Endocrinology and Metabolism,
Год журнала:
2024,
Номер
39(2), С. 206 - 221
Опубликована: Апрель 16, 2024
Obesity
is
a
significant
risk
factor
for
health
issues
like
type
2
diabetes
and
cardiovascular
disease.
It
often
proves
resistant
to
traditional
lifestyle
interventions,
prompting
need
more
precise
therapeutic
strategies.
This
has
led
focus
on
signaling
pathways
neuroendocrine
mechanisms
develop
targeted
obesity
treatments.
Recent
developments
in
management
have
been
revolutionized
by
introducing
novel
glucagon-like
peptide-1
(GLP-1)
based
drugs,
such
as
semaglutide
tirzepatide.
These
drugs
are
part
of
an
emerging
class
nutrient-stimulated
hormone-based
therapeutics,
acting
incretin
mimetics
target
G-protein–coupled
receptors
GLP-1,
glucose-dependent
insulinotropic
polypeptide
(GIP),
glucagon.
vital
regulating
body
fat
energy
balance.
The
development
multiagonists,
including
GLP-1–glucagon
GIP–GLP-1–glucagon
receptor
agonists,
especially
with
the
potential
glucagon
activation,
marks
advancement
field.
review
covers
clinical
efficacy
various
GLP-1-based
exploring
challenges
future
directions
management.
Diabetes Obesity and Metabolism,
Год журнала:
2023,
Номер
25(7), С. 1973 - 1984
Опубликована: Март 28, 2023
To
report
a
Phase
I
study
of
subcutaneous
glucagon
receptor
(GCGR)/glucagon-like
peptide-1
(GLP-1R)
dual
agonist
BI
456906
versus
placebo
in
healthy
Japanese
men
with
overweight/obesity.We
investigated
multiple
rising
doses
escalated
over
16
weeks
(maximum
doses:
1.8
mg
once
weekly
[dose
group
{DG}
1],
4.8
[DG
2]
and
2.4
twice
3])
body
mass
index
23
to
40
kg/m2
.Thirty-six
participants
were
treated
(n
=
9
per
DG
placebo).
Overall,
10
(37.0%)
withdrew
from
dose
escalation
due
adverse
events
(amylase
increase,
n
1;
decreased
appetite,
9),
the
proportion
was
higher
2
6,
66.7%)
DGs
1
3
(both
2,
22.2%).
No
receiving
escalation.
exposure
increased
each
DG.
Treatment
placebo-corrected
bodyweight
after
(placebo
+1.06%):
1,
-5.57%;
-12.37%;
3,
-9.62%.
Paracetamol
absorption
Week
for
indicating
transient
delayed
gastric
emptying.
reduced
plasma
alanine
levels,
indirect
target
engagement
at
GCGRs
GLP-1Rs.
Drug-related
reported
all
four
placebo,
most
frequent
being
appetite
24,
66.7%).BI
showed
no
unexpected
tolerability
concerns
it
by
up
12.37%
overweight/obesity
treatment.
Biomedicines,
Год журнала:
2024,
Номер
12(9), С. 2039 - 2039
Опубликована: Сен. 7, 2024
Type
2
diabetes
mellitus
(T2DM)
is
a
prevalent
chronic
metabolic
disorder
characterized
by
insulin
resistance
and
progressive
beta
cell
dysfunction,
presenting
substantial
global
health
economic
challenges.
This
review
explores
recent
advancements
in
management,
emphasizing
novel
pharmacological
therapies
their
physiological
mechanisms.
We
highlight
the
transformative
impact
of
Sodium-Glucose
Cotransporter
inhibitor
(SGLT2i)
Glucagon-Like
Peptide
1
Receptor
Agonist
(GLP-1RA),
which
target
specific
pathways
to
enhance
glucose
regulation
health.
A
key
focus
this
tirzepatide,
dual
agonist
glucose-dependent
insulinotropic
polypeptide
(GIP)
GLP-1
receptors.
Tirzepatide
illustrates
how
integrating
innovative
mechanisms
with
established
can
significantly
improve
glycemic
control
support
weight
management.
