abbas orabi.translating evidence
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By: Abbas Oraby
Translating evidence into patients’ benefits
Drugs in this class
• Acetohexamide
• Chlorpropamide
• Tolbutamide
• Tolazamide
• Glipizide
• Gliclazide
• Glibenclamide (glyburide)
• Gliquidone
• Glyclopyramide
Sulfonylureas were the first widely used oral anti-hyperglycaemic medications. Many types of these pills have been marketed but not all remain available.
MECHANISMS OF ACTION OF SUs
Insulin release
•
8
It involves 3 main steps :
1. Translocation of insulin granules.
2. Docking of insulin granules.
3. Fusion of insulin granules.
Microtubules form a network radiating from the perinuclear region outwords
10
.
It gives the way but not the force
The framework provides
the mechanical pathway
along which secretory
granules move toward the
exocytic sites close to the
plasma membrane.
12
Ca+ is essential for almost all steps
involved in insulin release, thus factors
increasing intracellular Ca+ will augment
insulin release.Mechanisms involved in
increasing intra-cytoplasmic Ca+ :
Ca-influx from outside.
Inhibition of Ca-reuptake by
intracellulas stores.
Increased Ca-sensitivity.
x Ca++ Store
13
Increased intracellular Ca+ is essential for
granules translocation and fusion hence release of
insulin.
Each B-cell contains up to 500 Ca channels
Glucose ATP-sensitive
K+ channel
K retention
3
Depolarization
4
Glucokinase
Translocation ATP
Voltage-gate Ca
channel
Fusion
Ca+
5
6
Glucose
1
G-6-P
2
GLUT2 X
Mechanisms of action cont.
• The rise in intracellular calcium leads to increased fusion of insulin granules with the cell membrane, and therefore increased secretion of (pro)insulin.
• There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis and decrease clearance of insulin by the liver.
Glimepiride binds to the 65 kDa subunit of the sulfonylurea receptor; glibenclamide binds to the 140 kDa subunit
Insulin Secretion (Glimepiride)
Therapeutic actions
16
Hyperglycaemia
Pancreas
Liver Muscle
Impaired
Insulin secretion
Metformin
Increased glucose production
Decreased glucose uptake
Insulin resistance
Sulfonylurea +
glimepiride
–
17
Attributes of sulfonylureas
* Substantially greater risk of hypoglycemia with chlorpropamide and glibenclamide (glyburide) than other second- generation sulfonylureas (gliclazide, glimepiride, glipizide)
Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.
How they work Enhance insulin secretion
Expected HbA1c reduction
1 to 2%
Adverse events Hypoglycemia* (but severe episodes are infrequent)
Weight effects ~ 2 kg weight gain common when therapy initiated
CV effects None substantiated by UKPDS or ADVANCE study
IDF Global Guideline for Type 2 Diabetes
Diagnosis
Lifestyle intervention then metformin
HbA1c 6.5 %
Add sulfonylurea
Meal-time + basal insulin + metformin ± thiazolidinedione
Add insulin
Start insulin
Add thiazolidinedione*
HbA1c 6.5 %
HbA1c 7.5 % HbA1c 7.0 %
HbA1c 6.5 %
IDF. Global Guideline for Type 2 Diabetes. 2005
*Alternatively, start
thiazolidinedione before
sulfonylurea,
and sulfonylurea later.
intensify insulin
ADA and EASD algorithm for the management of type 2 diabetes
Nathan et al., Diabetes Care 2008 [Epub]
aSUs other than glybenclamide (glyburide) or chlorpropamide. bInsufficient clinical use to be confident regarding safety.
Met=metformin; Pio=pioglitazone; SU=sulfonylurea
No hypoglycaemia Weight loss Nausea/vomiting
Lifestyle and
met + intensive
insulin
At diagnosis: Lifestyle
+
metformin
Step 1 Step 2 Step 3
Lifestyle and
met + pio No hypoglycaemia Oedema/CHF Bone loss
Lifestyle and met
+ GLP-1 agonistb
Lifestyle and met
+ pio + SUa
Lifestyle and
met + basal insulin
Tier 2: Less well validated therapies
Lifestyle and
met + SUa
Lifestyle and
met + basal insulin
Reinforce lifestyle interventions every visit and check HbA1C every
3 months until HbA1C is <7% and then at least every 6 months.
