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B cell exhaution.
Less effective
Hypoglycemia
Expensive
10 m
~ 10,000
granules
normal
apoptotic
New beta-cells by:
*Replication
*Neogenesis
~65%
Lipotoxicity
Amyloid deposition
Inflamatory
Cytokines& ROS
l
Insulin
Secretion
Apoptosis
B-cell Exhaustion
- A physical depletion of B-cell insulin stores
secondary to prolonged chronic stimulation
with glucose on non-glucose secretagogues.
- No defect in insulin synthesis.
- The B-cell function fully recovers as it rests.
Exhaustion is reversible
Glucotoxicity
Non physiological and potentially
irreversible B-cell damage caused by chronic
exposure to supra-physiological glucose
concentration with characteristic decreases in
insulin synthesis and secretion caused by
decreases insulin gene expression.
Glucotoxicity is irreversible
Treatment
ROS
Ca++
Cytokines
Frequently prescribed
oral hypoglycemic
?medications
Current A1C
Duration of diabetes
Effectiveness
Co-morbidities
Cradiovascular risk
Cost of medication
Compliance.
ADA/EASD:
Considerations for the Guidelines
1.
2.
3.
4.
5.
Add sulfonylurea
(least expensive)
Add TZD
If HbA1c 7%
Intensify
insulin***
Add TZD
Add basal
insulin***
Add
sulfonylurea
If HbA1c 7%
Add basal or
intensify insulin
At diagnosis:
Lifestyle
+
Metformin
Lifestyle+Metformin
+
Basal Insulin
Lifestyle+Metformin
+
Intensive insulin
Lifestyle+Metformin
+
Sulfonylurea
Step 1
Tier 2: less well-validated
therapies
*Useful when
hypoglycemia is to be
avoided
Step 3
Step 2
Lifestyle+Metformin
+
Pioglitazone
(No hypoglycemia, edema,
CHF, bone loss)
Lifestyle+Metformin
+
GLP1
(No hypoglycemia, wt loss,
Nausea/vomiting)
Lifestyle+Metformin
+
Pioglitazone
+
Sulfonylurea
Lifestyle+Metformin
+
Basal Insulin
AACE consensus
Algorithm (2009)
18
Big
SU
SU
+M
et
SU
Sulfonylureas - Drug
Profile
Advantages
Disadvantages
Sulfonylureas
Modes of action:
Most Sulphonylureas K+
Glimepiride
Glimepiride
140
kDa
- cell
membrane
65
kDa
Sulphonylurea
KATP channel
Receptor
K+
So What ??
Pharmakokinetics of
:sulphonylurea
*Glimepiride has a lower affinity to the cell
membrane than others
*The metabolites of glibenclamide are
active while those of glimipride and
gliclazide are inactive.
Sulfonylureas
tested in fasted
male beagle
dogs to
determine ratios
of mean plasma
insulin release/
blood glucose
decrease
Ratio
0.20
n=16
0.15
0.10
0.05
n=13
n=14
n=16
0.00
Hypoglycemia vs
Glibenclamide
Significantly lower incidence of severe hypoglycemic events with
6.5x
less
risk
of
hypo
# Episodes/1000 personyears
5.6
0.86
Glimepirid
Glibenclamide
e
*Defined
requiring
IV glucose
glucagon
Holstein
A et al.as
Diabetes
Met
Res Rev or
2001;
17:467-73
Prospective,
population-based, 4year study to compare
frequency of severe
hypoglycemia in
patients with T2DM
treated with Amaryl
(estimated n=1768)
versus glibenclamide
(estimated n=1721)
Insulin Resistance
The extrapancreatic effect of Glimipride
Translocation of
GLUT4 transporters
from low-density
