Welcome to the Deep Dive. Today we're taking
a close look at liraglutide. It's a really interesting
drug involved in managing both weight and blood
sugar. Yeah, and you know, with all the buzz
around newer weight loss meds lately, it feels
like a good time to explore one of the, well,
foundational players in this space, understand
its story. Exactly. So for this deep dive, we've
pulled together quite a bit of material. clinical
reviews, scientific papers on its discovery,
pharmacology. How it's made, the regulatory side
of things, even analyses looking at its economic
and social effects. It's pretty comprehensive.
Definitely. So our mission today is basically
to unpack liraglutide. What is it? How does it
actually work? How did we get from discovering
the basic science to using it in clinics? And
what's the bigger picture? It's wider impact.
Right. OK, let's get into it. Where do we start?
The history, I suppose. Yeah, I think to really
grasp lyrical glutide, you have to go back, way
back actually, to the discovery of incretins.
Think 1902. 1902. Yeah, Bayless and Starling.
They found this chemical substance from the intestine
that could stimulate the pancreas. They didn't
call it incretin yet, but that was the seat.
OK, so that's the very beginning. And then things
picked up later with specific hormones. Right.
Fast forward to the late 60s. And GIP gastric
inhibitory polypeptide gets identified. That's
one of the two big incretins we know. But not
the only one. No, exactly. By the early 80s,
researchers were pretty sure there was something
else. Intestinal extracts still boosted insulin
even when GIP was removed. Ah, so the hunt was
on for the other player. Pretty much. And then
in 83, Graham Bell in Chicago cloned the hamster
pre -proglucogon gene. And inside that sequence?
Was GLP -1. Bingo. Well, the blueprint for GLP
-1 and GLP -2, actually. Got it. So the genetic
code pointed the way, but which specific piece
was the active hormone? Well, initially they
thought it was a longer version, GLP -1 -137,
but then two groups, Joel Heydner in Boston and
Jens Juhl -Holst in Copenhagen, figured out it
gets processed. Processed into shorter forms.
Yeah, into GLP -1 -7 -37 and GLP -1 -7 -36 amide.
Those are the active ones, the ones that really
trigger insulin release. It's amazing how those
little tweaks make all the difference biologically.
Now, you mentioned something earlier about some
mouse studies that were maybe a bit confusing.
Ah, yes, that's a good point. The GLP -1 receptor
knockout mice. So mice engineered without the
receptor. You'd expect big problems with glucose
and weight, right? You would think. Yeah. But
surprisingly, their phenotype, their observable
traits, were relatively mild regarding glucose
metabolism and body weight. Huh. That's unexpected.
It really is. It just shows that sometimes you
don't see the full picture until you study it
in humans, you know. So those early human studies
were really crucial then. What did they show?
Absolutely critical. In 1987, Crayman and his
team showed definitively, yes, GLP -1 is an incretin
in humans. OK, proof in people. And then in 92,
gutniac at all. showed its potential against
diabetes. Not just type 2, but surprisingly it
showed some effect in type 1 as well. That was
big. That really set the stage and these studies
started revealing the key advantages we see today.
Exactly. Two major things stood out early on.
First, the insulin secretion was glucose dependent.
Meaning it only kicks in when blood sugar is
high. Precisely. Which means a much lower risk
of hypoglycemia, you know, dangerously low blood
sugar. That was a huge advantage over older drugs.
Makes sense. And the second thing... The glucagonostatic
effect. It suppresses glucagon. Glucagon tells
the liver to make sugar, right? Right. So by
suppressing glucagon, it helps lower the liver's...
Glutose production, so you get this dual benefit,
more insulin when needed, less glucose production
from the liver. Very promising for type 2 diabetes.
Okay, so we have the hormone, GLP -1, and we
know it works well in humans. But the big problem
was, it disappears really fast in the body. Native
GLP -1 has a half -life of just a couple of minutes.
Totally impractical as a drug you'd inject. So
how did they solve that? This is where liraglutide
itself starts to emerge, right? This is where
the clever chemistry comes in. Around 2000, Knudsen
and his team published work on designing GLP
-1 derivatives that could last long enough for
once daily dosing. And their trick was? Fatty
acid derivatization. Basically, attaching a fatty
acid chain to the GLP -1 molecule. Okay, why
do that? That fatty acid acts like a handle,
allowing the modified GLP -1 to bind to albumin.
