KONSEP PENGGUNAAN TERAPI

DIABETES MELLITUS ORAL DAN

INSULIN

Achmad Rudijanto
2011

Diabetes Mellitus Management

2. Exercise

1. Diet
3. BW Management

4. drugs : Pills / Insulin

5. Routinely Control

The New Paradigm of (Type 2) Diabetes

Treatment

Aggressive Treatment Driven by Target (AIC <

7%)
Early Combinations (including with insulin)
Aggressive Insulin Treatment

Hyperglycaemia and complications

% Incidence per 1000 patient-years

Type 2 diabetes
60

Myocardial
infarction
Microvascular
disease

50

40
30
20

10
0

<6

6-<7

7-<8

8-<9 9-<10

10+

Updated HbA1c (%)

UKPDS 35, BMJ 2000; 321: 405-12

HbA1c targets in current guidelines

HbA1c target (%)
ADA/EASD

<7.0

IDF

6.5

NICE

<6.5

AACE

6.5

France

<6.5*

Canada

7.0

Australia

7.0

Latin America

<6.5

*If on single or double therapy; if on triple therapy or insulin, then HbA 1c <7% Nathan
DM, et al. Diabetes Care 2009;32 193-203
http://www.idf.org/home/index.cfm?node=1457
http://www.nice.org.uk/nicemedia/pdf/CG66diabetesfullguideline.pdf
Endocrine Practice Vol 13 (Suppl 1) May/June 2007

Drouin P, et al. Diabetes & Metabolism (Paris) 1999;25:72-83.

Canadian Diabetes Association Canadian J Diab:32(suppl. 1):S1-201
http://www.nhmrc.gov.au/publications/synopses/_files/di10.pdf
http://www.revistaalad.com.ar/guias/GuiasALAD_DMTipo2_v3.pdf

GLYCEMIC TARGETS
Parameter
Premeal plasma
glucose (mg/dL)
Postprandial plasma
glucose (mg/dL)

Hb A1c

Normal

ADA

ACE

<100 (mean 90)

90-130

<110

<140

<180

<140

4%-6%

<7%

<6.5%

From American Diabetes Association. Standards of Medical Care in Diabetes2006.

Diabetes Care 2006; 29:s4-42; American College of Endocrinologists. American
College of Endocrinology consensus statement on guidelines for glycemic control.
Endocr Pract 2002;8(suppl 1):5-11.

ACE, American College of Endocrinologists; ADA, American Diabetes Association;

Dosing, efficacy and cost of oral agents for treatment of

type 2 diabetes mellitus patients
Doses (mg)

Maximum
dose (mg)

Maximum
effective
dose (mg)

HbA1c
reduction
(%)

Cost/year
($)

Glyburide

1.25, 2.5, 5

10 bid

10 qd

1.5 - 2.0

130

Glipizide

5, 10

20 bid

10 qd-bid

1.5 2.0

175

2.5, 5, 10

20 qd

5 20qd

1.5 2.0

300

Glimepiride

1, 2, 4

8 qd

4 qd

1.5 2.0

330

Repaglinide

0.5, 1, 2

4 tid

2 tid

1.5 2.0

910

Neteglinide

60, 120

120 tid

120 tid

0.5 1.0

1.100

Metformin*

500, 850, 1000

850 tid

1000 bid

1.5 2.0

600

Glucophage-XR*

500

2000 qd

2000 qd

1.5 2.0

1.000

Rosiglitazone

4, 8

8 qd, 4 bid

4 bid

1.5

1.875

15, 30, 45

45 qd

45 qd

1.5

2.110

50, 100

100 tid

50 tid

0.5 1.0

700

25, 50, 100

100 tid

100 tid

0.75 1.2

880

Glucovance*

1.25/250, 2.5/500, 5/500

5/500, 2 bid

2.5/500, 2 bid

1.3

1.400

Avandamet*

1/500, 2/500, 4/500

2/500, 2 bid

2/500, 2 bid

N/A

2.170

2.5/250, 2.5/500, 5/500

5/500, 2 bid

5/500, 2 bid

2.1

1.400

Agent

Glipizide-GITS*

Pioglitazone
Acarbose
Miglitol

Metaglip*

Incretin mimetic / DPP IV inhibitor

Sheehan MT. Clinical Medicine & Research 2003; 1 (3): 189-200

Thier-1: Well-validated core therapies

At diagnosis:
Lifestyle
+
metformin

Step-1

Lifestyle + Metformin
+
Intensive insulin

Lifestyle + Metformin
+
Basal insulin

Lifestyle + Metformin
+
Sulfonylureaa

Step-2

Step-3

Thier-2: Less well-validated core therapies

Lifestyle + Metformin
+
Pioglitazone
No hypoglycemia,
CHF, edema, bole loss

Lifestyle + Metformin
+
GLP1 agonistb
no hypoglycemia
weight loss
nausea/vomiting

Lifestyle + metformin
+
Pioglitazone
+
Sulfonylureaa

Lifestyle + Metformin
+
Basal insulin

Algorithm for the metabolic management of type 2 diabetes; Reinforce lifestyle interventions at every visit and check A1C every 3
months until A1C is 7% and then at least every 6 months. The interventions should be changed if A1C is 7%. a Sulfonylureas other
than glybenclamide (glyburide) or chlorpropamide. b Insufficient clinical use to be confident regarding safety.

