Ozempic, Mounjaro & GPL-1 Agonists for Weight Loss | Dr. Zachary Knight & Dr. Andrew Huberman
00:00:00.000 | I mean, I think it's important sometimes to distinguish between pharmacologic and physiologic
00:00:06.440 | effects.
00:00:07.440 | So physiologic is what the hormone naturally does in your body and what can be modulated
00:00:11.640 | by natural things like eating a different food.
00:00:14.480 | And you might get a twofold change in your GLP-1 by eating a different food, you know,
00:00:18.520 | one food versus the other.
00:00:19.520 | But as we know from those DPP-4 inhibitors, it's not going to really change your appetite
00:00:22.760 | because the drugs increase it threefold.
00:00:26.200 | These GLP-1 agonists are really a pharmacologic effect, an effect that only happens with drugs.
00:00:30.560 | So you get 1,000 to 10,000-fold higher concentrations of these drugs in your blood than the natural
00:00:36.800 | hormone.
00:00:37.800 | And so it's just, there's no diet that's ever going to give you that.
00:00:41.200 | And there's no precedent for it either.
00:00:43.000 | So should we be at all concerned about that?
00:00:45.320 | I mean, they run clinical trials and address safety.
00:00:48.400 | But when you're talking about 1,000-fold increase in essentially a peptide hormone, if we were
00:00:54.520 | talking about different peptide hormone, you know, pick one, you know, oxytocin or estrogen,
00:01:01.400 | testosterone, they're not really, you know, broadly speaking, most people would be concerned
00:01:06.840 | about 1,000-fold dosing of something like that.
00:01:10.220 | And obviously there are clinical indications where that's important.
00:01:13.080 | However, my observation of the ever-expanding literature on GLP-1 agonists is that there
00:01:21.880 | seems to be improvements in like reduction in alcohol consumption.
00:01:29.160 | And by the way, why would increasing GLP-1 reduce craving for alcohol?
00:01:34.760 | It seems like there's an ever-expanding list of things that GLP-1 agonism is good for.
00:01:40.000 | But we are talking about, I would say, supraphysiological levels when one takes it.
00:01:45.120 | And again, I'm not against it nor for it, I'm just paying attention to the literature.
00:01:49.960 | I would say that that's absolutely right.
00:01:52.080 | When you're increasing the level of a hormone 1,000-fold, you need to be careful, see what's
00:01:55.640 | happening.
00:01:56.640 | But at the end, it's an empirical question.
00:01:58.880 | What does it actually do to a person?
00:02:00.360 | And it can only be answered through experiments.
00:02:02.280 | And I think the nice thing about these GLP-1 drugs that a lot of people don't realize is
00:02:06.280 | they've been around and approved since 2005, the earliest ones.
00:02:09.720 | And even something like Ozempic, which maybe only entered the public consciousness in the
00:02:13.040 | last year or two, right, it's been around for seven-ish years, I think, and big clinical
00:02:18.700 | trials with these drugs.
00:02:21.080 | And the evidence so far is that they seem to be incredibly safe.
00:02:24.280 | And as you said, not just incredibly safe, but they seem to have all these unexpected
00:02:28.760 | health benefits that seem to be, in some cases, even unrelated to weight loss.
00:02:33.800 | And so, because of the reasons you mentioned, one of the things the FDA requires from these
00:02:38.320 | pharmaceutical companies for diabetes drugs is these large cardiac outcome trials, so
00:02:43.880 | basically where you measure stroke and where you measure heart attacks and death from any
00:02:48.600 | cardiac cause.
00:02:49.600 | Big trials, like 20,000 people, four years, cost like a billion dollars to run.
00:02:55.160 | And the data from the semaglutide, the Ozempic trial, came out last year and, as expected,
00:03:02.080 | reduced the rate of heart attacks, strokes, all-cause mortality, according to cardiac,
00:03:07.640 | for cardiac reasons.
00:03:08.640 | But what's really surprising was a lot of that seemed to happen before the people even
00:03:12.240 | lost weight.
