The

Principle Management
of Type 2 DM

Objectives
Natural history of disease progression
Early detection and diagnosis
Principle management of type 2 DM
Treatment recommendation
Perkeni algoritm
The Role of Oral Hypoglycemic Agent
(OHAs) in Type 2 DM Management
Initiation Insulin Therapy

Natural History of Disease Progression

Aggressive treatment of established c ardiovascular
risk factors
Macrovascular complications
Microvascular complications

Aggressive glycemic control

-cell function
Insulin
resistance
Blood
glucose

10

Prevention

0
Diagnosis

Treatment

10

Years

2 d iabetes
Type
IGT/IFG
Prevention of IGT

Prevention of progression of IGT to Type 2 DM

Adapted from Bergenstal RM, et al. Diabetes mellitus, carbohydrate metabolism and lipid disorders. In Endocrinology. 4th ed. 2001.

Early detection and diagnosis

Plasma glucose (mmol/L)

Prediabetes
28
21
14

Healthy
lifestyle
promotion

Normal

Type-2 DM

Early
detection of
Risk Factors &
newly DM

Early
detection of
newly DM
(?)

Undiagnosed
diabetes

Type 2
diabetes
Micro-
vascular
disease

IGT

0
1

Up to 10 years

Macro-
vascular
disease

NHANES: National Health and Nutrition Examination Survey

www.cdc.gov/nchs/products/elec_prods/subject/nhanesii.htm
4
Janka HU. Fortschr Med 1992;110:63741

High Risk Screening

High-risk population at age < 30 years old
Family history of diabetes
Cardiovascular
abnormalities
Overweight
Sedentary life
History of IFG or IGT
Hypertension

Increase of TG/
decrease of HDL or
both
History of gestational
diabetes
History of delivering
infant > 4000 g
Polycystic ovary
syndrome
PERKENI Consensus Guidelines, 2011.

Algorithm of T2DM Diagnosis

Diabetes Symptoms
Diabetes Classic
Symptoms (+)

Diabetes Classic
Symptoms (-)

GDP
GDS

FPG

126

< 126

126

RBG

> 200

< 200

> 200

FBG and PPG

FPG

126

< 126

RBG

> 200

< 200

140-199

< 100
< 140

OGTT
2 hour BG
> 200

Diabetes Mellitus
Evaluation of Nutritional Status
Evaluation Diabetic Complications
Evaluation Dietary Need and Dietary Planning

FBG (Fasting Blood Glucose)

RBG (Random Blood Glucose)

100-125

IGT (Impaired Glucose Tolerance)

IFG (Impaired Fasting Glucose)

140-199
IGT

< 140
IFG

Normal

Education
Dietary Planning
Physical Exercise
Achieving Ideal Body Weight
PERKENI Consensus
Guidelines, 2011.
6

Recommendation for Glycemic Control

Parameter

Target

A1c

< 7 %

Pre-prandial capilary plasma glucose

90-130 mg/dL

Peak prandial capillary plasma glucose

after 1-2 hour meal

180 mg/dL

ADA Consensus Statement 2011

 A1c is the primary target for glycemic control should

be individualized based on:
Duration of diabetic
Age/life expectancy
Comorbid conditions
Known cardiovascular disease
Advanced microvascular complication
Hypoglycemia unawereness
Individual patients considerations

Certain population (children, pregnant women, and

elderly) need special considerations.
Less stringent glycemic goals maybe appropriate for
individual patients

Correlation between A1c with Glucose Level

Mean Plasma

Glucose

A1c (%)

mmol/L

mg/dL

4
5
6
7
8
9
10
11
12

3.5
5.5
7.5
9.5
11.5
13.5
15.5
17.5
19.5

65
100
135
170
205
240
275
310
345

Rohlfing et al. Diabetes Care 25: 275-278, 2002

Lessons From Ukpds:

Better Control Means Fewer Complications

Microvascular complications
Peripheral vascular disorders

- 14%
- 37%

Heart attacks

- 43%

Deaths from diabetes

- 21%

Reduced Risk*

Every 1%
reduction in HBA1c

*p<0.0001

UKPDS 35 BMJ 2000;321:405-412

The Problems Therapy in Type 2 DM

1. Delayed in diagnosis and treatment
2. Cannot achieve the target goals
3. Decreased effectivities of OHAs
4 . Decreased of beta cell function
5. Delayed to aggressive/ combination therapy
6. Reactive treatment paradigm, not think cell reserve

UKPDS: progressive decline of

-cell function over time

-cell function (%)

100
80

Start of treatment

60
40
P < 0.0001

20
0
10 9 8 7 6 5 4 3 2 1
Time from diagnosis (years)

HOMA model, diet-treated (n = 376)

Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(Suppl.):S21S25.

