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CLINICAL MANAGEMENT OF

TYPE 2 DIABETES : Matching


Therapy to Patophysiology
Djoko Wahono Soeatmadji

2004 (4)

Diabetes and Endocrinology Section, Department of


Internal Medicine, Faculty of Medicine, Brawijaya
University, Malang

VALUATIONS OF THERAPEUTIC GOALS


By professionals

Qualtity of Life

Quality of Life

Perspective in Life

By patients
1

(Secondary and tertiary prevention)

Expectation of Life

Dreyer,1997

GOALS OF DIABETES MANAGEMENT

Reliev symptoms
Maintain normal weight
Achieve normal activity
Maintain normal blood glucose levels (70
140 mg%)
Achieve acceptable HbAIc (< 7%)
Prevent long-term and short-term
complications
Prevent hypoglycemic and hyperglycemic
reactions

The New Paradigm of Type 2


Diabetes Treatment
Aggressive Treatment Driven by
Target (AIC < 7%)
Early Combinations
Early Insulin Treatment

Tighter Glycaemic Control


Biochemical Index

Normal

Goal

Additional Action
Suggested

(mg/dl)
Plasma value
Average preprandial
Average bedtime

< 100
< 120

90 130
110 150

< 90 or > 150


< 110 or > 180

Whole blood
Average preprandrial
Average bedtime

< 100
< 110

80 120
100 140

80 or > 140
< 100 or > 160

AIC

< 6%

<7

>8

Blood pressure
Lipids
- LDL
- Triglycerides
- HDL

< 130/80 mmHg


< 100 mg%
< 150 mg%
> 40 mg%

Correlation Between AIC level and


Mean Plasma Glucose
AIC (%)
6
7
8
9
10
11
12

Mean Plasma Glucose


mg%

mmol/L

133
170
205
240
275
310
345

7.5
9.9
11.5
13.5
15.5
17.5
19.5

Rohlfing CL et al. Diabetes Care 25; 275:, 2002

Prevalence of retinopathy by deciles of the distribution of FPG, 2-h


PG, and HbA1c in Pima Indians (A) described by McCance et al. (129),
in Egyptians (B)

Treatment of DM
Nutrition Therapy, Exercise, Lifestyle
Changes
Pharmacological Treatment
- Insulin
- Oral diabetes medications
Pancreas/Islet-cell transplantations

Education

Nutrition Therapy, Exercise,


Lifestyle Changes
Nutrition therapy

decrease fat content and total calories


decrease saturated fat
decrease salt for hypertension
healthy diet
weight reduction in obese patients

Exercise
increase energy expenditure with
moderate-intensity exercise

Lifestyle changes to reduce cardiovascular risk factors


(eg, smoking cessation)
Training in self-management and SMBG

PHARMACOTHERAPY
Oral Diabetic Medications

Treatment Based on the Pathophysiology


of Hyperglycemia in Type 2 Diabetes

-cell dysfunction

Insulin resistance

Insulin
Secretagogues

Insulin
Sensitizer

Treatment Based on the


Pathophysiology of Hyperglycemia in
Type 2 Diabetes
Fasting Hyperglycemia Prandial Hyperglycemia

Insulin basal
Sulfonylureas
Metformin

Insulin prandial
Glinide
Glitazones
(-Glucosidase
inhibitors)

Causes of Hyperglycemia in Type 2 Diabetes :


Site of action of oral agents
Peripheral Tissues

Metformin
Liver

Receptor +
postreceptor defect

Glucose

Muscle

Insulin
resistance

Glucose uptake
Prandial plasma
glucose

Insulin
resistance
Glucose production
Fasting plasma glucose

Pancreas

Fat
Glitazones

Impaired insulin Insulin secretagogues


secretion

Insulin Secretagogues

MECHANISM OF ACTION

Sulfonylureas: Efficacy
Approximately 50% of patients with newly
diagnosed type 2 diabetes achieve
acceptable glycemic control
About 15%-20% of patients have little or no
glycemic response

1997 PPS

Lebovitz HE. In: Joslin's Diabetes Mellitus. 1994:508-529.

Nateglinide Controlled
Postprandial Spikes

Nateglinide Controlled
Postprandial Spikes

INSULIN SENSITIZER
- Predominant Action in the Liver (Metformin)
- Predominant Action in the Peripheral InsulinSensitive Tissues (Thiazolidine diones)

METFORMIN

Metformin Monotherapy:
Effects on Lipids
10

5
Mean
change
from
baseline (%)

0
-1

-2

-5

Metformin (n=143)

-10
-15

-11*

-11*

Placebo (n=146)
-17

-20
Total-C

LDL-C

Triglycerides

HDL-C

*P<0.05 vs placebo

1998 PPS

DeFronzo RA et al. N Engl J Med. 1995;333:541-549.

