CV: dr.

R Bowo Pramono SpPD KEMD

Lahir TEGAL 27-jan 1959 Istri: dr. Astuti SpS, 2 putri Dokter Umum: FK UGM 17-01-1985 SPPD : FK UGM 24-11-1997 KEMD : 14-05-2008 Pekerjaan: 1987-2002 PKM Kedung Waringin Bekasi 1999-2004 RSU Selong Lombok Timur 2004-2010 RS DR Sardjito/FK UGM 2006-2013 Sekretaris Bagian Penyakit Dalam FK UGM 2007-2011 Sekretaris PAPDI Cabang Yogyakarta
1

DIAGNOSIS & MANAJEMEN DM TIPE 2

DIAGNOSIS:
DIAGNOSED FASTING BG/mg% 80 - <110 POST PRANDIAL BG/mg% 80 - <140 RANDOM BG/mg% 80 - <140

NO DIABETES PRE DIABETES DIABETES

110 - 125

140 - 199

126

200

200

Prinsip Dasar Terapi Diabetes Mellitus

1 2 3

PENGATURAN MAKAN 4

LATIHAN JASMANI 5

PENYULUHAN

OBAT HIPOGLIKEMIK

CANGKOK PANKREAS

Correlation between HbA1c level and mean plasma glucosa levels on multiple testing over 2-3 months
HbA1c 6 7 8 9 10 11 12 Mean plasma glucose (mg/dL) 135 170 205 240 275 310 345

Hasil dari UKPDS: Kontrol yang baik pada DM T2 mampu menurunkan resiko komplikasi
Penurunan1%HbA1c Kematiankarenadiabetes Menurunkanresiko*
21%

Infarkmiokard

14%

1%
Komplikasimikrovaskuler
37%

Gangguanpembuluhdarahperifer
*p<0.0001n=3,642type2diabetespatients

43%

StrattonIMetal.BMJ2000;321:405412

PRINSIP PENGOBATAN DIET

Kebutuhan kalori sesuai : kelamin, umur , berat badan, aktifitas fisik, pekerjaan, kehamilan, menyusui, komplikasi 3 kali makan utama dan 3 kali makan kecil Jumlah dan waktu makan harus tepat

JADWAL MAKAN DIABETES

Komposisi diet: 60-70 % hidrat arang
20-25 % lemak 10-15 % protein
20% 10% 25% 10% 25% 10%

6.30

9.30

12.00

15.00

19.00

21.00

PRINSIP OLAHRAGA PADA DIABETES

Pilih olahraga yang disenangi Melibatkan otot-otot besar
Frekuensi Intensitas Durasi Tipe : Teratur 3-5 kali perminggu : Ringan sampai sedang : 30 60 menit / 5 X30 menit /minggu : Aerobik (jalan, joging, ber sepeda)

Program Latihan
Teratur (3-4 kali seminggu)
20- 40 menit didahului pemanasan 5-10 mnt dan cool-down 10 mnt

CRIPE:
Continous Rythmis Interval Progresif Endurance

Treatment options for type 2 diabetes

Sulfonylureas
1st generation e.g. chlorpropamide, tolbutamide 2nd generation e.g. glyburide, gliclazide, glipizide, gliquidone 3rd generation e.g. glimepiride Modified release

-glucosidase inhibitors
e.g. acarbose

Insulin
regular intermediate/long acting pre-mixed analogs

Glinides/meglitinides
Non-sulfonylureic e.g. repaglinide Amino acid derivatives e.g. nateglinide

rapid acting long acting

Biguanides
e.g. metformin

Fixed-dose oral antidiabetic drug combinations

e.g. glyburide/metformin, glipizide/metformin, rosiglitazone/metformin

Thiazolidinediones
e.g. rosiglitazone, pioglitazone

Metformin
How it works
Decreases hepatic glucose output Lowers fasting glycemia

Expected HbA1c ~ 1.5% reduction Adverse events GI side effects Weight effects CV effects

Lactic acidosis (quite rare) Weight stability or modest weight loss Unconfirmed beneficial effect demonstrated in UKPDS

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

Sulfonylureas
How they work Expected HbA1c reduction Adverse events Weight effects CV effects
Enhance insulin secretion ~ 1.5% Hypoglycemia (but severe episodes are infrequent) ~ 2 kg weight gain common when therapy initiated UGDP suggested potential cause of increased CVD mortality; not substantiated by UKPDS
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

INCREASED INSULIN SECRETION

Sulfonylurea
Glibenclamide Gliclazide Glipizide Chlorpramide Tolbutamide Glimepiride gliquidon

Length of action
16 24h 10 24h 6 24h 24 72h 6 10h 24h 18 - 24h

Begins of action
2 4h 2 4h 2 4h 2 4h 2 4h 2 4h 2 - 4h

Daily dose (mg)

