ueda2011 type 2 diabetes-d.adel

1. Type 2 Diabetes
The real progressive disease
Prof. ADEL A EL-SAYED MD
Chairman Elect
Middle East and North Africa (MENA) Region
International Diabetes Federation (IDF)
Professor of Internal Medicine
Suhag Faculty of Medicine
Suhag
EGYPT

2. Millions
0
10
0
20
0
30
0
1995 2000 2025
150
300
140
280
Millions per year
3.6 5.0
TYPE 2 DIABETES – Global burdenTYPE 2 DIABETES – Global burden
McCarthy and Zimmet, 1997
King et al 1998;
Green, 1998
“Diabetes
will double
in
25 years”
TYPE 2 Diabetes ~90%TYPE 2 Diabetes ~90%

3. Pathogenesis of Type 2Pathogenesis of Type 2
Variable degrees of Combination of :
Beta Cell DefectBeta Cell Defect + Insulin ResistanceInsulin Resistance
GeneticGenetic
FactorsFactors
EnvironmentalEnvironmental
FactorsFactors

4. Microvascular
complications
Myocardial
infarction
HbA1c
16%
Low ering HbALow ering HbA1c1c reduces the riskreduces the risk
of Diabetes complicationsof Diabetes complications
25%
1%
UKPDS

5. Recent ADA recomendations for type 2Recent ADA recomendations for type 2
diabetes managementdiabetes management
DIAGNOSIS
Lifestyle Intervention +
Metformin
No A1CA1C>>7%7% Yes
Add Basal Insulin
(the most effective)
Add Sulfonylurea
(the most economic)
Add Glitazone
(with precautions)
Diabetes Care 2006 American Diabetes Association, Inc.
or or

6. Glimepride

7. Main
Characteristics:
Product Profile

8. Glimepiride is a third generation sulfonylurea
Oral blood glucose-lowering drug (fasting & postprandial
blood glucose)
Once daily
Available as 1, 2, 3 and 4 mg
100% bioavailability
No food interactions
Can be combined with metformin, glitazones and insulins
No special risk: elderly, hepatic and renal impairment
Product Profile
Amary®
l Summary of Product Characteristics, March 15, 2002

9. Main Characteristics:
Unique
Dual Mode of Action

10. Glimepride is the only
anti-diabetic drug
with a dual mode of action
Unique Dual Mode of Action
Insulin secretion
Insulin resistance

11. Unique Dual Mode of Action
Action on insulin
secretion
Action on insulin
resistance
GlimeprideGlimepride ++ ++
Conventional
Sulfonylureas
+ -
Glinides + -
Biguanides - +
Glitazones - +
α-Glucosidase
Inhibitors
- -

12. Glimepride
Dual Mode of Action:
Insulin Secretion

13. Insulin Secretion
Del Guerra S et al. Acta Diabetol 2000; 37:139-141
Insulinrelease(μU/islet/45min)
Glimepride concentration
0.5
1.5
2.5
0 µmol/L 1.0 µmol/L 10 µmol/L 100 µmol/L
2.5 mmol/L glucose 5.0 mmol/L glucose 10 mmol/L glucose 20 mmol/L glucose
1
2
3
Insulin release in response to varying Glimepride
concentrations
The amount of insulin released from human islets
after Glimepride treatment is dose-dependent and insulin dependent
The effects of
prolonged (24 h)
exposure to Amaryl®
on insulin secretion
were assessed using
human islets from
the pancreas of
7 cadaveric donors

14. 6.6
8.2
10.2
5
6
7
8
9
10
11
Baseline 4 weeks 8 weeks
Plasmaconcentration(µg/dl)
Tsunekawa et al, Plasma Adiponectin Plays an Important Role in Improving Insulin Resistance With Glimepiride in
Elderly Type 2 Diabetic Subjects Diabetes Care 26:285–289, 2003
Glimepride usage Is Accompanied by
Increases in Plasma Adiponectin (the key marker of insulin sensitivity
increase)
+ 54%
Hyperinsulinemic-euglycemic clamp study 17 elderly T2 diabetic patients 12 weeks of treatment with 1 to 6 mg glimepiride.
Insulin Resistance

15. Müller G et al. Diabetes Res Clin Pract 1995;28 (suppl):S115-S137
Insulin Resistance
Amaryl®
has greatest extrapancreatic activity among sulfonylureas
Mean plasma insulin increase (µU/ml) PI
Mean blood glucose decrease (%) BG
Glimepride
Mean increase in plasma insulin (PI) and mean % decrease
in blood glucose (BG) over 6 hours after single dose
50 10 15 20
Sulfonylurea
Glibenclamide
Gliclazide
Glipizide
PI/BG ratio
0.03 (n=16)
0.16 (n=16)
0.07 (n=14)
0.11 (n=13)
Sulfonylureas tested
in fasted male
beagle dogs to
determine ratios of
mean plasma
insulin release/
blood glucose
decrease

16. Efficacy:
Monotherapy

17. Glimepride reduces A1C significantly
Schade DS et al. J Clin Pharmacol 1998;38:636
ΔinHbA1c(%)*
6.7%
*median
Change in HbA1c at week 22 according to treatment
Placebo n=99
9.1%
Tight glycemic control (HbA1c<7.2%) was achieved in 69%
of Glimepride patients and 32% of placebo patients
7.9%
-1%
8.9%
Baseline HbA1c
*
-4
-3
-2
-1
0
Glimepride n=106
HbA1c at Endpoint*
-2.4%#
Prospective,
randomized, double-
blind, placebo-
controlled, dose-
titration study. T2DM
patients received
Amaryl®
(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 Amaryl®
#
p < 0.01 vs. placebo