(ADA-EASD, Diabetes care 32:193, 2009)

Type-2 DM management
DIiagnosis

STEP-1

STEP-2

STEP-3

GHS
Oral mono-therapy
GHS
2 combo-therapy
GHS
2 combo-therapy
+
Basal insulin

3 combo-therapy

Perkeni, 2011

GHS
Intensive Insulin
Basal plus
Basal bolus

Policy for the Selection of Glucose Lowering Therapy

Glucometabolic Situation

Policy

Postprandial hyperglycemia

-glucosidase inhibitors, Shortacting SU, Glinides, Short/rapid-acting insulin

Fasting hyperglycemia

Biguanides, long-acting SU,

glitazones, long-acting insulin

Insulin resistant

Biguanides, glitazones,
-glucosidase inhibitors

Insulin deficiency

SU, glinides, insulin

Reyden L. Eur Heart J 2007; 28: 88-136

Target of Treatment
Mechanism of Hyperglycemia

-Cell defect

Insulin resistance
(liver, muscle, fat tissue)

Fasting - hyperglycemia

PP - hyperglycemia

Manifestation of Hyperglycemia

Choice of agents in future use ?

Glipizide
Gliclazide
Glimepiride
Glibenclamide

TZDs

insulin
Sulphonylureas

Metformin

Rosiglitazone
Pioglitazone

insulin

Acarbose
Miglitol
Voglibose

a-glucosidase
inhibitors

Meglitinides

DPP-IV inhibitor / GLP-1 ?

Repaglinide
Nateglinide

How can we treat patients with >10% of

A1C?
Initiating therapy with oral agents is a

reasonable approach to take most patients.

The exception being patients with extreme
hyperglycemia as:
FBG >250 mg/dl
RBG levels consistently > 300 mg/dl
when A1C >10.4%
Severe metabolic disturbances
Nathan, Diabetes Care 32:193203, 2009
De Fronzo, Ann Intern Med 131:281-303, 1999
Hayward, JAMA 278:1663-1669, 1997

Type-2 DM management
DIiagnosis

STEP-1

STEP-2

STEP-3

GHS
Oral mono-therapy
GHS
2 combo-therapy
GHS
2 combo-therapy
+
Basal insulin

3 combo-therapy

Perkeni, 2011

GHS
Intensive Insulin
Basal plus
Basal bolus

PHARMACOKINETIC PROPERTIES OF INSULIN

PREPARATION
Preparation

Onset (hr)

Peak (hr)

Duration (hr)

RAPID ACTING
Regular

0.5-1

2-4

6-8

Lispro

0.25

3-4

Aspart

0.25

3-4

Glulisine (apidra)

0.25

3-4

INTERMEDIATE ACTING

NPH

1-3

6-8

12-16

LONG ACTING

Glargine

NA

11-24

Detemir

3-9

6-23

NPH, neutral protamine Hagedorn

The relative contribution of FPG and mealtime glucose

spikes to 24-hour glycemic control

Plasma glucose
(mg/dl)

300

200

Prandial BG

Prandial BG target
of treatment

Fasting BG

100
Normal BG

0600

1200

1800
Time (hours)

2400

0600

The relative contribution of FPG and mealtime glucose

spikes to 24-hour glycemic control

Plasma glucose
(mg/dl)

300

200

Prandial BG

Prandial BG target
of treatment

Fasting BG

100
Normal BG

0600

1200

1800
Time (hours)

2400

0600

Impact of fasting and postprandial glycemia on overall

glycemic control in type 2 diabetes. Importance of
postprandial glycemia to achieve target HbA1c levels
Fig. 2: Relative contribution of postprandial glycemia over HbA1c sixtiles

Contribution (%)

80
60

40

Contribution (%)

100

fast. BG
pp BG

20
0

HbA1c sixtiles (%)

4.7-6.2 6.2-6.8 6.8-7.3 7.3-7.8 7.8-8.9 8.9-15.0
HbA1C sixtiles

Woerle, H. J., et al; Diabetes Research and Clinical Practice 77 (2007) 280-285

Kapan diberikan insulin sebagai

langkah pertama?

INSULIN AS FIRST STEP OF

DIABETES TREATMENT

Body Mass Indexs Profile

BMI : > 23
BMI: 18 23

BMI: < 18

Metformin, AGI, TZD, DPP-IV Inh.

