Penatalaksanaan Diabetes Terkini Penanganan Awal Bagi Dokter Umum

KETUT ANDRIYASA

Presentation Outline

Rationality of Insulin Therapy for Type 2 DM

What is Analogue Insulin?

How & strategy of Insulin treatment ?

Barrier of using insulin

Take Home Message

InsulinInsulinResistanceResistance

Type 2 Type 2 DiabetesDiabetes

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

Definition of Diabetes MellitusDefinition of Diabetes Mellitus

Diabetes mellitus is a group of metabolic Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia diseases characterized by hyperglycemia resulting from defects in insulin secretion, resulting from defects in insulin secretion, insulin action, or bothinsulin action, or both

ββ-cell-cellDysfunctionDysfunction

PATHOPHYSIOLOGY OF HYPERGLYCEMIAPATHOPHYSIOLOGY OF HYPERGLYCEMIATHE QUINTETOPATHY OF HYPERGLYCEMIATHE QUINTETOPATHY OF HYPERGLYCEMIA

Increased Increased LipolysisLipolysis

Increased HGPIncreased HGPDecreased Decreased

Glucose UptakeGlucose Uptake

Impaired Impaired insulin insulin

secretionsecretion

HYPERGLYCEMIHYPERGLYCEMIAA

Normal

5

Impaired glucose

tolerance

Type 2 diabetes

Fasting plasma glucoseInsulin sensitivityInsulin secretion

Insulin sensitive

Normal insulin secretion

Normoglycaemia

Hyperglycaemia

β-cell exhaustion

Insulin resistance

Late type 2 diabetes

complications

Adapted from Bailey CJ et al. Int J Clin Pract 2004;58:867–876. Groop LC. Diabetes Obes Metab 1999;1 (Suppl. 1):S1–S7.

Insulin resistance

6

Obesity/genetic

Insulinresistance -cell

defect

Impairedglucose tolerance

Earlydiabetes

Latediabetes

Hyperinsulinaemia

Decreased insulinsecretion

-cell failure

Adapted from Saltiel AR. J Clin Invest 2000;106:163–164.

Normal

Why does elevated glucose cause complications?

Blood glucose/ prolonged hyperglycaemia

Oxidative stress

Structural changesto vessels

Insulin resistanceand beta-cell failure

Impaired cardiovascular regulation

Brownlee M. Nature 2001;414:813–20 Del Prato S. Int J Obes Rel Metab Disord 2002;26 (Suppl 3):S1–9 Evans JL et al. Diabetes 2003;52:1–8; Haller H. Diabetes Res Clin Pract 1998;40 (Suppl):S43–9

Komplikasi• Akut :• Ketoasidosis diabetik (KAD)

• Hiperosmolar hiperglikemia

• Hipoglikemia

• Kronis : • Komplikasi makrovaskular (penyakit

jantung koroner, stroke, penyakit vaskuler perifer)

• Komplikasi mikrovaskular (retinopati, nefropati, neuropati)

Cerebrovascular

disease

Eyes

(retinopathy)

Coronary

heart disease

Kidney

(nephropathy)

Peripheral

nervous system

(neuropathy)

Diabetic foot

Peripheral

Vascular disease

Konsensus pengelolaan dan pencegahan DM tipe 2 di Indonesia, PERKENI, 2011

Adapted from Mudaliar S et al. In: Adapted from Mudaliar S et al. In: Ellenberg and Rifkin’s Diabetes Mellitus,Ellenberg and Rifkin’s Diabetes Mellitus, 6th ed. New York, NY: Appleton and Lange; 6th ed. New York, NY: Appleton and Lange; 2003:531-557.2003:531-557.

Add insulin

Oral agent2 Oral agents

Inadequate nonpharmacologic therapy

3 Oral agents

1. Turner RC et al. 1. Turner RC et al. JAMA. JAMA. 1999;281:2005-2012.1999;281:2005-2012.2. UKPDS 24. 2. UKPDS 24. Ann Intern Med. Ann Intern Med. 1998;128:165-175.1998;128:165-175.