Model for the mechanism by which metformin mediates effects on


lipid and glucose metabolism (Zhou G et al. JCI; 2001: 108, 1167-

Genes regulated by SREBPs

DHCR, 7-dehydrocholesterol reductase; FPP, farnesyl diphosphate; GPP, geranylgeranyl


pyrophosphate synthase; CYP51, lanosterol 14 -demethylase; G6PD, glucose-6-phosphate
dehydrogenase; PGDH, 6-phosphogluconate dehydrogenase; GPAT, glycerol-3-phosphate
acyltransferase (Horton et al. JCI 2002; 109; 1125)

Effects of Metformin Monotherapy or


Combination Therapy With Glyburide
Change in
fasting plasma
glucose (mg/dL)
Diet + placebo

20

40
20

Glyburide

Metformin

-20

-20
Diet + metformin

-40

-60
0

13 17

21 25 29

Week

-40

Metformin + glyburide

-60
-80

13 17

21 25 29

Week

*P<0.001

P<0.001 glyburide-metformin vs glyburide

P<0.001 metformin vs glyburide

P<0.01 metformin vs glyburide

1998 PPS

DeFronzo RA et al. N Engl J Med. 1995;333:541-549.

Adjunctive Metformin Therapy in InsulinTreated Patients With Type 2 Diabetes and


Suboptimal Glycemic Control
HbA1c (%)

FPG
100

50

Change
0
after
treatment
(mg/dL) -50

Change
0
after
treatment
-1

-100

-2

Placebo Metformin

-3
Placebo

Metformin

P<0.001; mean SD

Robinson AC et al. Diabetes Care. 1998;21:701-705.

The New Paradigm of Type 2


Diabetes Treatment
Aggressive Treatment Driven by
Target
Early Combinations (Oral-oral/OralInsulin)
Early Insulin Treatment

Thiazolidinediones
(Glitazones)

Fasting and Postprandial Blood Glucose and


HbA1c Responses to Pharmacologic Treatment in
Patients With Type 2 Diabetes
Decrease in
HbA1c
1-h PPBG (
Drug
Sulfonylurea
Repaglinide
Metformin
Troglitazone
Roziglitazone
Pioglitazone
-GI
Insulin

FBG (mg/dl)

from baseline)
(mg/dl)

( from baseline)

40 60
30.3
53
24 48
25 55
20 55
20 30
Potentially
normalized

.
56.5
.
.
.
.
20 74
Potentially
normalized

1 2%
1.1%
1 - 2%
0.2 1%
0.1 0.7%
0.3 0.9%
0.5 0.1
Potentially
normalized

The Triumvirate : -cell, muscle, liver. A collusion


responsible for NIDDM

Tissue uptake of glucose in nondiabetic and diabetic subjects


during hyperinsulinemic-euglycemic clamp (Diabetes 1998; 37:

The New Paradigm of Type 2


Diabetes Treatment
Aggressive Treatment Driven by
Target
Early Oral-agents Combinations
Early Insulin Treatment

ORAL DIABETIC MEDICATION


HAS ITS LIMITATIONS

Cross-sectional and 10-Year Cohort Data:


Patients on SU/Insulin vs Conventional Treatment
200

FPG

HbA1c

180
Median
160
FPG
(mg/dL)
140

Median
HbA1c
(%)

120
6
0

100
Time from randomization (y)

Time from randomization (y)

Patients followed for 10 years


All patients assigned to regimen
Conventional
Glibenclamide (glyburide) Conventional
Glibenclamide
Chlorpropamide
Insulin
Chlorpropamide
Insulin
UKPDS Group. Lancet. 1998;352:837-853.

UKPDS Cross-sectional and 10-Year Cohort


Data: HbA1c: Intensive (Metformin) vs
9
Conventional Treatment
8
Median
HbA1c
(%)

6
0
0

6
9
12
15
Time from randomization (y)
10-year cohort
Cross-sectional
Patients followed for 10 years
All patients assigned to regimen
Conventional
Conventional
Intensive
Intensive
UKPDS Group. Lancet. 1998;352:837-853.

ORAL AGENT FAILURE RATES


Agent
Sulfonylurea
Glinide
Biguanides
-Glucosidase
inhibitor
Thiazolidinediones

Primary failure
rate

Secondary
failure rate

15 30%

5 10%/year

< 10%

5 10%/year

Dependent on diet
adherence

Unknown

As high as 25%

Unknown
Feingloss,1999

-Cell function decline steadily in type 2 diabetes.


