KLG here: Drugs known as GLP-1 Receptor Agonists (GLP-1RAs) – Ozempic, Mounjaro, Wegovy and others – are the next big thing for Big Pharma and Big Medicine. These drugs lead to weight loss by manipulating normal nutritional physiology. They were, for the most part, developed to treat adult-onset (Type 2) diabetes (T2DM). Overweight and obesity are usually precursors to T2DM, and the incidence of T2DM has tracked the obesity epidemic of the past 30-40 years. Obesity is now considered to be “a chronic, relapsing, and multifactorial disease” that can now be treated with expensive drugs. True. But overweight and obesity did not just drop out of the sky. They are caused by the conscious but mistaken scientific promotion of a high-carbohydrate, low fat diet that consists of highly processed, even ultra-processed, food-like substances instead of food. Thus, GLP-1RAs are technical solutions to a problem that does not have to exist. Such an approach to a sociogenic disease is not sustainable. The only good way to deal with the obesity epidemic is to go back to the future and eat real food, close to home, wherever that may be. Big Ag, Big Pharma, and Big Food notwithstanding, this is the only correct way to reverse course.
By KLG, who has held research and academic positions in three US medical schools since 1995 and is currently Professor of Biochemistry and Associate Dean. He has performed and directed research on protein structure, function, and evolution; cell adhesion and motility; the mechanism of viral fusion proteins; and assembly of the vertebrate heart. He has served on national review panels of both public and private funding agencies, and his research and that of his students has been funded by the American Heart Association, American Cancer Society, and National Institutes of Health.
According to a recent sound and publicly available article published on 31 August 2024, “Obesity is a chronic, relapsing, and multifactorial disease that is expected to affect around half of the United States population by 2030…(and)…650 million adults and 340 million children and adolescents (5-19 years) live with obesity around the world.” Obesity is destructive of personal health. It leads directly to adiposity-associated risk factors for cardiovascular disease (CVD), including hypertension, dyslipidemia, and type-2 diabetes mellitus (T2DM); frank cardiovascular disease; and cancer, through chronic inflammation that accompanies obesity.
From the same article, obesity is also expensive, responsible for $481 billion in direct healthcare costs and an indirect cost of $1.24 trillion attributed to lost economic productivity. However these calculations are made, the numbers seem reasonable. Therefore, something must be done! And that something is currently drugs known as Glucagon-like Receptor-1 Agonists – GLP1-RAs. Their tradenames include Ozempic, Rybelsus, Wegovy, Mounjaro, and Zepbound. These drugs and their cognates were originally developed as treatments for T2DM. Before continuing, a gloss on human metabolism is in order.
After we eat and are in what clinicians and biochemists call the “fed state,” insulin is released into the circulation in response to rising glucose levels. Insulin binds to its receptors on liver and muscle cells and instructs these cells to take up the glucose and store it for later use. Insulin is our major anabolic hormone. When we are in the “fasting state,” e.g., while sleeping overnight, the hormone glucagon binds to liver cells and tells them to release its stored glucose into the circulation so that blood glucose levels are maintained at a normal level [80-100 milligrams per deciliter (100 ml), an odd unit used in the United States going back to a time when 100 ml was a standard volume for analysis; today is one drop to 5 ml].
People with Type-1 diabetes mellitus (T1DM) are insulin-deficient due to the autoimmune destruction of beta cells of the pancreas that produce insulin. The previous name for T1DM was juvenile onset diabetes, which appears typically at age 8-12. Those with T2DM are insulin-resistant, which gets worse during the course of the disease. Untreated, high blood glucose eventually leads to lethal complications in both types of diabetes. Insulin can be replaced in T1DM and the disease is manageable for most patients who remain in the healthcare system, such as it is.
Like all things physiological, metabolism is more complicated than originally conceived. It turns out that we also have a hormone called Glucagon-like Peptide 1 (GLP-1; there is another) that binds to its own receptor, GLP-R1. [1] GLP-1 was a target for Big Pharma immediately after its discovery. Only through the persistence and perspicacity of the scientist Lotte Bjerre Knudsen did this remarkable bit of research lead to long-lived drugs, i.e., GLP-1 receptor agonists (GLP1-RAs), that are useful in treating T2DM. An agonist as defined by the National Cancer Institute is “a drug or substance that binds to a receptor inside a cell or on its surface and causes the same action as the substance that normally binds to the receptor.”