Oral Monotherapy Failure Is Inevitable

Failure rates for oral monotherapy in type 2 diabetes*1,2

StudyStudy 3 Years 6 Years 9 Years 3 Years 6 Years 9 Years

UKPDS 49 >45%UKPDS 49 >45% NS NS >75% >75%(N=4075)(N=4075)

UKPDS 24 UKPDS 24 NSNS 52% 52% NSNS(N=458)(N=458)

*Failure rates defined as A1C concentration >7% in UKPDS 49 and >8% in UKPDS 24.*Failure rates defined as A1C concentration >7% in UKPDS 49 and >8% in UKPDS 24.NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.NS, not studied; UKPDS, United Kingdom Prospective Diabetes Study.

Type 2 DMType 2 DM

OHA, oral hypoglycaemic agent; TZD, thiazolidinedione, troglitazone.OHA, oral hypoglycaemic agent; TZD, thiazolidinedione, troglitazone.Yale JF et al. Yale JF et al. Ann Intern Med.Ann Intern Med. 2001;134:737-745. 2001;134:737-745.

Patients uncontrolled on sulphonylurea + metformin (N=178)

Add TZD Add placebo

Patients on sulphonylurea + metformin + TZD (n=92)

Patients on sulphonylurea + metformin + placebo (n=86)

48 weeks

85%Not controlled

15%Controlled

99%Not controlled

1%Controlled

Type 2 DMType 2 DM

The typical clinical course of type 2 diabetes, including the progression of glycemia and the development of complications, and the usual sequence on interventions

Year

0 4 7 10 16 20 Diet and Oral agents Combination Insulin

exercise therapy with oral agents

Risk factors for CVD

IGT and Development Diagnosis Microvascular More advanced More advanced Death

IR of diabetes of diabetes complications microvascular disease and CVD

Usual sequenceof intervention

Typical clinicalcourse

Nathan, NEJM 347: 1342-11349, 2002

Decrease inDecrease in A1CA1CFBG (mg/dL)FBG (mg/dL) (( from baseline) from baseline)

SulphonylureasSulphonylureas 40-6040-60 1.0-2.0%1.0-2.0%Repaglinide/nateglinideRepaglinide/nateglinide 30.330.3 1.1%1.1%MetforminMetformin 5353 1.4%1.4%Rosiglitazone (across dose range)Rosiglitazone (across dose range) 25-5525-55 0.1-0.7%0.1-0.7%PioglitazonePioglitazone 20-5520-55 0.3-0.9%0.3-0.9%-Glucosidase inhibitors-Glucosidase inhibitors 20-3020-30 0.5-1.0%0.5-1.0%

*FBG, fasting blood glucose.*FBG, fasting blood glucose.

Adapted from Feld S. Adapted from Feld S. Endocr Pract.Endocr Pract. 2002;8(suppl 1):41-82. 2002;8(suppl 1):41-82.

Type 2 DMType 2 DM

In contrast, insulin can be customized without dose limit to achieve target

Early Insulin Therapy in Type 2 Diabetes

InsulinInsulin(pmol/L)(pmol/L)

C-peptideC-peptide(pmol/L)(pmol/L)

GlucoseGlucose(mmol/L)(mmol/L)

Pre-CSII CSII Post-CSII

CSII, continuous subcutaneous insulin infusion.CSII, continuous subcutaneous insulin infusion.

Adapted from Ilkova H et al. Diabetes Care. 1997;20:1353-1356.Adapted from Ilkova H et al. Diabetes Care. 1997;20:1353-1356.

13 newly diagnosed diet- unresponsive T2DM patients CSII for 2 weeks diet alone 9 patients were adequate control 9-50 months 6 patients without medication 16- 59 monthsConclusions: Significant proportion of T2DM patients who fail to respond to dietary measures, short-term intensive treatment can effectively establish responsiveness, allowing long-term glycemic control without medication

Short-term intensive insulin therapy in newly diagnosed type 2 diabetes

0

5

10

15

20

25

0 30 60 90 120 150 180

before insulin therapy immediate after insulin therapy at 1-year follow-up

0

100

200

300

400

500

600

0 30 60 90 120 150 180

Fig. Mean for serum glucose and insulin concentrations during OGTT, before insulin therapy, immediate after insulin therapy and at 1-year follow-up16 newly diagnosed T2DM patients had 2-3 week course of intensive insulin therapy – discontinued. Conclusions: a 2-3 week course of intensive insulin therapy can succesfully lay a foundation for prolonged good glycemic control. The ease with which normoglycemia is achieved on insulin may predict those patients who can latter succeed in controling glucose levels with attention to diet alone

Ryan et al. Diabetes Care 27: 1028-1032, 2004

Time (min)

Glu

cose

(m

mol/l)