00:03:13.240 | So there was already a difference between the placebo group and the semaglutide group
00:03:16.640 | before the people on the drug had lost a significant amount of weight.
00:03:19.800 | And there was no correlation between the amount of weight they lost and how well they were
00:03:23.600 | protected from heart disease.
00:03:25.240 | And that's led many people to think that some of these effects actually could be due
00:03:28.880 | to other things the GLP-1s are doing that we didn't expect.
00:03:31.760 | And so one thing is there's an idea emerging that they are anti-inflammatory.
00:03:37.520 | So these brain regions, the areoposteum and the NTS, are also really important for this
00:03:42.280 | reflex, known as the inflammatory reflex, that basically acts, starts with the vagus
00:03:48.000 | nerve, goes to these brain regions in the brainstem, and then goes back down to the
00:03:51.640 | body to basically suppress, to prevent out-of-control inflammation.
00:03:56.240 | And so it's thought that these drugs perhaps have an anti-inflammatory effect that explains
00:03:59.880 | some of that.
00:04:00.880 | - It sounds like the patent on these drugs just got extended by another hundred years.
00:04:06.880 | That's a biopharma joke.
00:04:09.680 | - I mean, just to put context on it, drugs can be patented and sold as a commercial version
00:04:16.040 | and not as generic versions until the patent runs out, unless companies are able to find
00:04:19.800 | another approved clinical use, in which case it can be remarketed only as a brand name,
00:04:27.120 | not generic version.
00:04:28.120 | So a lot of companies, once they do the safety testing and all, given everything they put
00:04:33.520 | into the R&D, into the research and development, there's a very big incentive to not necessarily
00:04:39.400 | finding new drugs, but finding new uses for the same drugs and not allowing generic versions
00:04:44.620 | into the picture.
00:04:46.760 | And that's why it's likely to be, based on these, what sounds like additional uses of
00:04:54.120 | ozempic-related compounds, a long time before there's generic ozempic available.
00:04:59.400 | - Yeah, I think it will be a while.
00:05:00.800 | I don't know the exact status of the patents, but I'm guessing it's gonna be a while before
00:05:04.400 | there are generic versions, but there's a lot of competition coming.
00:05:07.640 | So every major pharmaceutical company, or almost every major pharmaceutical company
00:05:11.160 | now has a GLP-1 program.
00:05:13.920 | And some of them are really exciting, actually.
00:05:18.280 | So I mean, the general trend in this area is what people call GLP-1+, which means you
00:05:22.640 | take the GLP-1 agonist, which is already giving you 15% weight loss or so, and then you add
00:05:28.160 | additional things to that to give it additional properties.
00:05:31.680 | So one compound is from Eli Lilly, so there's this other drug on the market that we haven't
00:05:36.240 | talked about, but terzepatide, which is known as Moonjaro for diabetes and ZepBound for
00:05:40.440 | obesity, which is even better, really, in almost every respect, a better drug than ozempic.
00:05:46.200 | People lose more weight, so it's about 21% weight loss at a year.
00:05:51.160 | Fewer side effects, at least at comparable doses.
00:05:55.720 | That seems to be because this other drug, terzepatide, it has two targets, not one.
00:06:02.640 | Whereas ozempic is just GLP-1 receptor agonist, terzepatide is a dual agonist of GLP-1 and
00:06:08.920 | this other incretin that we talked about, JIP, G-I-P.
00:06:12.280 | And it seems like having that JIP agonism actually acts as an anti-nausea effect, that
00:06:18.440 | sort of counteracts some of the nausea caused by the GLP-1 in the area post-treatment.
00:06:22.080 | There are JIP receptor neurons in the area post-treatment, this nausea center, just sort
00:06:25.280 | of allows you to crank up the dose of the GLP-1 agonism even further while you're suppressing
00:06:29.840 | the nausea and just get even more weight loss.
00:06:33.120 | So now, talking about the future, things that aren't available yet but will be in the next
00:06:36.560 | couple of years.