Albumin, the main protein in blood plasma. Exactly.
By hitching a ride on albumin, The drug is shielded
from the enzymes that normally chew up GLP -1
very quickly, and it gets filtered out by the
kidneys much slower. So it's like giving it a
protective disguise and making it too big to
get kicked out easily. That's a great way to
put it. And that study specifically mentioned
the peptide that became liraglutide as a really
promising candidate. And they kept refining this
idea. Oh yeah. A 2007 paper by Madsen's group
dug deeper into the structure -activity relationship.
They looked at how the length of the fatty acid
chain and the space were connecting it to the
peptide. How those details affected how well
it worked and how long it lasted. Exactly. It
was all about finding the sweet spot, good binding
to the GLP -1 receptor, but also strong enough
reversible binding to albumin for that long duration.
A real molecular balancing act. It really was.
And a 2005 paper also involving Biara Knudsen,
really nailed down that reversible albumin binding
as the key mechanism for extending the action.
That paved the way for Lyraglutide. Such a cool
journey from basic physiology to drug design.
Okay, so we have Lyraglutide. Let's shift to
how it's actually used now. What are the main
approved uses? Right, so Lyraglutide... Being
a GLP -1 receptor agonist has two main jobs,
therapeutically speaking. First, improving glycemic
-controlled blood sugar in adults and also kids,
usually 10 or 12 and up, depending on the brand,
with type 2 diabetes. And that's always alongside
lifestyle change. Always. Diet and exercise are
fundamental. It's an adjunct therapy. OK, so
that's rule number one. Diabetes management,
what's the second? Chronic weight management.
It's approved for adults who are overweight,
so a BMI of 27 or more, with a weight -related
health issue, like high blood pressure or cholesterol.
or adults with obesity, which is generally a
BMI of 30 or more. And for kids too. Yes. Also
for adolescents 12 to 17 who have obesity and
weigh over 60 kilograms. And again, it's meant
to be used with a reduced calorie diet and more
physical activity. It's interesting that BMI
criteria differ slightly depending on comorbidities.
Suggests the risk -benefit calculation changes.
It does. And, you know, it's not the only drug
option for weight management. In Canada, for
instance, you also have Orlistat and the Naltrexonobupropion
combo. Lyraglutide is one. tool in the toolbox.
Our clinical expert really stressed the need
for a multi -component approach for obesity.
Why is just diet and exercise often not enough
long -term? Well, lifestyle changes, diet, activity,
behavioral strategies, they absolutely should
be the first line. They can work. But the reality
is sustaining significant weight loss long -term
with just lifestyle changes is incredibly difficult
for many people. The body fights back, right?
Compensatory mechanisms kick in. Precisely. Metabolism
might slow down. Hunger hormones can increase.
So weight regain is very common, unfortunately.
And that's where medications like liraglutide
can potentially help. Yes, they can be a really
valuable addition. They can help people achieve
more weight loss initially and maybe more importantly
help maintain it. Our expert noted that even
losing 5 to 10 kilos, which might sound modest,
can bring clinically meaningful improvements
in things like cholesterol and blood pressure.
So if someone starts sex endo, the weight management
version, what's the dosing like? Is it straightforward?
It's a gradual process. You start low, typically
0 .6 milligrams injected once a day. OK. Then
you increase the dose each week, usually by 0
.6 milligrams over about four weeks, until you
reach the target maintenance dose of 3 milligrams
daily. Why the slow ramp up? Mainly to help manage
side effects, particularly nausea, which can
be common at the beginning. It gives the body
time to adjust. Makes sense. And is there a checkpoint,
a time to see if it's actually working for that
person? Yes, there is. Generally, after someone's
been on the full three milligram dose for 16
weeks, so about four months, you assess their
weight loss. And what's the benchmark? If they
haven't lost at least 4 % of their initial body
weight by that point, the guidelines suggest
it's less likely they'll get a significant long
-term benefit, and stopping the medication should
be considered. That's a useful, practical guideline
for decision -making. What about using it in
type 2 diabetes? Is it often combined with other
meds? Oh, absolutely. The Big Phase 3 trials
showed it works well in combination with many
standard diabetes drugs. Metformin, sulfonylureas,
TZDs, even basal insulin. So it's quite versatile
in fitting into different treatment regimens.
