OBESITAS

DISLIPIDEMIA
SINDROMA METABOLIK
Mahatma
FKUMS
Presentation Point of View
 Pendahuluan
- I,4 milyard Diantara 7 milyard penduduk dunia Obese
atau over weight

- Prevalensi Obesitas di Indonesia sekitar 15 persen

- Dislipidemia terjadi pada orang Obese, Berat

Badan normal, kurus

- Sindrome metabolik adalah kumpulan gejala

Faktor resiko penyakit jantung koroner

- Sindrome metabolik meliputi , kenaikan tekanan darah,

dislipidemia, intoleransi glukosa
Pendahuluan
Metabolism of Fat
 Cholesterol balance
Extrahepatic Dietary
Organs LDL IDL VLDL Cholesterol
300 mg/day
25%
Cholesterol
Synthesis
900 mg/day Biliary
Cholesterol Cholesterol
Synthesis 75%

Transport
via HDL & LDL Chylomicron transport
50% intestinal Faecal sterols
Cholesterol absorbed 50% cholesterol
excreted
 Metabolisme
LDL HDL
Atherogenicity
small dense
LDL
 Inhibits oxidation Inhibits endothelial
of LDLs HDL adhesion molecules

Inhibits Stimulates
tissue factor endothelial NO
production

Enhances reverse
cholesterol transport

Opposes atherothrombosis

Potential mechanisms by which HDLs oppose atherothrombosis.

(Barter. EMCNA (2004):398)
Presentation Point of View
 Definition
Obesity is caused by imbalance of high
Food intake and or low energy expenditure
Klasifikasi dan Patogenesa
Eropa Asia
BMI > 30 kg/m2 > 25 kg/m2
Waist ♀ > 90 ♀ > 80 cm
Circumference ♂ > 102 ♂ > 90 cm
Faktor genetik :
BMI Classification
 Gen penyebab :
- Leptin
<18.5 Underweight
- Melanocortin receptor – 4
18.5-24.9 Normal weight
- Alpha-melanocyte stimulating
25-29.9 Overweight hormone
30-34.9 Obesity Class I - Prohormone convertase – 1
35-39.9 Obesity Class II Faktor Lingkungan :
40-49.9 Obesity Class III - Nutrisional - Medikasi
> 50 Super Obesity - Aktifitas fisik - Sosial ekonomi
Mengapa Orang Jadi Gemuk ?

Coca
Makanan yang
Di konsumsi

Banyak gerak Hidup santai

25 tahun 50 tahun
 Macam Obesitas

Android/ sentral Ginekoid/ trunkal

Gemuk tidak sehat Gemuk “sehat”
“Overweight and Obesity widespread, serious
But treatable”
 Obat Penurun Berat Badan

02/22/22
Surgery : - Roux-Y gastric Bypass ( RYBG )
- Laparascopy Adjustable Gastric Banding (LABG )
- Vertical Banded Gastroplasty ( VBG )

Indikasi Roux-Y
gastric Bypass :
- BMI > 40
- >35 dg 2 komorbid
- Gagal non bedah
 Complications of Obesity
Pulmonary disease
abnormal function Stroke
obstructive sleep apnea
hypoventilation syndrome
Cataracts
Non Alcoholic fatty liver disease CHD
steatosis DM
steatohepatitis Dyslipidemia
cirrhosis Hypertension
Gall stone disease
Severe pancreatitis
Gynecologic abnormalities Cancer
abnormal menses breast, uterus, cervix
infertility colon, esophagus, pancreas
PCOS Osteoarthritis kidney, prostate
Phlebitis
Gout venous stasis
Presentation Point of View
 Dislipidemia
Kelainan metabolisme lipid, ditandai
dengan peningkatan serta penurunan
fraksi lipid plasma
Normal
TRIAD LIPID
 Kol-total/ kol-LDL
Gemuk

 Trigliserid (TG)

