Adipose tissues

JMF Adam

Adipose Tissues
Storage of fat (TG)
Endocrine organ : produced
hormone
(adipocytokine),
leptin, TNF-, IL-6, resistin
pro-inflammatory
adiponektin

antiinflammatory

Jaringan perifer
Jaringan
lemak

Asam
lemak bebas
(proses lipolisis)

Adiponectin
TNF- ,
IL-6,
Leptin,
Resistin

Ambilan glukosa

Ambilan glukosa

Otot

Ambilan glukosa
Sekresi insulin terganggu,
apoptosis

Produksi glukosa
meningkat

Pankreas

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
C

H
CH3

H
CH2

CH2

CH2

CH3

(CH2)7

Kolesterol

CH3

CH3

HO

H3C

O
H
C

CH2

O
C

(CH2)7

CH
CH2

(CH2)1

CH3

Trigliserida

(CH2)16

CH3

O
C H2.O.CO.R
R.COO.CH
C H2O

O
P
O

OCH2.CH2.N+

CH3
CH3
CH3

Fosfolipid

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

K
TG

Lipid Plasma

Apo
TG

Apo

Apo
F

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.

JENIS LIPOPROTEIN
Lipoprotein
class

Relative size,
triglyceride and
cholesterol content

Chylomicrons

Major
apoproteins
B48, E,
CII

VLDL

B100, E,
CII

IDL

B100, E

LDL

B100

HD
L

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
Liver

VLDL
Apo B100

VLDL

Endogenous

(metabolisme LDL,
TG)
IDL
LDL
Foam cells

Enz. Lipoprotein lipase

TG, kol

HDL
Miskin kol. Apo A, C, E

Cholesterol

remnants
kilomikron

Cholesterol

Intestine

Food (kolesterol , TG)

Macrophage

RCTP (HDL)

Exogenous
(metabolisme
LDL,TG)

TGFFA
Stool

Adipose
RCTP = reverse cholesterol
transport pathway

Shepherd J. Eur Heart J Supplements 2001;3(suppl

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

Adenosine
triphosphatebinding
cassette transporter-1 (ABCSRB-1
1)

VLDL
VLDL

Chol
C
E

VLDL
IDL
Chol

CETP
Chol
TG

C
E

TG

Macrophage

LD
L

C
E

Cholesterol
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

L iv
e
r

LDL

HDL

THE METABOLIC PATHWAY

OF LIPOPROTEIN
IN
TYPE 2 DIABETES MELLITUS
AND
METABOLIC SYNDROME

Reverse cholesterol transport

LDL Receptor

Liver
VLDL
VLDL
large

Scavenger receptor-A / CD 36
ABC-1 transporter

VLDL
VLDL
large

SRB-1 receptor

IDL
Triglyceride

LDL
` small
LDL
density

Macrophage

Cholesteryl ester

Cholesterol

FFA
Adipocytes

Insulin Resistance

HDL

ApoA1

Nascent HDL

Kidney

DISLIPIDEMIA
Dislipidemi diabetes tipe 2 / resistensi
insulin
Resistensi

insulin

mengakibatkan
meningkat hati, menjadi sumber VLDL

FFA

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

Jumlah kematian 10-tahun

(PAK),kematian per 1000

50
40
30
20
10
0
0

150
(3.87)

200
(5.17)

250
(6.46)

300
(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

PAK / 1000

Trigliserid > 200 mg/dl

100
73

55

50
10
0

18

17

22

25

130 - 160
160 - 190
> 190
LDL-kolesterol
1000 orang dalam 4 tahun menurut kadar
LDL-kolesterol.

< 130

Insiden PAK /
trigliserid dan

Assman G. Am J Cardiol 1992;70:10H-

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, Totalcholesterol, HDL-cholesterol
and Triglycerides
NCEP-ATP III

KLASIFIKASI TOTAL, LDL, HDLKOLESTEROL, DAN TRIGLISERID MENURUT

NCEP ATP III
LDL kolesterol
< 100
mg/dl
100 129 mg/dl
130 159 mg/dl
160 189 mg/dl
> 190
mg/dl
Total kolesterol
< 200
mg/dl
200 239 mg/dl
> 240
mg/dl
HDL kolesterol
< 40
mg/dl
> 60
mg/dl

Optimal
Mendekati optimal
Sedikit tinggi (Borderline)
Tinggi
Sangat tinggi
Diinginkan
Sedikit tinggi (Borderline)
Tinggi
Rendah
Tinggi

JAMA 2001;285:24862-497

TRIGLISERIDA (NCEP-ATP III)

Optimal

< 150 mg/dl

Sedikit tinggi(borderline)
mg/dl
Tinggi
mg/dl
Sangat tinggi

150 - 199

200 - 499
> 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)

The 8th MADAM

Risk factors
Irreversible
Modifiable
Age
(men > 45 years, women >
55 years)
Family
history
of
premature CHD* (CHD in
male first-degree relative
< 55 years: CHD in female
first-degree relative < 65
years)