Very much so. It shows it can be useful at various
stages of type 2 diabetes management. And beyond
just lowering blood sugar in those patients,
did the trials show other benefits? Yes, and
this is quite important. In people with type
2 diabetes, laryl glutide was also shown to help
with weight reduction, lower systolic blood pressure,
and there's even evidence suggesting it might
improve the function of the pancreatic. beta
cells, the insulin producers. Those are significant
extra benefits, like pleiotropic effects. Exactly.
It adds to its value in managing such a complex
disease. I also recall something about pre -diabetes,
preventing the progression. Yes. An extension
phase of one of the big studies, study 1839,
found that the three milligram dose of liraglutide
was significantly better than placebo at delaying
or even preventing the progression from pre -diabetes
to full -blown type 2 diabetes. That's potentially
huge for early intervention. It really is. Yeah.
Suggests a role for people at high risk. Our
expert also mentioned using it around bariatric
surgery. Yeah, that was interesting. Apparently,
it's sometimes used before surgery, but more
often after. especially if someone starts regaining
weight, which can happen. The 3 -milligram dose
is used to help manage that post -surgical regain.
underscores that weight management is often a
long -term challenge, even after surgery. The
expert also made a point about when to consider
medication, not necessarily just as a last resort.
That's right. While lifestyle is the foundation,
pharmacotherapy like liraglutide can be considered
earlier, especially for people with higher BMIs
or those who've tried lifestyle changes but haven't
been able to sustain the loss. Because of those
compensatory mechanisms we talked about. Exactly.
The long -term data for just lifestyle interventions
can be a bit discouraging because the body adapts.
But, and this is crucial, liraglutide for weight
management should always be combined with ongoing
lifestyle efforts. They work together. Makes
sense. What about combining liraglutide with
other weight loss drugs, like or Eulastat or
Naltrex and Dupropion? Is that done? Well, combination
therapy is standard practice in things like type
2 diabetes or high blood pressure. But for weight
loss, specifically combining liraglutide with
those other drugs, there isn't a lot of strong
evidence supporting it right now. So not a routine
thing, maybe more of an individual clinical decision?
Pretty much. Some doctors might try it based
on the different ways the drugs work, but we
need more research to really know if it's effective
and safe routinely. Okay. Let's dig into the
clinical trial evidence a bit more, especially
for weight loss. You mentioned some key studies.
Yes. The review highlighted four major Phase
III trials. Study 1839, 1922, 1923, and 3970.
These were large, well -conducted studies. What
were the key features? They were all randomized,
double -blind, placebo -controlled, multi -center,
The gold standard, really, involved over 5 ,000
adults in total, conducted internationally, including
Canada. And the main takeaway on weight loss.
Across the board, Lear Glutide 3 mg led to significantly
greater weight loss than placebo. This held true
whether people had diabetes or not, had pre -diabetes,
or even obstructive sleep apnea. And this was
always compared against placebo plus lifestyle
advice. Yes. Both groups got advice on diet and
exercise. but the liraglutide group consistently
lost more weight. And we're talking clinically
meaningful amounts, not just a kilo or two. Definitely.
The odds of achieving at least a 5 % weight loss
and also more than 10 % weight loss were significantly
higher with liraglutide compared to placebo.
Can you give an example, like how much more weight
loss? Sure. In study 1839, after 56 weeks, the
average weight loss in the liraglutide group
was about 5 .6 kilograms more than in the placebo
group. So a noticeable difference. How did it
stack up against something like arelastat? Were
there comparisons? There weren't many direct
head -to -head trials, but network meta -analyses,
which kind of compare treatments indirectly using
common comparators like placebo, suggested lower
glutide 3 milligram was better than orlastat
for achieving that bigger target, like 10 % weight
loss. OK, so potentially more effective in those
analyses. Yes, greater weight loss over placebo
compared to orlastat. However. There's always
a however. Right. Those same analyses suggested
people were more likely to stop liraglutide due
to side effects compared to oralist death. Ah.
