Pharma Darlings
From a land without trade-offs
Passions are running high for the newest weight loss drugs. Finally—finally!—you can have the body you deserve, a body that has been trapped in fat for too many years.
For those who feel thus trapped, but also responsible for a body that isn’t quite what they want, know these things: Those who have been overweight since childhood will have a particularly difficult time becoming thin. Those who are old or have low muscle mass or mobility issues will as well. Age and hormones change our bodies. After menopause, women’s bodies “want” to hold on to fat even more than they did before. I suspect that there are similar if not as discrete a set of changes in men’s bodies as they age. Those who eat a typical 21stcentury American diet, or even who do so occasionally, are also going to find it challenging to stay healthy and fit. Those who used to be fit, but have slid into a haze of alcohol, soft middle age1, will also have a difficult time becoming thin, although they have more control over their situation than perhaps they are willing to confront.
Meanwhile, we are not just a fat people. We are a sick people. Our food is largely not food. Even on the relatively healthy perimeter of the grocery store, “conventionally-grown” produce is full of agrochemicals, some of which are carcinogens, others of which demasculinize male frogs2. If you head towards the center of the store, things get even worse—food dyes made from coal tar, shelf stabilizers that may contribute to autism, and products designed to addict you and your children with everything from celebrity endorsements and pseudo-science to sugar, sugar, and more sugar.
This past Summer, did you buy raspberries from Driscoll’s? I did. They tasted like…nothing. Vaguely sweet, barely tart, mostly water. Similarly: most radishes aren’t peppery anymore. Oranges are bland. Blueberries flat. Might as well be greyberries.
Our water is simultaneously polluted and demineralized—full of things it shouldn’t be, and lacking things that we need.
Our soils are dying—the very soils that grow the plants that we eat, and feed the insects that our most content chickens eat, and the grass that our best-fed cattle eat. Because the land itself is depleted, even those of us who eat local, organic food grown by ourselves or by people whose names we know, even our food is suspect.
We feel an aching void. We call it hunger. Probably, in part, it is, because our bodies are craving food that is becoming impossible to grow.
So yes, there is an obesity epidemic in America. We have a fatness problem. And while you can be healthy at a range of sizes, you cannot be healthy at any size, despite what fat activists would have you believe. Thus, all else being equal, Americans would be better off if there were less of us, rather than fewer3.
We could fix our food. That would be smart.
We could also fix our behavior. That would be smart too. We could push ourselves to speed, to sport, to challenge. But those things will be out of reach for some people. We could even just walk more. That would go a long way to reducing how much of us, collectively, there is.
The smart choices, though, take some effort. Increasingly, we are a people who have a hard time with a long time horizon. We want what we want, and we want it now.
Rather than fixing our food or fixing our behavior, we could just take some pills and hope for the best. That does seem like the new American way.
Alas, there’s no such thing as a free lunch.
The newest pharma darlings are a class of drugs known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). That’s a mouthful, to be sure, and those words do indicate a high level of precision in what we understand about what these drugs do.
Humans make the same errors over and over again though, including this one: we find precision sparkly and enticing, especially when it comes from people who have gravitas, credentials, and large federal grants. Those who bring us sparkly, enticing precision are easy to trust, while we grow impatient with those who make caveats and speak in probabilities, warn of long time horizons and evolutionary implications.
A lot of things are indeed known about glucagon-like peptide-1 receptor agonists (GLP-1 RAs)4. GLP-1 RAs mimic the naturally occurring human hormone, glucagon-like peptide-1 (GLP-1). GLP-1 is released in the gut when food is eaten. Like all hormones, GLP-1 has myriad effects, only some of which are immediately obvious. Two of the more obvious effects that GLP-1 has are slowing the emptying of the stomach, and reducing appetite.
GLP-1 RAs—the new pharma darlings—mimic GLP-1s—the original human hormones. Before GLP-1 RAs, there was venom from Gila monsters, which was, back in the ‘90s, the first substance found by scientists that did a similar job. But how precisely do they—either the Gila monster venom or the GLP-1 RAs—mimic what we already have on board? More important—what else in our complex physiologies is disrupted by adding a hormonal signal that is unhooked from its ancestral cue?