Kurus
 Kol-HDL.
DISLIPIDEMI BISA TERJADI PADA.......
 Klasifikasi Dislipidemia

- Dislipidemia primer :
Kelainan Enzym, genetik
- Dislipidemia sekunder :
Pathological states : Drugs :
- Diabetes – Oral estrogens, Progestins
- Hypothyroidism
– Anabolic steroids
- Cushing’s syndrome
– Corticosteroids
- Nephrotic syndrome
- Chronic renal failure – Retinoids, such as isotretinoin
- Monoclonal gammapathy – Sertraline hydrochloride
– ARV – protease inhibitors
Lifestyle habits :
– Non-selective -adrenergic inhibitor
- Obesity, Alcohol
– Cyclosporine, Thiazide diuretics
- Stress, Merokok
 Dyslipidemia
Major of Atherogenicity
Non modifiable risk factors : Age, gender, family
DM, Merokok Rongga Pembuluh Darah
Agregasi trombosit
LD MONOSI
L T
tissue factor + PAI-1
S S S i i i i i

ENDOTEL
PLAQUE
PLAQUE

Radikal LDL ox
bebas.
AGEs

INTIM Makrofag Migrasi

A
Sitokin+ f. pertumbuhan Proliferasi
MEDIA
SEL OTOT
 Aterosklerosis Infark, SNH
Atherosclerosis Atherothrombosis
Foam Cells Intermediate Lession Plaque
Fatty Streak ATHEROMA Rupture

ACS

Dekade ke I - III Dekade IV Dekade V

ATHEROSCLEROSIS DIMULAI UMUR 5 TAHUN

PENATALAKSANAAN DISLIPIDEMIA

Non-farmakologik :
Life style ,Terapi nutrisi, Batasi minuman beralkohol, Hindari merokok
Farmakologik : Obat hipolipidemik
1. Penghambat HMG-CoA reduktase (statin)
2. Sequestran asam empedu (resin)
3. Asam fibrat
4. Asam nikotinat (niacin)
5. Penghambat absorbsi kolesterol (ezetimibe)
6. Probucol

Obat baru :
- NIACIN extended release (NIASPAN)
- Fix kombinasi NIACIN ER + LOVASTATIN (advicor)
Obat masa depan:
- Penghambat cholesteryl ester transfer protein (CETP)-- > HDL 

- Penghambat microsomal transfer protein (MTP)

- Penghambat intestinal bile-acid transporter. (IBAT)

Intensive LDL-C Goals for High-Risk Patients
Recommended LDL-C treatment goals

2004 ATP III AHA/ACC guidelines 2006

Update 2004 Update
Update 20041 <100 mg/dL:
Goal for all
<100 mg/dL : patients with CHD risk
Patients with <100 mg/dL
- CHD
- CHD risk <70 mg/dL:
equivalents A reasonable
(10-year risk>20%)1 goal for all patients
1% <70 mg/dL with CHD†,2
- very
decrease 1%
high-risk patients1 And
Very High Risk increase
in LDL-C
reduces Patients in HDL-C
CHD risk reduces
by 1%1 Lower LDL-C goals; wider target population CHD risk
by 3%2-5
need for more effective therapies
Very high risk: established CVD plus: major risk factors
especially diabetes, poorly controlled cigarette smoking, TG
≥200 mg/dL + LDL ≥130 mg/dL with HDL-C <40 mg/dL
 TARGET HIPOLIPIDEMIK ORAL
Extrahepatic Dietary
Organs LDL IDL VLDL Cholesterol
300 mg/day
25%
Cholesterol
Synthesis
900 mg/day Biliary
Cholesterol Cholesterol
Synthesis 75%

Transport
via HDL & LDL Chylomicron transport
50% intestinal Faecal sterols
Cholesterol absorbed 50% cholesterol
excreted

