Adipose tissues

JMF Adam
 Adipose Tissues
Storage of fat (TG)
Endocrine organ : produced
hormone (adipocytokine), leptin,
TNF-, IL-6, resistin pro-
inflammatory
adiponektin anti-inflammatory
 Jaringan perifer
Jaringan Adiponectin
Ambilan glukosa
lemak
TNF-,
IL-6,
Leptin, Ambilan glukosa
Asam Resistin
lemak bebas
(proses lipolisis) Ambilan glukosa Otot

Sekresi insulin terganggu,

apoptosis
Pankreas

Produksi glukosa
meningkat Hati
 Pro inflammatory
Adipocytokines
Leptin : dgn pe BB, bekerja pada
sistem saraf perifer dan pusat
TNF- : berperan pada resistensi insulin
perifer, mengganggu insulin signaling,
menekan ekspresi glucose transporter
(GLUT-4)
IL-6 : meningkatkan glukoneogenesis
Resistin : resistensi insulin
 Anti-inflammatory
Adipocytokines

Adiponektin : hormon peptida

diproduksi oleh adiposit
mencegah terjadinya resistensi
insulin.
Adiponektin jika p BB
 LIPID
LIPOPROTEIN METABOLISM
AND
THE MANAGEMENT OF DYSLIPIDAEMIA

1. Lipid and dyslipidaemia

2. Lipoprotein Metabolism
3. Lipoprotein Metabolism in insulin resistance and
type 2 diabetes
4. Management of dyslipidaemia
LIPID PLASMA
CH3 H
H C CH2 CH2 C
CH2 CH3 Kolesterol
CH3 CH3
CH3

HO
O

O CH2 O C (CH2)1 CH3

H
4
H3C (CH2)7 C C (CH2)7 C O CH Trigliserida
CH2 O C (CH2)16 CH3
O
C H2.O.CO.R

R.COO.CH
O CH3
P OCH2.CH2.N+ CH3 Fosfolipid
C H2O
CH3
O

Pickup J, Williams G. Lipid Disorders in diabetes mellitus. Text Book of Diabetes. 1997:p. 55.1-31
LIPOPROTEIN

Lipid plasma tidak larut

Untuk melarutkan perlu Apolipoprotein =
Apoprotein = Apo
9 Apo : Apo A1, Apo A2, Apo A3, Apo B48,
Apo B100, Apo C1, Apo C2, Apo C3, Apo
E
Kompleks lipid plasma + apoprotein
disebut lipoprotein
 TG
K
F
Lipid Plasma
+ Apo

Apo Apo
K
F
TG
Apo

LIPOPROTEIN
LIPOPROTEIN

Jenis Lipoprotein :
- HDL : high density lipoprotein
- LDL : low density lipoprotein
- IDL : intermediate density lipoprotein
- VLDL : very low density lipoprotein
- Kilomikron
- Lipoprotein a kecil (Lp(a))

Setiap Lipoprotein t.d :

kolesterol (bebas/ester), trigliserida,
fosfolipid, dan apoprotein
APAKAH LIPOPROTEIN ?

Apolipoprotein + Lipid = Lipoprotein

Feher MD, Richmond W. Lipids and Lipid Disorders Second ed. Bayer. 1996
JENIS LIPOPROTEIN
Relative size, triglyceride
Lipoprotein class Major apoproteins
and cholesterol content

Chylomicrons B48, E, CII

VLDL B100, E, CII

IDL B100, E

LDL B100

HDL AI,AII

Triglyceride Cholesterol
 PARTIKEL KOLESTEROL HDL
Apo A-1
Apo A-2

Apo E

Apo C Trigliceride
Phospholipid
Cholesterol Ester

Unesterified cholesterol

Diameter : 75-100

Feher MD, Richmond W. Lipids and Lipid Disorders Second ed. Bayer. 1996
 THE METABOLIC PATHWAY OF
LIPOPROTEINS

Endogenous pathway (LDL, TG)

Exogenous pathway (LDL, TG)
Reverse cholesterol transport (HDL)
Lipoprotein Metabolism
Endogenous
(metabolisme LDL, TG)
Liver
Foam cells
Apo B100
Enz. Lipoprotein lipase
TG, kol Macrophage

Miskin kol. Apo A, C, E

RCTP (HDL)

remnants
Exogenous
Cholesterol (metabolisme LDL,TG)

kilomikron TGFFA Adipose

RCTP = reverse cholesterol

Cholesterol Intestine Stool
transport pathway

Food (kolesterol , TG) Shepherd J. Eur Heart J Supplements 2001;3(suppl E):E2-E5

Endogenous pathway
Reverse cholesterol and reverse
transport
cholesterol transport Reseptor LDL
Liver Scavenger receptor-A / CD 36

