulted for Novo Nordisk and Eli Lilly, among others. Drug designers try for precision — a drug should go only to the cells where it is needed.
GLP-1, because of its chemical structure, should not even get into some areas of the brain where it slips in.
“Nobody understands that,” Dr. Seeley said.
Wegovy, though, is just the start.
Lilly’s diabetes drug, tirzepatide or Mounjaro, is expected to get F.D.A. approval for obesity this year. It hooks GLP-1 to another gut hormone, GIP.
GIP, on its own, produces, at best, a modest weight loss. But the two-hormone combination can allow people to lose a median of about 20 percent of their weight.
“No one fully understands why,” Dr. Drucker said.
Lilly has another drug, retatrutide, that, while still in early stages of testing, seems to elicit a median 24 percent weight loss.
Amgen’s experimental drug, AMG 133, could be even better, but is even more of a puzzle. It hooks GLP-1 to a molecule that blocks GIP.
There is no logical explanation for why seemingly opposite approaches would work.
Researchers continue to marvel at these biochemical mysteries. But doctors and patients have their own takeaway: The drugs work. People lose weight. The constant chatter in their brains about food and eating is gone.
And, while the stigma of obesity and the cultural stereotype that obese people aren’t trying hard enough to lose weight endures, some experts are optimistic. Now, they say, patients no longer have to blame themselves or feel like failures when they can’t lose weight.
“The era of ‘just go out and diet and exercise’ is now gone,’” said Dr. Rudolph Leibel, a professor of diabetes research at Columbia University Irving Medical Center. “Now clinicians have tools to address obesity.”
A correction was made on
Aug. 17, 2023
:
An earlier version of this article misstated the name of a drug approved for diabetes in 2010. It was Victoza, not Saxenda. It also misattributed a quote from a video about persuading a chief executive that obesity was not just a lifestyle condition. It was said by Mads Krogsgaard Thomsen, not Lars Rebien Sorensen.
Thank you OP for providing the whole text and not just a link to a Coockie-popup-paywalled site.
All potentially useful public health news should be publicly available :)
Hear hear!
I can’t recommend reading A Chemical Hunger enough. These scientists are right, obesity isn’t a willpower issue, despite common belief to the contrary.
TL;DR: We don’t know why obesity is. Yeah sure you eat to much, you get fatter. But why do some people crave so much excess food? Why does their metabolism try so hard to keep the fat in? Why is the obesity epidemic worsening everywhere in the world, despite measurably improved eating habits over the last ~15 years?
The article goes at length to disprove mainstream myths like “not enough exercise”, “too much shit in our food”, etc. Truth is, we don’t know what’s happening chemically (same issue as the scientists encounter in the NYT article). However, the thesis of A Chemical Hunger is that there are good reasons to think that everyone has a “lipostat” which dictates how much fat we should have. Too skinny, and you will want to eat more and gain weight faster, and vice-versa. Yet for an increasing number of people, the lipostat is breaking.
The open question is, why? Right now, we don’t really know, but we really aren’t studying the biochemical causes of obesity hard enough due to this stupid belief that fat people are fat because they’re “weak minded” or whatever.
I like the concept of the lipostat, but I disagree that it will be a purely biochemical model that will explain how it is regulated, because fat accumulation is not just about past and present, it may also be about stress and more generally about the subjective feeling of “how you perceive your future ability to eat to be at risk”. It’s certainly not just about willpower in general, but about mechanisms different people use to handle frustration, about certain types of depression, even when they have plenty of willpower to do other things.
However, I read somewhere else (can’t find the specific article) that Ozempic seems to act as an anti-depressant (some anti-depressants make you lose weight e.g. SSRIs) to cause weight loss. So, hey, maybe it is biochemical :)
And there may also be an epigenetic component on top of all that.
plus that on top. Epigenetics+psichiatry+nutrition the combination of unholy medical arcane topics that is entwined with sociology and economics, no wonder it’s much harder to figure out than cancer.
It’s a mix of willpower and habits, America has bad regulations on foods making that most foods have added sugars, portions in American culture are massive and everyone drives everywhere because cites were built for the cars.
