[0:00] Adam:
This video is sponsored by Squarespace. Hi,  
[0:03] it's Adam Ragusea, and yes, my weight is yo-yoing 
as it has my whole life. From the 1960s, there  
[0:12] grew a social movement to de stigmatize fatness. 
That is where we get the National Association to  
[0:19] Advance Fat Acceptance, which most famously 
has pushed for better public accommodations,  
[0:26] bigger seats for big bodied people. You also get 
the Association for Size Diversity and Health,  
[0:32] which pushes this public health frame 
they call health at every size. What the  
[0:39] health at every size people observed is that 
people who carry a lot of body fat tend to be  
[0:45] discriminated against in the healthcare system.
There are many permutations of the same old joke  
[0:52] and it goes something like this. What did the 
doctor say to the fat guy with the gaping head  
[0:56] wound? Have you tried diet and exercise? It's 
actually a fair amount of research to back up  
[1:04] this claim that doctors tend to look at a person 
and assume that all of their problems stem from  
[1:09] their obesity. And what obese people have 
said in response is, number one, no, I have  
[1:16] health problems that have nothing to do with my 
weight and you need to pay attention to those.  
[1:20] Number two, even if my health problems are related 
to my weight, I still deserve treatment. Judging  
[1:29] by the study outcomes, it is nearly impossible 
for people to lose a lot of weight and keep it  
[1:35] off without serious medical help, so let's not 
wait for something to happen that is statistically  
[1:41] almost impossible before you start treating me 
for my problems. Treat me now as I am. Anyway.
 
[1:49] Over on the other side of this particular 
discourse, you had the medical traditionalists  
[1:55] saying this is all hogwash, it's very well 
established that people who are carrying  
[1:59] a lot of extra body fat have much worse health 
outcomes in almost every area you could imagine.  
[2:06] It is not possible to be healthy at every size. 
Now, in the 21st century, I think that we've  
[2:14] seen an enlightened consensus emerge where we 
acknowledge that fatness is associated with lots  
[2:21] of bad things, but fatness is not necessarily the 
cause of those things. Cardiovascular disease, and  
[2:29] diabetes, and kidney disease, and non-alcoholic 
fatty liver disease, and all these things exist  
[2:35] in a dense web of causality that we now call 
the metabolic syndrome, and a person's fatness  
[2:42] is at most an imperfect proxy for the total 
problem. People with these problems do tend  
[2:48] to be fat, but they're not always fat, and the 
relationship between the fatness and the problem  
[2:54] is murky. Anyway, I think the emergence of that 
enlightened consensus seemed to ease tensions a  
[3:01] bit between the fat acceptance crowd and the fat 
rejection crowd, but now enter the new drugs.
 
[3:10] Speaking of consensus, we cannot seem to form one 
about what to call these drugs. You can call them  
[3:18] GLP-1 drugs, but that's not quite right. These 
drugs do imitate the natural GLP-1 peptide hormone  
[3:26] that all our bodies produce to make us feel full 
when we've had plenty to eat. But some of these  
[3:32] drugs also imitate different peptides like GIP, 
which works on a totally different receptor,  
[3:38] and there are more things like that on 
the way, so calling them GLP-1 drugs is  
[3:42] incomplete. It's like calling all of my cups 
glassware. They're not all made out of glass.
 
[3:50] You could call these drugs incretin mimetics. 
The chemicals that our bodies make that  
[3:56] regulate blood sugar and appetite are known 
as incretins. And a mimetic is something that  
[4:02] imitates another thing, which is what these 
drugs do. They imitate your hunger hormones.  
[4:08] But, incretin mimetic is even harder to say out 
loud than GLP-1 so I can understand why that name  
[4:17] hasn't caught on among the general public.
I suppose you might just start calling these  
[4:24] weight loss drugs because they are the only safe 
weight loss drugs ever proven to have dramatic  
[4:32] and long-lasting effects. These are the only 
weight loss drugs that actually work according  
[4:39] to any reasonable, real world standard of what it 
means for something to work. So let's just call  
[4:47] them the weight loss drugs, they're the weight 
loss drugs. The fat acceptance crowd naturally  
[4:52] views these drugs with some amount of suspicion. 
The medical industrial complex has made a lot  
[4:59] of money selling false hope to generations of 
fat people. And even if the hope is not false,  
[5:07] which seems to be the case this time, the body 
acceptance crowd is still worried that these drugs  
[5:12] will reinforce a toxic, thin ideal in society. 
Now, there will be even more pressure to conform  
[5:21] to that ideal since, hey man, all you need to 
do to stop being fat is to take a medicine,  
[5:27] which is still extremely expensive and 
not all people's bodies can tolerate it.
 