As it turned out, GLP1-RAs are also effective weight-loss drugs, in this case by making people feel full when eating, i.e., they reach satiety earlier than when they are not taking the drugs. Thus, their current blockbuster potential. As noted here (paywall):
A two-part message is permeating the halls of medicine and the fabric of society, sliding into medical school lectures, pediatricians’ offices, happy hours, and social feeds: Obesity is a chronic biological disease – and it’s treatable with a new class of medications.
Big Pharma is responding as expected, with construction of billion-dollar manufacturing plants and public messaging – ads and videos by influencers – that obesity is a chronic biological disease, nothing more, and it can be fixed with an injectable drug. According to STAT, “Novo (Nordisk)…(has also)…funded the development of coursework on obesity for medical students.” After some pointed reactions from a few academic physicians, “Novo said its education activities are non-promotional and developed by third parties.” No doubt, but as noted in this series previously (here, for example) these third parties know where their money is coming from. This also highlights a severe deficiency in medical education, which generally does not “do nutrition” very well. That is a subject for another time, but these drugs have been received enthusiastically by the medical students in my recent gastrointestinal system tutorial groups. I believe this to be generally true among medical students, along with the use of AI (Algorithmic Intelligence) as the new “magic fairy dust” that makes the study of medicine “easy.”
And there are other matters to consider. Advocates for patients with eating disorders worry that this focus on obesity as a simple, chronic biological disease will adversely affect their patients, for whom their chronic biological disease is not “so simple” at all. Their physicians and therapists and families are right to be worried. The medicalization of other conditions with “Why, yes, we have a pill for that” necessarily changes how people think about health and disease. [2] The results are not always favorable. Thalidomide was a tranquilizer and anti-nausea drug used to treat morning sickness. It also causes serious birth defects. This tragedy was largely avoided in the United States due to the work of Frances Oldham Kelsey (short video, 5:31) who was a scientist at a previous Food and Drug Administration (FDA). The weight loss combination of Fen-Phen ended badly. Few outcomes are as stark as thalidomide or Fen-Phen. Thalidomide is now useful as a treatment for lymphoma, which should remind us that repurposing drugs for emerging diseases can be a good clinical strategy in the face of a novel disease. But drugs can also be technical fixes for problems that do not have to exist. Or perhaps do not exist at all except at the far, but lucrative, margin.
Which brings us to sociomedical significance of GLP-1RAs. Yes, they work, and early results show that they reduce the incidence of bad cardiovascular outcomes in people taking them. [3] Yes, they are the result of good research by good scientists. Yes, T2DM is a scourge that must be treated. But what is lacking according to my reading in the bulk of the GLP1-RA literature is recognition that neither obesity nor T2DM is a disease that simply happened to most people living with overweight and obesity. The paper referred to at the beginning of this post accepts obesity as a “chronic, relapsing, and multifactorial disease.” But if half of all Americans will be overweight or obese in 2030, less than six years from now, how is this even possible? Why is overweight and obesity costing us so much in morbidity (mental and physical), mortality, and money?
The answer is straightforward. The obesity epidemic is thoroughly sociogenic and it was brought on by poor science and poor politics. This has been covered previously here and here. To summarize, beginning in the 1950s the American diet was changed at the behest of leading scientists and healthcare politicians because of what has become known as the Diet-Heart Hypothesis. The short version is that dietary cholesterol and fat are unhealthy and our diet should be much less rich in these essential nutrients. Cholesterol was to be avoided and fats should be replaced by substitutes (vegetable oil, margarine). The missing calories were replaced by carbohydrates, mostly refined sugars. The simple, but not simple minded, physiological mechanism can be stated as follows: Eat too much sugar and the insulin response is overworked. Insulin is our primary anabolic hormone and this leads to the conversion of carbohydrates into fats, which are stored in both fat cells (adipocytes) and in liver cells where these unnatural droplets lead to non-alcoholic fatty liver disease (NAFLD).