In Europe we have strict regulations on food, with food scores on the packages telling you how bad it’s for your health, our portions are smaller and we generally prefer fresh ingredients to heavily processed products and most European cities are made for walking and cycling.
40% Americans are obese vs ~22% in Europe
You get the same with Australia another car centric country
But obesity rates in Europe are still steadily climbing, despite food scarcity not being a widespread issue for decades and food quality increasing in the 21st century. Sure we’re behind America, but it’s not getting any better; we’re seeing the same kind of linear increase in obesity cases, on both sides of the former Iron Curtain (and obesity was already growing in many communist countries where access to cars was… elusive at best before the fall of the Wall):
The essay I linked talks about The Australian Paradox where “obesity in Australia nearly tripled between 1980-2003, while sugar consumption dropped 23%”.
It’s not as simple as “our food is better” or “they have more cars”. Yes it’s better (significantly so), and we aren’t as car dependent as Americans (though it’s still very bad here outside of historical city centers), but the correlation with obesity in particular is more elusive to find than you’re implying since things have also been steadily getting worse on this side of the Atlantic.
I would highly recommend reading the article I linked, it goes to great lengths to thoroughly debunk common myths like this about the causes of obesity.
Willpower is bullshit.
You, as a human being, have a limited ability to resist temptation.
Anything within your means that you want badly enough you’ll eventually have. The only way around it is to want something else, mutually exclusive to the first temptation, more.
And when it comes to weight loss, even if you’re in the 5% of attempts that are successful, most people will still gain weight back because once the motivation of setting numbers go down fades, old habits are always just as easy to fall back on as all the new ones are.
I can eat for hours at an all you can eat buffet but I don’t want to become massive so I prevent myself from doing so, I’m now athletic build
So yeah willpower is a thing, I guess some people just want excuses
Clearly, you want the athletic build more than you want the food. Congratulations.
Not everybody is you.
Nutrition is also particularly hard to study because there’s no way to accelerate it. It happens at a snails pace and we can’t speed up the human digestive system. It’s why so much food science is disproven 10-15 years later as new results appear.
“The era of ‘just go out and diet and exercise’ is now gone,’”
Horseshit. Especially if they can’t manufacture the drugs fast enough. I’m type 1, so I follow the #diabetes hashtag on Mastodon, and the number of people complaining that they can’t get their GLP-1 drug refilled because of shortages is ridiculous.
Yeah, I have family members who are diabetic. They’ve haven’t been able to get their Ozempic for a couple of months now
Instead of trying to get better food to americans lets just use more pills to keep their weight under control
It’s not just Americans. The obesity epidemic is a worldwide problem, and is still worsening in Europe for instance despite increasingly tighter regulations and an actual, significant improvement in eating habits for the past ~15 years.
Truth is, we have no fucking clue what truly causes obesity. Sure, eating less means less weight gained, but why do some people crave so much more food, and/or why does their body work so much harder to accumulate/not burn fat than others? We do know that several chemicals will change a person’s “natural BMI” (or whatever you wanna call it). But we don’t know how these chemicals work.
(More reading on this in A Chemical Hunger, which is absolutely fantastic)
Of course American food is terribly regulated, but there are good reasons to think this is largely unrelated to obesity. Which is not to discount the health benefits that would be reaped if you didn’t stuff tons of corn syrup, hormones, and antibiotics into everything of course.
I think we should definitely try to understand the fundamental processes of weight gain/loss, because the idea that it’s all based on willpower is demonstrably wrong. And I do not think that, in the absence of finding the root cause of the obesity epidemic, providing patients with medication is obviously the right move to improve their quality of life. It’s not their fault that we don’t understand jack shit about why their bodies are rebelling or why the medication works, but the health benefits are undeniable.
Understanding why I crave food, constantly and aggressively would do so much towards helping with weight loss goals.
I’m sure sugars and the like have lots to do with it, but even abandoning sugars (Which I did for a good 4 months) didn’t seem to change it.
My understanding is taking sugars/carbs off is good because they don’t seem to count towards the body’s “I’m full!” detection, unlike actual fat, despite being highly caloric and easily metabolized. If you’re eating till you’re full, fat is better, because you’ll be full sooner.