[5:34] I am, as you can tell, very sympathetic to the 
fat acceptance arguments. But, I do think that  
[5:41] the ongoing research on these drugs points to 
something that the body positivity community  
[5:47] should view as something of a vindication. The 
latest evidence is on your side, my friends,  
[5:55] because these drugs work even if you aren't 
fat, or even if they don't change your level  
[6:03] of fatness. In clinical trials, in people who 
either did not lose weight or did not need  
[6:09] to lose weight, we are still seeing dramatic 
improvements in cardiovascular health, kidney  
[6:15] health, brain health, addiction, substance abuse 
disorders. Science is still untangling all the  
[6:22] whys and the hows, but it sure seems like these 
drugs are proving the enlightened consensus about  
[6:29] weight to be essentially correct. If a drug treats 
some elements of the metabolic syndrome without  
[6:36] impacting weight, if you get healthier on these 
drugs, even if you keep your calories exactly  
[6:42] the same, that would indicate that weight is only 
one node on this whole dense web of causality.
 
[6:52] I think that body acceptance advocates should 
view these developments as vindication. It's not  
[6:57] just about fatness. It might not even be primarily 
about fatness. It's about our brains. The common  
[7:05] denominator here is the hormones that influence 
how we relate to food, both physiologically and  
[7:12] psychologically. We are evolved to live a 
life where food is only available some of  
[7:19] the time. And so to be healthy, our bodies seem 
to need some downtime when we are not eating,  
[7:28] or when we are not getting the hormonal signal 
to eat. The signal itself may have a role in how  
[7:37] these very complicated biological systems 
actually operate. We ought not view these  
[7:43] drugs as a miracle cure, and we certainly 
ought not drop our guard around big pharma.
 
[7:51] I am curious about the side effects that we're 
starting to see now that vast numbers of people  
[7:57] are taking these drugs. I'm curious about how 
effective they will be in the very long term  
[8:03] after decades of use. And I am curious about why 
they seem to work for so many different things.
 
[8:13] A great expert on the internet to follow for 
this stuff is David White. David is a nurse  
[8:21] practitioner. That is a nurse whose level of 
education entitles them to prescribe medications  
[8:26] in the US system. He doesn't need to go through 
a doctor to give you medicine. And nothing that  
[8:31] David says on my channel should be construed as 
medical advice, yada, yada, yada. He's just a real  
[8:38] smart guy who deals with these drugs every day in 
his practice, and he spends a lot of time at night  
[8:44] reading and posting about the latest research. 
His blog is called The Incretin Space. That and  
[8:51] his social links are in the description.
So, here's the first of what I hope will  
[8:55] be some ongoing conversations with Nurse David 
about weight loss drugs. First thing to ask is,  
[9:02] what kind of side effects are we seeing?
David:
 
[9:05] I mean, the biggest one, and the trial data 
bears this out as well, is usually nausea. I  
[9:11] just informally call it the big four. So whenever 
you see a top line result or a published result,  
[9:17] they'll almost always have nausea, 
vomiting, constipation, and diarrhea.
 
[9:21] Adam:
Guess what? There's an over-the-counter  
[9:22] medication that I've heard can treat all four 
of those things, and it even has a song.
 
