I mean, I think it's important sometimes to distinguish between pharmacologic and physiologic effects. So physiologic is what the hormone naturally does in your body and what can be modulated by natural things like eating a different food. And you might get a twofold change in your GLP-1 by eating a different food, you know, one food versus the other.

But as we know from those DPP-4 inhibitors, it's not going to really change your appetite because the drugs increase it threefold. These GLP-1 agonists are really a pharmacologic effect, an effect that only happens with drugs. So you get 1,000 to 10,000-fold higher concentrations of these drugs in your blood than the natural hormone.

And so it's just, there's no diet that's ever going to give you that. And there's no precedent for it either. So should we be at all concerned about that? I mean, they run clinical trials and address safety. But when you're talking about 1,000-fold increase in essentially a peptide hormone, if we were talking about different peptide hormone, you know, pick one, you know, oxytocin or estrogen, testosterone, they're not really, you know, broadly speaking, most people would be concerned about 1,000-fold dosing of something like that.

And obviously there are clinical indications where that's important. However, my observation of the ever-expanding literature on GLP-1 agonists is that there seems to be improvements in like reduction in alcohol consumption. And by the way, why would increasing GLP-1 reduce craving for alcohol? It seems like there's an ever-expanding list of things that GLP-1 agonism is good for.

But we are talking about, I would say, supraphysiological levels when one takes it. And again, I'm not against it nor for it, I'm just paying attention to the literature. I would say that that's absolutely right. When you're increasing the level of a hormone 1,000-fold, you need to be careful, see what's happening.

But at the end, it's an empirical question. What does it actually do to a person? And it can only be answered through experiments. And I think the nice thing about these GLP-1 drugs that a lot of people don't realize is they've been around and approved since 2005, the earliest ones.

And even something like Ozempic, which maybe only entered the public consciousness in the last year or two, right, it's been around for seven-ish years, I think, and big clinical trials with these drugs. And the evidence so far is that they seem to be incredibly safe. And as you said, not just incredibly safe, but they seem to have all these unexpected health benefits that seem to be, in some cases, even unrelated to weight loss.

And so, because of the reasons you mentioned, one of the things the FDA requires from these pharmaceutical companies for diabetes drugs is these large cardiac outcome trials, so basically where you measure stroke and where you measure heart attacks and death from any cardiac cause. Big trials, like 20,000 people, four years, cost like a billion dollars to run.

And the data from the semaglutide, the Ozempic trial, came out last year and, as expected, reduced the rate of heart attacks, strokes, all-cause mortality, according to cardiac, for cardiac reasons. But what's really surprising was a lot of that seemed to happen before the people even lost weight. So there was already a difference between the placebo group and the semaglutide group before the people on the drug had lost a significant amount of weight.

And there was no correlation between the amount of weight they lost and how well they were protected from heart disease. And that's led many people to think that some of these effects actually could be due to other things the GLP-1s are doing that we didn't expect. And so one thing is there's an idea emerging that they are anti-inflammatory.

So these brain regions, the areoposteum and the NTS, are also really important for this reflex, known as the inflammatory reflex, that basically acts, starts with the vagus nerve, goes to these brain regions in the brainstem, and then goes back down to the body to basically suppress, to prevent out-of-control inflammation.

And so it's thought that these drugs perhaps have an anti-inflammatory effect that explains some of that. - It sounds like the patent on these drugs just got extended by another hundred years. That's a biopharma joke. - I mean, just to put context on it, drugs can be patented and sold as a commercial version and not as generic versions until the patent runs out, unless companies are able to find another approved clinical use, in which case it can be remarketed only as a brand name, not generic version.

So a lot of companies, once they do the safety testing and all, given everything they put into the R&D, into the research and development, there's a very big incentive to not necessarily finding new drugs, but finding new uses for the same drugs and not allowing generic versions into the picture.

And that's why it's likely to be, based on these, what sounds like additional uses of ozempic-related compounds, a long time before there's generic ozempic available. - Yeah, I think it will be a while. I don't know the exact status of the patents, but I'm guessing it's gonna be a while before there are generic versions, but there's a lot of competition coming.