There are a lot of true things that I might say about what GLP-1 RAs do—they are used to treat type 2 diabetes; they are much more potent than the human hormone GLP-1; downstream effects include an increase in insulin release and decrease in glucagon release, both being contingent on glucose levels. I could say these things, and more, but you might get lulled into a false sense of security. My knowledge might appear so vast that my conclusions must be indisputable. Certainly you need not concern yourself with what we do not know. Leave the thinking to me.
In fact, I knew little enough of the precise mechanisms of action of GLP-1 RAs a few days ago that, when Elon Musk extolled the virtues of these drugs on X, and I critiqued his perspective, I failed to catch his error in referring to them as GLP-1 inhibitors. I even repeated the error. GLP-1 RAs are (receptor) agonists, not antagonists. The words agonist and antagonist have roughly but not exactly opposite meanings. While I regret my error, I will not be chastened into silence as if I have proven my ignorance in all things.
Scientific thinking does not inherently require precision, although it always relies on accuracy, and willingness to find the errors in your own model. Engaging in scientific thinking—be it for fun, or for health, or for greater understanding of how the world works—also does not require that you come in armed with all of the details that the experts already (claim to) have. Many people are cowed into believing that without a full quiver of facts and figures, however, they must remain silent. This trick has become common: convince the people that they lack the expertise to do any analysis for themselves, bring in the experts bearing conclusions that they have arrived at behind closed doors, and feed the foregone, pre-digested conclusions to a placid public who are going to take it on the chin one more time.
There’s an old quotation, sometimes attributed to Otto von Bismarck, that goes “Laws are like sausages, it’s better not to see them being made.”
I believe that we have moved past that bleak perspective, however, to a bleaker one still. Laws may be ugly to watch in their creation, but once created, they are what they are. The law is what is written, whereas science is the process. The final written product can only be as good as the process that led to its creation.
Meanwhile, much of our science has been cryptically replaced with scientism, and the studies that are published, the research that prompts press releases and coverage in the media and becomes the next big thing, may look like science, but that doesn’t mean that they are in fact science. A Results section with well labeled graphs and significant p-values can be a good proxy for a piece of science, but once you’re in the business of relying on proxies, expect your proxies to get gamed. Add to that the perverse incentives of federal granting agencies to get in bed with pharma and other private industry, universities to favor expensive research funded by those very agencies, and peer reviewers to not critique those who might later be in a position to critique them (to name just three), and well—game on.
It might seem, from the perspective of late 2024, like the game has been on for so long that now, the game is effectively over. They have won. We have lost. What can be done.
No. Those who would steal science from us—from all of us—and turn it into a profit-driven ideology, have defined the rules of the game for long enough. It’s not theirs to do.
ScienceTM—that’s the kind that you follow, and make colorful yard signs about—ScienceTM is like sausages, in that it’s better not to see it being made. Better for them that run the ScienceTM that we not see it, anyway.
Science, though—the beautifully inefficient method by which we come to understand what is true about our universe—that we should all watch being made. We should do it ourselves. Get our hands dirty. And our minds. Take risks and make errors. And discover, in so doing, how to do better in the future.
Researchers have known for some time that GLP-1 RAs cause muscle loss. Concerns about loss of skeletal muscle, and therefore loss of strength, resilience, ability to exercise, quality of life, have driven some research in this realm.
Anecdotally, some people on these drugs—the most common of which is Ozempic—have complained of Ozempic face5, Ozempic butt, and even Ozempic personality. There are widespread reports of nausea, too, and more limited ones of intestinal obstruction6. Gee, what could go wrong. To the problem of muscle loss, though, never fear—the heroes who brought us Ozempic7 are working hard behind the scenes to bring us new drugs that will combat the loss of muscle caused by Ozempic. Pitched as if they care about the muscle loss that occurs after immobilizing surgeries like hip replacements, it’s abundantly clear that the pharma companies have their eyes on the prize of the vast population who have jumped, or might yet jump, on the Ozempic bandwagon. For such people, what’s one more pill to pop, especially if it comes with the sheen of precision and more magical promises?
Brand new research finds that Ozempic doesn’t just take a toll on skeletal muscle: it’s not kind to cardiac muscle, either8. Experiments done on lab mice found that, whether the mice were at a healthy weight—achieved by eating a nice standard diet of laboratory mouse chow for ten weeks—or were overweight—achieved with ten weeks on a High Fat High Sugar diet—their hearts and heart muscle cells shrank on Ozempic.