The interventions should be changed if HbA1C is ≥7%
Tier 1: Well validated therapies
Action on insulin
resistance
Action on insulin
secretion
► Glimepiride ►
► - Glitazones1,6
► - Biguanides1,3-5
- Glinides1,2
- ► Conventional Sulfonylureas1
►
Unique Dual Mode of Action
1Medical Management of Type 2 Diabetes. 4th ed. Alexandria, Va: American Diabetes Association; 1998:1-139; 2Goldberg 1998, et al. Diabetes Care
21:1897-1903; 3Bell & Hadden. Endocrinol Metab Clin 1997;26:523-37; 4De Fronzo, et al. N Engl J Med 1995;333:541-9; 5Bailey & Turner. N Engl J Med
1996;334:574-9; 6Henry. Endocrinol Metab Clin 1997;26:553-73
1
27 Müller & Wied. Diabetes. 1993;42: 1852-1867
The extrapancreatic effect of Glimepiride
Rate limiting step for glucose
utilization is glucose uptake via GLUT4
transporter
Glimepride↑ translocation of GLUT4
transporters from low-density
microsomes to plasma membrane
of insulin-resistant fat and muscle
cells
Glimepiride appears to ↑ peripheral
glucose uptake and to mimic the
action of insulin
2nd Action: Extra-Pancreatic
28
Glimepiride Controls Glycemia with Less Insulin Secretion
• For an equivalent glycemic effect, Glimepiride induces a lower secretion of insulin
Mean variation of insulin and
glycemia over a 36-h period
Mean ratio between increased level of
insulin and reduced glycemia
5
10
15
0
1
2
3
Glimepiride Glibenclamide Gliclazide Glipizide
20
0
Gly
ce
mic
va
ria
tio
n (
%)
Ins
ulin
em
ia
(U
/mL
)
Glimepiride Glibenclamide Glipizide Gliclazide
0.00
0.05
0.10
0.15
0.20 n=16
n=13
n=14
n=16
Ratio
Muller G, et al. Diabetes Res Clin Pract 1995; 28 (Suppl): S115-37
Sulfonylureas tested in
fasted male beagle dogs
to determine ratios of
mean plasma insulin
release/ blood glucose
decrease
29
Glimepiride Beneficial Effect on Adiponectin Levels
• Glimepiride increases plasma adiponectin levels whilst achieving control of glycemia
Tsunekawa T, et al. Diabetes Care 2003; 26(2); 285-289
11
10
9
8
7
6
5
9
8
7
6 Baseline 4 weeks 8 weeks 12 weeks
Plasma adiponectin HbA1c (%)
Pla
sm
a a
dip
on
ec
tin
co
nc
en
tra
tio
n (
g/m
L)
Hb
A1c (
%)
8.2
6.5
7.5 6.9 6.6
10.2
Evolution of adiponectin and HbA1c levels during 12 weeks of
Glimepiride treatment
A study in 17 elderly
patients with type 2
diabetes who were
treated with Glimepiride
for 12 weeks.
GLIMEPIRIDE IS MORE THAN AN INSULIN SECRETAGUGE !!!
31
Glimepiride : Efficacy Proven in Monotherapy
Schade DS et al. J Clin Pharmacol 1998;38:636-51
Δ i
n m
ed
ian
Hb
A1c (
%)
6.7%
Change from baseline to week 22
in median HbA1c
9.1%
Tight glycemic control (HbA1c<7.2%) was achieved in 69% of Glimepiride patients and 32% of placebo patients
7.9%
-1%
8.9%
Baseline HbA1c
-4
-3
-2
-1
0
HbA1c at Endpoint
-2.4%#
Glimepride : decreased FPG by 46 mg/dL more and 2-hour PPG by 72 mg/dL more than placebo (p<0.001)
Change from baseline to week 22 in
median FPG and 2-hour PPG
n=117 n=118 n=108 n=101
Δ i
n g
luc
ose
co
nce
ntr
ati
on
(m
g/d
L)
FPG PPG
-59*
-117*
-13
-31
-140
-120
-100
-80
-60
-40
-20
0
Glimepiride Placebo
*p<0.001 vs placebo
Prospective,
randomized, double-
blind, placebo-
controlled, dose-
titration study. T2DM
patients received
Glimepiride (n=123) or
placebo (n=126) for a
10-week dose-titration
period and then the
optimal dose (1 to 8
mg) for 12 weeks.
54% of patients on
active treatment
received <4 mg/day
Glimepiride
SAFETY ?!!!
Incidence of severe* hypoglycemic events
according to treatment
*Defined as requiring IV glucose or glucagon
Significantly lower incidence of severe hypoglycemic events
with Glimepiride vs glibenclamide (0.86 vs 5.6/1000 person-years)
Holstein A et al. Diabetes Met Res Rev 2001; 17:467-73
0.86
5.6
Glibenclamide Glimepiride
# E
pis
od
es
/10
00 p
ers
on
-ye
ars
0
2
4
6
Prospective, population-
based, 4-year study to
compare frequency of
severe hypoglycemia in
patients with T2DM
treated with
Glimepiride (estimated
n=1768)
versus glibenclamide
(estimated n=1721)
Safety: Hypoglycemia vs Glibenclamide
6.5x
less
risk of
hypo
CARDIAC SAFETY ?!!!
Reductions metabolic parameters after 12 months of
treatment with Glimepiride
Glimepiride Beneficial Effect on Cardiovascular Risk Factors
De Rosa, et al. Clin Ther 2003; 25(2); 472-484
Glimepiride significantly reduces cardiovascular risk markers
-45
-40
-35
-30
-25
-20
-15
-10
-5
0
Lp(a) mg/dL
PAI-1 (ng/mL)
Hcy (mol/L)
Ch
an
ge
fro
m b
ase
lin
e
-39.7* mg/dL
-21.4†
ng/mL
-40.1* mol/L
*p<0.01; †p<0.05 vs baseline
Lp(a) = Lipoprotein A PAI-1 = plasminogen activator inhibitor-1
Hcy = homocysteine
Randomized, double-
blind study in which
patients with type 2
diabetes were treated
with Glimepiride
(n=62)or repaglinide
(n=62) for 12 months.