[9:26] David:
Yeah, yes. Yeah. And the fifth that I would  
[9:30] add is usually some form of heartburn. You'll 
hear patients, and I don't even have to mention  
[9:35] my patients. You can look on Reddit, or really any 
social media circle, people will call it sulfur  
[9:42] burps, which is just the drugs delay your gastric 
emptying, they delay your stomach from moving  
[9:50] forward, and so you get a little fermentation.
Adam:
 
[9:54] Yeah.
David:
 
[9:57] But even that, same thing, there are ways of 
managing that like pineapple or to go to the  
[10:04] cooking side of things, pineapple, papaya.
Adam:
 
[10:07] The enzymes.
David:
 
[10:08] Yeah, the enzymes will help. And people look 
at you funny, but I'm like, "I'm telling you  
[10:13] it'll work." But yeah, that's one thing with 
the side effects. I tell patients all of it's  
[10:20] manageable.
Adam:
 
[10:21] Yeah.
David:
 
[10:22] A lot of it too in the trials is their goal 
is let's get you up to the highest dose,  
[10:26] let's lose the most amount of weight as fast as we 
can. But if you are slow in titrating these drugs,  
[10:35] they're really actually quite tolerable. 
And even when you look at the side effects,  
[10:41] the actual absolute rate of side effects, even 
with the nausea, you're talking a 20% absolute  
[10:49] rate. And over time, because most of the drug 
companies will publish the side effects over time,  
[10:57] you'll watch it just slowly drops away as 
the body gets used to the new normal and.
 
[11:04] Adam:
The new normal, right.  
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[12:24] Squarespace. Anyway, we were talking 
with David White about side effects  
[12:28] associated with the new weight loss drugs.
What about the more serious stuff like  
[12:33] muscle wasting, which I've understood to 
essentially just be the normal amount of  
[12:38] muscle loss that you would expect with 
any kind of rapid weight loss, right?
 
[12:42] David:
If you talk to people in obesity  
[12:44] medicine research, they will reference something 
like a three to one ratio or 75/25. And by that,  
[12:52] they mean you should... If you were to just crash 
diet, we would expect you to lose about 75% fat  
[13:01] mass and about 25% lean mass.
Adam:
 
[13:04] Yeah.
David:
 
[13:04] And when you look at these drugs, it's 
usually anywhere from about 25 to about 35%  
[13:11] lean mass loss and the rest is fat mass loss. 
But even with lean mass, that depends on your  
[13:18] definition of lean mass. It depends on, are you 
using a DEXA scan? Are you using an MRI? I have  
[13:26] the conversation with patients like, "If you are 
going to eat anything, at least get your protein  
[13:32] in and at least do resistance training." Those are 
the two things that I ask, because those are the  
[13:39] things that will at least preserve your functional 
strength, preserve what you already have.
 
[13:44] Adam:
I mean, this is territory that has been explored  
[13:47] by bodybuilders and people like that.
David:
 
[13:51] Yes.
Adam:
 
[13:52] They know that when you diet down, you're going 
to lose some muscle, but if you keep lifting  
[13:57] the weights and if you keep getting protein, 
you're going to be able to keep most of it.
 
[14:01] David:
Yes, yeah. Correct, exactly.
 
[14:03] Adam:
Any other big side effects  
[14:05] that are concerning you so far?
David:
 
[14:08] There's a slightly increased risk of gallstones 
and inflamed gallbladder, but even that too is  
[14:18] also more related to the weight loss and not 
the drug without getting into the physiology,  
[14:24] but you lose weight rapidly and sometimes your 
gallbladder's not happy about that. And even that,  
[14:31] patients can get their gallbladder out and then 
just continue on with treatment like nothing ever  
[14:37] happened.
Adam:
 
[14:39] And then there's the big unknown that not 
even all of the clinical trials can tell us,  
[14:44] which is what happens to people when 
they've been on these drugs for decades.
 
[14:47] David:
Yes. Yeah. I mean, there's a subset. I mean,  
[14:53] there is probably a reasonable subset of diabetics 
that have been on them for an extended period of  
[15:00] time just.
Adam:
 
[15:01] At this point.
David:
 
[15:02] Yeah. I mean, liraglutide or Victoza, that was FDA 
approved in 2012. I'd have to double check my.
 