Management
Medical Nutrition
Therapy

Physical activity

Education
Oral hypoglycemic
agent

Monitoring

 Management of Type 2 DM : Long-term

Challenges
Prevent microvascular
complications

- Glycemic control

Prevent macrovascular
complications

- Glycemic control
- Improve dyslipidemia
- Control blood pressure
- Control other risk factors
(smoking etc.)

Prevent long-term
deterioration of
glucose homeostasis

Lifestyle Modicaeon
Dietary intervention
Reduce intake by 5001000 kcal/day from total daily
intake

Increased physical activity

Moderate acevity 30-45 mins/day, 3-5 emes/week
Overweight and obese individuals: Moderate acevity
45-60 mins/day 5 emes/week .

Purnamasari D et al. Identification, Evaluation and treatment of overweight and obesity in adults: Clinical
15
Practice Guidelines of the Obesity Clinic, Wellness Cluster Cipto Mangunkusumo Hospital, Jakarta, Indonesia

Evolving Treatment Paradigm in Type 2 DM

100%

- 10

-5

+5

+10

+15
Amylin (pramlintide
)

B-cell function

Insulin
GLP-1 Analogues and
DPP-IV inhibitor

Oral combination
Oral monotherapy
Diet management + exercise
0 %

Pre-diabetes

Years from Diagnosis

Joslin Diabetes Centre

Type 2 DM

Algoritme Pengelolaan DM Tipe 2 Tanpa Disertai Dekompensasi (PB PERKENI 2011)

DM

Tahap I

GHS

GHS
+
Monoterapi

Catatan
1.Dinyatakan gagal bila
dengan terapi 2-3 bulan
tidak mencapai target
HbA1c <7%

GHS
+
Kombinasi OHO

2.Bila tidak ada

pemeriksaan HbA1c dapat
digunakan pemeriksaan
glukosa darah. Rata-rata
glukosa darah sehari
dikonversikan ke HbA1c
menurut kriteria ADA 2010

Jalur alternatif
jika tidak dapat
insulin dan target
glukosa belum
optimal
Konsensus PERKENI 2011

Tahap II

GHS
+
Kombinasi OHO
+
Insulin
GHS
+
Kombinasi
3 OHO

Tahap III

Insulin

Kadar HbA1c
<7%

7-8%

GHS

GHS

Gaya Hidup
Sehat
Penurunan
berat badan
Mengatur diit
Latihan Jasmani
teratur

8-9%

>9%

9-10%

>10%

+
Monoterapi

GHS

Met, SU,
AGI, Glinid,
TZD, DPP-IV

Catatan
1.Dinyatakan gagal bila dengan
terapi 2-3 bulan tidak mencapai
target HbA1c <7%
2.Bila tidak ada pemeriksaan HbA1c
dapat digunakan pemeriksaan
glukosa darah. Rata-rata glukosa
darah sehari dikonversikan ke HbA1c
menurut kriteria ADA 2010

Konsensus PERKENI 2011

Kombinasi
2 obat

GHS

Met, SU,
AGI, Glinid,
TZD, DPP-IV

Kombinasi
3 obat

GHS

Met, SU,
AGI, Glinid,
TZD, DPP-IV

Kombinasi
2 obat

+
+

Met, SU,
AGI, Glinid,
TZD
+

GHS

Basal Insulin

+
Insulin
Intensif

Mechanism of ac]on
Agents
Insulin secretagogue
Increen
Biguanides
Thiazolidinediones
-glucosidase
-
inhibitors
Thiazolidinediones
(biguanides)

DeFronzo. Ann Intern Med 1999;131:281-303

Site of ac]on

MOA
Insulin secreeon
Glucagon and insulin
Glucose
produceon
Slow carbohydrate
digeseon
Peripheral insulin
sensievity

Therapeu]c Ac]ons of Me^ormin:

correc]ng the pathophysiology of type 2 DM
Pancreas
Impaired
Insulin secreeon
Increased
glucose
produceon

Liver

Decreased
glucose
uptake

Hyperglycaemia

Memormin

Muscle

Dose
Inieal dose: 500 mg OD improving dose in 1-2 weeks
Max dose 2.250 mg BID or TID
If goals have not been reached within 2-3 months,
medicaeon should be increased or medicaeon from a
dierent class added
Target levels should be reached within 6 months

Clinical implica]on
Advantages
Do not cause hypoglycaemia when used as mono-therapy
Do not cause weight gain; may contribute to weight loss