It should be noted that in 2015 the United States Department of Agriculture announced there would be no further updates on dietary cholesterol because there is no reason to believe that dietary cholesterol causes disease in people who do not have well understood defects in cholesterol metabolism. For these people and others with frank cardiovascular disease statins that reduce circulating cholesterol levels are indicated. However, this development did not make the cover of Time magazine, the equivalent of which today would be the “front page” of the Daily Mail. So much for scientific “truth.”
Recent research has developed this thesis further by including ultra-processed foods as a major contributor to the obesity epidemic. Ultra-Processed People in an Ultra-Processed World by Chris van Tulleken has been discussed here previously. A paper published by Kevin D. Hall, of the US National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), From Dearth to Excess: The Rise of Obesity in an Ultra-Processed Food System (2023) is readily accessible. Ultra-processed food is loaded with sugar and other unnatural ingredients. Thus, it may not be possible to tease out the individual contributions of sugar, which is natural and not a poison in moderation, and chemicals that improve “mouth feel” in ultra-processed food-like substances but should never be eaten.
So, this brings us back to GLP-1RAs. They are powerful drugs. They work. Relatively minor but not inconsequential and sometimes serious problems have been identified in some who use them, such as poor preparation for colonoscopy and an increased incidence of aspiration of stomach contents while under general anesthesia. The latter can be fatal. “Ozempic butt” can be inconvenient, but perhaps plastic surgery can repair it?
We do not know the long-term effects GLP-1RAs will have on people who take them primarily for weight loss. But we do know what has caused the overweight/obesity epidemic: Our modern diet of over- and ultra-processed food-like substances that are consumed in abundance, partly because this diet leads to higher calorie consumption (pdf).
GLP-1RAs treat the symptom effectively, as far as we can tell. On the other hand, the durable solution to the obesity epidemic is a diet consisting of real food. This is coming, notwithstanding the wishes of Big Food, Big Ag, and Big Pharma, as the world shrinks as we (all of us) adapt to climate change. This can be managed for good or ill, but that depends on the political genius of an awakened people.
Still, GLP-1RAs are a triumph of modern biomedical science and the “next big thing” in Biomedicine. But like Roundup Ready commodity (keyword: Editor’s Introduction) crops and Concentrated Animal Feeding Operations (CAFOs) essential for the category error that is industrial agriculture, GLP-1RAs are technical fixes for a problem that does not have to exist. It is a problem that did not exist fifty years ago. That Big Pharma may collect $100B a year in the near future from GLP-1RAs is business as usual but outrageous, nevertheless. That the obesity epidemic is also a consequence, in large part, of industrial agriculture just adds another level of irony to the “need” for GLP-1RAs.
We, all of us – citizen and scientist and physician – can do better. And we must.
Notes
[1] The glucagon and GLP receptors are members of a large family of receptors called G-protein coupled receptors (GPCRs). GLP-1R is here. The functions of many of these receptors are unknown and are called orphan receptors that are likely drug targets for many diseases. The first two GPCRs were discovered in the budding yeast (bread and beer!) Saccharomyces cerevisiae as receptors required for mating type switching. Yeast have sex, so to speak, but are also perfectly happy living as haploid organisms (only one set of chromosomes instead of two in the diploid state) which is a boon for genetics. Just another triumph for basic biomedical research.
[2] I am not implying in any way that modern medicine is superfluous. As the beneficiary, so far, of modern clinical oncology, quite the contrary.
[3] This reminds me that a current justification for the widespread use of statins to lower plasma cholesterol levels is that statins have anti-inflammatory activity. Yes, they do. Apparently. But dyslipidemia and associated pathologies are caused, usually, by a poor diet that leads to overweight and obesity. As I put it to a colleague who is a pathologist and advocate of prophylactic use of statins, losing twenty pounds also lessens the inflammation burden in the overweight/obese person. And without a drug, unless the drug is a GLP-1RA, which seem to require continual use to maintain weight loss.
“We do not know the long-term effects GLP-1RAs will have on people who take them primarily for weight loss.”