Adenosine triphosphatebinding
cassette transporter-1 (ABC-1)

VLDL SRB-1
Chol

CE
IDL
Chol
CE LDL Macrophage
CETP
Chol
CE Cholesterol
TG TG pool
Chol

HDL Chol
Chol
Nascent HDL
Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein,
and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L
LDL

HDL
THE METABOLIC PATHWAY OF
LIPOPROTEIN
IN
TYPE 2 DIABETES MELLITUS
AND
METABOLIC SYNDROME
Reverse cholesterol transport
Liver LDL Receptor
Scavenger receptor-A / CD 36
VLDL
large ABC-1 transporter
VLDL
VLDL SRB-1 receptor
large
IDL
LDL
Macrophage
`small
LDL
Triglyceride density
Cholesteryl ester

Cholesterol
FFA
Adipocytes HDL
ApoA1 Nascent HDL

Insulin Resistance Kidney

DISLIPIDEMIA
Dislipidemi diabetes tipe 2 / resistensi insulin

Resistensi insulin mengakibatkan FFA meningkat

hati, menjadi sumber VLDL

VLDLLDL, pertukaran TG dan kolesterol LDL kecil

padat
ApoA1 dikeluarkan oleh ginjal, sehingga HDL
kolesterol rendah

Kesimpulan : TG tinggi,
HDL-kol rendah,
LDL-kol kecil padat tinggi
Management of dyslipidaemia

All three lipid profiles

kolesterol LDL, kolesterol HDL, dan trigliserid

play a role in the formation of

atherosclerosis
 50

40

30

20

10

0
0 150 200 250 300
(3.87) (5.17) (6.46) (7.75)
Kadar serum kolesterol (mg/dl / mmol/L)
Hubungan antara kadar serum kolesterol dan risiko penyakit arteri koroner
Dari penelitian Multiple Risk Factor Intervention Trial (MRFIT)

Farnier M, Davignon J. Am J Cardiol. 1998;82:3J-10J

 156

150 Trigliserid < 200 mg/dl

Trigliserid > 200 mg/dl

100
73

50 55
22 25
18
10 17

0
< 130 130 - 160 160 - 190 > 190
LDL-kolesterol
Insiden PAK / 1000 orang dalam 4 tahun menurut kadar trigliserid
dan LDL-kolesterol.
Assman G. Am J Cardiol 1992;70:10H-13H
 120
PROCAM Study
100

80

Insidens PAK
60
(per 1.000 dalam 6
tahun)
40

20

0
< 35 35 - 55 > 55
HDL-kolesterol (mg/dl)

Hubungan HDL-kolesterol dengan insiden penyakit arteri koroner (PAK):

Dari Prospective Cardiovascular Munster (PROCAM) Study.
HDL-kolesterol secara meyakinkan berhubungan dengan risiko PAK ( p < 0.001).
 CLASSIFICATION OF
LDL-cholesterol, Total-cholesterol,
HDL-cholesterol and Triglycerides
NCEP-ATP III
KLASIFIKASI TOTAL, LDL, HDL-KOLESTEROL,
DAN TRIGLISERID MENURUT NCEP ATP III

LDL kolesterol
< 100 mg/dl Optimal
100 129 mg/dl Mendekati optimal
130 159 mg/dl Sedikit tinggi (Borderline)
160 189 mg/dl Tinggi
> 190 mg/dl Sangat tinggi
Total kolesterol
< 200 mg/dl Diinginkan
200 239 mg/dl Sedikit tinggi (Borderline)
> 240 mg/dl Tinggi
HDL kolesterol
< 40 mg/dl Rendah
> 60 mg/dl Tinggi

JAMA 2001;285:24862-497
 TRIGLISERIDA (NCEP-ATP III)

Optimal < 150 mg/dl

Sedikit tinggi(borderline) 150 - 199 mg/dl
Tinggi 200 - 499 mg/dl
Sangat tinggi > 500 mg/dl
 Risk assessment: first step in
the management of
dyslipidaemia
Langkah pertama dalam terapi dislipidemia
adalah dengan menghitung berapa faktor
risiko yang dimiliki penderita tersebut (risk
assessment)
Faktor risiko dikelompokkan atas tiga kelompok
risiko rendah(low risk) , risiko sedang
(moderate risk), dan risiko tinggi (high risk)
 RISK FACTORS FOR CORONARY ARTERY DISEASE (CAD)
AS DEFINED BY
THE NATIONAL CHOLESTEROL EDUCATION PROGRAM (NCEP 2001)