Statins Ezetimibe Plant stanols Resins

 Terapi Farmakologi untuk koreksi profil Lipid
KELOMPOK
NAMA OBAT EFEK THD LIPOPROTEIN KONTRA INDIKASI
PREPARAT
Statin Lovastatin 10mg-20 mg LDL  18-55% Gangguan fungsi hepar
Pravastatin 10mg-20 mg HDL  5-30% akut atau kronik
Simvastatin 10mg- 20 mg Trigliserid  7-30%
Fluvastatin 20mg- 80mg
Atorvastatin 20mg- 80mg
Rosuvastatin 20mg- 40mg
Ezetimibe LDL  15-20% Bila dikombinasi dgn
HDL  1-4% statin, kontra indikasi
utk ggn fungsi hepar
Trigliserid  5-10%
akut atau kronik
Bile acid Cholestyramin LDL  15-30% Disbetaliproteinemia
squestrants Colestipol HDL  3-5% Trigliserid > 400 mg/dl
Colesevalam Trigliserid sqa
Nicotinic LDL  5-25% Gangguan hepar kronik
acid HDL  15-35% gout
Trigliserid  20-50%
Fibric acid Gemfibrozil LDL  5-20% (mgk  pd Gangguan fungsi hepar
derivatives Fenofibrat kasus2 dgn trigliserid tinggi) berat
200 mg 3 x sehari HDL  10-20% Gangguan fungsi ginjal
100 mg 3 x sehari Trigliserid  20-50% berat
 Pleiotropic effects of statins
 RhoA

 TXA2  t-PA  Macrophage growth  Rac1  RhoA  ET-1

 PAI-1  AT1 receptor
 MMPS  hs-CRP
 TF  Adhesion molecules  ROS  NO

Θ Θ Θ  Θ Θ Θ Θ Θ Θ
Platelet Thrombotic Plaque Vascular SMC Endothelial SMC
Vasoconstriction
activation effect stability inflammation hypertrophy dysfunction proliferation

 Atherosclerosis  Hypertension

CVD/ CVA Θ

Takemoto MArterioscler. Thromb Vasc Biol. 2001; 21:1712-1719

Presentation Point of View
 JARANG OLAHRAGA
PENUAAN
OBAT OBATAN
SEBAB LAIN PRE SAKIT
STROKE

DIABETES MELLITUS
HIPERTENSI
Insulin resistance P C O S dan NAFLD
HIPERURICEMIA
DISLIPIDEMIA
- Glycemic disorders ATHEROSCLEROSIS
( Prediabetes ) ACANTHOSIS NIGRICANS
- << HDL , >> LDL
- Hypertriglyceridemia
- Hypertension
- Endothel Disfunction
- Hiperuricemia
- Microalbuminuria
CHD
- Inflammation (hsCRP)
- Impaired thrombolysis -
 PAI-1

Central Obesity
ATHEROSCLEROSIS +++
 Components of Metabolic Syndrome
ATP III that related to CVD (2006)
1. Abdominal obesity
( Waist circumference :
♂ ≥ 90 Cm / ♀ ≥ 80 Cm )
♂ ≥ 102 Cm / ♀ ≥ 88 Cm )

2. Atherogenic dyslipidemia
HDL-Chol.( ♂ < 40 / ♀ < 50 mg/dl )

?
TRIGLYCERIDE ( > 150 mg/dl)

3. Raised blood pressure

130- 140 mmHg / 85 - 90 mmHg

4. Glucose intolerance
Fasting blood sugar 100 mg/dl – 126 mg/dl

5. Proinflammatory state
(Elevated of CRP)

6. Prothrombotic state
Central Obesity (Elevated of PAI-1)
 Autocrine
Endocrine
Paracrine

PAI-1 Leptin
TGF-β ?TNFα
?IL-6
TF
Adipsin/ASP Sex steroids
Glucocorticoids
?TNF-α /IL-6/Leptin
?Angiotensin
Renin-Angiotensin
system ?PAI-1

Steroid hormones ?Adiponectin

Adipose tissue
?AdipoQ

1. ESTROGEN 16. VISFATIN

Factors FFA, TNF  and PAI-1 can 31. RBPtissues
affect peripheral
CARDIO
PROTECTIVE 17. HSL 32. APO-E
2. Adiponectin 18. LIPOTRANSIN 33. ICAL
3. AGOUTI RELATED PROTEIN 19. PERILIPINS 34. LPL

Resistensi Insulin

Resistensi Insulin
TNF α 20. FFAs 35. CETP

Aterosklerosis
4.