Well, I’m your huckleberry. About a year ago, my BMI reached 39%. I started joking with my doctor…”Just give me a few more weeks. I feel certain I can reach this milestone!” She told me it wasn’t a joking matter, and I needed to get serious. After a long lifetime of yo-yo weight loss where I lost at least 40 pounds (and regained 50) a dozen times, I decided to try tirzepatide. It has totally transformed my relationship with food for the better. Food is finally “fuel” for the mechanism only. I no longer stress eat, and am actually a bit surprised to see myself looking forward to a meal from time to time. I am down 60 pounds in 11 months with 20 more pounds to go. I have eliminated or greatly reduced prescription medications for high blood pressure, cholesterol, gout, anxiety.
Alcohol has never been problematic for me, but I can’t remember the last time I had a drink, or wanted one. When my sweet tooth kicks in, it is satified with 100 calories, not 750. The only downside, so far, is that my wife loves to cook, and she has mentioned that my “meh” attitude towards food is disappointing at times. Long -term effects remain to be seen, but I am in it for the long haul.
Now, let’s nationalize Big Pharma and make these drugs more available to the masses without insurance or other means of funding.
As a long time user of psychological medications I have some info for you. The effect at the dose you are taking will wear off. This is a natural body process. So you will need a higher dose. And them later an even higher dose. People are already starting to experience this:
https://www.reddit.com/r/Ozempic/comments/18qjuv3/its_not_working_anymore/
Also known as the plateau effect:
https://www.medicalnewstoday.com/articles/why-weight-loss-drugs-stop-working-how-to-break-past-ozempic-plateau
Yes, indeed. 100% correct. I lost my weight using the smallest dose, then the second level (of 6). Then I stalled out and maintained for 2 months. I just increased to the third level to knock off those last 20 pounds, and think this will ultimately be my maintenance dose (for the rest of my life). Time will tell.
Also, the links you provided are for semiglutide. I use terzepatide, a different chemical compound noted for larger weight loss. But your point is valid and well taken. Thanks
Thanks, and yes, I am familiar with the difference.
If you want to go down a metabolic rabbit hole check out the molecule cAMP which lower levels of are, in my opinion, the basis for most people’s weight gain. cAMP alterations are triggered by Tirzepatide. (I also think low cAMP is linked to depression and addiction.)
https://www.biologicalpsychiatryjournal.com/article/S0006-3223(12)00629-4/abstract
https://www.sciencedirect.com/science/article/abs/pii/S1877117315002070
Magnesium will increase cAMP.
https://link.springer.com/article/10.1007/BF01581572
Well it is nice that you have found success, it is highly likely you will have to be on this drug for the rest of your life.
Not sure how I feel about nationalizing access to weight loss drugs when the money could be better spent improving access to healthy food and improved working conditions.
Getting fat is the symptom not the disease.
“The obesity epidemic is thoroughly sociogenic and it was brought on by poor science and poor politics.”
Why does this, once again, feel so familiar?
Why won’t I be surprised in 5 – 10 years when the consequences of manipulating bodily mechanisms not fully understood become more apparerent?
Is there not an overarching theme linking most Naked Capitalism stories together? How can looking at this all in separation lead to real solutions that challenge assumptions and societal beliefs and require a fundamental reconfiguration of society to fix?
Where are the leaders who are not captured or invested in not solving for meeting the needs of the many over the profits of the few, but have the bigger picture in view?
We are the leaders we have been waiting for. Unfortunately, we waited too long and now most of us are too old to lead anything. As Lambert says, “Oopsie.”
oh well…
“GLP-1RAs are technical solutions”
I disagree. They are not solutions, they are band aids, and bad ones at that. Anytime you take a drug that affects a biological receptor there is a whole bunch of adverse effects when you need to stop.
https://pubmed.ncbi.nlm.nih.gov/35441470/
Pharma knows this and that is how they make their money. They want you on them so you can never stop them.
https://www.goodrx.com/ozempic/what-happens-when-you-stop-taking-ozempic
Dealing with the poor science and poor politics involves fighting neoliberalism and shareholders. For profit, manufacturers have used science to make food that with the cheapest fats and cheapest refined carbohydrates, while making it appealing to taste buds and minimizing satiety.