Risk factors
Irreversible Modifiable
Age Cigarette smoking
(men > 45 years, women > 55 Hypertension (BP* > 140 / 90
The 8th MADAM

years) mmHg or on antihypertensive

Family history of premature medication)
CHD* (CHD in male first- Low HDL C < 40 mg/dl
degree relative < 55 years:
CHD in female first-degree
relative < 65 years)

* CHD = coronary heart disease; BP = blood preesure

HDL cholesterol > 60 mg/dl counts as a negative risk factor,

its presence removes 1 risk factor from the total count
JAMA 2001;285:24862497
 NCEP ATP III, THREE CATEGORIES OF RISK
THAT MODIFY LDL CHOLESTEROL GOALS

Risk Category LDL Goal

(mg/dl)
The 8th MADAM

CHD, DM*, or equivalent < 100

Multiple (2+) risk factors < 130

0 1 risk factors < 160

* Risk equivalents : Diabetes Mellitus, Stroke, PAD

JAMA 2001; 285: 2486-2497
 EQUIVALENT CONDITIONS

Other atherosclerotic disease , peripheral

arterial disease, aorta abdominalis aneurism,
stroke
Diabetes melitus ( type 2)
Multiple risk factors, which is in 10 years have
20% risk of CAD

diabetes melitus, stroke, peripheral

arterial disease

JAMA 2001;285:24862-497
 NCEP REPORT 2004
Grundy SM Circulation. July, 2004;110:227-239

In high risk persons,

the recommended This therapeutic
LDL-C goals is < option extends also
100 mg/dl, but to patients at high
The 8th MADAM

when the risk is risk who have a

very high, an base line LDL-C <
LDL-C of < 70 100 mg/dl
mg/dl is a
therapeutic
option
 THE VERY HIGH RISK PATIENTS
Established CVD, plus:

1 Multiple major risk factors (especially

diabetes)
The 8th MADAM

2
Severe and poorly controlled risk factors

3 Multiple risk factors of the metabolic

syndrome

4 Acute coronary syndromes (PROVE IT)

 Mortality from coronary heart disease in
subjects with type 2 diabetes and in non-
diabetic subjects with and without prior
myocardial infarction
Haffner SM, et al.
N Engl J Med 1998; 339: 229234
 50 45,0%
45 Non diabetic Diabetic
7-year incidence of MI

40
35
30
25
20
15
18,8% 20,2%
10
3,5%
5
0
No DM, No MI No DM, MI DM, No MI DM, MI
Type 2 diabetes mellitus (DM) and coronary artery disease (CAD). The 7 year
incidence of fatal or nonfatal myocardial infraction (MI) is essentially the same in
patients who have diabetes without a history of CAD and in patients with CAD who
are not diabetic. P < 0,001 for the difference between patients with and without MI in
both group.
Haffner SM, et al. N Engl J Med 1998;339:229-34
 PREVENTION OF CORONARY HEART
DISEASE IN TYPE 2 DIABETES MELLITUS

Heart Protection Study with Simvastatin

40 mg

RESULTS
Lowering LDL-cholesterol from
< 116 mg/dl to < 77 mg/dl
The lower the better ?
 PREVENTION OF CORONARY HEART
DISEASE IN TYPE 2 DIABETES MELLITUS
Heart Protection Study with Simvastatin
Conclusions
The present study provides direct evidence that
cholesterol-lowering therapy is beneficial for people
with diabetes even if they do not already have
manifest coronary disease or high cholesterol
concentrations
Statin therapy should now be considered routinely
for all diabetic patients at sufficiently high risk of
major vascular events, irrespective of their initial
cholesterol concentrations
PENATALAKSANAAN

Perubahan gaya hidup

Obat lipid
No over-eating!!
Exercise
Stop smoking, stop alkohol
PENATALAKSANAAN

Perubahan gaya hidup

Obat lipid
 OBAT PENURUN LIPID
Persentasi penurunan LDL-kolesterol dan
trigliserid, serta kenaikan HDL-kolesterol