%
ch
an
ge
in
me
an
ST
shift
Baseline After drug administration
Mean ST segment depression during
balloon occlusion according to treatment
Klepzig et al. Eur Heart J 1999;20:439-446
Unlike glibenclamide, Glimepiride does not block the beneficial
cardioprotective effect of ischemic preconditioning
Double-blind,
randomized,
placebo-controlled
trial in 45 patients
with stable coronary
artery disease.
Mean ST segment
shift (mV) after
repetitive balloon
dilatation was
measured to
compare the effects
of Glimepiride
glibenclamide and
placebo on ischemic
preconditioning.
50
100
Placebo
(n=15)
Glimepiride(n=15) Glibenclamide
(n=15)
p = 0.01 p = NS p = 0.049
0
Cardiovascular Safety: Ischemic Preconditioning
Safety: All-Cause Mortality
Retrospective,
observational cohort
study in T2D
outpatients. A total of
696 patients received
insulin secretagogues
in combination with
biguanides. A Kaplan-
Meier survival analysis
was conducted in
patients treated with
metformin in
combination with
glibenclamide,
gliclazide, repaglinide
or Glimepiride .
Monami M, et al. Diabetes Metab Res Rev 2006; 22(6): 477-482
Kaplan-Meier survival analysis
In combination with metformin, Glimepiride is associated with lower all-cause
mortality than other sulfonylureas with less selectivity for β-cell receptors
Glimepiride or gliclazide
Repaglinide
Glibenclamide
Time
(months)
Cu
mu
lati
ve
su
rviv
al
1.0
0.9
0.8
0.7
0.6
0 10.0 20.0 30.0 40.0
Glimepiride Gliclazide
Repaglinide
Glibenclamide
Yearly mortality
0.4%
2.1%*
3.1%*
8.7%**
* P < 0.05 vs Glimepiride
**P <0.01 vs all comparators
GLIMEPIRIDE IN 2010 A NON-STOPPING WEALTH OF EVIDENCE
2010
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
2010
Research Design and methods
• Objective:
– To investigate the effects of Glimepiride on blood glucose in patients with newly diagnosed type 2 diabetes mellitus (T2DM) in connection with plasma lipoproteins and plasminogen activity.
• Methods – A total of 565 T2DM patients received Glimepiride (n =
333) or Glibenclamide (n = 232) for 12 weeks. The level of blood glucose (BG), glycated hemoglobin (HbA1C), the insulin resistance (IR) state, plasma lipoproteins, tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type I (PAI-1) were observed before and after a 12 weeks of treatment.
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
2010
Results Cont.
Conclusion: Glimepiride can rapidly and stably improve glycemic control and lipoprotein metabolism, significantly alleviate insulin resistance and enhance fibrinolytic activity.
Xu dan-yan et al. diabetes research and clinical practice 88(2010 ) 71–75
2010
2010
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
2010
Research Design and methods
• Objective: The purpose of this study is to assess the relationship of individual sulfonylureas and the risk of overall mortality in a large cohort of patients with type 2 diabetes.
• Methods: A retrospective cohort study , 11,141 patients with type 2 diabetes (4,279 initiators of monotherapy with glyburide, 4,325 initiators of monotherapy with glipizide, and 2,537 initiators of monotherapy with glimepiride), ≥ 18 years of age, with and without a history of coronary artery disease (CAD), and not on insulin or a non-insulin injectable at baseline. The patients were followed for mortality
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
2010
Results
• No statistically significant difference in the risk of overall mortality was observed among these agents
in the entire cohort,
But • evidence of a trend towards an increased overall
mortality risk with glyburide vs. glimepiride (HR 1.36; CI 0.96-1.91) and glipizide vs. glimepiride (HR 1.39; 95% CI 0.99-1.96), in those with documented CAD was found.
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
2010
Conclusion: The results did not identify an increased mortality risk among the individual sulfonylureas but did suggest that glimepiride may be the preferred sulfonylurea in those with underlying CAD.
Mortality Risk with Sulfonylurea Monotherapy
Pantalone K. M. et al. DIABETES CARE(33)-6, 2010, 1224 - 29
2010
Glimepiride the 3rd generation SU:
– Unique dual mode of action
– Fast and sustained blood glucose lowering effect
– Ideal for combination with insulin and/or other oral
antidiabetic agents
– Benefits beyond blood glucose-lowering
– Clinically proven safety profile
– Glimepiride and Metformine in fixed dose combination presentation offer a synergistic combination serving the efficacy and safety objectives needed in the management of T2DM and Described in ADA/EASD Guidelines.
61
Conclusion
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