Diabetes III - Diabetes III Learning Objectives

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Unformatted text preview: Diabetes III Learning Objectives • Appreciate
the
risks
of
intensive
treatment
to
 lower
BG
in
Type
2
Diabe;cs
at
high
risk
for
CVD

 • Describe
the
effect
of
weight
loss
on
managing
 Type
2
Diabetes
 • Discuss
the
two
views
of
T2DM:

glucocentric
 versus
lipocentric

 • Describe
drug
op;ons
for
trea;ng
T2DM
and
 their
mechanism
of
ac;on Central Question #1 Given the devastating effect of hyperglycemia on macro and microvascular blood vessels, How
low
should
clinicians
 target
their
pa;ent’s
Hb
 A1C
values?
 ACCORD Trial •  Ac;on
to
Control
Cardiovascular
Risk
in
Diabetes
 Trial
 –  Adults
with
Type
2
diabetes
at
especially
high
risk
for
 heart
aKack
and
stroke
 –  Objec;ve
was
to
compare
the
efficacy
of
an
intensive
 treatment
to
lower
blood
glucose
below
current
 recommenda;ons
(<
6%)
versus
a
less‐invasive
 standard
treatment
(7‐7.9%)
on
CVD
endpoints
 •  10,251
par;cipants
(average
age
62y)
par;cipated
 Intensive treatment led to lower A1C Intensive therapy: More likely to take insulin along with 2 to 3 additional BG lowering medications Intensive treatment resulted in more deaths •  Trial
STOPPED
a^er
3.5
years!
 –  17
months
ahead
of
schedule
 –  20%
more
of
the
par;cipants
assigned
to
the
intensive
 versus
the
standard
treatment
died
(257
vs
203)
 •  Greater
number
of
deaths
from
any
cause
as
well
as
deaths
 from
CVD
 •  Results
do
not
apply
to
individuals
with
 T1DM
 –  Diabetes
Control
and
Complica;ons
Trial
(DCCT)
 in
type
1
diabe;cs
showed
that
intensive
blood
 sugar
control
aimed
at
a
near
normal
A1C
level
 reduced
complica;ons
of
the
eyes,
nerves,
and
 kidneys.
 Two additional aims of ACCORD study: • Blood
Pressure

 ‐
Intensive
versus
standard
treatment
for
blood
 pressure
 ‐
No
benefit
of
achieving
treatment
goal
(<
120
mm
 Hg)
versus
standard
<140
mm
Hg
(~
134
mm
Hg)
 • Lipid
Profile
 ‐
Sta;n
+
fibrate
(raise
HDL
and
lower
TGs)
versus
 sta;n
alone
(lower
LDL)
 ‐
No
benefit
of
adding
fibrate
to
sta;n
regimen
 despite
an
improved
lipid
profile
 http://www.accordtrial.org Central Question #2 How
effec;ve
is
weight
 loss
in
trea;ng
T2DM?
 Gastric banding versus lifestyle changes for Type 2 Diabetes •  Two
year
randomized
controlled
trial
 •  60
obese
(BMI
30‐40)
pa;ents
with
 recently
diagnosed
type
2
diabetes
 •  Treatment
groups:
 –  Laparoscopic
adjustable
gastric
 banding
(LAGB)
+
conven;onal
 therapy
(no
an;glycemic
meds‐
 weight
management
approach)
 –  Conven;onal
therapy
 •  Research
goal:
remission
of
type
2
 diabetes
and
A1C
<
6.2%
 Dixon
et
al.
(2008)
JAMA
299(3): 316
 • Holds
~
100‐200
 g
food
 • Get
full
first
and
 sends
message
to
 brain
to
stop
 ea;ng
 20% weight loss results in remission of T2D in most individuals Dixon
et
al.
(2008)
 JAMA
299(3):316 
 Two Views of Type 2 Diabetes “GLUCOCENTRIC”