Aterosklerosis
5. IL1B 21. TGF-β 36. PLTP
Resistensi Insulin

6. IL-6 22. VEGF 37. NO

Aterosklerosis

7. ANGITENSINOGEN 23. IGF-1 38. PC-1

8. ASP 24. PGE2 39. AQUAPORINS
9. ADIPSIN 25. PGI1 40. FIAF
10. FACTORS B,C3 26. GLUCOCORTICOID 41. LACTATE
11. ADHESIVE PROTEIN 27. 11βHSD 42. MONOBUTYRIN
12. PAI-1 28. AROMATASE 43. GALACTIN-12
13. TF 29. METALLOTHIONIEN 44. ESM-1
14. RESISTIN 30. MIF 45. APELIN
15. Leptin
ANTI INSULIN RESISTANCE ANTI ATHEROSCLEROSIS
1 ENDOTHELIUM
1 ↓ TISSUE TG CONTENT
•↓ THE Expression of Adhesion Mol. :
ICAM-1, VCAM-1, E-selectin, also

5 ROLES OF
↓ TNFœ-induced NFkB Activation
2 UPREGULATE INSULIN •↓ Endothelial Cell Apoptosis via
SIGNALING
AMPK Activation by HMW multiform
ADIPONECTIN Of Adiponectin
3 ACTIVATE PPARœ Dan ESTROGEN 2 MACROPHAGE ↓ SRA- 1
↓ Uptake of Ox-LDL,↓ Foam Cell

4 ACTIVATE AMPK 3 SMC : ↓ Cell Proliferation

↓ Migration

V IV III

↓ APOPTOSIS ANTI INFLAMMATION ANTI OXIDANT

BRAIN, HEART, β - CELL ↓ INFLAMMATORY MARKERS ↓ OXIDATIVE STRESS

CARDIOPROTECTIVE PROPERTIES
Ouchi et al 2000-2001, Yamauchi et al 2001-2003, Arita et al 2002
Kobayashi et al 2004, IIIustrated : Tjokroprawiro 2007-2011
 Fatty acid
Elevated in obesity and diabetes
 Whole-body+hepatic+muscle insulin sensitivity
 -cell function,  insulin clearance
 Liver triglyceride secretion
 Organ fat content, oxidative stress

Leptin
Elevated in obesity Corticoids
 Whole-body+muscle+hepatic insulin sensitivity  11-HSD-1 in fat (not liver) in obesity
 Metabolic rate,  appetite,  organ fat content  Fat cell size, insulin resistance
May  blood pressure,  endothelial function  glucose, BP, lipids

Apelin Endocannabinoids (EC)

Insulin stimulates fat expression Insulin inhibits fat expression
Elevated in obesity+hyperinsulinemia Fat insulin resistance   circulating EC
Decreased BP, increase HR and inotropy (affecting liver, muscle, brain)

Resistin TNF-, IL-6

Elevated in obesity and diabetes Stimulate lipolysis, VLDL secretion
 Whole-body+muscle+hepatic insulin sensitivity  Whole-body+hepatic insulin sensitivity
 Liver triglyceride secretion  Adiponectin expression
Visfatin, Omentin, Vastin
Mostly from visceral fat
 Whole-body insulin sensitivty

Adipose tissue is the largest endocrine organ in the body. The diagram summarize the main roles and effects of
Representative fat-derived products that have been related to insulin resistance and metabolic risk. BP,
blood pressure; HR, heart rate (Iozzo, 2009)
 Adipose tissue in Central Obese

ADIPOCYTE
WEIGHT GAIN WEIGHT GAIN
IR

JNK
NFB
TNF-
Leptin
VEGF
Endothelial IL-6
Cell IL-1
Angiogenesis
TNF-
Physical stress/oxidative
damage to endothelium?
MCP-1
PREADIPOCYTE
FFA
MCP-1
MACROPHAGE
RECRUITMENT
MACROPHAGE – PREADIPOCYTE MACROPHAGE
RECRUITMENT

