Geen diatitel

1
Perorale anti-diabetica
2
Classificatie van diabetes mellitus
Type 1 diabetes Destructie van de insuline
producerende betacellen Type 2 diabetes
Weerstandigheid aan insuline -
betacelfalen Andere vormen Moleculaire
defecten Zwangerschapsdiabetes Pancreasafwijking
en .
3
ADA criteria voor diagnose diabetes mellitus
(1997)
4
High blood sugar is a sign of type 2 diabetes,
but not the only abnormality in this disease
5
Insulin Resistance Syndrome

• Obesity
• Insulin resistance
• Hyperinsulinaemia (initially)
• Type 2 diabetes or impaired glucose tolerance
• Dyslipidaemia
• Blood pressure
• Atherosclerosis

DeFronzo, Ferrannini. Diabetes Care 1991 14 (3)
173-94
6
Type 2 Diabetes - Insulin Resistance and
Progressive ß-cell failure
Insulin resistance
Hyperinsulinaemia
Impaired glucose tolerance
Increasing insulin resistance
Hyperglycaemia / TYPE 2 DIABETES
Adapted from Edelman SV. Advances in Int Med.
1998 43 (Ch 14) 449-500
7
Type 2 Diabetes - Insulin Resistance and
Progressive ß-cell failure
Insulin resistance
Hyperinsulinaemia
Impaired glucose tolerance
Increasing insulin resistance
Hyperglycaemia / TYPE 2 DIABETES
ß-cell failure
Adapted from Edelman SV. Advances in Int Med.
1998 43 (Ch 14) 449-500
8
Type 2 Diabetes - Insulin Resistance and
Progressive ß-cell failure
Insulin resistance
Hyperinsulinaemia
Impaired glucose tolerance
Increasing insulin resistance
Hyperglycaemia / TYPE 2 DIABETES
ß-cell failure
Hypoinsulinaemia
Adapted from Edelman SV. Advances in Int Med.
1998 43 (Ch 14) 449-500
9
Reducing insulin resistance may be the key to
controlling type 2 diabetes and its
cardiovascular complications
DeFronzo, Ferrannini. Diabetes Care 1991 14 (3)
173-94
10
Tissues involved in glucose homeostasis
Upper GI Tract - Glucose absorption
Adipose Tissue - Glucose storage, FFA release
Pancreas - Insulin secretion
Muscle - Energy consumption (FFA gt glucose)
Liver - Energy storage, glucose release
11
Treatments for Type 2 Diabetes
Acarbose Reduces absorption
-
Sulphonylurea Repaglinide Stimulates pancreas

Metformin Reduces hepatic glucose
output (??muscle/fat effects)
-
-
-

Thiazolidinediones Reduce Insulin Resistance
12
Orale antidiabetica
Insulin-augmenting agents Insulin-assisting
agents Sulfonylurea Biguanides
(Metformin) Glinides
Alpha-glucosidase inhibitoren
Thiazolidinediones
13
Oral antidiabetic drugs

• Insulin-augmenting agents Sulfonylurea
• Short acting (administration before meals)
• 
  Diamicron-Glurenorm
• Long acting (once daily) Amarylle,
  Uni-Diamicron
• Reason for choice short/long compliance of
  patient
• When failing of insulin secretion- high glucose
  , adding to metformin, intolerance of
  metformin

14
Characteristics of commonly used sulfonylurea
Generic name Brand name Posology
Duration of action Excretion (h)
(Tolbutamide) Rastinon (Tolazamide) Tolinase
Chlorpropamide Diabinese 125-250mg/d 60 Renal Gl
ibenclamide Daonil 2.5-15mg/d 60 Renal Eugluco
n Glipizide Glibenese 2.5-20mg/d 24 Renal
80 Minidiab Gliquidone Glurenorm 30-90mg/d 7
Hepatic 95 Gliclazide Diamicron 40-120mg/d 24 Re
nal 70 Glimepiride Amarylle 1-8mg/d 24 Renal
60
15
Oral antidiabetic drugs
Insulin-augmenting agents Glinide Novonorm (1
mg, 2 mg, max 12 mg/d) When early diagnosis of
diabetes type 2, postprandial hyperglycemia
problem, adding to metformin
16
Characteristics of Metiglinides
Generic name Brand name Posology
Duration of action Excretion (h)