[15:10] Adam:
Oh, 2010 in the US. He got real close.
 
[15:13] David:
But that's been around, I mean, that's  
[15:15] generic now. That's how long it's been around. So 
even Ozempic, semaglutide, that was FDA approved  
[15:22] in 2017, so we're going on 10 years for that even. 
There are definitely people that have been on them  
[15:31] for a while. But even the clinical trials, the 
longest clinical trials are about five years,  
[15:37] and obviously we just continue to see a benefit as 
time passes. I say this understanding I don't have  
[15:44] any evidence to back this up.
Adam:
 
[15:47] Very scientific.
David:
 
[15:48] But also, I mean, it doesn't make... Just 
on the mechanism, how the drug works.
 
[15:54] Adam:
You're making a mechanistic  
[15:55] argument. There you go. Go ahead.
David:
 
[15:57] Yeah. On a mechanistic argument, there shouldn't 
be... It's like if I can use another well-known  
[16:04] drug class, with statins, we know the longer 
you're on them, the lower your risk of  
[16:11] cardiovascular diseases.
Adam:
 
[16:12] Sure yeah.
David:
[16:13] And so I have a feeling it's going to be the same 
thing. If you're on a drug that caused you to lose  
[16:19] 20% of your body weight and you stay on it for 
20 years, you probably will live longer. You'll  
[16:25] probably have less comorbid conditions. You'll 
probably have less healthcare utilization. I mean,  
[16:33] and actually there's already starting 
to be... Do you know what QALYs are?
 
[16:39] Adam:
Yeah. Go ahead.
 
[16:41] David:
Yeah. Or you can define it in the video, but.
 
[16:47] Adam:
Oh, okay. QALY stands for  
[16:50] quality adjusted life year. We don't just want to 
be alive, we want to be healthy while we're alive,  
[16:57] and QALY is a crude way of measuring that. It's 
like how many healthy years this medicine gets  
[17:03] you. That's a QALY. Anyway.
David:
 
[17:05] The QALY data is already starting to line up that 
if patients are on these for X amount of time,  
[17:11] they do start paying for themselves, even with the 
current costs. And insurance companies obviously,  
[17:21] and actuaries everywhere, that's 
what they're looking for, right?
 
[17:24] Adam:
If you'll permit me  
[17:26] to make a mechanistic argument, and also I suppose 
one drawn from anecdotal experience, when you have  
[17:32] a receptor in your body and you pummel it.
David:
 
[17:35] Yeah.
Adam:
 
[17:36] With stimulus a little bit more than it would 
normally get, you're going to start to notice some  
[17:42] weird things happening among them. It's just going 
to take more and more stimulation in order to make  
[17:49] that receptor feel anything.
David:
 
[17:51] Yeah.
Adam:
 
[17:52] Are we not seeing that with these drugs? We're not 
seeing people just get used to it and the whole  
[17:56] system just equilibrates to it?
David:
 
[17:59] There was a cardiovascular outcomes trial called 
SURPASS-CVOT, C-V-O-T, that Eli Lilly published  
[18:07] last year, and it was almost five year long 
trial of tirzepatide in diabetics and looking  
[18:13] at cardiovascular outcomes. And they included 
a graph and it showed the patient's weight.
 
[18:21] Adam:
Yeah.
 
[18:21] David:
And A1C control over that  
[18:24] was about four and a half year period and there's 
almost no... They lose that weight. The A1C comes  
[18:30] down, and if you look at the error bars and the 
confidence intervals, they're so tight. This is  
[18:39] 15,000 patient trial and no one is... I don't want 
to say no one, but the vast majority of people not  
[18:49] regaining weight, not requiring a higher dose, 
their diabetes is under control. This is maybe  
[18:58] above my pay grade in terms of understanding, but 
from what I can gather and from what I've talked,  
[19:04] for some reason, there's just not that 
receptor desensitization that you would see  
[19:09] with cannabinoids or opioids or various other. 
And it may be related to the fact that I mean,  
[19:21] GLP-1 as a receptor is so integral to just 
our day-to-day physiological function.
 
