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.