Disadvantages
Gastrointesenal (nausea, abdominal discomfort or diarrhea and
occasional consepaeon)
Lacec acidosis

Contraindicaeons
Renal insuciency
Liver failure
Heart failure
Severe gastrointesenal disease

Class

Generic

Brand

mg/tab

Biguanid Memormin Glucophage 500, 850

Diabex
Glumin

Daily
dose

Ini]al Dura]on Frequency

dose of ac]on
/day

250-3
000

6-8

1-3

Mechanism of Glucose-Mediated Insulin Secre]on

GLUT-2
Glucose

Glucokinase
Glucose
G-6-P

Sulfonylurea/non
sulfonylurea

Metabolism
Signal (S)
Secretory
Granules

ATP K+
ATP
ADP
Ca++

Depolarization

Ca++
Insulin Secretion

Clinical implica]on
Advantages
Increase insulin secreeon regardless of blood glucose levels
Many dierent medicines in this class
Disadvantages
Hypoglycaemia
Semulate appeete and provoke weight gain
Nausea, fullness, heartburn
Occasional rash
Swelling

Class

Sulfonyl
urea

Generic

Brand

Glibenclamide Daonil

mg/tab

Daily dose

Ini]al
dose

Dura]on
of ac]on

Frequency
/day

2.5 , 5

2.5 15

2.5

12-24

1-2

5, 10

5-20

10-16

1-2

Euglucon
Glipizide

Minidiab
Glucotrol XL

Non-
sulfonyl
urea

Gliclazide

Diamicron

80

80-240

80

10-20

1-2

Gliquidone

Glurenorm

30

30-120

30

1-3

Glimepiride

Amaryl

1, 2, 3, 4

Nateglinide

Starlix

60, 120

TID with
meal

60

6-8

With meal

Repaglinide

Novonorm

1, 2, 3, 4

TID with
meal

6-8

With meal

0.5

-glucosidase inhibitors (Acarbose)

Acarbose inhibits -
glucosidases enzyme in
the gut
This reduces and delays
the postprandial
hyperglycemia

Mechanism of ac]on
Without
Acarbose

With acarbose
Stomach

Carbohydrate
absorption

Upper small
intestine
Carbohydrates

Lower small
intestine

Carbohydrate
absorption

Clinical implica]on
Advantages
Slow digeseon of sucrose and starch and therefore delay absorpeon
Prevent post-meal hyperglycemia

Disadvantages
Flatulence, abdominal discomfort , diarrhea
As mono-therapy will not cause hypoglycemia

Contraindicaeons
Intesenal diseases, such as Crohns
Autonomic neuropathy aeceng the gastro-intesenal tract

Must be taken just during a meal

Class

Generic

Brand

-
Acarbose Glucobay
glucosidase
inhibitor

mg/tab
50, 100

Daily
dose

Ini]al Dura]on Frequency

dose of ac]on
/day

150

50

1-3

Thiazolidinedione
Troglitazone*
Rosiglitazone*
Pioglitazone
Specic to PPAR- receptor

* Has been withdrawn

Pioglitazone reduced Insulin resistance

Insulin
Insulin
receptor

Glucose

transloca

tion

PPAR +RXR
Synthesis GLUT 4

mRNA
Pio

transcription

PPRE

promoter

Coding reg

Modied from Howard L. Foyt et al. Thiazolidinediones. Diabetes Mellitus: a Fundamental and Clinical Text, 2nd Ed.

Clinical implica]on
Dose : 15-30 mg once daily
Advantages

Improve insulin sensievity

Reduce glucose output from liver
Changes fat distribueon
Reduced levels of LDL-C and increased level of HDL-C

Disadvantages
Weight gain, uid reteneon
Upper respiratory infeceon and headache
Decrease in haemoglobin

DPP-4 Inhibitor decrease

glucagon secre]on in type 2DM
T2DM
Incretin
response
diminished

Insulin
Further impaired
islet function

Hyperglycemia

Glucagon
DPP-4 inhibitor
Incretin
activity
prolonged

Insulin
Improved islet
function

Improved
glycemic control

Glucagon
DPP-4=dipepedyl pepedase-4
T2DM=type 2 diabetes mellitus
Adapted from Unger RH. Metabolism. 1974; 23: 581593. Ahrn B. Curr Enzyme Inhib. 2005; 1: 6573.

Which the alterna]ve therapy?