[19:31] Adam:
Sure.
 
[19:31] David:
And it's one of those things that  
[19:34] it took pharmacology to realize, oh, hey, this 
thing actually does way more than anyone...  
[19:45] Simplistic understanding is, sure, it suppresses 
your appetite, it helps with insulin secretion,  
[19:50] but I mean, it is-
Adam:
 
[19:51] Tip of the iceberg.
David:
 
[19:52] Yeah, half inch view. I mean, I'm working on 
a blog post right now on the anti-inflammatory  
[20:01] infects, and I've been writing for a month and 
a half now because I'm just trying to translate  
[20:05] it down to regular, in English, but also it's 
so... It's just like every time I read one paper,  
[20:11] I'm like, "Oh, wait, there's another 
thing, do I need to add this now?"
 
[20:17] I actually found an evolutionary development paper 
about where this came from, and you can track the  
[20:27] development of the GLP-1 class, or I guess I shape 
more appropriately what's called pre-pro glucagon.  
[20:38] So you get GLP-1, which everyone knows about. You 
get GLP-2, which is another intestinal hormone,  
[20:47] and you also get glucagon, and then you get a 
couple other random bits that don't do much. And  
[20:52] that family of those three hormones are so deeply 
conserved, evolutionarily speaking. So there's a  
[21:04] really great paper that talks about some of the 
benefits of these drugs outside of the weight  
[21:11] loss, and it had the actual amino acid sequences 
of glucagon. And I mean, you can go way back, way  
[21:20] off from the primate family tree, and you could 
get whale glucagon and it would work in a human.
 
[21:30] Even some of the bony fish glucagon is still 
similar enough that you could give it to a  
[21:36] human and get an effect. So clearly evolution was 
like, "We need this, this class of hormones." And  
[21:44] I think that's my speculation as to why you don't 
see desensitization, because it's like, this is  
[21:50] actually mission-critical to keeping you alive.
Adam:
 
[21:55] Well, I suppose all of that is a lot of reason 
to be excited, but also reason to proceed with  
[21:59] caution.
David:
 
[22:00] Yes.
Adam:
 
[22:00] If we're dealing with such a 
powerful primordial force.
 
[22:03] David:
Yeah.
 
[22:04] Adam:
I, about three years ago, publicly predicted that  
[22:11] obesity as we know it would be over as a pandemic 
in highly developed countries within 10 years.  
[22:21] I've got seven more years for that admittedly 
bold prediction to come true. I wonder how  
[22:31] on schedule you reckon we are. I actually 
feel kind of good about it so far because  
[22:37] it is preceding the way I imagined, where you're 
starting to not see fat rich people anymore.
 
[22:45] David:
Not to be crass, but that's your signal, right?
 
[22:52] Adam:
Yeah. That's where it begins.
 
[22:54] David:
But there was a big  
[22:56] hullabaloo about how the rate of obesity in the 
US has flattened out in the last couple years. And  
[23:04] it's like, is that the drugs? Is that the first 
signal that, oh, enough people are on these that  
[23:11] we're starting to see a downward deflection in the 
obesity rate? You might be a little aggressive,  
[23:20] but at the same time, I mean, some of the 
stuff that's in develop... So retatrutide,  
[23:26] which is a triple agonist that will have phase 
three data, weight loss data here in about,  
[23:34] I mean, it's mid-April when we're recording this, 
and the data's due to be published the first week  
[23:39] of June, so not too long for that. And that drug 
is going to show bariatric surgery outcomes.
 
[23:47] Adam:
Outcomes comparable to  
[23:49] bariatric surgery, you mean?
David:
 
[23:50] Yeah.
Adam:
 
[23:51] And by triple agonist, you mean it's 
acting on three different receptors?
 
