Type 2 Diabetes The real progressive disease

Prof. ADEL A EL-SAYED MDChairman Elect

Middle East and North Africa (MENA) RegionInternational Diabetes Federation (IDF)

Professor of Internal MedicineSuhag Faculty of Medicine

SuhagEGYPT

Mil

lio

ns

0

100

200

300

1995 2000 2025

150

300

140

280

Millions per year

3.6 5.0

TYPE 2 DIABETES – Global burden TYPE 2 DIABETES – Global burden

McCarthy and Zimmet, 1997King et al 1998; Green, 1998

“Diabetes will double

in 25 years”

TYPE 2 Diabetes ~90%TYPE 2 Diabetes ~90%

Pathogenesis of Type 2Pathogenesis of Type 2

Variable degrees of Combination of :

Beta Cell DefectBeta Cell Defect + Insulin ResistanceInsulin Resistance

GeneticGenetic FactorsFactors

EnvironmentalEnvironmentalFactorsFactors

Microvascular complications

Myocardial infarction

HbA1c

16%

Lowering HbALowering HbA1c1c reduces the risk reduces the risk of Diabetes complicationsof Diabetes complications

25%

1%

UKPDS

Recent ADA recomendations for type 2 Recent 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

Glimepride

Main Characteristic

s: Product Profile

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

Main Characteristics:

UniqueDual Mode of Action

Glimepride is the only anti-diabetic drug

with a dual mode of action

Unique Dual Mode of Action

Insulin secretion Insulin resistance

Unique Dual Mode of Action

Action on insulinsecretion

Action on insulinresistance

GlimeprideGlimepride ++ ++ConventionalSulfonylureas + -

Glinides + -

Biguanides - +

Glitazones - +

-Glucosidase Inhibitors - -

GlimeprideDual Mode of Action:

Insulin Secretion

Insulin Secretion

Del Guerra S et al. Acta Diabetol 2000; 37:139-141

Insu

lin

rele

ase (

μU

/isle

t/4

5

min

)

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 fromthe pancreas of7 cadaveric donors

6.6

8.2

10.2

5

6

7

8

9

10

11Baseline 4 weeks 8 weeks

Pla

sma

con

cen

trat

ion

(µ

g/d

l)

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

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) PIMean 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

Su

lfon

ylu

rea

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

Efficacy:

Monotherapy

Glimepride reduces A1C significantly

Schade DS et al. J Clin Pharmacol 1998;38:636

Δ in

Hb

A1c (

%)

*

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

Schade DS et al. J Clin Pharmacol 1998;38:636

Δ in

FP

G (

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

*median # p < 0.001 vs. placebo

Schade DS et al. J Clin Pharmacol 1998;38:636

Δ in

PP

G (

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

Efficacy:Combination

Therapy

125

150

175

200

225

0 20

Amaryl® Metformin Metformin + Amaryl®

Treatment Duration (wk)

Titration Maintenance

Mean

FB

G (

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.

Mean insulin dosage required to restore glycemic control according to treatment

Un

its/D

ay

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%

Safety:Hypoglycemic events

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®

# E

pis

od

es/1

00

0 p

ers

on

-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)

Safety:Impact on weight

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

Mean

weig

ht

ch

an

ge (

kg

)

*vs. baseline

4 12

- 1

- 2

- 3

180

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.

Convenience

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

08.00Meal

12.00Meal

18.00Meal

Blo

od

glu

cose (

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.

Conclusions

Glimepride: Conclusions

Suitable for use in all T2DM patientsUnique dual mode of action

Improves 1st and 2nd phases of insulin secretion Improves peripheral insulin resistance (extrapancreatic effects)

Significant change in HbA1c in monotherapyFast and sustained blood glucose lowering effect in monotherapySafe and effective when combined with insulin and/or other hypoglycemic agentsClinically proven safety profile

Lower incidence of hypoglycemic eventsNo weight gainLower risk of cardiovascular complications

Single dose confers 24-h blood glucose controlConvenient, once daily dosing resulting in excellent compliance

Thank you.