GLP-1 Aren’t Just Weight Loss Drugs: A Provocative Discovery

About a year ago, I thought if I said GLP-1 or GLP-1 receptor agonist, your average non-medical person would have no idea what I'm talking about. Oh, how that's changed. This family of weight loss drugs has taken the obesity and metabolism world by storm. With mixed opinions. Some people think they're God's gift to modern medicine. A secular scientific miracle. Others are skeptical, given the history of weight loss drugs in medicine is, well, not so great and riddled with missteps. But what if GLP-1 receptor agonists, these weight loss drugs, are different? What if they're not weight loss drugs, or at least not only weight loss drugs? In this video, I'll prove this to you. And by the end, we'll come full circle to acknowledge a shocking truth that's deeper than muffin tops and love handles. And I'll end by telling you what's even better than GLP-1. It may surprise you, or it may not. But first, a big caveat. I am not here to place judgment on the clinical use of these medications. That is not my place. That place is the doctor's office. I'm here to talk science. But because my opinion is probably relevant to my audience, I'll just say my opinion on these medications is that they're powerful tools that should be used in the right patients, like many medications. However, at a societal level, I am personally concerned about adopting a widespread cultural position that injections and drugs are the answer to the obesity epidemic, to the point that we lose sight of this fact and that the obesity epidemic— obesity is a disease of lifestyle, it's a disease of environment, and that these are also things we must change if we are truly to succeed in forcing obesity towards extinction. Anyway, on to the science. A recent review article published in the journal Science discussed many of the applications of GLP-1 medications, including beyond obesity in cardiovascular disease, liver disease, mental health and neurological disorders, and so on. It makes the point that the benefits of GLP-1s are not just related to weight loss, but also that, and now I'm quoting, "A potentially unifying mechanism of action for GLP-1 receptor agonism is the reduction of inflammation. And this led me to another paper published in Cell Metabolism earlier this year, where they showed that the actions of GLP-1 on the brain caused a decrease in inflammation in the body. I'll repeat that: GLP-1 actions on the brain caused a decrease in inflammation in the body. And in this study, what they did is they treated mice with a substance that causes inflammation, lipopolysaccharide, or LPS, which can be measured— inflammation can be measured by an increase in inflammatory signaling molecules like TNF-alpha. And then they also treated some mice with a GLP-1 receptor agonist and observed reduced inflammation in the GLP-1-treated mice. But then they did something else very important. They did the same experiment, treating mice with the inflammatory substance to induce inflammation and trying to dampen that inflammation with a GLP-1 receptor agonist, but they applied it in mice missing the receptor for GLP-1, the GLP-1 receptor, in various tissues and organs. So in one experiment, they deleted the GLP-1 receptor from various blood cells and cells that line blood vessels, endothelial cells. And interestingly, in these mice lacking the GLP-1 receptor in those tissues, GLP-1 could still reduce inflammation. So those receptors were dispensable. They weren't that important for the anti-inflammatory effects of GLP-1. But in another experiment, they deleted the GLP-1 receptor from the brain of the mice exclusively, and in these mice, GLP-1 did not reduce inflammation. And they even verified this with another mouse model lacking GLP-1 in the brain. And all this strongly suggests that it's the action of GLP-1 on the brain that mediates the systemic whole-body anti-inflammatory effects of GLP-1 drugs, at least in animals. But what about humans? Because you can't very well delete GLP-1 receptors from various organs in humans, especially not the brain. However, there are signals that the benefits of GLP-1s in humans can be independent of weight loss, or separable. For example, in the SELECT cardiovascular outcomes trial studying people with obesity, the extent of weight loss did not correlate with the effects of the drug to reduce heart attack, stroke, and cardiovascular death. Also, another prior long-acting GLP-1 therapy was withdrawn from the market owing to its modest effects on reduction of glucose and body weight in people with type 2 diabetes. However, it still reduced the rates of major adverse cardiovascular events by 22%. So again, in humans, we see the signal where GLP-1s can have benefits even independent of or separable from weight loss. So point being, GLP-1s in humans almost certainly have benefits beyond weight loss, and in part, this might be due to reduced whole body inflammation. So now pivoting a little bit and getting more abstract or zooming out, here's the core truth I want to communicate in this video. Metabolic health is not simply about weight. Duh, right? But more importantly, good metabolic health causes healthy weight, not the other way around. As applies to obesity, one could reframe this is that eating in a way that promotes high blood sugar, high insulin, and inflammation, and overall throws your body into metabolic disarray, that's what causes obesity. And this is in contrast with the overly simplistic calorie balance, energy surplus mindset that still plagues society like a mind virus. And this critical contrast is really important to acknowledge since we are living in a world where calories remain king from a mechanistic point of view on obesity, but where we're leaning into drugs to solve the problem and inappropriately attributing their benefits to simply less hunger and fewer calories eaten. When the effects of these GLP-1s are clearly more metabolic and more complex, as I hope I've convinced you in this video. And that brings me to the intervention that's even better than GLP-1s, albeit a little bit harder to implement, which is living a healthier lifestyle. Okay, I'll give you a moment to finish your eye roll or groan or moan, but hear me out. The lifestyle line live a healthier lifestyle has taint because it's often seen as victim blaming in the camp of eat less, move more advice. But that is not what I'm suggesting. I'm suggesting that as a society, we have lifestyle and environmental creep, where being more sedentary and eating worse— not more calories, but worse food in terms of food quality— is facilitated by changes of our social norms and physical environment. I could provide many examples, but I know you know what I'm talking about. So the solution, as I see it, needs to be talking about these social norms and changing our environmental structure. I want to see a world where there aren't junk food-filled vending machines in hospitals, where it's not normalized to dump 10 teaspoons of sugar in your coffee, where supermarket aisles aren't themselves obese, with colorful sugary breakfast cereals targeting innocent children for profit. And that doesn't mean— it does not mean that GLP-1s aren't a useful tool, that they don't have their place, but they're not enough. Let's not lose sight of the metabolic forest for one very financially fruitful tree. Stay curious, ask hard questions. I hope this opens up a productive dialogue.