So a trade -off perhaps between efficacy and
tolerability for some people. It often is. Balancing
how well it works with how well someone feels
on it is key. Did the trials look at quality
of life? Did losing weight with liraglutide make
people feel better in broader terms? They did
measure it. using questionnaires like the IWQOL
light, which is specific to weight's impact on
life quality. Yeah. There were some improvements
seen in the lower glutide groups, but honestly,
the results were a bit mixed. Sometimes the differences
weren't statistically significant after they
adjusted for all the comparisons being made.
So not a clear home run on the quality of life
measures. Not consistently. Across all studies
and all measures, no. Results from more general
scales like the SF -36 were also a bit inconsistent.
It suggests weight loss and metabolic improvements
don't automatically translate perfectly to these
broader QL scores in trial settings. Interesting.
What about lipids? Cholesterol? Triglycerides?
Yeah, they track those. There were some statistically
significant changes, especially triglycerides
tended to improve. But our clinical expert source
felt the changes seen in LDL cholesterol specifically
weren't really large enough to be considered
clinically meaningful on their own. Good point.
Statistical significance versus clinical relevance.
Now we have to acknowledge the newer GLP -1 drugs
like semaglutide. How does the liraglutide compare
there? Right. The landscape is evolving fast.
There was a head -to -head trial comparing semaglutide
2 .4 milligrams weekly. to liraglutide 3 mg daily.
And the results? Semaglutide came out significantly
ahead on weight loss. Average was about 15 .8
% loss with semaglutide versus 6 .4 % with liraglutide
at 68 weeks. Wow, that's a substantial difference.
It is. Interestingly, the proportion reporting
GI side effects was similar, but more people
actually stopped taking liraglutide in that specific
trial. for various reasons. Shows the progress
being made in this drug class. You also mentioned
an ICER report. What did they conclude about
liraglutide's value? ICER, the Institute for
Clinical and Economic Review, they do these assessments
of clinical effectiveness and value. They compared
Saxinda liraglutide to other obesity treatments,
including the newer GLP -1s and older meds. Aiming
for a comparative picture of benefits and costs.
Exactly. Trying to provide context for decision
-making about which treatments offer the best
value for patients and the healthcare system.
Okay, that covers the clinical picture well.
Let's switch gears to how it works, the mechanism
of action. What's liraglutide actually doing
in the body? So at its core, it's a GLP -1 receptor
agonist. It mimics the action of our natural
GLP -1 hormone by binding to and activating the
GLP -1 receptor. And these receptors are found
in various places. Yes, key locations include
the pancreas and the brain. Let's start with
the pancreas. What happens there? Activating
GLP -1 receptors on pancreatic beta cells stimulates
them to release insulin. But as we mentioned,
it's glucose dependent. Only when sugar is high.
Right. So it helps lower blood sugar after meals,
for instance, without driving it too low otherwise.
It also suppresses glucagon release from alpha
cells in the pancreas. The double whammy for
glucose control we talked about. Exactly. Now
in the brain. This is for the weight effect.
Yes. GLP -1 receptors are present in brain regions
that control appetite and satiety, that feeling
of fullness. So activating those receptors tells
your brain you're full. Essentially, yes. It
promotes satiety, reduces hunger, and that leads
to eating less, lower energy intake, and ultimately
weight loss. So pancreas for sugar, brain for
weight. Are there other potential brain effects
being explored? There is ongoing research, yeah.
Looking into potential neuromodulatory roles,
could GLP -1 signaling affect things like neurodegenerative
diseases, Alzheimer's, Parkinson's, maybe mood
disorders, addiction? Wow, really broad potential.
It is, but still very much in the research phase
for those areas. There's a lot more investigation.
What about the heart and blood vessels? I saw
mentions of cardiovascular effect. Yes, this
is a really important area. GLP -1 receptors
are found on heart cells, blood vessel walls,
immune cells, even in the kidneys. Suggesting
multiple ways it could be protective. Potentially,
yes. The mechanisms aren't fully mapped out,
but several things seem to happen. Like what?
Improving endothelial function. The health of
the blood vessel lining. It seems to boost nitric
oxide, which helps vessels relax. Better blood
flow. Right. And it might inhibit endothelin
1, which constricts vessels. There's also some
animal data suggesting anti -atherogenic effects
may be slowing down plaque buildup in arteries.
Does this translate clinically? We mentioned
blood pressure and lipids earlier. We do see
those improvements in risk factors. Lower vasolic
blood pressure better triglycerides. There's
also a theory it might help heart muscle cells
use energy more efficiently. But there was that
point about heart rate. Yes. One consistent finding
is a small increase in resting heart rate in
some patients. The clinical significance of that
long term is still debated and being studied.
