Welcome to the deep dive. This is where we take
the sources you send us, jump right in and pull
out the key stuff, those aha moments you're looking
for. Yeah, making sense of complex topics fast.
Exactly. And today we're focusing on a medication
many people know or use. Citagliptin. You probably
know it as Genuvia, maybe Genumet. That's right.
We've gone through a lot of material clinical
studies, regulatory docs, market reports, to
really get a handle on this drug. Our listener,
the learner, this you, someone curious, wanting
the knowledge without drowning in data, ask us
to unpack Citagliptin. And we're ready to do
that. We'll look at its history, how it works,
its uses, how it's made, the rules around it,
and, well, the impact it's had. Okay, let's dive
in. Where did Citagliptin even come from? Well,
this story really kicks off back in the 1990s.
Scientists made a really key discovery. Oh, yeah.
What was that? They figured out that an enzyme
called dipeptidylpepsidase 4, or DPP4 for short,
was responsible for shutting down these hormones
called incretins. Incretins, like GLP1, I've
heard of that one. Exactly. GLP1 and another
one called GIP. These are super important for
managing blood sugar. Think of them as signals.
It signals. Yeah, they tell your pancreas, hey,
release some insulin, blood sugar's up. And they
also tell your liver to maybe chill out on making
more glucose. OK, so DPP4 stops these helpful
signals. Pretty much. It inactivates them. So
the thinking was, what if we could stop DPP4
from doing that? Could we keep those encretins
working longer? Ah, I see. the light bulb moment,
keep the good hormones active. Precisely. And
that led to the idea of DPP4 inhibitors drugs
designed to block that enzyme. Cidagliptin was
one of the first ones developed that you could
just take as a pill. Sounds great for now, but
I bet it wasn't quick. Oh, definitely not. Our
sources highlight that. turning that basic science
into an actual medicine that takes years. Lots
of research collaboration between universities
and drug companies, persistence. It's a long
road. Right. Citigliptin and others like it finally
got regulatory approval and hit the market, mostly
between 2006 and 2013. OK, so that's the why.
Now, for the learner out there, maybe taking
it or knowing someone who does. Yeah. How does
it actually work? So at its core, it does exactly
what we just talked about. It slows down that
DPC4 enzyme. By inhibiting it. Yes. Stay active
longer. And what does that do for blood sugar?
It has a really neat dual effect. First, higher
levels of active GLP -1 and GIP mean more insulin
release from the pancreas. But, and this is important,
it's glucose dependent, meaning It mostly ramps
up insulin release when your blood sugar is actually
high. It's not just pushing insulin out all the
time. OK. That sounds smart. Prevent lows, maybe?
That's a big part of it. The second effect is
it lowers glucagon secretion. Glucagon is the
hormone that tells the liver to make more glucose.
So less glucagon means less glucose production
from the liver. Got it. So smarter insulin release,
less liver glucose. Makes sense. You mentioned
selectivity earlier. Right. At the usual doses,
citaglyptin is much better at targeting DPP4
than some related enzymes, like DPP8 or DPP9.
That selectivity is thought to help with its
safety profile. And the low blood sugar thing,
hypoglycemia. Yeah, that's a key point. On its
own, cytaglyptin has a low risk of causing hypoglycemia
because its action is tied to glucose levels.
Now if you take it with something like a sulfonylurea
or insulin... Then the risk goes up. Then the
risk can increase, yes. Because those other drugs
can lower blood sugar independently, so... Doctors
might need to lower the dose of the sulfonylurea
or insulin in that case. Makes sense. And interestingly,
when you take it with metformin, another really
common diabetes drug, studies show it actually
boosts the levels of active GLP -1 even more,
an additive effect. Huh. Anything else on how
it works? What about the heart checks? Oh, right.
The ECG studies. They looked at the heart's electrical
rhythm, specifically the QTC interval, and found
no significant changes at therapeutic doses.