This is a globalization problem, from Mexico to China. Look at the ubiquitous presence of corn or potato chips, soda, and instant ramen.
Highly informative and timely article, thanks for posting.
“…The answer is straightforward. The obesity epidemic is thoroughly sociogenic and it was brought on by poor science and poor politics…”
“…GLP-1RAs treat the symptom effectively, as far as we can tell. On the other hand, the durable solution to the obesity epidemic is a diet consisting of real food…”
In the big picture, the poor science, corrupt politics/junk economics, are a feature not a bug: Since Congress is legally bribed, and captured by oligarchy, any change in the politics is unlikely. The relationship between BigAg/BigFood, BigPharma, and lack of a comprehensive health system is a mutually beneficial and symbiotic relationship. The obesity and ill health of the population leads to more BigPharma solutions, more monopolization, more profits. How convenient.
Personally, I have maintained good health and weight by simply eating less sugar, less carbs, almost no processed foods, cooking real food at home and getting moderate exercise. I am lucky, since I have the time and money to buy good quality food, plan and prepare healthy, tasty meals for my wife and I. Many people do not have that luxury.
Also, the perversity of the economics here: it is usually cheaper to eat food-like substances than real food. BigAg is heavily subsidized, and GMO food (another topic entirely) is also subsidized. HFCS “corn sugar” is a cheap by-product of this and most food in the US is chock-full of sugars. I have noticed that foods that did not contain added sugars, do now – even bread.
I’m not sure about this, but it seems that Mexico’s obesity rates skyrocketed after NAFTA and the flood of cheap US GMO corn and corn sugar may have something to do with it.
Pressure-cooking the American public in more obesogenic fuud will obesify even more people and lead to even more use of anti-obesity drugs.
It sounds like a self-basting suet pie, if I might dare to craft a new saying.
This is particularly interesting to me as my wife has lost 80 pounds and greatly improved her quality of life using Ozempic, and I work in the pharma industry supporting the clinical trials being conducted on these drugs.
Ozempic literally changed my wife’s life. She has battled her weight as long as I’ve known her, and she says this drug is the only thing that’s ever shut off the constant urge or desire to eat, and she’s set on taking it for the rest of her life. I get annoyed when I read arguments about how the drugs are treating a symptom of a much worse, underlying societal issue because I totally agree, but so what? This sort of implies that people should stop taking the drugs while we courageously solve this complicated problem. More power to you if you want to go solve the root cause of the obesity epidemic, but in the meantime, don’t mess with people’s ability to use these drugs.
Only time will tell whether this is the right choice, but my wife decided that the health risk from long-term GLP use is a lot less than the health risk from living the rest of her life obese.
Bravo!
My wife’s coworker has type II diabetes. She has taken ozempic for over 2 years. About a month ago, she was was diagnosed with a tumor. Friday they removed her gall bladder, part of her kidney, and part of colon. I don’t know if ozempic caused or contributed to her tumor. Another friend took wegovy. He told me he urinated blood at times while taking it. For some people, the trade off of weight loss vs may be worth it, but GLPs seem to carry an elevated risk.
‘Seaweeds as a Potential Resource in Diabetes Management’ –
https://fjps.springeropen.com/articles/10.1186/s43094-024-00583-8
RTT
Thank you KLG, and Lambert, for this post, and the links to two related posts from 2022. The 2nd comment from Psyched mentions the role of cAMP, so I want to add that the natural supplement coleus forskolii raises cAMP. Btw, I take it to (indirectly) raise my testosterone levels for exercise and strength training specifically, but there are other benefits. https://www.advance-health.com/coleus.html
Related to the first linked KLG post mentioning the FDA-enabled tragedy of thalidomide and fen phen, I would add DES. It was approved in the 1940’s by the newly created FDA, and used off-label to prevent miscarriage– based on the recommendation of one OB-GYN clinician– and was subsequently prescribed to between 3-5 million pregnant women over a period of decades.