In short: put a fat mouse on Ozempic, and he’s going to lose weight, but his heart and muscle cells will also shrink. Compare to: put a thin mouse on Ozempic, and he will not lose weight, but his heart and muscle cells will, nevertheless, shrink.
Thus, the heart and muscle cell shrinkage do not seem to be a result of the weight loss, but of the Ozempic itself.
To all of those hoping that this latest pharma wonder drug will be the answer you’ve been waiting for—it’s not. We don’t yet know what kind of horrors it will release on the human body. But we already have plenty of evidence that it’s not safe. The people who are selling it to you don’t need it to be safe. They just need plausible deniability.
I’ll finish with a few sage words from Benjamin Bikman, PhD, who, like me responded critically to Elon Musk’s admiring tweet about these drugs. Unlike me, Bikman did so without error, so far as I know, and with a high degree of appropriate precision. He begins his response, “I think you're great, but you're not right on this.” His four dietary pillars are simple and, unlike anything coming out of pharma or the FDA, actually constitute good advice:
Rather than promoting a family of drugs with frustrating complications, we ought to provide better education on the value of four dietary pillars:
1. Control carbs: Don't eat carbs that come from a bag or a box with a barcode.
2. Prioritize protein: Eat high-quality protein (i.e., animal-sourced) often and freely.
3. Don't fear fat: All natural proteins come with fat; that's how we should eat it. Fat helps the guts digest protein better and promotes greater satiety. Avoid seed oils and focus on natural fats from animal and fruit (e.g., coconut, olive) sources.
4. Frequently fast: Once you learn to manage your macros (via the three points above), you're in a good position to burn your own fat for fuel, and hunger often drops. Take advantage of this metabolic shift by eating less frequently.
Pink Floyd nails it, again. This line is from Paranoid Eyes, from the album The Final Cut (1983).
Atrazine doesn’t turn the frogs gay, but it does turn them hermaphroditic. Hayes et al 2002. Hermaphroditic, demasculinized frogs after exposure to the herbicide atrazine at low ecologically relevant doses. Proceedings of the National Academy of Sciences, 99(8): 5476-5480.
Rare grammar check: Should this phrase read “if there were less of us” or “if there was less of us”? I honestly can’t figure it out. Admittedly, it’s a weird sentence.
Most people will be most familiar with the GLP-1 RA known as Semaglutide. Semaglutide, in turn, is more familiarly marketed under the brand names Ozempic and Wegovy.
Despite being about how cosmetic dermatologists can respond to the “need” to address Ozempic face—sagging skin, loss of facial elastin, collagen, fat and muscle—I must give kudos to this paper for being transparent about the difference between understanding and describing, a distinction apparently lost on many in the reductionist, scientistic framework. “While the mechanism of action of semaglutide is not fully understood, it is well-characterized.” Montecinos et al 2024. Semaglutide “Ozempic” Face and Implications in Cosmetic Dermatology. Dermatological Reviews, 5(5): e70003.
This week, the award for “Best unintentional humor in a scientific paper” goes to Itoh et al 2024. Food-induced small bowel obstruction observed in a patient with inappropriate use of semaglutide. Diabetology International, 15(4): 850-854, for this line in their Abstract, referring to a thin woman who, inadvisably, had put herself on a GLP-1 RA: “More than 6 months after titrating up to 1.0 mg, she got drunk and chomped on a lot of scallops sandwiched between sheets of kelp…and half a day later complained of abdominal pain.”
To read more like English and less like scientistic-acronyming, I’m using Ozempic from here on as a synonym for GLP-1 RA.
Martens et al 2024. Semaglutide Reduces Cardiomyocyte Size and Cardiac Mass in Lean and Obese Mice. JACC: Basic to Translational Science.
Americans would be better off if there were less of us, rather than fewer³.
I laughed out loud at the beautifully correct use of less and fewer. To answer your grammar question, what you want is the subjunctive (hypothetical) mood. Again, your construction is correct.
I think the true "original sin" of human beings is the need so many of us have for learning things "the hard way". I remember thalidomide. Sometimes I wonder who else does. From drugs that make it easier to lose weight to the ones that make it easier to put on muscle mass most people seem to have lost (or more likely never had) any ability to discern the payoffs of their actions. Almost as if advertising was NOT entended to make you believe side effects do not exist.