That was important for safety assessment. Good
to know. Okay, so we understand how it works.
What happens in the body after someone swallows
the pill? The pharmacokinetics. Right, how the
body handles it. Well, it gets absorbed pretty
quickly. You usually see peak levels in the blood
within about, say, one to four hours. Does food
affect it much? Not really significantly. Maybe
slows absorption just a tiny bit, but the overall
amount absorbed is similar. Studies in healthy
folks give us numbers, like a 100 -milligram
dose gives a total exposure, the AUC around 8
.5 micromolar hour, peak level around 950 nanomolar.
And the half -life. How long does it stick around?
The half -life is about 12 .4 hours. Ah, okay.
That explains the typical one -to -day dosing.
Exactly. And the more you take, the higher the
levels, pretty much dose proportionally. It also
seems the body handles it similarly whether you're
healthy or have type 2 diabetes. How does the
body get rid of it? Metabolism? Excretion? It's
not heavily metabolized, actually. Some breakdown
happens via liver enzymes. CYP3A4 and CYP2C8
are the main ones, but it's limited. So mostly.
Mostly it's cleared out by the kidneys. About
87 % of the dose comes out in the urine, largely
unchanged. It uses active transport systems in
the kidneys to get there. Okay, kidneys. That
sounds critical for people with kidney problems.
Absolutely critical. If your kidney function
is reduced, the drug can build up, so dose adjustments
are really important. How do they figure that
out? Based on kidney function tests, specifically
the EGFR estimated glomerular filtration rate.
There are specific guidelines. If your EGFR is
say between 30 and 45, the dose is usually half
to 50 milligram daily. And if it's lower? Below
30 or if someone's on dialysis, the dose typically
drops to 25 milligrams daily. It's worth noting,
dialysis does remove some sitagliptin, maybe
around 13 .5 % in a typical session, but the
lower daily dose is still needed. Really crucial
info for doctors and patients. Okay, let's switch
gears to how it's actually used. Clinical applications.
Its main job is helping control blood sugar in
adults with type 2 diabetes, alongside diet and
exercise, of course. And you take it by itself.
You can, yes, as monotherapy if lifestyle changes
aren't enough. But honestly, it's very often
used in combination with other diabetes meds.
Like Metformin. Metformin is a very common partner,
but also sulfonylerias, pioglitazone, even insulin.
The goal is better overall glucose control. And
does it work well? What do the studies show?
Yeah, clinical trials consistently show it lowers
HbA1c, which is that key measure of long -term
blood sugar control. How much? As monotherapy,
usually around 0 .5 % to 1 .0 % reduction. Added
cement formin, maybe a bit more, like 0 .6 %
to 1 .1%. And interestingly, people starting
with higher A1c levels tend to see a bigger drop.
Does it help with both fasting and after meal
sugar? Yes, it helps lower both fasting glucose
and those post meal spikes. What about weight?
is a concern with diabetes meds. That's actually
one of Cytagliptin's selling points. It's generally
weight neutral. Meaning it doesn't cause weight
gain? Right. Unlike some older drugs like sulfonylureas
or TZDs, which often cause weight gain. Now,
it's also different from some newer classes like
GLP -1 agonists or SGLT -2 inhibitors, which
can actually lead to weight loss. But for many,
just not gaining weight is a win. Yeah, definitely.
So low hypoglycemia risk when used alone. weight
neutral. Sounds pretty good. How well do people
tolerate it generally? Generally well tolerated
in trials across different ages and BMIs. There
was even a study looking specifically at patients
with mild kidney problems. Oh, yeah. Compared
to another drug, Dapaglucin, Citagliptin actually
showed better glycemic control in that group
and was still well tolerated. Interesting. And
adding it to metformin and insulin, studies showed
that combo led to significantly better A1C reductions
and helped more people reach that target A1C
of less than 7%. OK, that paints a good picture
of its use. Now, a quick look behind the scenes.