00:06:37.560 | So Eli Lilly, the company that makes this drug, terzepatide/Mujaro, they have a triple
00:06:43.840 | agonist that's in phase three clinical trials now.
00:06:46.200 | So this is now three hormones in one.
00:06:49.000 | It's the GLP-1, which all these drugs have, the JIP, which is the anti-nausea component,
00:06:55.160 | and then glucagon itself.
00:06:56.880 | And so these three hormones all combined in one pill.
00:07:00.240 | And what the glucagon does is it increases energy expenditure.
00:07:04.240 | This is a well-known effect of glucagon.
00:07:06.840 | And so you're basically eating less, your nausea isn't as bad, and now you're just burning
00:07:10.700 | more calories at baseline.
00:07:12.280 | And the results from this drug are incredible.
00:07:14.240 | So basically, there's been one phase two trial published, and people lost 25% of their body
00:07:19.260 | weight at the end of the, I think it was 48-week period.
00:07:24.120 | And they were still losing weight.
00:07:25.120 | So we don't know where the end point.
00:07:26.120 | We don't know what the maximum is.
00:07:28.160 | So there are bigger, longer trials going on now to figure that out.
00:07:31.520 | But at that point, when you get beyond 25% body weight, you're talking about basically
00:07:35.420 | bariatric surgery, which is currently the best thing we have, like these surgeries people
00:07:39.520 | do to--
00:07:40.520 | - Stomach staples.
00:07:41.520 | - Yeah.
00:07:42.520 | - Removing a portion of the stomach.
00:07:43.520 | - Removing a portion of the gut.
00:07:44.520 | So really, it's a pharmacologic version of bariatric surgery.
00:07:48.240 | The other one that I think is really exciting, there's this compound from Amgen, it's called,
00:07:51.800 | right now it's just a code, it's like AMG-133, but it's like terzapotide in the sense that
00:07:59.120 | it targets both GLP-1 and GYP, so it's a dual targeted.
00:08:04.600 | But unlike terzapotide, which activates the GYP receptor, this Amgen compound inhibits
00:08:09.320 | it.
00:08:10.320 | And for reasons that people don't understand, either activating or inhibiting this receptor
00:08:14.360 | causes you to lose weight.
00:08:15.920 | So it's still a mystery, but a lot of debate about what's going on there.
00:08:19.600 | But the way this Amgen compound activates the GYP receptor, or inhibits the GYP receptor
00:08:25.920 | rather, is that it's an antibody.
00:08:29.160 | So all these other things were peptides, but this is a much bigger, it's an actual protein,
00:08:31.760 | this is an antibody.
00:08:33.800 | Because it's an antibody, it has a much longer lifetime, even than something like semaglutide,
00:08:37.880 | which is seven days, so it lasts like a month in the blood or something.
00:08:40.520 | And so you can give people monthly injections of this, and they lose dramatic amounts of
00:08:44.960 | weight.
00:08:46.080 | And then at least in this initial trial, at the end of this they stopped, and people maintained
00:08:50.780 | the weight loss for six months.
00:08:52.480 | That's impressive.
00:08:53.560 | Potentially because of the long-lasting effects of this antibody, or potentially because of
00:08:56.560 | other things that we don't understand.
00:08:58.480 | So those are just two, there's all sorts of other crazy things happening.
00:09:01.080 | So really, I think it's just created this explosion of interest in pharma.
00:09:04.920 | Basically, it's one of these things, once you see that something can be done, all of
00:09:09.680 | a sudden that changes everyone's perspective.
00:09:11.760 | And so now, obesity drug discovery has gone from something that 10 years ago everyone
00:09:15.740 | wanted to stay away from, because there were so many nightmare stories about drugs that
00:09:19.060 | turned out to be not safe, until now everybody's sort of all in on this.
00:09:22.880 | Yeah, I remember in college, the fen-fen debacle, where a diet drug was released and people
00:09:28.240 | had cardiac issues, started dying, so it was pulled from market.
00:09:30.760 | And then it was essentially a quiet field for a long time.
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