Rationale of Early and Aggressive

Insulin Treatment

Agus Yuwono

Division of Endocrinology, Department of

Medicine, Ulin Hospital, Medical Faculty,
Lambung Mangkurat University

Sejarah Perkembangan
insulin

s/d 1983

1921
: penemuan insulin
: era insulin hewan
Menggunakan ekstrak pankreas hewan (sapi / babi)

1983

: era Human insulin

Menggunakan rDNA manusia untuk menghasilkan insulin

1999

: era insulin modern (analog) dimulai

Menggunakan teknologi bioengineering untuk memodifikasi
rantai DNA human insulin untuk membuat insulin baru yang
lebih baik dalam hal farmakologi
Saccharomyces cerevisiae

Sejarah Perkembangan

The New Paradigm of (Type 2)

Diabetes Treatment
Aggressive Treatment Driven by
Target (AIC < 7%)
Early Combinations (including with
insulin)
Agressive Insulin Treatment

Rationale for
Aggressive Treatment

r:ndei:6855:slides:bernsteintitle

Type 2 diabetes is NOT a mild

disease
Stroke
Diabetic
Retinopathy
Leading cause
of blindness
in working age
adults1

2 to 4 fold increase in
cardiovascular
mortality and stroke3

Cardiovascular
Disease
8/10 diabetic patients
die from CV events4

Diabetic
Nephropathy
Leading cause of
end-stage renal disease2

Diabetic
Neuropathy
Leading cause of
non-traumatic lower
extremity amputations5

Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99S102. 2Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94S98.
3
Kannel WB, et al. Am Heart J 1990; 120:672676. 4Gray RP & Yudkin JS. In Textbook of Diabetes 1997.
5
Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78S79.

Serious Complications of Type 2

Diabetes are Present at Diagnosis
Complication

Prevalence
(%)*

Any complication

50

Retinopathy

21

Abnormal ECG

18

Absent foot pulses ( 2) and/or ischaemic feet

Impaired reflexes and/or decreased vibration sense

14

Myocardial infarction/angina/claudication
* Some patients had more than one complication at time of diagnosis
Stroke/transient
ischaemic attack
ECG = electrocardiogram

7
~23
~1

Adapted from UKPDS Group. UKPDS 6. Diabetes Res 1990; 13:111.

DCCT: Results Summary

Improved control of blood glucose
reduces the risk of clinically meaningful
Retinopathy

76%

(P0.002)

Nephropathy

54%

(P<0.04)

Neuropathy

60%

(P0.002)

Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993;329:9

Hubungan Kadar HbA1C dengan

Risiko Komplikasi pada DM
124.9

Komplikasi Diabetes
per 1000 pasien / tahun

140
120

103.2

100

74.5
65.5

80
48.7

60

35.9

40
20
0

10

11

Nilai Rata-rata HbA1C selama Pengobatan

UKPDS 35. BMJ 2000; 321: 405-1

The UKPDS
Type 2 diabetes

1%
HbA1c

> 5,000 patients; 14 years

Life-style vs oral vs
insulin

35% microvascular complication

14% myocardial infarction

-cell function (% of normal by HOMA)

Decline of -cell function determines

the progressive nature of T2DM
100

Time of diagnosis

80

60

Pancreatic function
= 50% of normal

40

20

0
10

Time (years)
HOMA=homeostasis model assessment.
UKPDS Group. Diabetes 1995;44:124958.
Adapted from Holman RR. Diabetes Res Clin Pract 1998;40(suppl 1):S215.

PRINCIPLES OF INSULIN
TREATMENT
Insulin regiment mimicking
(endogenous) physiologic
insulin secretion

Treatment Based on the

Pathophysiology of Hyperglycemia
in Type 2 Diabetes
Fasting Hyperglycemia Prandial Hyperglycemia

Insulin long-acting
(Insulin basal)
Long-acting SU
Metformin
Glitazone

Insulin prandial
Short-acting Insulin
Short-acting SU
Glinide
Glitazones
Acarbose

The Physiological Requirement for Insulin

Basal

Pancreatic output :
basal prandial

Basal insulin : the amount of insulin necessary to prevent fasting

gluconeogenesis (fasting hyperglycemia) and ketogenesis
Prandial insulin : the amaount of insulin necessary to cover meals
without development of posprandial hyperglycemia

Physiologic Plasma Glucose and Insulin Secretion:

24-hour profile
Meals

Prandial insulin

Basal insulin

Prandial glucose

Basal glucose

Normal Insulin Secretion

The Basal-Bolus Insulin Concept
Endogenous Insulin

Insulin Effect

Bolus Insulin
Basal Insulin

HS

Time of Administration
B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB et al. Diabetologia. 1999;42:1151-1167.