[23:55] David:
Yes, yeah. So it acts on GLP-1,  
[23:57] it acts on GIP, and then it acts on glucagon so 
acts on three things at once. The initial phase  
[24:07] two data showed 24% weight loss at 48 weeks. There 
was a shorter phase three trial that showed 29%  
[24:14] weight loss at 68 weeks with patients still losing 
weight at 68 weeks. And the trial that will have  
[24:21] data published in June will have an 80-week and 
104-week data arm. So yeah, my expectation is,  
[24:30] I mean, 29%, you're one point away from 30%, 
and 25% is the start of bariatric surgery  
[24:38] loss. 30% to 35% is usually what most bariatric 
surgeons will say is the goal. So yeah, we could  
[24:47] have a drug that has that level of efficacy.
And if that becomes broadly accessible, then yeah,  
[24:56] it's pretty reasonable to expect obesity 
rates to plummet. And then even ignoring that,  
[25:03] there are so many other drugs in development that 
it seems like the floor is about 15% to 20% weight  
[25:11] loss, which again, like that's going to drive a 
significant number of people into just overweight  
[25:18] and not obese anymore. So yeah, I mean, by 2035, 
I think it's reasonable to see significantly less  
[25:27] obesity.
Adam:
 
[25:28] What are you most excited about looking ahead?
David:
 
[25:32] I mean, so the drug that I just mentioned, 
retatrutide, very excited for that. Just on  
[25:42] the mechanism alone, I mentioned it, it acts on 
glucagon. If you ask most people in the medical  
[25:51] field, they're like, "Oh, that's the drug we 
give to raise people's blood sugar." And except  
[25:59] that in this case, when you are depressing the 
lever for it for an extended period of time,  
[26:06] the opposite happens so it increases insulin 
sensitivity. It actually helps lower blood sugar  
[26:15] as counterintuitive as that sounds, but it also 
is... So I like to explain this as glucagon is  
[26:24] like a starvation signal to your body and you 
can, again, go back to maybe before clinical  
[26:31] trials were as ethical as they are now where 
we did starvation studies on live human beings,  
[26:38] but glucagon is the signal that comes through when 
people don't eat for a prolonged period of time,  
[26:43] their insulin levels drop, and it forces 
your body to start burning fat.
 
[26:50] Adam:
Right.
 
[26:51] David:
And so another way to put this,  
[26:54] so GLP-1 basically reduces your intake through 
appetite suppression and then glucagon's adding,  
[27:02] basically telling your body, "Hey, grab the 
firewood out back and throw that on as well."
 
[27:08] Adam:
Yeah. It's saying, "This is not a temporary  
[27:12] decline in available calories. This is winter, 
we're in this for the long haul, we need to adjust  
[27:17] our whole system to this new reality."
David:
 
[27:19] Yeah. So you get less intake and then you are 
burning more. And so that's obviously a recipe  
[27:26] for weight loss. And then side benefit, because 
you're burning lipids, that includes cholesterol  
[27:34] so you will see pretty profound, again, going 
back to some of the earlier data on that drug,  
[27:42] they saw almost 25% drop in LDL cholesterol, the 
bad cholesterol. That's what you would see with  
[27:48] taking a statin medication. So I look at it as, 
imagine if you could take a drug that makes you  
[27:54] lose weight and it drops your cholesterol like 
a statin. Again, on the economic argument-
 
[28:00] Adam:
Yeah.
 
[28:00] David:
... that's very compelling to me as  
[28:04] a clinician like, "Oh, hey, you can take this one 
drug once a week and that fixes what ails you."
 
[28:12] Adam:
Yeah. Awesome, so now  
[28:15] you've met Nurse David and he's going to be our 
guy watching the incretin space for a while here.  
[28:21] Check his blog and his socials in the description. 
There's clinical trials underway using these drugs  
[28:26] to treat major depressive disorder, bipolar, 
schizophrenia, alcohol and opiate addiction.  
[28:32] Like the man said, these drugs work on your 
brain more than they work anywhere else. Make  
[28:39] good choices with your brain and your body, 
and we'll talk about this stuff again soon.