1,25 15 40 320 2,5 40 100 500 100 1000 1-6 30 - 120

Route of excretion
R = 50%, B = 50% R = 70%, B = 30% R = 80%, B =20% Renal Renal R = 40%, B =60% R = 5%, B = 95%

15

Glinides
How they work Expected HbA1c reduction Adverse events Weight effects CV effects
Stimulate insulin secretion (but differently from sulfonylureas) ~ 1.5% (repaglinide) Hypoglycemia (may be less frequent than some sulfonylureas) ~ 2 kg weight gain common when therapy initiated None mentioned in ADA recommendations

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

Dipeptidyl Peptidase IV Inhibitors

How they work Expected HbA1c reduction Adverse events Weight effects CV effects
Inhibit degradation of endogenous GLP-1 ~0.8% Minimal Neutral Unknown

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

-Glucosidase Inhibitors
How they work Expected HbA1c reduction Adverse events Weight effects CV effects
rate of digestion of polysaccharides in proximal small intestine (primarily lowering PPG levels without causing hypoglycemia)

0.50.8% Increased gas production GI symptoms Weight neutral Unconfirmed report of reduction of severe outcomes in one clinical trial

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

Thiazolidinediones
How they work Expected HbA1c reduction Adverse events Weight effects CV effects
Increase sensitivity of muscle, fat, and liver to endogenous and exogenous insulin 0.51.4%

Weight gain and fluid retention Increase in subcutaneous adiposity Redistribution from visceral deposits New / worsened CHF or peripheral edema (due to fluid retention) Reduction in some secondary CV endpoints demonstrated in PROactive study
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Glucagon-like Peptide 1 Agonist

(exenatide)
How it works
Stimulates insulin secretion

Expected HbA1c 0.51% reduction Adverse events GI side effects (nausea, vomiting,
diarrhea)

Weight effects CV effects

Weight loss of ~ 23 kg over 6 months (may be result of GI effects) None mentioned in ADA recommendations

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

Dipeptidyl Peptidase IV Inhibitors

How they work Expected HbA1c reduction Adverse events Weight effects CV effects
Inhibit degradation of endogenous GLP-1 ~0.8% Minimal Neutral Unknown

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

Amylin Agonists (pramlintide)

How it works Expected HbA1c reduction Adverse events Weight effects CV effects
Synthetic amylin analogue that inhibits glucagon production in a glucosedependant fashion 0.50.7% GI effects (nausea) Weight loss ~ 11.5 kg over 6 months (may be due to GI effects) None mentioned in ADA recommendations
Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Insulin
How it works Expected HbA1c reduction Adverse events Weight effects CV effects
Direct compensation for lack of insulin sensitivity 1.52.5% Hypoglycemia Weight gain of ~ 24 kg

Beneficial effect on TG and HDL Weight gain may have an adverse effect on CV risks

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

Indikasi terapi Insulin:

DM tipe 1 DM tipe 2 yang tidak terkontrol diet, olah raga, OHO. DM gestasional Gangguan faal hati & ginjal yang berat. Dengan infeksi akut (selulitis, gangren), TBC berat, penyakit kritis (stroke/AMI) Dengan KAD/HHS Dengan fraktur atau pembedahan mayor Kurus (BB rendah), terkait malnutrisi (DMTM) Dengan penyakit Graves Dengan tumor ganas Dengan pemberian kortikosteroid

100

Stages of Type 2 Diabetes

75
Beta Cell Function (%)

IGT
50

Postpandrial Hiperglycemi

T-2 DM phase I Beta Cell function 50 %

T2 DM phase I T2 DM phase II
T2 DM phase III

25 0 -12 -10
Lebovitz, 2000

-6

-2

10
25

14

Years From Diagnosis

Summary: Expected HbA1c Reduction

Intervention Insulin Metformin Sulfonylureas Glinides TZDs -Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
a

Expected in HbA1c 1.5 to 2.5% 1.5% 1.5% 1 to 1.5%a 0.5 to 1.4% 0.5 to 0.8% 0.5 to 1.0% 0.5 to 1.0% ~0.8%
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Repaglinide is more effective than nateglinide

Factors that May Affect Compliance

Weight Gain
Insulin intermediate/long Insulin short/rapid Metformin Sulfonylurea Glinides TZDs -Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

GI Side Effects

2-3x Daily Dosing X

X X X X X X X X X X X X X X

Which second-line therapy?