Insulin Analog (Generasi Baru)

Modifikasi dengan mengubah,
mengganti atau menambah asam
amino ke dalam struktur Insulin
Lispro dan Aspart: absorbsi cepat
dan durasi kerja lebih singkat
dibanding reguler insulin
Glargin dan Detemir: absorbsi
lambat dan durasi kerja lebih
panjang
Tujuannya::agar profil aksi yang
dihasilkan lebih fisiologis dan
lebih optimal

Insulin Analogs:
Fatty Acid Acylated insulins
Insulin Lispro (Humalog) (1996)
Insulin Aspart (NovoRapid) (2000)
Insulin Glargine (Lantus) (2002)
Insulin Detemir (Levemir) (Jun.,2005)
Insulin Glulisine (Apidra) (Jan., 2006)

 Insulin Bolus
Disuntikkan sesaat sebelum
makan atau sesudah makan
Menurunkan GD postprandial
Dapat digunakan untuk drip iv
Larutan jernih

30% Insulin Bolus dan 70% Insulin Basal

Disuntikkan sesaat sebelum makan atau sesudah
makan, 1-3 kali sehari
Menurunkan GD postprandial dan GD puasa
Tidak dapat digunakan untuk drip iv
Suspensi keruh

- Insulin Basal
-Disuntikkan sesaat sebelum tidur
malam, sekali sehari
- Menurunkan GD puasa
- Tidak dapat digunakan untuk drip iv
- Larutan jernih

Indikasi Terapi Insulin Intravena

1.

Indikasi kuat (evidence based medicine)

Ketoasidosis Diabetikum
HyperOsmolar Nonketotic Coma (HONC)
Penyakit Berat / Kritis
Infark miokard atau syok kardiogenik
Periode pasca operasi kardiak

Indikasi Terapi Insulin Intravena

2. Indikasi relatif (evidence belum banyak bila
dilihat dari data-data outcome)
DM tipe 1 atau 2 yang perlu total parenteral
nutrition (TPN)
Persiapan operasi (perioperative care)
GD akibat terapi steroid dosis tinggi
Stroke
Strategi penentuan dosis insulin
Kehamilan dan persalinan
Infeksi, atau keadaan lain yang perlu GD ketat

PRINSIP TERAPI
Insulin Basal: mengatasi hiperglikemia puasa akibat
glukoneogenesis (intermediate-acting insulin long-acting
insulin)
Insulin Prandial/ Nutrisional: mengatai glukosa yang
diberikan lewat intravena, TPN, lewat sonde lambung,
nutrisi tambahan dan makanan bebas (rapid-acting
insulin short-acting insulin)
Insulin suplemen/koreksi: memenuhi kebutuhan insulin
yang meningkat akibat penyakit akut / stres (rapid-acting
insulin atau short-acting insulin)

Syarat Metoda Pemberian Insulin

Efektif dengan risiko hipoglikemia minimal
Mudah dilaksanakan di semua unit rumah
sakit
Mudah untuk diinstruksikan
Mudah untuk dilaksanakan
Cost effective

Why Acting Insulin Analogs ?

Kelemahan Human Insulin

(Actrapid/Mixtard)
Period of unwanted
hyperglycemia

Change in serum insulin

Normal insulin secretion

at mealtime
Human insulin
Period of unwanted
hypoglycemia

Human Insulin HARUS

Baseline
disuntikkan
30 menit
sebelum level
makan

Time (h)
SC injection

Kelemahan Human Insulin Insulatard (NPH)

Memiliki puncak risiko nokturnal hipo sangat tinggi

Absorbsi insulin bervariasi, bahkan

di pasien yang sama kendali gula darah
tidak terprediksi

tidak bekerja 24 jam

Treatment Based on the

Pathophysiology Hyperglycemia in
Type 2 Diabetes
Fasting Hyperglycemia

Insulin basal

Prandial Hyperglycemi

Insulin prandial

Profil Insulin Analog sangat mirip dengan Insulin Endogen

-------

Insulin endogen
Levemir
NovoRapid
NovoMix

Makan
Pagi

Makan
Siang

Makan
Malam

Sebelum tidur

Insulin Regiments

Insulin Treatment
for Type 2 Diabetes Patients
Basal First
Basal Plus
Basal Bolus

When to Start With

Insulin Therapy ? Which
insulin ?

Tahap 1

Tahap 2

Tahap 3

Gaya hidup +
Saat diagnosis:

Metformin +

Gaya hidup

Insulin basal

+
Metformin
Well validated
core therapies

Gaya hidup +
Metformin +

Metformin +

Insulin intensif
+
Basal insulin

Sulfonilurea
Gaya hidup +
Metformin +

Less well
validated core
therapies

Gaya hidup +

Gaya hidup +
Metformin +

Pioglitazon

Pioglitazon +
sulfonilurea

Gaya hidup +

Gaya hidup +

Metformin +

Metformin +

GLP-1 agonis

Basal insulin
Nathan DM et al, Diabetes Care 32:193203, 2009

Insulin can be initiated anytime

Traditionally, insulin had been reserved as the last line of therapy
Considering the benefits of normal glycemic status,
insulin can be initiated earlier, as soon as is required.