So every major pharmaceutical company, or almost every major pharmaceutical company now has a GLP-1 program. And some of them are really exciting, actually. So I mean, the general trend in this area is what people call GLP-1+, which means you take the GLP-1 agonist, which is already giving you 15% weight loss or so, and then you add additional things to that to give it additional properties.

So one compound is from Eli Lilly, so there's this other drug on the market that we haven't talked about, but terzepatide, which is known as Moonjaro for diabetes and ZepBound for obesity, which is even better, really, in almost every respect, a better drug than ozempic. People lose more weight, so it's about 21% weight loss at a year.

Fewer side effects, at least at comparable doses. That seems to be because this other drug, terzepatide, it has two targets, not one. Whereas ozempic is just GLP-1 receptor agonist, terzepatide is a dual agonist of GLP-1 and this other incretin that we talked about, JIP, G-I-P. And it seems like having that JIP agonism actually acts as an anti-nausea effect, that sort of counteracts some of the nausea caused by the GLP-1 in the area post-treatment.

There are JIP receptor neurons in the area post-treatment, this nausea center, just sort of allows you to crank up the dose of the GLP-1 agonism even further while you're suppressing the nausea and just get even more weight loss. So now, talking about the future, things that aren't available yet but will be in the next couple of years.

So Eli Lilly, the company that makes this drug, terzepatide/Mujaro, they have a triple agonist that's in phase three clinical trials now. So this is now three hormones in one. It's the GLP-1, which all these drugs have, the JIP, which is the anti-nausea component, and then glucagon itself. And so these three hormones all combined in one pill.

And what the glucagon does is it increases energy expenditure. This is a well-known effect of glucagon. And so you're basically eating less, your nausea isn't as bad, and now you're just burning more calories at baseline. And the results from this drug are incredible. So basically, there's been one phase two trial published, and people lost 25% of their body weight at the end of the, I think it was 48-week period.

And they were still losing weight. So we don't know where the end point. We don't know what the maximum is. So there are bigger, longer trials going on now to figure that out. But at that point, when you get beyond 25% body weight, you're talking about basically bariatric surgery, which is currently the best thing we have, like these surgeries people do to-- - Stomach staples.

- Yeah. - Removing a portion of the stomach. - Removing a portion of the gut. So really, it's a pharmacologic version of bariatric surgery. The other one that I think is really exciting, there's this compound from Amgen, it's called, right now it's just a code, it's like AMG-133, but it's like terzapotide in the sense that it targets both GLP-1 and GYP, so it's a dual targeted.

But unlike terzapotide, which activates the GYP receptor, this Amgen compound inhibits it. And for reasons that people don't understand, either activating or inhibiting this receptor causes you to lose weight. So it's still a mystery, but a lot of debate about what's going on there. But the way this Amgen compound activates the GYP receptor, or inhibits the GYP receptor rather, is that it's an antibody.

So all these other things were peptides, but this is a much bigger, it's an actual protein, this is an antibody. Because it's an antibody, it has a much longer lifetime, even than something like semaglutide, which is seven days, so it lasts like a month in the blood or something.

And so you can give people monthly injections of this, and they lose dramatic amounts of weight. And then at least in this initial trial, at the end of this they stopped, and people maintained the weight loss for six months. That's impressive. Potentially because of the long-lasting effects of this antibody, or potentially because of other things that we don't understand.

So those are just two, there's all sorts of other crazy things happening. So really, I think it's just created this explosion of interest in pharma. Basically, it's one of these things, once you see that something can be done, all of a sudden that changes everyone's perspective. And so now, obesity drug discovery has gone from something that 10 years ago everyone wanted to stay away from, because there were so many nightmare stories about drugs that turned out to be not safe, until now everybody's sort of all in on this.

Yeah, I remember in college, the fen-fen debacle, where a diet drug was released and people had cardiac issues, started dying, so it was pulled from market. And then it was essentially a quiet field for a long time. Thank you for tuning in to the Huberman Lab Clips channel. If you enjoyed the clip that you just viewed, please check out the full-length episode by clicking here.