The process begins 10 12 years before diagnosis

The New Paradigm of Type 2


Diabetes Treatment
Aggressive Treatment Treat to
Target
Early Oral-agents Combinations
Early Insulin Treatment

Algorhytm of Type 2 Diabetes Treatment


Lifestyle (dietary and activity)
Add 1st OHA
(SU or Metformin)
Titrate dose
Add 2nd OHA
(Combo)
Titrate dose
years

COMBO
(SU + Metformin)
Titrate dose
te
a
r
le

months

ce
T
c
N
A
CE
E
R

T
Add 3rd OHA
S
PA(Combo)
Begin Insulin
(Continue 1 OHA)
Titrate dose

Begin Insulin
(Continue 1 OHA)
Titrate dose

RULE OF COMBINATION
2 Drugs (or more ?) With
Different Mechanisms of Action
SULFONYLUREA + METFORMIN
METFORMIN + THIAZOLIDINEDIONE
INSULIN + ANY OTHER DRUGS

Patients who fail to respond to


monotherapy with an oral agent are
treated with combination of two
When this fails, combination of three oral
agents are unlikely to be effective
Williams G. Lancet 1994; 343: 95 -100
ADA 1998: 56 - 72

Treatment Based on the


Pathogenesis of Type 2 Diabetes
-cell dysfunction

Insulin resistance

Insulin
Secretagogues

Insulin
Sensitizer

Glibenclamide

Metformin

The New Paradigm of Type 2


Diabetes Treatment
Aggressive Treatment Driven by
Target
Early Oral-agents Combinations
Early Insulin Treatment

Algorhytm of Type 2 Diabetes Treatment


Lifestyle (dietary and activity)
Add 1st OHA
(SU or Metformin)
Titrate dose
Add 2nd OHA
(Combo)
Titrate dose
years

T
Add 3rd OHA
S
PA(Combo)
Begin Insulin
(Continue 1 OHA)
Titrate dose

COMBO
(SU + Metformin)
Titrate dose

months

te
a
r
le

Begin Insulin

ce
c
T
A
N
CE
E
R

Begin Insulin
(Continue 1 OHA)
Titrate dose

1 OHA
Titrate dose

N
A
TH

O
Y
K

O
F
U

U
O
Y
R

E
T
T
RA

N
O
I
NT

Treatment Targets for Type 2 Diabetes


(European diabetes Policy Group)
Gycaemic control
AIC (%)
Venous Plasma glucose
Fasting (mg%)
SMBG (mg%)
Fasting
Postprandial (peak)
Body mass index (kg/m2)*
Men
Women
Blood lipids
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides (fasting)
Blood pressure (mmHg)

Low risk

Arterial risk

Microvascular
risk

6.5

>6

> 7.5

110

> 110

126

5.5
7.5

> 5.5
> 7.5

> 110
9.0

At risk
4.8 6.0
3.0 4.0
1.0 1.2
1.7 2.2

High risk
6.0
4.0
< 1.0
> 2.2

< 25
< 24
Low risk
< 4.8
< 3.0
< 1.2
< 1.7

< 140/85
(European Diabetes Policy Group. Diabetes Med 1999; 16: 716-30)

Treatment Targets for Type 2 diabetes


(American Diabetes Association)
Gycaemic control (ADA,2004)
AIC (%)
Venous Plasma glucose
Fasting (mg%)
SMBG (mg%)
Fasting
Postprandial (peak)
Body mass index (kg/m2)
Men
Women
Blood lipids (ADA,2004)
Total cholesterol
LDL-cholesterol
HDL-cholesterol
Triglycerides (fasting)
Blood pressure (mmHg)
(ADA,2004)

Normal

Goal

Additional
action needed

>7

>8

100

< 110

126

100
140

< 110
90 - 130

> 110
9.0

Border line
4.8 6.0
3.0 4.0
1.0 1.2
1.7 2.2

High risk
6.0
4.0
< 1.0
> 2.2

< 23
< 22
Low risk
< 4.8
< 3.0
< 1.2
< 1.7

< 130/80

Dual defect of type 2 diabetes: treating


a moving target
Insulin
Resistance
In

su

lin

Ac
ti o

Type 2
Diabetes

Insulin
Concentration

-cell
Dysfunction

ia
em
a
yc
l
rg
e
p
y
-cell Failure H

Insulin
Resistance

Euglycaemia
Normal

IGT Obesity

Diagnosis of
type 2 diabetes

Progression of
type 2 diabetes

DeFronzo et al. Diabetes Care 1992;15:318-68

Glucovance tablet technology:


engineered to optimise drug delivery

25%

50%

Metformin
soluble matrix

75%
Glibenclamide
particle range

Donahue et al. Clin Pharmacokinet 2002;41:1301-9.