It did not prevent miscarriage, but did cause serious birth defects, as well as epigenetic changes that can be passed down through multiple generations. Decades later a few doctors noticed a rare form of cervical cancer in DES daughters as young women and published their findings. https://www.amazon.com/Toxic-Bodies-Hormone-Disruptors-Legacy/dp/0300171374
The medical guild eventually stop prescribing it this way, but DES is still on the market. Unfortunately, since the harm was done to fetuses, which are (were?) not considered persons by the courts, DES Daughters and Sons who were harmed have no standing to sue, or pursue class action. Incidentally, it turns out that DES is the ‘mother’ of and model for all Endocrine Disrupting Chemicals (EDCs).
I don’t suppose med schools will ever teach students about these scandalous mass medical tragedies?
I am always astounded to learn from experts that Ozempic’s impact lessens over time, and that people who quit the drug gain weight back.
[I was also stunned to hear from James Cramer on CNBC that Ozempic makes it impossible for a user to eat a piece of chocolate. He said the food (whatever it is, including chocolate) tastes horrible. In addition to being a horrible tout of stocks (see his results from 2000), he is a big idiot about actual life, apparently….albeit, a rich one]
I’ve had weight problems all of my life (I am now 71). I have been on all kinds of diets, including a non-drug doctor-administered program on which I lost 55 pounds in about 7 months. The problem with that one? The hospital that ran the program ENDED IT. I believe it was terminated because someone got very sick, or sued….in other words, the lawyers told the hospital Stop Doing This.
Self-control would be wonderful. I have none, apparently. Ozempic puts in place something with which I cannot fight!
To cut to the chase: All of the diets in which I’ve participated, medically monitored or not, were the same. When I got off of them, it ended up with me gaining back most or all of the weight.
It might well be the same with Ozempic, as the skeptics/critics say.
So what?
Stop subsidizing commodity crops (corn, wheat, soy) AND SUGAR. Fund NCRS/USDA or state level recommendations for conservation growers and livestock raisers. Get industry reps off these committees.
Put a warning label on all ultra-processed foods, and designate the total amount of added sugars and any hormone disruptors or residual antibiotics. Drop the cute animals, pulling kids to the cookie shelf – like we already do for cigarettes. Get industry lobbyists off these committees.
Prohibit use of food stamps for sugar water, and subsidize purchase of whole, no added sugar, fruits and vegetables. Get vested interests off the committees.
Cover a few or ongoing courses of addiction-style counseling with actual assistance (not some video) for anyone seeking it (cheaper than lifelong drugs (@1500/mo) and secondary problems from metabolic problems due to continuing poor diet). For most, it requires more than willpower. These drugs can lead to loss of lean muscle mass, a major problem with aging. Long term study is warranted before widespread use, using selectively once risks are reviewed thoroughly and alternatives offered. Ignore the screaming insurers, and keep them off the committee as well – they could lose a fortune once we are in better health.
Get your suggestions passed on to every regulatory body which deals with our food systems and pharmaceuticals. Post this in local newspapers, X, Tik-Tok, magazines, etc.
We need a complete overhaul of our food system with regulators who actually understand the problem and are willing to advocate for the people.
The only way “we”, the deplorable little people, can do better is to eliminate the 1% in their current incarnation. We don’t have the power to alter the toxic society that is causing so many of our problems as long as these demons totally control the direction of businesses, the creation of money, the propaganda spigot of the media, and the upper echelons of government. We’re barreling toward extinction so that the plutocrats and their highest paid servants can continue to live lives of unimaginable excess. There’s really only one answer to this.
We need a word for . . . ” food-like substances instead of food “.
I suggest ” fuud” . It looks like it sounds the same as ” food” in the same way that fuud itself tastes the same as food, but it is clearly not the same word as “food”, just as fuud itself is not the same thing as food.
I offer it in the spirit of other people who have invented other words which have proved useful. Words like jawbs, moar, groaf, etc.
Moar kunsumpshun of moar fuud will lead to moar groaf and jawbs in the fuud sector. And who could argue with that?
I think I may start using it now and again to see if it catches on or just falls by the wayside.
You don’t mention excessive alcohol intake. Or how our autocentric world minimizes body movement.