Insu

lin (

pm

ol/l)

Time (min)






Take Home Message

Sejarah insulin

Animal Insulin Preparations

Recombinant Human Insulin

Rapid-acting Insulin Analogs

Basal Insulin Analogs

New GenerationInsulin Analogs

Isolation of Insulin(Banting & Best)

Time1922 1977

BiphasicInsulin Analogs

1990s 2000s

Advance

men

ts

Kelemahan Human Insulin (Actrapid/Mixtard)

Time (h)

Baseline

level

Human insulin

SC injection

Normal insulin secretionat mealtime

Ch

an

ge i

n s

eru

m i

nsu

lin

Period of unwanted hypoglycemia

Period of unwanted hyperglycemia

Human Insulin HARUS disuntikkan 30 menit

sebelum makan

Kelemahan Human Insulin Insulatard (NPH)

tidak bekerja 24 jam

Memiliki puncak risiko nokturnal hipo sangat tinggi

Absorbsi insulin bervariasi, bahkandi pasien yang sama kendali gula darahtidak terprediksi

20

Struktur kimia Human Insulin

Thr

Glu

Lys

ValPhe

Asn

Glu

Leu

Gln

TyrLeu

SerCysIleSerCysCys

Gln

GluVal

Ile

GlyTyr

CysAsn

Lys

ThrTyr

Phe Phe ArgGlyGlu

GlyCys

Val

Leu

Tyr

Leu

Ala

Val

Leu

HisSer

GlyCys

Asn Gln LeuHisB1

A21

A1

B29

C14 fatty acid chain

(Myristic acid)

Thr

Pro

Asp

Levemir (Insulin Detemir)NovoRapid (Insulin Aspart)

Pro

MakanMakanPagi Pagi

MakanMakanSiang Siang

MakanMakanMalam Malam

Sebelum tidur Sebelum tidur

Levemir Levemir

NovoRapidNovoRapid

Insulin endogenInsulin endogen

----------------

Profil Insulin Analog sangat mirip dengan Insulin Endogen

NovoMixNovoMix

Efektivitas : Superior mengendalikan GD 2 jam pp Superior mengendalikan GD puasa Superior mengendalikan HbA1c

Keamanan Risiko Hipoglikemi lebih minimal Fleksibilitas Waktu penyuntikan lebih fleksibel (tidak menunggu 30

menit)

Profil farmakokinetik insulin analog yang lebih mirip insulin alami, sehingga menghasilkan : Efektivitas, Keamanan dan Flexibility lebih baik dibanding human Insulin

Insulin Analog vs Human Insulin

Dose to Dose (1:1)

Sebelumnya Actrapid 6 unit 3x sehari NovoRapid 6 unit 3 x sehari

Mixtard 14 unit malam dan 16 unit siang NovoMix 14 unit malam dan 16 unit siang

Insulatard 14 unit malam Levemir 14 unit malam

Dose to Dose (1:1)

Sebelumnya Actrapid 6 unit 3x sehari NovoRapid 6 unit 3 x sehari

Mixtard 14 unit malam dan 16 unit siang NovoMix 14 unit malam dan 16 unit siang

Insulatard 14 unit malam Levemir 14 unit malam

Pasien sudah menggunakan Human Insulin? Bagaimana cara untuk merubah ke Insulin Analog?






Take Home Message

How to start Insulin Therapy ??How to start Insulin Therapy ??

What is good glycemic control?

• Overall aim to achieve glucose levels as close to normal as possible

• Minimise development and progression of microvascular and macrovascular complications

FPG <130 mg/dL

HbA1c

< 7.0%PPG

<180 mg/dL

FPG <110 mg/dl

HbA1c

< 6.5%PPG

<145 mg/dL IDF2

ADA1

PERKENI3

1. American Diabetes Association Diabetes Care 2009;32 (Suppl 1):S1-S972. IDF Clinical Guidelines Task Force. International Diabetes Federation 2005. 3. PERKENI 2011 Konsensus .