microsomes to
plasma membrane
of insulin-resistant
fat and muscle cells
+ 54%
Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride
in Elderly Type 2 Diabetic Subjects Diabetes Care 26:285289, 2003
Glimepiride Dual
Mechanism for Dual
Problem
INSULIN
RESISTANCE
FPG / PPG
HbA1C
INSULIN
SECRETION
Normal
IGT
Type 2
Graphic interpretation based on: Type 2 Diabetes BASICS. Minneapolis, MN: International Diabetes Center; 2000
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37; Massi-Benedetti M. Clin Ther 2003; 25(3): 799-816
1c
Lifestyle interventions
1 to
2%
Metformin
1 to
2%
Sulfonylureas
1 to
2%
Insulin
1.5 to
3.5%
Glinides
1 to
1.5%1
Thiazolidinediones
0.5 to
1.4%
-Glucosidase inhibitors
GLP-1 agonist
0.5 to
0.8%
0.5 to
1.0%
Pramlintide
0.5 to
1.0%
DPP-IV inhibitors
0.5 to
0.8%
UKPDS
Active
10
9
UKPDS
Follow-up
Conventional
Biochemical
data no
longer
collected
Intensive
7
6
0
1977
10
15
5
1997
10
2007
Intervention
ends
An
re y d
la ia
te b
d et
M end espo
di icro
se v
as as int
e cu
la
M
r
y
in oc
fa ar
rc d
tio ial
n
Al
m l-ca
or u
ta se
lit
y
0
5
9%
10 P = 0.040
13%
15%
P = 0.007
P = 0.014
15
20
24%
25
P = 0.001
30
Glycemic
Control
In Monotherapy
-1
9.1%
FPG
8.9%
-1%
n=117
-20
-2.4%#
PPG
n=118
n=108 n=101
-13
-31
-40
-2
-60
7.9%
-3
-4
in glucose concentration
(mg/dL)
Baseline HbA1c
-59*
-80
-100
6.7%
HbA1c at Endpoint
-120
*p<0.001 vs placebo
Glimepiride
-140
Placebo
-117*
Suitable for
Combination
Therapy
Efficacy of Glimepiride + Metformin
Efficacy of Glimepiride + Gliptins
Efficacy of Glimepiride + Insulins
7.8
11.7
6.4
in HOMAIR (%)
-10
Metformin
+ diet & exercise
(n=29)
-20
-30
Metformin + Glimepiride
+ diet & exercise
(n=21)
-40
-50
-60
-70
-46.9
-52.4
-65.3*
*p<0.01 vs metformin and vs diet and exercise alone
Bermdez-Pirela VJ, et al. Am J Therapeutics 2007; 14: 194-202
Efficacy: Glimepiride +
Gliptin Combination
Baseline HbA1c
8.4%
8.3%
in HbA1c (%)
0
-0.1
-0.2
Glimepiride + sitagliptin
-0.3
-0.4
Glimepiride +
metformin +
-0.57*
-0.5
sitagliptin
-0.6
-0.7
-0.89*
-0.8
-0.9
-1
*p<0.001 vs placebo 1Hermansen K, et al. Diabetes Obes Metab 2007; 9: 733-745
The EUs Committee for Medicinal Products for Humans (CHMP) recently recommended that sitagliptin be
pproved for use in combination with a sulfonylurea and for triple therapy in combination with metformin +
sulfonylurea2
300
Units/day
75
* * *
50
-38%
49 U/day
25
0
78 U/day
12
16
Weeks
20
24
100
250
*
*
200
150
100
0
12
Weeks
16
20
24
Additionnal
Benefits for the
Patient Beyond
Blood Glucose
Control
Pancreatic beta-cell
SUR1/Kir6.2
Cardiac and skeletal muscle
SUR2A/Kir6.2
Vascular smooth muscle
SUR2B/Kir6.1
Non-vascular smooth muscle
SUR2B/Kir6.2
Brain
SUR1-2B/Kir6.2
PAI - I
Hcy
Lp (a)
PAI - I
months 12
Hcy
p = 0.049
p = 0.01
p = NS
% change in mean ST
shift
100
50
0
Placebo
(n=15)
Glimepiride
(n=15)
Baseline
Glibenclamide
(n=15)
After drug
administration
Sulfonylureas
1
2
Advantages of Glimepiride
Review
Annals of Internal Medicine