But yeah intuitively I can see how that wouldn’t do so much if the internal fat control system is fucked up to a point that you’re never full. (Though I’d assume that metabolization rates still matter? IDK I’m no dietetician).
Hopefully we can get some progress on the science side of things now that academic views on obesity are finally shifting. The medications in the OP also sound interesting, if they actually reduce the source of the problem (the cravings), but that’s a discussion to be had with your GP, not an unqualified internet stranger.
Part of the problem is access to better foods, but another part is addiction to bad foods. If we can remove the craving for bad foods, people can make better choices between the foods available to them.
Ah, yes, just remove the natural human craving for fats and sugars. Simple as.
That’s not what they’re talking about, it’s the designer foods that make you crave more and more. MSG makes you crave more, salt and sugar combined make you crave more, etc.
I agree that highly refined foods are designed to make you eat more of them. What I don’t agree with is that we fix it by removing our craving for them, rather than restricting them at the source.
One thing that would help a lot is limiting food advertising. The more you eat these superfoods the more you’re conditioned to want them, and seeing pictures and video of them prompt increased consumption like Pavlov ringing a bell.
I think we’re on the same page.
If these drugs help people then fantastic, but I find it infuriating how little press the dangers of sugar gets.
We are finally waking up to the fact that fat in foods was never the cause of people getting fat. Terrible studies decades ago created a whole generation that shunned (or at least tried to shun) fatty foods, but never looked at the danger that sugar and carbs are to our health. Billions were wasted on chemicals and drugs that reduced the fat in processed foods that ultimately did very little in helping folks lose weight. Sugar, which is seemingly in everything we eat, on the other hand, has rarely been accused to being the cause for people’s weight problems. At least until fairly recently. Now the tide is turning and there are certain diets (such as keto) which finally show that cutting carbs and sugar can get results.
If these new drugs listed in the article can produce similar or better results with little consequences then fantastic. But sometimes cutting something out, it better than adding more drugs into one’s diet.
Yes, but nutrition has always been a battlefield and will continue to be one, because it is the contact point between health, personal choice, belief, economics, marketing, self-control, there are always new fad diets and controversies that get pumped by tension between researchers and manufacturers e.g. fat, sugar, gluten, vitamins, antioxidants, wheat, aspartame, salt, cholesterol in eggs, hydrogenated fat, and this will go on.
About the personal part, I’ve got a very good friend who is a super grounded, mild-manered and knowledgeable retired schoolteacher who turns crazy when anyone mentions nutrition and diets, not because she hates the concept, but because she has this set of rules to combine foods to stay healthy, like it’s her religion. She’s also clearly overweight 😑. It’s about the need/illusion of self-control and the industry taking advantage of that to sell shit.
It’s about the need/illusion of self-control and the industry taking advantage of that to sell shit.
It’s all about the dollar bills, y’all!1!!
Is your school teacher friend into horoscopes and healing stones too? It seems like certain personalities get attracted to similar things.
No, that’s what’s so surprising. She seems to be extremely rational, empathetic and understanding until you casually mention the word “diet”, then all hell breaks loose about “matching foods or else they rot in your stomach to produce infection and…wa wa wo wa wa wo wa …” :shrug:
This is what happens when people have just enough knowledge (especially scientific knowledge) to be dangerous but not enough to actually fully understand what they are talking about. Like they watched a couple of YT videos or read a couple of articles (but not research papers) and now think they know everything about a topic.
but I find it infuriating how little press the dangers of sugar gets.
I think this there is part of the problem though. Even when we accept that the last thing that was bad for you, isn’t actually as bad for you as we thought, we fail to learn the lesson in favour of pouncing on the next food that’s bad for you.
Moderation is the name of the game. And I don’t even really mean in terms of how much you eat, though obviously that matters. But more so in terms of what and how much, as a combination.
Like… the amount of sugar in commercial bread is nuts and really isn’t required, but it’s being added in the process because lollies sell better, so to speak. But you could comfortably remove most, if not all of it, and still have perfectly delicious bread.
So, don’t cut stuff out, but do think about how and how much you use.