How do they actually make this stuff? Manufacturing.
It's evolved over time, become more efficient.
The current main process involves basically three
key chemical steps. Well, three main transformations.
First, forming something called an enamine. Then,
the really crucial step, asymmetric hydrogenation.
Sounds complex. It uses a special catalyst to
make sure the molecule has the exact right 3D
shape. That shape is vital for it to work in
the body. It's very selective, makes the right
version. They're over chemistry. Yeah, and they've
figured out how to recycle a lot of that expensive
catalyst, which is good for costs and, you know,
sustainability. The final step is turning it
into a stable phosphate salt. That's what's in
the pill. Fascinating. OK, let's talk regulation.
Approvals, safety issues, legal stuff. What's
the story there? It got the green light from
major agencies like the FDA in the US back in
2006 and the EMA in Europe. And like all drugs,
it's been watched closely ever since it hit the
market post -marketing surveillance. Keeping
an eye out for problems. Exactly. Looking at
safety and effectiveness in the real world over
the long term. Studies in Japan, for instance,
have provided good long -term data. Have there
been any significant safety flags or controversies?
Yes, there have been a few things over the years.
Pancreatitis was one of the early ones. Inflammation
of the pancreas. Right. There were reports after
it launched, including some serious cases. FDA
analysis suggested maybe a higher reporting rate
compared to some other drugs. Did the big trials
confirm that? The big TACOS trial that was its
cardiovascular safety study didn't find a statistically
significant increase with cytagliptin itself.
But looking at the whole class of DPP4 inhibitors
together, a meta -analysis did suggest a small
increased risk. So what's the situation now?
There are warnings about pancreatitis on the
label. Doctors are told to stop the drug if it's
suspected. Any other major concerns? Pancreatic
cancer was mentioned sometimes. Yeah, that came
up partly linked to the pancreatitis concerns.
But again, the TACOS trial actually had slightly
fewer cases in the cytogliptin group, though
not statistically significant. And bigger analyses
haven't found a clear link, but, you know, they
keep monitoring. What about heart failure? That's
been an issue for some diabetes drugs. It has.
Some other DP3 -4 inhibitors did show an increased
risk in their big trials. But the TECOS trial,
specifically for citagliptin, did not find an
increased risk of hospitalization for heart failure.
OK, that's reassuring for citagliptin itself.
It is. But the label still advises caution, telling
doctors to weigh risks and benefits in patients
who already have heart failure risk factors.
Makes sense to be cautious. Anything else? A
few other things flagged by regulators based
on post -marketing reports. Severe joint panarthralgia.
The FDA noted this could happen with any DPP4
inhibitor. Usually goes away if you stop the
drug. Ouch. Also, a rare autoimmune skin condition
called bullis pemphigoid. Reports led to label
warnings. Serious allergic reactions, hypersensitivity
have also been reported. And kidney issues. Acute
kidney problems, sometimes needing dialysis,
were reported, especially in people who already
had kidney issues and weren't on the right. Adjusted
dose. Underscores the importance of correct dosing
we talked about earlier. Absolutely. And more
recently, in 2022, there was the issue with NTTP,
a type of nitrosamine empiric - found in some
batches. I remember hearing about nitrosamines
in other drugs too. Yeah, it's been an issue
across the industry. Health authorities assessed
the immediate risk as low, but allowed slightly
higher temporary limits to avoid shortages, while
the manufacturer fixed the process to meet the
strict long -term limits. Quite a regulatory
journey. What about patents and generics? That
must be a big factor now. Huge factor. The main
patent on the Cytaglyptan molecule itself actually
expired in the U .S. in January 2023. So generics
should be everywhere now. Well, not quite in
the U .S. Merck, the original maker, has another
patent on the specific phosphate salt form used
in Genuvia and Janumet. And through lawsuits
and settlements, they've managed to keep exclusivity
for those brands until May 2026 in the U .S.