Obat LDL-K HDL-K TG

Statin 18 - 55% 5 - 15% 7 - 30%

Resin 15 - 30% 3 - 5% - /

Fibrate* 5 - 25%* 10 - 20%* 20 - 50%*

Nicotinic acid 5 - 25% 15 - 35% 20 - 50%

Ezetimibe 10 - 15% - -
* bezafibrat, cipofibrat dan fenofibrat menurunkan LDL-kolesterol
lebih banyak daripada gemfibrozil
Overview of Cholesterol Metabolism:
Absorption and Synthesis
Statin
 SASARAN LDL - KOLESTEROL
PENGOBATAN PERUBAHAN GAYA HIDUP
(DIET, OLAHRAGA), DAN PENGOBATAN STATIN

Sasaran LDL Kadar LDL dimana Kadar LDLdimana

Kelas risiko
(mg/dl) dimulai diet - dimulai obat (mg/dl)
olahraga (mg/dl)

PJK atau yang < 100 > 100 > 130

disamakan
(100-129 dapat
dipertimbangkan
obat)
> 2 faktor risiko < 130 > 130 > 160

0 - 1 faktor risiko < 160 > 160 > 190

PJK ekuivalen : DM, strok, peny pembuluh darah perifer

JAMA 2001;285:2487-2497
 THE VERY HIGH RISK PATIENTS
Established CVD plus:
1. Multiple major risk factors (especially diabetes)
2. Severe and poorly controlled risk factors (especially
continued cigarette smoking)
3. Multiple risk factors of the metabolic syndrome
(especially high triglycerides > 200 mg/dl plus non-
HDL-C > 130 mg/dl with low HDL-C < 40 mg/dl
4. On the basis of PROVE IT, patients with acute
coronary syndromes

LDL GOAL : < 70 mg/dl

Grundy SM et al. Circulation. July, 2004; 110: 227-239
 CONTOH KASUS (1)
Pria umur 50 tahun, ke dokter untuk pemeriksaan
kesehatan. Ia tidak merokok, melakukan olah
raga teratur. Kedua orang tua masih hidup.
Pada pemeriksaan ditemukan sbb: TB 150 cm, BB
76 kg, TD 185/95 mmHg. Pemeriksaan fisik lain
baik. Pem jantung : dlm bts normal
Ia membawa hasil laboratorium sbb: pemeriksaan
rutin baik, GDP 114 mg/dl, total -kol 198 mg/dl,
LDL- kol 138 mgdl, HDL 35 mg/dl, TG 186 mg/dl.
Diagnosa? Berapa sasaran LDL-kol?
 Pria , 50 tahun LDL < 130 mg/dl
Hipertensi
GDPT/ IFG
HDL < 40 mg/dl
TG > 150 mg/dl TTGO : 332 mg/dl

LDL < 100 mg/dl

 CONTOH KASUS (2)
Wanita umur 56 tahun, ke dokter untuk pemeriksaan
kesehatan. Ia tidak merokok, melakukan olah raga
teratur. Kedua orang tua masih hidup. Riw DM
tdak berobat teratur, Riwayat PJK + berobat
teratur
Pada pemeriksaan ditemukan sbb: TB 150 cm, BB 65
kg, TD 150/90 mmHg. Pemeriksaan fisik lain baik
Ia membawa hasil laboratorium sbb: pemeriksaan
reduksi positif, GDP 256 mg/dl, A1C 9,0%, total -
kol 180 mg/dl, LDL- kol 110 mg/dl, HDL 50 mg/dl,
TG 156 mg/dl.
Diagnosa ? Berapa sasaran LDL-kol?
Wanita 56 thn
Riw DM LDL < 70 mg/dl
Riwayat PJK
Obesitas
Hipertensi
HDL 50 mg/dl
TG 156 mg/dl
 Lipoprotein Metabolism
in Insulin Resistance
Adipocytes
Liver
FFA
CE
VLDL
(CETP) HDL
large
TG
IR
ApoA1
CE (CETP) TG

Insulin LDL
LDL Kidney
small
FFA : Free Fatty Acid density
CE : Cholesteryl Ester (lipoprotein or
CETP : Cholesteryl Ester Transfer
Protein
Hepatic lipase i)

Kwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein,
and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L
 ADULT TREATMENT PANEL REPORTS
ATP III update 2004
Since the publication of ATP III, 5 major clinical trials
with statin therapy and clinical endpoints have been
published
Heart Protection Study (HPS)
Prospective Study of Pravastain in the Elderly at Risk
(PROSPER)
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial Lipid-Lowering Trial (ALLHAT LLT)
Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering
Arm (ASCOT-LLA)
Pravastatin or Atorvastatin Evaluation and Infection Throm-
bolysis in Myocardial Infraction 22 (PROVE IT-TIMI 22)
Primary Prevention of Cardiovascular Disease With Atorvas-
tatin in Type 2 Diabetes in the Collaborative Atorvastatin
Diabetes Study (CADRS)
 Jaringan
lemak Adiponectin Jaringan perifer
TNF-,
IL-6, Ambilan glukosa
Leptin,
Substrat
Resistin
glukoneogenik Asam
lemak bebas