Repaglinide Novonorm 2-12 mg/d 6 Hepatic Nategli
nide Starlix 20-120 mg/d 4 Hepatic
17
Loss of early-phase insulin release in type 2
diabetes
Pattern of insulin release is altered early in
type 2 diabetes
Normal
Type 2 diabetes
120 100 80 60 40 20 0
120 100 80 60 40 20 0
20gglucose
20g glucose
Plasma insulin (µU/ml)
Plasma insulin (µU/ml)
30 0 30 60 90 120
30 0 30 60 90 120
Time (minutes)
Time (minutes)
Ward WK et al. Diabetes Care 19847491502
18
Clinical Evidence for NovoNorm

• Designed to match the meal time insulin response
  of a healthy individual

19
Insulin Secretion Profiles in Type 2Diabetic
Patients and Healthy People
800
Normal obese Type 2 DM
700
600
500
400
Insulin Secretion (pmol/min)
300
200
100
0600
1000
1400
1800
2200
0200
0600
Time
Polonsky et al
20
Oral antidiabetic drugs

• Insulin-sensitizing agents Metformin
• Glucophage - Metformax
• Reason for choice Metformax easier to swallow,
  breakable
• When all patients with weight problem (BMI gt
  26)- first drug of choice !!!

21
Characteristics of
Available
Agents
that
Enhance the
Effectiveness of
Insulin
Class and
Approved
Duration of
generic name
Brand name
Site of
daily
action (
hours)
Clearance
action
dosage range
Biguanide
Glucophage
Liver,
500 - 2550 mg
6
to 12 (?)
Renal

Metformin
muscle
22
Characteristics of
Available
Agents
that
Enhance the
Effectiveness of
Insulin
Class and
Approved
Duration of
generic name
Brand name
Site of
daily
action (
hours)
Clearance
action
dosage range
Biguanide
Glucophage
Liver,
500 - 2550 mg
6
to 12 (?)
Renal

Metformin
muscle
a
-
Gluc.
Inhibitor
Glucobay
Intestine
25 - 300 mg
lt 4
Not
absorbed

Acarbose
23
Oral antidiabetic drugs

• Insulin-sensitizing agents thiazolidinediones
  or glitazones
• Avandia (GSK) Actos (Lilly)
• Reason for choice -
• When when insulin resistance is predominant
• Contra-indication heart failure

24
Activation of PPAR? Alters Expression of Specific
Genes
Co-activators (SRC-1, PGC-1) etc.
Co-repressors (SMRT, N-COR) etc.
retinoic
TZD
PPAR??
RXR
AGGTCA X AGGTCA
PPRE (DR-1)
coding sequences
25
Thiazolidinediones Structurally Diverse PPARg
agonists