Janumet XR lasts until July 2026. Interesting.
So a later patent is keeping the generics at
bay for a bit longer there. Essentially, yes.
Though the FDA has approved a generic version,
it's one that pharmacists can't automatically
substitute. Merck themselves expect price and
volume to drop in the U .S. during 2024 as that
date gets closer. What about outside the U .S.?
Different story. Generic Citiglipton has been
available in Europe since late 2021, early 2022.
And competition is happening in China, too. That's
definitely hitting the branded sales in those
regions. Which leads us straight to the economic
impact. It sounds like Genuvia Janumet was a
massive product for Merck. Oh, absolutely. A
true blockbuster. It was their top selling drug
for a while. Peak sales for the franchise were
around $9 .2 billion globally in 2020. Wow. But
declining now. Yeah, the trend is downward, still
significant revenue, like $3 .4 billion in 2023,
but definitely declining. And that's mostly down
to the patent explorations and generic competition.
That's the main driver, especially where generics
are already launched, but also increasing competition
from newer diabetes drug classes, general pricing
pressures. Maybe the nitrosamine issue had some
small impact, too. But the U .S. market is still
holding up relatively well because of that extended
patent protection. For now, yes, that U .S. market
is crucial for its remaining sales, though even
there, as we said, they expect erosion. We also
see different trends regionally, like sales are
still growing in Japan recently. How do analysts
track all this? They use various models looking
at correlations, regressions, time series analysis
to try and understand the market dynamics and
predict future sales. The market itself is broken
down by dosage form two, catering to different
patient needs. And the DPP4 class overall. Still
important. Definitely. Despite newer options,
DPP4 inhibitors like citagliptin are still considered
a cornerstone treatment for type 2 diabetes by
many, largely because they work well and have
that low risk of hypoglycemia when used alone.
Okay, last area. Cultural influence. How has
a drug like sitagliptin shaped things beyond
just the pharmacy shelf? Well, think about it.
It's a widely used pill for a very common chronic
disease. That alone gives it a huge impact on
how type 2 diabetes is managed globally. The
convenience factor. Yeah, the once -daily oral
dose probably helps a lot with people actually
taking their medication, regular adherence, we
call it. And its success probably spurred more
research. For sure. The focus on DPP4 as a target
definitely encouraged more research and development
in that whole class of drugs. and the safety
discussions we had. pancreatitis, heart failure
signals. Right. Those controversies have absolutely
influenced treatment guidelines and how closely
doctors monitor patients on these drugs now.
You see information about it everywhere, too.
Exactly. Websites like Medline Plus, the drug
zone website. It reflects how many people use
it and need reliable information. Even things
like Merck's investor reports. Highlighting its
financial importance. Yes. And showing the real
world business impact of patent clips and competition.
And finally, programs like patient assistance
programs, trying to get the drug to people who
can't afford it, that speaks to a broader societal
role in healthcare access. Okay, so summing it
all up. Citagliptin, a DbP4 inhibitor, really
changed the game in type 2 diabetes management.
It works by boosting in cretins, improving insulin
release smartly, and lowering glucose production.
Right. It became a massive commercial success,
but now faces the inevitable decline due to patent
expirations and competition. And its journey
has been marked by important safety evaluations
that continue to shape how it's used. Absolutely.
This deep dive aimed to give you... our learner,
that comprehensive picture based on the sources,
a shortcut to getting up to speed on this significant
medication. Hopefully we've achieved that, pulling
together the science, the clinical use, the business
side. And for a final thought, something for
you to consider. We see all this ongoing research,
newer diabetes drugs coming out with different
mechanisms, some even showing direct heart benefits.
So how do you think the role of DPP4 inhibitors
like cytagliptin might shift or evolve in the
future of diabetes care? Yeah, where will they
fit in five, 10 years from now? It's a really
interesting question to keep in mind. Definitely
something to mull over. Thanks for joining us
on this deep dive.