Inadequate
Lifestyle

1 OAD

2 OAD

Initiate

3 OAD

Insulin

Indication: Permanent

Not permanent

T1DM

Infection

OAD failure

Pregnancy

OAD Contra Indication

Hospitalized

Diabetic Ketoacidosis

Perioperative

Strategy of
Insulin Treatment ?

1. If Fasting BG is elevated, start for basal insulin

with long acting insulin (Levemir)
2. If Prandial BG is elevated, start for prandial
/bolus insulin with rapid acting insulin
(NovoRapid)
3. If Fasting and Post Prandial are elevated :
- Oral agent with basal insulin
- premix insulin (NovoMix)
- basal/bolus as in multiple daily injection (MDI)

Treatment Based on Type of Hyperglycemia

BASAL PRANDIAL CONCEPT
Prandial

Hyperglycemia

Basal

Treat fasting hyperglyc. first

Continue oral agent
SMBG is important

Prandial Insulin

Basal Insulin (Levemir)

(NovoRapid)

Untuk mensimplekan terapi gunakan NovoMix

(30% : Prandial Insulin & 70% : Basal Insulin)

Recommendation

Insulin Treatment
for Type 2 Diabetes Patients
Basal First !!!

Insulin after oral failure

Continue oral agent
Start one injection NPH at bed-time or longacting analogue
Insulin by night tablet(s) by day

Insulin Regimen Consisting of Bedtime

Injection
of Intermediate-acting Insulin ( NPH or
LENTE )
INSULIN EFFECT

A
Morning

Evening
Afternoon

Night

Oral

DETIMIR/glargin

S
MEALS

HS

Oral

Starting Basal Insulin

Start dose around 10
Ajust NPH/Long-acting analogue dose by
fasting SMBG
Increase insulin dose every 3 to 5 days as
needed (2 4 )
Treat to target basal (fasting)< 110 mg%)

The Basal Plus Concept

When basal insulin added to oral agents
does not sustain target A1c
Add mealtime insulin stepwise:
Basal +1 2nd injection before the largest
meal
Basal +2 3rd injection before 2nd largest
meal
Basal +3 4th injection before 3rd meal
(basal bolus)
Meal related insulin (short-/rapid-acting insulin)

The Basal Plus Concept

When basal insulin added to oral agents
does not sustain target A1c
Add mealtime insulin stepwise:
Basal +1 2nd injection before the largest
meal
Basal +2 3rd injection before 2nd largest
meal
Basal +3 4th injection before 3rd meal
(basal bolus)
Meal related insulin (short-/rapid-acting insulin)

The Basal Plus Concept

When basal insulin added to oral agents
does not sustain target A1c
Add mealtime insulin stepwise:
Basal +1 2nd injection before the largest
meal
Basal +2 3rd injection before 2nd largest
meal
Basal +3 4th injection before 3rd meal
(basal bolus)
Meal related insulin (short-/rapid-acting insulin)

Basal/Bolus Treatment Program

Breakfast

Lunch

Dinner

RI, Aspart, Lispro

or Glulisine

Plasma
insulin

Glargine
Or Detemir

4:00
Date

8:00

12:00

16:00

Time

Presentation title

20:00

24:00

4:00

8:00
54

The Basal/Basal Plus strategy for T2DM

Stepwise intensification of treatment for continuity of control
FBG at target
HbA1c above target

Basal bolus
Additional prandial
doses as needed

FBG above target

HbA1c above target

Basal Plus
Add prandial insulin at main meal

HbA1c above target

Basal
Add basal insulin and titrate

Oral agents
Lifestyle changes
Date

Progressive deterioration of -cell function

Presentation title

Adapted from Raccah D, et al. Diabetes Metab Res Rev 2007 (in press).

55

10

Starting Basal-Bolus Program

In general
Calculate Total Daily Dose by using 0.5 times to
Patient Body Weight (kg)
Example :
Patients Body weight
: 60 kg
Total daily dose is : 0.5 x 60 kg : 30 iu

Use 60% of Total Daily Dose as Prandial dose

(divided by 3) and 40% of TDD as Basal dose

Date

PERKENI, Petunjuk praktis terapi insulin pada pasien DM, 2007

Presentation title

56

Petunjuk Praktis Basal Bolus

Regimen Basal Bolus

Date

Presentation title

57

Summary
Starting insulin therapy with basal insulin
analogue to achieve optimum FPG
Insulin treatment must be evaluated
because diabetes as progressive disease
Novomix as simple and effective
intensification after basal failed
Basal bolus is an ideal treatment option,
since provide optimal A1C control but has
a limitation as 4 times injection daily
58

continuous glucose monitoring system

(CGMS). The CGMS records up to 288
glucose readings per day

Smart insulin pumps. Smart insulin pumps have several software enhancements
that estimate the appropriate correction bolus based on the current blood glucose
(BG) minus any active insulin on board from a prior insulin bolus plus the amount of
insulin to cover the carbohydrates consumed.