Cigarette smoking
Hypertension (BP* > 140 /
90
mmHg
or
on
antihypertensive
medication)
Low HDL C < 40 mg/dl

* 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

NCEP ATP III, THREE CATEGORIES OF

RISK THAT MODIFY LDL CHOLESTEROL
GOALS

The 8th MADAM

Risk Category

LDL Goal
(mg/dl)

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

The 8th MADAM

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

In high risk persons,

the recommended
LDL-C goals is <
100
mg/dl,
but
when the risk is

very high,
an
LDL-C of < 70
mg/dl is
a
therapeutic
option

This
therapeutic
option extends also
to patients at
high risk who have
a

base line LDL-C <

100 mg/dl

THE VERY HIGH RISK PATIENTS

Established CVD, plus:

The 8th MADAM

Multiple major
diabetes)

risk

factors

(especially

Severe and poorly controlled risk factors

Multiple risk factors of the metabolic

syndrome

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

7-year incidence of
MI

Non
diabetic

40

Diabeti
c

35
30
25
20
15
10
5
0

18,8%

20,2%

3,5%

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

PENATALAKSANAA
N

Perubahan gaya hidup

Obat lipid

No over-eating!!

Exercise

Stop smoking, stop alkohol

PENATALAKSANAA
N

Perubahan gaya hidup

Obat lipid

OBAT PENURUN
Persentasi LIPID
penurunan LDL-kolesterol

trigliserid, serta kenaikan HDL-kolesterol

dan

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
Kelas
risiko

Sasaran
LDL
(mg/dl)

Kadar LDL
dimana dimulai
diet - olahraga
(mg/dl)
> 100

Kadar LDLdimana
dimulai obat
(mg/dl)

PJK atau yang

disamakan

<
100

> 130

> 2 faktor
risiko

<
130

> 130

> 160

0 - 1 faktor
risiko

<
160

> 160

> 190

(100-129 dapat
dipertimbangk
an obat)

PJK ekuivalen : DM, strok, peny pembuluh darah perifer

JAMA 2001;285:2487-2497

THE VERY HIGH RISK PATIENTS

Established CVD plus:
1. Multiple

major
diabetes)

risk

factors

(especially

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:

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
Hipertensi
GDPT/ IFG
HDL < 40 mg/dl
TG > 150 mg/dl

LDL < 130 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
Riwayat PJK
Obesitas
Hipertensi
HDL 50 mg/dl
TG 156 mg/dl

LDL < 70
mg/dl

Lipoprotein Metabolism
in Insulin Resistance
Adipocytes
FFA

Liver
VLDL
large

CE

(CETP)
TG

IR
CE

Insulin
FFA : Free Fatty Acid
CE
: Cholesteryl Ester
CETP : Cholesteryl Ester Transfer
Protein

(CETP)
LDL

HDL

ApoA1

TG
LDL
small
density

Kidney

(lipoprotein or
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 Thrombolysis in Myocardial Infraction 22 (PROVE IT-TIMI 22)
Primary Prevention of Cardiovascular Disease With Atorvastatin in Type 2 Diabetes in the Collaborative Atorvastatin
Diabetes Study (CADRS)

Jaringan
lemak
Substrat
glukoneogenik

Adiponectin

Asam
lemak bebas

TNF- ,
IL-6,
Leptin,
Resistin

Jaringan perifer
Ambilan glukosa

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 LDLcholesterol) That Modify LDL Goals

Cigarette smoking

Hypertension
mmHg,

(blood pressure > 140/90

or on antihypertension)

Low HDL cholesterol

(< 40 mg/dl)*
Family history of premature (CHD in male first-degree
relative <
55 years; CHD in female
firstdegree relative < 65
years
HDL cholesterol > 60 mg/dl counts as a negative risk
factor,
Age
male > 45 years, female > 55
years
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

(high risk)
Faktor risiko multipel ( > 2)
(moderate risk)

< 100

< 130

0 - 1 Risk Factor
(low risik)

< 160
JAMA 2001;285:24862-497

HEART PROTECTION STUDY WITH

SIMVASTATIN (HPS)
Baseline LDLC (mg/dl)

Statin
(n
=10,269)

Placebo
(n =10,267)

< 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%)

Event Rate
Ratio

2,585 (25.2%)

0.4

Statin
Worse

Statin
Better

0.76 (0.72 0.81)

p<0.0001
0.6

0.8

1.0

1.2

1.4

Major vascular events by baseline low-density lipoprotein cholesterol (LDLC) 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
diabetes)

risk

factors

(especially

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

PENATALAKSANAA
N

Perubahan gaya hidup

(therapeutic lifestyle changes )

Perencanaan makan (diet)
Olahraga
Berhenti merokok
Batasi alkohol

Obat penurun lipid