FPG<100 mg/dl

HbA1c

< 7%PPG

<140 mg/dl

Insulin can be initiated at any time

• Traditionally, insulin has been reserved as the last line of therapy…

• …However, considering the benefits of normal glycemic status, Insulin can be initiated earlier and as soon as possible

Inadequate Lifestyle

+ 1 OAD + 2 OAD + 3 OAD

INITIATE INSULININITIATE INSULIN

Oral agent 2 Oral agents

3 Oral agents

Add Insulin Earlier in the Algorithm

Severe symptomsSevere

hyperglycaemiaKetosisPregnancy

Inadequate non-pharmacologic therapy

Strategy of insulin treatmentStrategy of insulin treatment

Jika gula darah puasa meningkatJika gula darah puasa meningkat

• Gunakan insulin basal

• Gunakan insulin basal

Jika gula darah sesudah makan meningkatJika gula darah sesudah makan meningkat

• Gunakan insulin bolus

• Gunakan insulin bolus

Jika gula darah puasa dan sesudah makan meningkat

Jika gula darah puasa dan sesudah makan meningkat

• Gunakan insulin premix

• Atau tambahkan insulin basal pada terapi OAD

• Atau mulai terapi basal bolus

• Gunakan insulin premix

• Atau tambahkan insulin basal pada terapi OAD

• Atau mulai terapi basal bolus

Perkeni, Petunjuk praktis terapi insulin pada pasien diabetes, 2011

Konsep Basal - Prandial

PrandialPrandial

Insulin PrandialInsulin Prandial

BasalBasal

Insulin BasalInsulin Basal

Hyperglycemia

Perbaiki gula darah puasa dahulu•Lanjutkan OAD•SMBG penting

Untuk memudahkan terapi gunakan insulin premix (30% insulin prandial & 70% insulin

basal)

33

RECOMENDATION

8.5-9.27.4-8.4 9.3-10.2 >10,3< 7.3

HbA1c

30%

70%50%

50%55%

45%40%

60%

30%

70%

Kontribusi kadar glukosa puasa

Kontribusi kadar glukosa prandial

Kon

trib

usi

te

rhad

ap

Hb

A1c

Monnier L et al. Diabetes Care 2003

Kontribusi kadar glukosa puasa dan glukosa prandial terhadap HbA1cKontribusi kadar glukosa puasa dan glukosa prandial terhadap HbA1c

34

“FIX THE FASTING FIRST”START WITH BASAL INSULIN

“FIX THE FASTING FIRST”START WITH BASAL INSULIN

New position statement of the ADA and EASD on management of hyperglycemia in type 2 diabetes

Inzucci SE, et al. Diabetologia. 2012

Start Levemir

ONCE daily

10 U pada makan malam atau sebelum tidur

Time of day (hours)

400

300

200

100

006.00 06.0010.00 14.00 18.00 22.00 02.00

Pla

sma g

lucose

(m

g/d

l)

NormalMea

lMeal Meal

20

15

10

5

0

Pla

sma g

lucose

(mm

ol/l)

Suntikkan 10 iu Levemir sekali sebelum tidur. Atur dosisnya (+3 atau -3) setiap 3 hari sampai GDP mencapai target :< 100 mg/dL (Perkeni 2011)

Hyperglycaemia due to an increase in fasting glucose

T2DM

Fix the Fasting First

Profile T2DMGDP, mencapai targetGDP, mencapai target

Levemir® Dose Titration Guidelines: 3-0-3 Algorithm

Dose Adjustment for Each Arm

Patients who experienced hypoglycemia reduced their daily dose by 3 units

FPG target range70-90 mg/dL

FPG <70 mg/dL (3.8 mmol/L)

FPG>90 mg/dl (5.0 mm/L)

Mean 3-day FPG (mg/dL)

0 maintaindose

3 units

3 units

increase dose

decrease dose

FPG target range80-110 mg/dL

FPG <80 mg/dL (4.4 mmol/L)

FPG>110 mg/dL (6.1 mmol/L)

Blonde L et al. Diabetes Obes Metab. 2009; 11(6):623-631.

Start with Levemir 10 U or 0,1-0,2 U per Kg BB

Korelasi Hba1C dengan Gula Darah

Cek PPG, if high goes to Basal – Bolus or switch to Premix

MakanMakanPagi Pagi




Levemir Levemir

NovoRapidNovoRapid

Insulin endogenInsulin endogen

----------------

REGIMEN BASAL-BOLUS

Kelebihan :

1. Sangat ideal, dapat menghasilkan terapi yang menyerupai profil insulin endogen

2. Sangat mudah mengatur dosis insulin basal maupun bolusnya

Kelemahannya :

1. Pasien tidak menyukainya karena 4 x suntik

2. Pasien harus menggunakan 2 jenis insulin (berisiko pasien salah suntik) dan biaya terapi lebih mahal

Time of day (hours)