HbA1C
SU TZD Insulin AGI GLP-1 analogue Meglitinide 1.5 0.51.4 1.53+ 0.50.8 0.51.0 1.01.5

Pros
Large clinical database, inexpensive No hypoglycaemia, some benefits on lipids

Cons
Weight gain and hypoglycaemia Oedema, heart failure, weight gain, expensive

Large clinical database, most effective Hypoglycaemia, weight gain, need for SMBG No hypoglycaemia, weight neutral No hypoglycaemia, weight loss Fewer hypos than sulfonylurea GI side-effects, expensive GI side-effects, expensive, injected TID dosing, expensive

SU: sulfonylurea; TZD: thiazolidinedione; AGI: -glucosidase inhibitor SMBG: self monitoring of blood glucose
ADA/EASD. Diabetes Care 2006; 29: 1963-1972, Diabetologia 2006; 49: 1711-21

100

Stages of Type 2 Diabetes

75
Beta Cell Function (%)

IGT
50

Postpandrial Hiperglycemi

T-2 DM phase I Beta Cell function 50 %

T2 DM phase I T2 DM phase II
T2 DM phase III

25 0 -12 -10
Lebovitz, 2000

-6

-2

10
29

14

Years From Diagnosis

Effectiveness of Type 2 Diabetes Therapy

Starting HbA1c

Diet & Exercise

1.5-2%
Metformin Insulin Secretagogues

1%

<7%

TZD
Alpha-glucosidase Inhibitors

<8%
1-1.5%

Combination Oral Agents

3-4%

<8-10%

Insulin

5% or more

>10%

Klasifikasi Insulin
Kelas
Aksi pendek Actrapid, Humulin R Campuran (premixed) Humulin 30/70,Mixtard 30/70 Aksi sedang Humulin N, Insulatard Aksi panjang Lantus , Levemir

Mulai efek Puncak Lama 15-30 mnt 2-4jam 6-8jam 60 mnt 2-4jam 1-8jam 14-15 jam 1-8jam 14-15 jam

Tanpa Puncak 24 jam

What are the reasons for the shortcomings of insulin? That has to dissolve in SC fluids and dissociate into monomers..
Dissociation in subcutaneous tissue

Subcutaneoust issue Mol/l Diffusion

103 104 105 108

Capillary membrane
32
AdaptedfromBrangeJetal.DiabetesCare 1990;13:923

Klasifikasi Insulin yang baru

Kelas
Aksi cepat (analog) Lyspro (Humalog) Aspart (Novo Rapid) Apiora Campuran (premixed) Humalog Mix 25/75 Novomix 30/70

Mulai efek Puncak Lama 5-15 mnt 5-15mnt 2 jam 2-4jam 4-6jam 12-14 jam

LOKASI PENYUNTIKKAN

Insulin Regimen Evolution

35

Insulin > Cara pemberian insulin > Semprit dan jarum

Pemakaian semprit dan jarum memungkinkan Anda untuk mengatur dosis dan membuat formulasi campuran insulin. Keterbatasannya adalah membutuhkan ketrampilan yang cukup untuk menarik dosis insulin dengan tepat.
Cara menyuntik insulin

Dahulu: Agar tidak salah dosis, kemasan insulin 40U/ml atau 100U/ml disesuaikan dengan skala pada spuit, bisa 40 atau 100 Sekarang: ? Tidak tersedia lagi
38

NovoPen

39

Sistem NovoLet

40

INSULIN ANALOG:
1. NovoRapid 2. NovoMix 3. Levemir

45

Summary: Expected HbA1c Reduction

Intervention Insulin Metformin Sulfonylureas Glinides TZDs -Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
a

Expected in HbA1c 1.5 to 2.5% 1.5% 1.5% 1 to 1.5%a 0.5 to 1.4% 0.5 to 0.8% 0.5 to 1.0% 0.5 to 1.0% ~0.8%
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

Repaglinide is more effective than nateglinide

Factors that May Affect Compliance

Weight Gain
Insulin intermediate/long Insulin short/rapid Metformin Sulfonylurea Glinides TZDs -Glucosidase inhibitors GLP-1 agonist Pramlintide DPP-IV inhibitors
Adapted from Nathan DM et al. Diabetes Care 2006;29(8):1963-72.

GI Side Effects

2-3x Daily Dosing X

X X X X X X X X X X X X X X

ADA/EASD consensus algorithm

Tier 1:
well-validated therapies At diagnosis: Lifestyle + Metformin Call to action if HbA1c is 7% Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Intensive insulin

Lifestyle + Metformin + Sulfonylurea

STEP 2 STEP 3

STEP 1

Tier 2:
Less well validated therapies Lifestyle + Metformin + Pioglitazone
No hypoglycaemia Oedema/CHF Bone loss

Lifestyle + Metformin + Pioglitazone + Sulfonylurea

Lifestyle + metformin + GLP-1 agonist

No hypoglycaemia Weight loss Nausea/vomiting
Nathan DM, et al. Diabetes Care 2009;32 193-203.

Lifestyle + metformin + Basal insulin

48

DM tipe 1
49

1980

1980

2009