Metformin, SU/glinid, AGI, DPP-IV Inh.
Insulin

Choice of treatment based

on patient A1c distribution

<7
78
89
>9

life style modification

single/combination oral drugs
combination oral drugs
oral drugs combination
insulin (basal / combination)

Grading of type-2 DM based on level of fasting

glycemia and suggestion of insulin treatment
FPG
(mg/dl)

Grade

< 126

Mild

126-200

Insulin therapy and doses required

Virtually never needed

Moderate Basal insulin is needed:

-Intermediate acting insulin at bed-time or
-Long-acting insulin 1 - 2x/day
-Dose required: 0.3 0.4 u/kg BW/day

200

Severe

Intermediate acting insulin 2x/day + short

acting insulin

250

Very
severe

Treat as type-1 DM (initially)

1 2x basal + 3x bolus (pre-meal)
Skyler, 2005

HbA1c still out of target

Basal first

what next

Impact of fasting and postprandial glycemia on overall

glycemic control in type 2 diabetes. Importance of
postprandial glycemia to achieve target HbA1c levels
Fig. 2: Relative contribution of postprandial glycemia over HbA1c sixtiles

Contribution (%)

80
60

40

Contribution (%)

100

fast. BG
pp BG

20
0

HbA1c sixtiles (%)

4.7-6.2 6.2-6.8 6.8-7.3 7.3-7.8 7.8-8.9 8.9-15.0
HbA1C sixtiles

Woerle, H. J., et al; Diabetes Research and Clinical Practice 77 (2007) 280-285

The relative contribution of FPG and mealtime glucose

spikes to 24-hour glycemic control

Plasma glucose
(mg/dl)

300

200

Prandial BG

Prandial BG target
of treatment

Fasting BG

100
Normal BG

0600

1200

1800
Time (hours)

2400

0600

The relative contribution of FPG and mealtime glucose

spikes to 24-hour glycemic control

Plasma glucose
(mg/dl)

300

200

Prandial BG

Prandial BG target
of treatment

Fasting BG

100
Normal BG

0600

1200

1800
Time (hours)

2400

0600

Pharmacological treatment of Type 2

diabetes

29

Initiating and adjusting insulin

Bedtime intermediate-acting insulin, or
bedtime or morning long-acting insulin
(initiate with 10 units or 0.2 units per kg)

Check FG and increase dose until in target range

Pre-lunch BG out of range: add

rapid-acting insulin at breakfast

If FBG in target range, check BG before lunch, dinner, and bed. Depending on
BG results, add second injection
(can usually begin with ~4 units and adjust by 2 units every 3 days until BG in range)

Pre-dinner BG out of range: add NPH insulin at

breakfast or rapid-acting insulin at lunch

If HbA1c < 7%

Continue regimen; check

HbA1c every 3 months

3.89-7.22 mmol/L
(70-130mg/dL)

If HbA1c 7%

If HbA1c < 7%

Continue regimen; check

HbA1c every 3 months

Target range FBG:

Pre-bed BG out of range: add rapidacting insulin at dinner

If HbA1c 7%

Recheck pre-meal BG levels and if out of range, may need to add another injection; if
HbA1c continues to be out of range, check 2-hr postprandial levels and adjust preprandial
rapid-acting insulin

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

Intensify insulin if HbA1c is still 7%

ADA/EASD recommend the stepwise addition of
prandial insulin to intensify a basal insulin regimen
If fasting blood glucose (FBG) levels are in target range but HbA1c 7%,
check blood glucose before lunch, dinner, and bedtime and
add

If pre-lunch blood glucose is

out of range...

Add short acting

Insulin at breakfast

or

If pre-dinner blood glucose is

out of range...

or

Add NPH at breakfast or

short or rapid acting
insulin at lunch

If pre-bed blood glucose is

out of range...

Add short or rapid acting

insulin at dinner

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

2. The Basal Plus strategy: introduction

Matching treatment to disease progression

using a stepwise approach
Basal Plus
Basal : once-daily basal insulin
Plus
: once-daily rapid-acting insulin

Basal Bolus
Add prandial insulin before each meal

Basal Plus
Add prandial insulin at main meal

Basal
Add basal insulin and titrate

Lifestyle changes plus metformin ( other agents)

Progressive deterioration of -cell function
*As the disease progresses, a second daily injection of glulisine may be added
Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:25764

PREMIXED INSULIN

1.4 Insulin glargine and intensification

A proposed sequence for optimizing insulin

therapy for type 2 diabetes
Lifestyle modification and OHAs
Basal therapy
Long-acting insulin like glargine,
detemir or NPH

Premixed insulin x1

Premixed insulin x2
Basal-Plus therapy
e.g. glargine plus a prandial
rapid-acting insulin like glulisine

Premixed insulin x3

BasalBolus therapy
e.g. glargine plus 3 doses of a prandial rapidacting insulin like glulisine

No further options

Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007;23:25764