HbA1C

Advantages

Disadvantages

Me^ormin

1-2

No hypoglycemia,no weight gain,

Broad benet

Gastrointesenal (GI) symptoms

Contraindicated in renal insusiency

SU

1.5

Rapidly eeceve, inexpensive

Weight gain and hypoglycaemia

TZD

0.51.4

No hypoglycaemia, some benets

on lipids and inammaeon

Fluid reteneon, heart failure, weight

gain, expensive

Insulin

1.53+

Most eeceve, no maximum dose,

improved lipid prole

Hypoglycaemia, weight gain, need for

Self monitor blood glucose

AGI

0.50.8

No hypoglycaemia, weight neutral

GI side-eects, expensive

GLP-1
analogue

0.51.0

No hypoglycaemia, weight loss

GI side-eects, expensive, injected

DPP-4
inhibitor,

0.50.8

Weight neutral

Long-term safety not established,

expensive

Megli]nide

1.01.5

Fewer hypoglycemia than

sulfonylurea

TID dosing, expensive

Pramlin]de*

0.51.0

Weight loss

Three injeceons daily, frequent GI

side eects, long-term safety not
established, expensive

Nathan, et al. Diabetes Care 2009;32: 193-203

*not yet available in Indonesia

Factors to Consider when Choosing

an Oral Hypoglycemia Agents
Eeceveness in lowering glucose
Extraglycemic eects that may reduce long-term
complica]ons
Safety prole
Tolerability
Expense
Eect on body weight

1.
2.

ADA Consensus Statement 2011

Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Increasing or adding
Oral Hypoglycemia Agent
If goals have not been reached within 2-3 months,
medicaeon should be increased or medicaeon from a
dierent class added
Target levels (A1c) should be reached within 6 months
Insulin should be added if necessary to reach target
levels

Review of the Physiologic

Insulin Profile

Serum Insulin (mU/L)

50

Mealtime insulin excursions

Rapid rise; short duration

40
30

Smooth, steady
basal insulin profile

20
10
0

BP=blood
0800
pressure;
Breakfast
QOL=quality of life

1200
Lunch

1600
2000
Dinner

Adapted from Kruszynska Y et al. Diabetologia 1987;30:16.

2400

0400

0800

38

Insulin in Indonesia
Peak of
Action

Duration of
Action

Presentation

30-60 min

120-180
min

5-8 hour

Vial, Pen/
Cartridge

Insulin Lispro (Humalog)

5-15 min

30-90 min

3-5 hour

Pen/Cartridge

Insulin Glulisine (Apidra)

5-15 min

30-90 min

3-5 hour

Pen

Insulin Aspart (Novorapid)

5-15 min

30-90 min

3-5 hour

Pen, Vial

Type of Insulin

Onset of
Action

Insulin Prandial (Meal-Related)

Insulin Short-Acting
Regular (Actrapid,
Humulin R)
Insulin Analog Rapid-Acting

PERKENI Consensus Guidelines, 2011.

39

Insulin in Indonesia
Onset of
Action

Peak of
Action

Duration of
Action

Presentation

2-4 hour

4-10 hour

10-16 hour

Vial, Pen/
Cartridge

Insulin Glargine (Lantus)

2-4 hour

No Peak

20-24 hour

Pen

Insulin Detemir (Levemir)

2-4 hour

No Peak

16-24 hour

Pen

70% NPH 30% Regular

(Mixtard, Humulin 30/70)

30-60 min

Dual

10-16 hour

Pen/Cartridge

70% Insulin Aspart Protamin

30% Insulin Aspart (Novomix
30)

10-20 min

Dual

15-18 hour

Pen

75% Insulin Lispro Protamin

25% Insulin Lispro (HumalogMix
25)

5-15 min

Dual

16-18 hour

Pen/Cartridge

Type of Insulin
Insulin Intermediate-Acting
NPH (Insulatard, Humulin N)
Insulin Long-Acting

Insulin Campuran

PERKENI Consensus Guidelines, 2011.

40

Initiation and Titration of Basal Insulin

Bedtime or morning long-acting insulin
OR
Bedtime intermediate-acting insulin
Daily dose: 10 U or 0.2 U/kg

Check
FBG daily
Increase dose by 2 U every 3 days until
FBG is 3.97.2 mmol/L (70130 mg/dL)
If FBG is >10 mmol/L (>180 mg/dL),
increase dose by 4 U every 3 days

Initiate insulin with a single

injection of a basal insulin,
such as insulin glargine

In the event of hypoglycemia or

FBG level <3.9 mmol/L (<70 mg/
dL), reduce bedtime insulin dose
by 4 units, or by 10% if >60
units

Continue regimen and

check HbA1c every 3 months
Nathan DM et al. Diabetes Care 2009;32:193-203.

41