Viewpoint
 •  Hyperglycemia
(glucotoxity)
is
 the
primary
disease/problem
 and
is
caused
by
an
uncertain
 combina;on
of
obesity‐related
 insulin
resistance
and
β‐cell
 loss
 •  Treat
with
an;‐hyperglycemic
 agents,
including
high‐dose
 insulin
if
necessary
 “LIPOCENTRIC”
Viewpoint
 •  Lipotoxity
is
the
primary
 disease/problem
and
 hyperglycemia,
insulin
 resistance
andβ‐cell
loss
are
 secondary
to
metabolic
trauma
 caused
by
lipotoxicity
 •  Treat
by
elimina;ng
lipid
 overload
 Unger
(2008)
JAMA
299(10):1185
 T2D is a disease of lipotoxicity and glucotoxicity both of which play a role in atherogenesis Clinical Implications •  Intensive
insulin
therapy
is
 contraindicated
in
T2
diabe;cs
at
 high
risk
of
CVD
 •  Overweight
individuals
should
 restrict
calories
to
prevent
disease
 •  Eliminate
hyperglycemia
without
 exacerba;ng
the
underlying
lipid
 overload:
 –  Eliminate
caloric
surplus
 –  An;diabe;c
drugs
that
reduce
food
 intake,
lipids,
or
both
 Unger
(2008)
JAMA
299(10):1185
 Type 2 Diabetes Treatment Goals Glycemic Control A1C <7.0%* Preprandial capillary plasma glucose 90-130 mg/dl (5.0-7.2 mmol/l) Peak postprandial capillary plasma glucose† <180 mg/dl (<10.0 mmol/l) Lipids LDL cholesterol <100 mg/dl (<2.6 mmol/l) HDL cholesterol   Men >40 mg/dl (>1.1 mmol/l)   Women >50 mg/dl (>1.4 mmol/l) Triglycerides <150 mg/dl (<1.7 mmol/l) Blood Pressure <130/80 mm Hg Metformin: Targets fat and glucose (most presribed anti-diabetic drug) METFORMIN
 AMPK •  Increases
AMPK
(like
 adiponec;n)
 •  AMPK
is
liver
enzyme
that
 is
ac;vated
by
an
increase
 in
the
AMP.

It
in
turn
 phosphorylates
key
 enzymes
in
metabolic
 pathways
 •  AMPK
effects
include:

 
↑
fat
oxida;on

 
↑glucose
uptake
 
↓
hepa;c
glucose
 produc;on
(decreases
 mRNA
of
glucogenic
 enzymes)

 Peroxisome Proliferator-Activated Receptors (PPAR) agonists NEJM 2004; Volume 351:1106-1118 • PPAR
regulates
genes
 that
influence
glucose
 uptake,
lipoprotein
 metabolism,
and
faKy
 acid
uptake
and
 oxida;on.
 • Thiazolidinediones
 (Thy‐a‐zo‐li‐dean‐ diones;
TZDs)
are
PPARγ
 ac;vators
that
improve
 IR
in
T2D
pa;ents
 • Fibrates
are
PPARα
 ac;vators
useful
in
 trea;ng
dyslipidemia.
 • Dual
PPAR
ac;vators
 (or
PPAR‐alpha/gamma
 agonists)
are
under
 development
 Sensi;zers
 Insulin
 AMPK
ac;va;on
 • Meyormin
(Biguanides)
 PPAR
Agonists
 • TZDs
(PPAR
gamma)
 • Fibrates
(PPAR
alpha)
 K+/ATP
Channel
Inhibitors
 Secretagogues
 • Sulfonylureas
(1st,
2nd
,
3rd
genera;on)
 • Megli;nides
(different
target
on
channel)

 GLP‐1

(Incre;n)
Analogues
 • Exena;de
 DPP‐4
Inhibitors
 • Januvia,
galvus
 Analogues
 Different
types
of
insulin
 • Slow
ac;ng
 • Fast
ac;ng
 Can be used alone or in combination Inhibit
K
channel
in
B‐cells
 Incre;n
like
agent
 Synthe;c
form
of
Amylin
 Inhibit the destruction of GLP-1 and other incretins (Maltase)
 ...
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