Additionally,
we
explore
emerging
treatments
such
as
glimins
glucokinase
activators
(GKAs),
offer
strategies
for
enhancing
secretion
reducing
production.
also
address
future
perspectives
including
potential
retatrutide
triple
receptor
evolving
guidelines
advocating
comprehensive,
multifactorial
approach
care.
integrates
essential
lifestyle
modifications—such
dietary
changes,
physical
activity,
smoking
cessation—to
optimize
patient
outcomes.
By
focusing
on
these
new
therapies,
underscores
role
T2DM
management
highlights
importance
personalized
care
plans
complexities
disease.
holistic
perspective
aims
quality
life
long-term
Diabetes Obesity and Metabolism,
Год журнала:
2024,
Номер
26(6), С. 2368 - 2378
Опубликована: Апрель 1, 2024
Abstract
Aim
To
describe
the
biomarker
strategy
that
was
applied
to
select
survodutide
(BI
456906),
BI
456908
and
456897
from
19
dual
glucagon
receptor
(GCGR)/
glucagon‐like
peptide‐1
(GLP‐1R)
agonists
for
in‐depth
pharmacological
profiling,
which
led
qualification
of
as
clinical
development
candidate.
Materials
Methods
Potencies
increase
cyclic
adenosine
monophosphate
(cAMP)
were
determined
in
Chinese
hamster
ovary
(CHO)‐K1
cells
stably
expressing
human
GCGR
GLP‐1R.
Agonism
endogenously
expressed
receptors
investigated
insulinoma
(MIN6)
mouse
GLP‐1R,
rat
primary
hepatocytes
GCGR.
In
vivo
potencies
engage
GLP‐1R
or
determined,
measuring
improvement
oral
glucose
tolerance
(30
nmol/kg)
plasma
fibroblast
growth
factor‐21
(FGF21)
liver
nicotinamide
N‐methyltransferase
(NNMT)
mRNA
expression
(100
nmol/kg),
respectively.
Body
weight‐
glucose‐lowering
efficacies
diet‐induced
obese
(DIO)
mice
diabetic
db/db
mice,
Results
Upon
acute
dosing
lean
target
engagement
biomarkers
demonstrated
a
significant
correlation
(Spearman
coefficient
with
p
<
0.05)
vitro
investigated.
Survodutide,
selected
profiling
based
on
achieved
(area
under
curve
[AUC]
54%,
57%
60%
vs.
vehicle)
comparable
semaglutide
(AUC
45%
vehicle),
while
showing
different
degrees
engagement,
by
hepatic
NNMT
(increased
15‐
17‐fold
FGF21
concentrations
up
sevenfold
vehicle).
DIO
nmol/kg/once
daily),
daily)
(10
body
weight‐lowering
efficacy
baseline
25%,
27%
26%,
20
significantly
lowered
glycated
haemoglobin
(0.4%–0.6%);
no
effect
observed
(3
7
daily).
Conclusions
Survodutide
candidate
its
balanced
GCGR/GLP‐1R
pharmacology,
engaging
robust
exceeding
selective
agonists,
achieving
antidiabetic
agonism.
is
currently
being
Phase
3
trials
people
living
obesity.
Endocrinology and Metabolism,
Год журнала:
2024,
Номер
39(2), С. 206 - 221
Опубликована: Апрель 16, 2024
Obesity
is
a
significant
risk
factor
for
health
issues
like
type
2
diabetes
and
cardiovascular
disease.
It
often
proves
resistant
to
traditional
lifestyle
interventions,
prompting
need
more
precise
therapeutic
strategies.
This
has
led
focus
on
signaling
pathways
neuroendocrine
mechanisms
develop
targeted
obesity
treatments.
Recent
developments
in
management
have
been
revolutionized
by
introducing
novel
glucagon-like
peptide-1
(GLP-1)
based
drugs,
such
as
semaglutide
tirzepatide.
These
drugs
are
part
of
an
emerging
class
nutrient-stimulated
hormone-based
therapeutics,
acting
incretin
mimetics
target
G-protein–coupled
receptors
GLP-1,
glucose-dependent
insulinotropic
polypeptide
(GIP),
glucagon.
vital
regulating
body
fat
energy
balance.
The
development
multiagonists,
including
GLP-1–glucagon
GIP–GLP-1–glucagon
receptor
agonists,
especially
with
the
potential
glucagon
activation,
marks
advancement
field.
review
covers
clinical
efficacy
various
GLP-1-based
exploring
challenges
future
directions
management.