I mean, not knowing how a drug works really isn’t news. Hell, we don’t know for sure how Acetaminophen and Aspirin work.
Well how specific is enough to say we do or don’t know how a drug works?
In particular we do know that ASA and other NSAIDS work by inhibiting the activity of the enzyme called cyclooxygenase which leads to the formation of prostaglandins that cause inflammation, swelling, pain and fever. It blocks both COX 1 and 2, though only COX 2 is responsible inflammation. Furthermore, The antithrombotic action of aspirin is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase at the functionally important amino acid serine529.
Now contrast ASA with Acetaminophen …
We know that Acetaminophen also inhibits COX, but only in the CNS and not peripherally. Also, it is only thought that it potentially blocks pain signals via the serotonergic pain pathway.
I would say we know a hell of a lot about aspirin … Acetaminophen not so much on the MOA side of things, however it has been studied so much that we know the safety/toxicity profile like the back of our hands. Either way probably not the best 2 examples to use for your argument.
It isn’t just drugs. A whole ton of scientific things that we just accept are kind of unknowns. We can use them. We can even manipulate them to our will, we even have equations that can define their magnitudes and predict results, but we don’t fully understand them. In fact the more you know about some of these subjects, the more uncertainty there is. A layperson might think the subject is fully understood.
Here’s a scary example: Lift (like the kind a wing creates on an airplane).
Isn’t lift entirely understood?
If you’re arguing that the underlying behavior and existence of matter isn’t understood, and by extension lift isn’t, then that applies to anything and everything.
No, lift is not entirely understood. The mechanism of why it happens is still a mystery.
What are you even trying to say? That CFD doesn’t even exist? Just because a bad abstraction taught in schools isn’t really tethered to reality, doesn’t mean large laminar uncompressible fluid dynamics is unfathomable.
Those are both bad schoolbook abstractions. And that article is about how the full mathematical treatment (which is known) doesn’t fit a neat pat thought-terminating-cliche explanation. Plenty of people develop an intuitive understanding so it’s not rote symbolic formalism.
Air goes down. Plane goes up. The exact details of air goes down are complex and nuanced, but not at all unknown.
really, even Aspirin? But then, how do they design testing to ensure that it’s safe long-term? Without a model, all you have is “just test every possibility you can think of and pray”.
They test in animals with various doses. Then they test in humans.
Of course this can’t demonstrate that it’s safe over long periods of time, but we do the best we can with the tools we have.
No, not aspirin. We know aspirin very well in the medical community.
TBF there are drugs out there that we do not know the MOA of, like methocarbamol (from the national institute of health: “The exact mechanism of action of methocarbamol remains unknown; similarly unknown is the relationship between musculoskeletal pain and muscle spasm” lol)
So for long term safety, it is based on animal and human studies. These studies happen for multiple years prior to being put on the market (for the most part, though that is a story for a different day). Then after the drug is on the market, the drug company is required to do “Postmarket Clinical Studies” to show that their drug is still doing what it was initial shown to do; furthermore, to look for safety events of said drug.
A really famous case of a bungled postmark study was Vioxx. Vioxx is/was a Cox-2 specific pain medication. In the initial and postmarket studies they found that it had an increased risk of heart attack (in some cases up to 88% increased risk). The company Merck held the information from the public and FDA. They were forced to take the drug off the market in 2004. Technically in short bursts Vioxx was probably safe, but long term it was not.
Yes, that’s how modern medicine works. Much of how the body functions, especially when it comes to the brain, is largely unknown. There are just an almost insurmountable amount of variables to control for.
For every drug that makes it to market, there are hundreds if not thousands of similar drugs that failed at some point in testing. No one knows the longterm effects of any drug in humans until humans have been taking it for a long time.
Hinting turned out to be more than enough
Not wild about big pharma advertising an end run around the FDA
We have generative AI models that nobody really knows why they work and drugs that nobody really knows why they work!
That’s a wild read. I’m surprised so many people would take the pill without anyone knowing the side effects but I guess it’s worth it to them.
There are a lot of drugs that we use without really knowing why they work. It’s actually not that uncommon. The human body is complex.
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