So, a complex picture with effects across multiple
systems. Let's talk about how the body handles
the drug itself. Pharmacokinetics, pharmacodynamics,
how quickly is it absorbed? After you inject
it subcutaneously, it's absorbed pretty slowly.
Cake levels in the blood usually occur between
8 and 12 hours later. And that slow absorption
is part of why it lasts long? It contributes,
yes. The bioavailability how much actually gets
into circulation is estimated around 55%. Is
that slow absorption related to the drug structure?
Yes, partly. The lyric glutide molecules can
actually clump together self -associate, at the
injection site. These clumps then slowly break
apart, releasing the drug gradually for absorption.
Interesting. Once it's in the blood, where does
it go? Does it spread everywhere? Not really.
It binds very strongly to plasma proteins, mostly
albumin over 98 % bound. Ah, back to the albumin
binding. Exactly. And because it's so tightly
bound, it mostly stays within the bloodstream.
It doesn't distribute widely into other tissues.
Okay, so it circulates bound to albumin. How
does the body get rid of it eventually? It's
broken down, metabolized, similarly to how the
body breaks down large proteins. Enzymes like
DBP -IV and NEP are involved. But slower than
they break down natural GLP -1. Much slower because
of the modifications made to liraglutide. The
breakdown products are only found in tiny amounts
and eventually it's completely degraded into
amino acids. So it's not mainly cleared by the
kidneys or liver directly sending the whole drug
out? No. The main route is this metabolic degradation.
very little unchanged drug shows up in urine
or feces. The clearance rate is low, and the
elimination half -life is long, around 13 hours.
Then that 13 -hour half -life is what allows
for the once -daily dosing. Precisely. It sticks
around long enough. Understanding that PKPPP
profile is definitely key for using it effectively.
Okay, let's shift to manufacturing. Making this
stuff must be complicated. It really is. Lyraglutide
is a fairly large peptide with that fatty acid
chain attached. Acetylated peptide synthesis
is complex and generally expensive. Requires
specialized expertise. Absolutely. Companies
like Badgem, who are experts in peptide manufacturing,
were key partners in figuring out how to produce
it at scale. It highlights the role of these
specialist CDMOs, contract development, and manufacturing
organizations. So it's not like stamping out
simple pills. Not at all. use fragment -based
approaches, making smaller pieces of the peptide
separately, then carefully linking them together
and finally adding the fatty acid bit. Lots of
precise steps and purification needed. Sounds
very high -tech. Fits with the broader trend
of more complex biologic drugs. Now, the regulatory
side. We know it's approved, but what was the
journey like? Any bumps? Well, it gained approvals
initially as Victoza for diabetes, then Sexenda
for weight management, through the standard regulatory
processes in the U .S., Europe, and elsewhere.
A big recent development was the FDA approval
of the first generic liver glutide injection
in December 2024. Generics usually mean better
access and lower costs eventually. Typically,
yes. However, the journey wasn't entirely smooth.
There was a significant legal settlement in 2017.
Right. You mentioned that. What was it about?
Novo Nordisk paid about $58 .6 million to the
U .S. government to settle allegations involving
the False Claims Act and the Food, Drug and Cosmetic
Act. What were they accused of? The main issue
was around compliance with the FDA -required
REMES program, that's Risk Evaluation and Mitigation
Strategy for Fictosa, between 2010 and 2014.
And the problem was? The government alleged that
the company's sales reps were trained to downplay
or obscure the risk of medullary thyroid carcinoma,
MTC, which is a serious potential risk noted
in the boxed warning and REMES materials. So
basically allegations that the safety message
wasn't being delivered properly to doctors. That
was the core allegation. Things like telling
doctors the MTC risk was just in rodents or easily
treatable, which allegedly misrepresented the
FDA approved warning. That's serious. Did the
settlement cover anything else? Yes. It also
resolved allegations of illegal off -label promotion
marketing Victoza for uses it wasn't approved
for at the time, like weight loss before Saxenda
was approved or for type 1 diabetes. And Novo
Nordisk's position. They denied wrongdoing, but
agreed to the settlement to resolve the matter.