400

300

200

100

0

06.00 06.0010.00 14.00 18.00 22.00 02.00

Pla

sma g

lucose

(m

g/d

l)

NormalMeal Meal Meal

20

15

10

5

0

Pla

sma g

lucose

(mm

ol/l)

Suntikkan 10 iu Levemir sekali sebelum tidur. Atur dosisnya (+3 atau -3) setiap 3 hari sampai dgn GDP mencapai target GDP < 110 mg/dL (Perkeni 2011)

Hyperglycaemia due to an increase in fasting glucose

T2DM

Tambahkan Injeksi NovoRapid di setiap makan (2-6 iu) untuk mengendalikan Gula darah 2 jam PP mencapai target < 140 mg/dL (Perkeni 2011)

Basal – Bolus Concept dengan Levemir - NovoRapid

Profile T2DM

MakanMakanPagi Pagi




Insulin endogenInsulin endogen --------

Regimen Premix

NovoMix 2 x sehari (mulai 3 iu)NovoMix 2 x sehari (mulai 3 iu)



Kelebihan :

• Sangat disukai pasien karena cukup menggunakan 1 jenis insulin dan 1 jenis pen (Data Diabcare 2008, pada 1829 pasien Indonesia menunjukkan premix paling banyak digunakan)

Kelemahannya :

• Pengaturan dosis kurang fleksibel






Take Home Message

Kendala dalam terapi Insulin

Drug Drug addiction ?addiction ?

Expensive !Expensive !It hurts !It hurts !

I don’t want it.!I don’t want it.!


1. “Sekali mulai terapi insulin, tidak bisa di stop lagi ”

(Persepsi yang salah, seperti “kecanduan” obat )

– Berikan insulin dengan “percobaan” jangka pendek :

“Cobalah suntik insulin selama 1 bulan saja, lalu kita evaluasi lagi”

2. “Suntik insulin sangat merepotkan”

( Pasien merasa tidak sanggup suntik sendiri)

• Demonstrasikan kepada pasien betapa simple nya suntikan insulin

• Berikan insulin 1x/hari untuk mengurangi ketidaknyamanan

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.

3. “Kegagalan terapi adalah kesalahan saya” (suntikan insulin sebagai hukuman karena kegagalan pribadi)

Jelaskan bahwa insulin diperlukan karena perjalanan penyakit DM yg progresif, bukan karena kegagalan pasien mengelola penyakitnya

4. “Famili saya disuntik insulin sebelum diamputasi kakinya” (Insulin diberikan bila Diabetes sudah berat)

Jelaskan bahwa suatu saat insulin diperlukan karena perjalanan alamiah penyakit DM yg progresif

5. “ Saya tidak berani suntik insulin sendiri, karena nyeri..! ” (Anxietas terhadap suntik insulin)

Show patient that insulin injection is less painful than BG monitoring with a glucose meter

Polonsky WH, Jackson RA. Clinical Diabetes 2004;22:147-50.







Take Home Message

Take Home Messages

1. DM tipe 2 adalah penyakit kronik yang progresif

2. Memulai inisiasi dengan insulin analog basal, akan bisa mencapai optimal FPG

3. Kendali glikemik yang baik sangat penting untuk mencegah komplikasi

4. Titrasi dosis insulin dilakukan sesuai algoritma 3-0-3 (perlu SMBG) sehingga risiko hipoglikemia dapat ditekan

5. Edukasi sangat penting sebelum & selama terapi insulin

6. Mulailah dengan mengendalikan gula darah puasa

7. Setelah GDP mencapai target (80-110 mg/dL) selama 3 bulan namun HbA1c masih tinggi, segeralah menambahkan penyuntikkan bolus (terapi basal-bolus) atau mengganti terapi dengan premix insulin (untuk pertimbangan yang lebih simpel untuk pasien)

8. Setelah 3 bulan menggunakan premix 2 x sehari tidak juga mencapai target HbA1c segeralah meningkatkan premix menjadi 3 x sehari atau menggunakan terapi Basal-Bolus

THANK YOU

Penatalaksanaan Diabetes Terkini Penanganan Awal Bagi Dokter Umum

Documents

insulin action

analogue insulin

actions of insulin

insulin resistance progresses

diabetes care

strategy of insulin

diabetes complicationsadapted

diabetes obes metab