• Sankyo/Parke Davis/Glaxo
• SmithKline Beecham
• Takeda

26
Targets for glycaemic control
HbA1C lt 7 lt 6.5
FPG mg/dL lt 120 lt 110
ADA 1 IDF (Europe) 2
1 Diabetes Care 1999 22(Suppl 1)S1-S114. 2
Diabetic Medicine 1999 16 716-30.
27
Patients achieving glycaemic targets
Pre-UKPDS a UK Salford Study 1993-8
Post UKPDS b German IRIS Study 2000
60
n4575
n6544
100
90
50
80
70
40
61
60
48
30
50
Cumulative of Patients
Annual of Patients Achieving Target
40
32
20
30
18
20
10
10
0
0
lt6.5 lt7.0 lt7.5 lt8.0
lt 7.0 lt 9.0
HbA1C
HbA1C
a UK study. Diabetologia 2000 43 836-43 b IRIS
study. German Diabetes Meeting 2001
28
Lessons from UKPDSBetter control means fewer
complications
EVERY 1 reduction in HBA1C
REDUCED RISK
-21
1
Deaths from diabetes
-14
Heart attacks
-37
Microvascular complications
-43
Peripheral vascular disorders
plt0.0001
UKPDS 35. BMJ 2000 321 405-12
29
Orale antidiabetica
Insulin-augmenting agents Insulin-assisting
agents Sulfonylurea Biguanides
(Metformin) Glinides Alpha-glucosidase
inhibitoren Thiazolidinediones
To reach targets, combinations are often needed
30
Efficiency of combining OAD
Sulphonylurea Antidiabetic agent Metformin (Gl
ucovance)a Metformin (2500 mg) (free
combination)b Rosiglitazone (4 mg)c Acarbose
(300 mg)d
HbA1C atbaseline 9.5 8.7 10.6 9.2
Comparatoragent Sulphonylurea Placebo Placebo
Placebo
Net changein HbA1C - 1.7 - 1.8 - 1.0 -
1.0
Net change difference between active and
comparator agents
aMerck Lipha, data on file bDeFronzo Goodman
(1995) cWolffenbuttel et al (2000)dWillms
Ruge (1999)
31
Efficiency of combining OAD
Comparatoragent Metformin Placebo Placebo Plac
ebo Placebo
HbA1C atbaseline 7.9 6.5 8.8 8.5 8.3
Net changein HbA1C - 1.2 - 0.8 - 1.2 -
1.1 - 0.8
Metformin Antidiabetic agent Glibenclamide(Gl
ucovance)a Glimepiride (26 mg)b Rosiglitazone
(8 mg)c Repaglinide (1.512 mg)d Acarbose (300
mg)e
Net change difference between active and
comparator agents
aMerck Lipha, data on file bCharpentier et al
(2001) cFonseca et al (2000) dMoses et al
(1999) eRosenstock et al (2000)
32
Basic Steps in the Management of Type 2 Diabetes
33
Polypharmacy is common in diabetes
a.m. noon
p.m. night
Glibenclamide Metformin Simvastatin Atenolol Ramip
ril Felodipine Aspirin Mononitrate Amitriptyline T
hyroxine
Typical daily regimen for diabetic patients with
concurrent disease
34
Glucovance at a glance

• Tablet design offers metered release of metformin
  and glibenclamide in three tablet strengths
• 250mg/1.25mg, 500mg/2.5mg, 500mg/5.0mg
• Bioavailability is similar to the free
  combination of agents.
• Metformin kinetics are unchanged but the time to
  maximum plasma concentrations of glibenclamide is
  earlier, allowing treatment to be taken with
  meals.

35
Trial treatment design
Monotherapy Failure
Randomised, double-blind
Met/Glib 500 mg/5 mg
Glibenclamide 5 mg
Metformin 500 mg
Met/Glib 500 mg/2.5 mg
Titrated
Up to 2 tablets twice daily for 16 weeks
Constant dose of 20 mg/day in the
post-sulphonylurea study
36
HbA1C response in metformin failures
HbA1C ()
8.5
8.0
7.5
7.0

p 0.0001 vs. monotherapies
6.5
Baseline
Week 16
Mean final doses
Metformin 500 mg 1660 mg Glibenclamide 5 mg 13.4
mg Glucovance 500 mg/2.5 mg 1225 mg / 6.1
mg Glucovance 500 mg/5 mg 1170 mg / 11.7 mg
Diabetes Res Clin Pract 200050 Suppl 1P1368.
IDF Abstract. In Press.
37
HbA1C response in sulphonylurea failures
10
9.5
? 1.7 to 1.9
HbA1C ()
9
8.5
8
p lt 0.001 vs. monotherapies
7.5
7
0
4
8
12
16
Weeks
Mean final doses Metformin 500 mg 1840
mg Glibenclamide 5 mg 20.0 mg Glucovance 500
mg/2.5 mg 1760 mg / 8.8 mg Glucovance 500 mg/5
mg 1740 mg / 17.0 mg
AACE 9th Annual Meeting. Atlanta, Georgia
(Abstract 45). In press.
38
Unwanted secondary effects of oral antidiabetic
agents
Campbell. Br J Cardiol 20007625-31
39
Targets for glycaemic control
HbA1C lt 7 lt 6.5
FPG mmol/L lt 6.7 (120) lt 6.0 (110)
ADA 1 IDF (Europe) 2
mg/dl
1 Diabetes Care 1999 22(Suppl 1)S1-S114. 2
Diabetic Medicine 1999 16 716-30.