It definitely underscores how critical, accurate
risk communication is. Absolutely. And it's approved
in Europe, too. Yes. The EMA approved Saxenda
for weight management across Europe. Both Victoza
and Saxenda are registered trademarks of Novo
Nordisk. OK, let's talk economics. This strike
has been around a while. It must have made a
significant impact financially. Oh, definitely.
It's been a major product for Novo Nordisk. Market
reports consistently show a large market for
liraglutide and project continued growth for
this whole class of drugs. How is the market
broken down? You can look at it by brand Victoza
versus Xenda and by distribution channels like
hospital pharmacies, retail, online pharmacies.
And how does liraglutide fit into the bigger
picture of the pharma market, especially diabetes
and obesity? It's been a huge part of the massive
growth in the GLP -1 agonist market overall.
Some analysts compare the potential impact of
these drugs on obesity to what statins did for
heart disease. A potential game changer. That's
the view. There's a strong belief that GLP -1s
are becoming, and will continue to be, a major
force in healthcare economics and treatment paradigms.
Fascinating how science translates to market
forces. Lastly, let's touch on the cultural side.
How are drugs like liraglutide influencing how
we think about weight? It's complicated, really.
On one hand, having effective medical treatments
could help shift the view of obesity away from
being just a matter of willpower. Towards seeing
it more as a treatable medical condition. Exactly.
That could potentially reduce weight stigma,
which is a huge problem. But there's a potential
downside. Yes. Access is a big issue. These drugs
are expensive. Insurance coverage varies wildly.
So... There's a risk it could actually worsen
stigma if only wealthier people can access them,
creating a kind of bias against those who can't
afford treatment. A potential new layer of inequality.
Potentially. And there's also the idea mentioned
in some sources that people using these drugs
might face stigma for taking the easy way out,
similar to negative attitudes sometimes seen
towards bariatric surgery patients. So we need
to be really careful about access and messaging.
Patient groups often report facing stigma already,
right? Absolutely. Significant social stigma
exists. impacting everything from employment
to healthcare interactions. People report feeling
shamed by doctors, sometimes avoiding care altogether.
There's still this pervasive misunderstanding
of obesity as purely self -inflicted. It's a
really complex intersection of medicine and societal
views. Okay, we've covered so much. Before we
wrap up, let's quickly hit the key safety points
for liraglutide. Right. Most common side effects
are GI issues. Nausea is very frequent, especially
when starting or increasing the dose. Vomiting,
diarrhea, constipation can also happen. Those
are the common ones. What about more serious
potential risks? Hypoglycemia, low blood sugar
is a risk, but mainly when it's used with other
drugs that also lower sugar, like sulfonylureas
or insulin. Dose adjustments might be needed
then. What else? That increase in resting heart
rate we mentioned needs monitoring. There have
been post -marketing reports of kidney problems.
sometimes linked to dehydration from the GI side
effects, and hypersensitivity reactions, though
rare, can occur. So monitoring is key, especially
kidney function, if someone has bad GI side effects.
Definitely. Patients need to know the signs of
hypoglycemia, too. And doctors need to be cautious
with patients who already have kidney issues.
All the details are in the official warnings.
What about the pancreatitis concerns that came
up early with GLP -1 drugs? That's a good point.
There were initial concerns based on other drugs
in the class, but specific large animal safety
studies on liraglutide in rats, mice, monkeys
didn't find evidence of pancreatitis at clinically
relevant doses. That was reassuring. Good to
know. Well, this has certainly been a comprehensive
deep dive. It really has. We've traced liraglutide
from those early in cretin discoveries all the
way to what's used today for diabetes and obesity.
We've looked at how it works, how the body handles
it, manufacturing, the regulatory path, economic
impact, and even how it intersects with cultural
views on weight. And it's clear that while it
offers real benefits, there are important things
to consider side effects, access issues, societal
perceptions. Absolutely. Which leads us to a
final thought for you, our listener, to maul
over. As these kinds of medications become more
common, How is our whole approach to chronic
conditions like obesity and type 2 diabetes going
to change? What are the bigger societal questions
we really need to grapple with? A really important
question. We hope this discussion gave you a
solid foundation. We definitely encourage you
to explore the sources and keep thinking about
this interception of science, medicine, and society.
Thanks for joining us on the Deep Dive.