Ambilan glukosa

Otot
Hati
Produksi glukosa
meningkat Pankreas
Sekresi insulin terganggu,
apoptosis
Mekanisme molekuler hubungan antara jaringan lemak dan resistensi insulin pada obesitas dan diabetes melitus.
Henry RR, Mudaliar S. Obesity, mechanisms and clinical management. Eckel RH (ed.). Lippincott Williams &
Wilkins, Philadelphia 2003; 229-272
Major Risk Factors (Exclusive of LDL-
cholesterol) That Modify LDL Goals

Cigarette smoking
Hypertension (blood pressure > 140/90 mmHg,
or on antihypertension)
Low HDL cholesterol (< 40 mg/dl)*
Family history of premature (CHD in male first-degree relative <
55 years; CHD in female first-
degree relative < 65 years
Age male > 45 years, female > 55 years

HDL cholesterol > 60 mg/dl counts as a negative risk factor,

its presence removes 1 risk factor from the total count
JAMA 2001;285:24862-497
 Three categories of risk that modify
LDL cholesterol goals

Risk group LDL-C goals (mg/dl)

Subjects with CHD or equivalent < 100

(high risk)
Faktor risiko multipel ( > 2)
(moderate risk) < 130
0 - 1 Risk Factor
(low risik) < 160

JAMA 2001;285:24862-497
 HEART PROTECTION STUDY WITH
SIMVASTATIN (HPS)
Baseline LDL-C Statin Placebo Event Rate Ratio
(mg/dl) (n =10,269) (n =10,267)
Statin Better Statin
Worse
< 100 282 (16.4%) 358 (21.0%)
100 129 668 (18.9%) 871 (24.7%)
> 130 1,083 (21.6%) 1,356 (26.9%)
All patients 2,033 (19.8%) 2,585 (25.2%) 0.76 (0.72 0.81)
p<0.0001

0.4 0.6 0.8 1.0 1.2 1.4

Major vascular events by baseline low-density lipoprotein cholesterol (LDL-C) level

in the Heart Protection Study (HPS). Numbers in parentheses represent event rates
for the subset of 3,421 patients with entry LDL-C levels < 100 mg/dl (2.6 mmol/l).
See Figure 1 for an explanation of event rate ratio figures. CI = confidence interval.

Ballantyne CM. Am J Cardiol 2003;92 (suppl):3K-9K

Subjects and methods

From the PROVE IT study

Divided into two groups:
LDL cholesterol > 70 mg/dl
< 70 mg/dl
hsCRP > 2 mg/L
< 2 mg/L

Is there a difference in recurrent myocardial

infarction and death from coronary causes
between these groups?
 RATIONAL FOR OPTIMAL VERY LOW
LDL-CHOLESTEROL GOAL (< 70mg/dl)

Lesson from HPS

Lesson from PROVE IT study

A question raised from these studies:

is LDL-C < 100 mg/dl sufficient low in high-
risk patients who already have low LDL-C
at base line?
 PROVE - IT

C-REACTIVE PROTEIN LEVELS AND

OUTCOMES AFTER STATIN THERAPY
Ridker PM, Cannon CP, Morrow D, Rifai N, Lynda M, Rose MS, Carolyn
H, McCabe BS, Preffer MA, Braunwald E.
N Engl J Med 2005; 352: 20 28
WHAT ARE NEW?

Circulation. July, 2004;110:227-239

 THE VERY HIGH RISK PATIENTS

Established CVD plus:

1. Multiple major risk factors (especially diabetes)
2. Severe and poorly controlled risk factors (especially
continued cigarette smoking)
3. Multiple risk factors of the metabolic syndrome
(especially high triglycerides > 200 mg/dl plus non-
HDL-C > 130 mg/dl with low HDL-C < 40 mg/dl
4. On the basis of PROVE IT, patients with acute
coronary syndromes

Grundy SM et al. Circulation. July, 2004; 110: 227-239

 PENATALAKSANAAN

Perubahan gaya hidup (therapeutic

lifestyle changes )
Perencanaan makan (diet)
Olahraga
Berhenti merokok
Batasi alkohol

Obat penurun lipid