18. Schade DS et al. J Clin Pharmacol 1998;38:636
ΔinFPG(mg/dL)*
153 mg/dL
Change in FPG at week 22 according to treatment
212 mg/dL
Glimepride decreased FPG by 46 mg/dL more than placebo
(p<0.001)
192 mg/dL
205 mg/dL
Baseline FPG*
FPG at Endpoint*
-80
-60
-40
-20
0
*median
-59 mg/dL#
-13 mg/dL
Placebo n=118Glimepride n=117
#
p < 0.01 vs. placebo
Prospective,
randomized, double-
blind, placebo-
controlled, dose-
titration study. T2DM
patients received
Amaryl®
(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 Amaryl®
Glimepride reduces FPG significantly

19. *median #
p < 0.001 vs. placebo
Schade DS et al. J Clin Pharmacol 1998;38:636
ΔinPPG(mg/dL)*
174 mg/dL
Change in 2-h PPG at week 22 according to treatment
291 mg/dL
237 mg/dL
268 mg/dL
Baseline PPG*
2-h PPG at Endpoint*
Amaryl®
decreased PPG by 72 mg/dL more than placebo (p<0.001)
-120
-90
-60
-30
0
-117 mg/dL#
-31 mg/dL
Placebo n=101Amaryl®
n=108
Prospective,
randomized, double-
blind, placebo-
controlled, dose-
titration study. T2DM
patients received
Amaryl®
(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 Amaryl®
Amaryl® reduces PPG significantly

20. Efficacy:
Combination Therapy

21. 125
150
175
200
225
0 20
Amaryl®
Metformin Metformin + Amaryl®
Treatment Duration (wk)
Titration Maintenance
MeanFBG(mg/dL)
3 126 9 15 18
glimepride + Metformin Combination
Charpentier G et al. Diabet Med. 2001;18:828-34
Superior glycemic control with metformin+glimepride®
than with metformin or glimepride alone
Evolution in FBG over time according to treatment
Prospective,
multicenter,
randomized, double-
blind, double-dummy
parallel group study of
372 T2DM patients
inadequately
controlled by
metformin 850 mg tid.
Patients received
metformin, Amaryl®
or
both for 20 weeks.

22. Mean insulin dosage required to restore
glycemic control according to treatment
Units/Day
Riddle et al. Diabetes Care 1998;21:1052-1057
* p<0.001; † p<0.05 for between group differences
At week 24, 38% less insulin required to control blood glucose
with insulin+Amaryl®
than with insulin+placebo (p<0.001)
glimepride®
+ Insulin Combination
Multicenter,
ambulatory,
randomized, double-
masked, parallel
comparison study.
T2DM subjects in
secondary sulfonylurea
failure whose body
weight was >130%
ideal were
randomized to
placebo plus insulin
(n=73) or Amaryl®
plus
insulin (n=72) for 24
weeks.
Placebo + Insulin (n=62) Amaryl®
+ Insulin (n=70)
Weeks
0
25
50
75
100
0 4 8 12 16 20 24
†
*
*
* * * *
78 U/day
49 U/day
-38%

23. Safety:
Hypoglycemic events

24. Incidence of severe* hypoglycemic events
according to treatment
*Defined as requiring IV glucose or glucagon
Safety: Hypoglycemia
Significantly lower incidence of severe hypoglycemic events with
Amaryl®
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
GlibenclamideAmaryl®
#Episodes/1000person-years
0
2
4
6
Prospective,
population-based, 4-
year study to
compare frequency
of severe
hypoglycemia in
patients with T2DM
treated with Amaryl®
(estimated n=1768)
versus glibenclamide
(estimated n=1721)

25. Safety:
Impact on weight

26. Weitgasser R et al. Diabetes Res Clin Pract 2003; 61: 13-19
Mean intra-individual weight change relative to baseline
-1.9 kg
(p<0.0001*)
-2.9 kg
(p<0.05*)
-3.0 kg
(p<0.005*)
Months of treatment
Safety: On Weight Gain
Treatment with Glimepride resulted in significant and stable weight loss
Meanweightchange(kg)
*vs. baseline
4 12
- 1
- 2
- 3
18
0
Open, uncontrolled,
observational study.
1770 T2DM patients
were enrolled and
284 were followed-up
for 1.5 years. Patients
received 0.5 to > 4
mg glimepiride once
daily.

27. Convenience

28. Sonnenberg G.E. et al. Ann Pharmacother. 1997;31:671-6
24-h glucose plasma profiles according to treatment schedule
300
250
200
150
0 2 4 6 8 10 12 14 16 18 20 22 24 hours
08.00
Meal
12.00
Meal
18.00
Meal
Bloodglucose(mg/dl)
placebo 3 mg Amaryl®
twice-a day 6 mg Amaryl®
once-a-day
Convenience
Glimepride controls blood glucose throughout the day
Prospective,
multicenter,
randomized, double-
blind, cross-over
study. 161 T2DM
patients received
Amaryl®
3 mg BID or
Amaryl®
6 mg QD for
4 weeks. After a 3-
week placebo
washout period, QD
and BID regimens
were crossed over for
a further 4 weeks.

29. Conclusions

30. Glimepride: Conclusions
Suitable for use in all T2DM patients
Unique dual mode of action
Improves 1st and 2nd phases of insulin secretion
Improves peripheral insulin resistance (extrapancreatic effects)
Significant change in HbA1c in monotherapy
Fast and sustained blood glucose lowering effect in
monotherapy
Safe and effective when combined with insulin and/or other
hypoglycemic agents
Clinically proven safety profile
Lower incidence of hypoglycemic events
No weight gain
Lower risk of cardiovascular complications
Single dose confers 24-h blood glucose control
Convenient, once daily dosing resulting in excellent
compliance

31. Thank you.