NORMAL ADIPOCYTE ADIPOCYTE DYSFUNCTION

ASK-DNC INFLAMED ADIPOSE TISSUE
Cardiometabolic Risk (CMR)
Definitions of the metabolic syndrome
(Bloomgarden 2004, 1st Conggress on Insulin Resistance Syndrome)

ATP III WHO AACE (IRS) EGIR (IRS)

IGT/HOMA-IR, One of ** Fasting hyperin-
IFG/DM and sulinemia( highest
2 of 4 below quartile) and
At least 3 of 5 And 2 of 4 2 of 4
Uirinary alb exc > 20 g / m
WHR male 90 in men
female 85 in women
Waist CF male >102 cm  94 cm
female > 88 cm  80 cm
Triglycerides  150 mg/dl 150 mg/dl or 150 mg/dl or 2.0 mmol/l or
HDL chol male 40 mg/dl 35 mg/dl 40 mg/dl  1.0 mmol/l
female 50 mg/dl 39 mg/dl 50 mg/dl
Blood pressure 130/8 5mmHg  140/90 mmHg 130/85 mmHg 140/90 mmHg or
treated for Hyp.
Blood glucose  110 mg/dl FBG 110-125 or FPG 6,1 mmol/l
2hpc 140-200 (exc.DM)

** CVD, hypertension, PCOS, NAFLD, family history of T2DM / hypertension / CVD, history of

Classification for Metabolic Syndrome

gestational diabetes, non Caucasian, sedentary lifestyle, BMI>125 or WC>40 male, >35 female,
age>40yrs
 Indonesian classification for Metabolic Syndrome
WC ( male ≥90cm / female ≥80 cm)
plus
2 of the 4 factors

1. Fasting Glucose 3. Triglyceride

100 mg/dl – 126 mg/dl > 150 mg/dl

4. HDL-Chol
2. Blood Pressure male < 40 mg/dl
> 130/85 mmHg female< 50 mg/dl

WC
male ≥ 90 cm

female ≥80 cm
Lose weight Losing as little as 5 to 10% of your body weight can reduce insulin levels thus reducing M S
Exercise Walking just 30 minutes a day can help prevent the serious diseases associated with MS.
Stop smoking Cigarettes increases insulin resistance and worsens health consequences with MS.
Eat fiber Whole grains, beans, fruits and vegetables, important to lower insulin levels.

Weight loss Sibutramine (Meridia) and Orlistat (Xenical).

drugs

Insulin
sensitizers Thiazolidinediones and Metformin

Aspirin Aspirin is often prescribed to help reduce the risk for a heart attack.
Medications to
Major types of medications angiotensin-converting enzymes (ACE)
lower blood
pressure inhibitors, calcium channel blockers and beta blockers.
Medications to
regulate
statins ( Pleitropic effect )
cholesterol
 Penurunan 10% Weight loss = 30%
Berat Badan 5-10% Viceral Adipose hormone loss
Diabetes Hipertensi

Trigliserid Kolesterol HDL

Jantung
koroner

Gemuk tidak sehat

46
Obesitas sentral
 Metformin
Improved Reduced
Insulin sensitivity Hypertriglyceridaemia
Fibrinolysis AGE formation
Nutritive capillary flow Cross-linked fibrin
Haemorrheology Neovascularisation
Post ischaemic flow Oxidative stress

Reduced cardiovascular risk

Vascular benefits of metformin
Presentation Point of View
 Definisi Dx Terapi Komplikasi
Exercise - Cancer, C H D
Akumulasi FAT Diet - Hipertensi, S N H
di Orlistat - Dislipidemia
O BESITAS
Obesitas Jaringan Lemak
BMI Sibutramine - OsteoArthritis
berlebihan, baik - D M, PCOS
Besar dan Akupunktur
Lipotripsy - Sleep Apneu
jumlahnya
Liposuction - Obesity H S
Surgery - Gout, Gallstone

Exercise
Kelainan TG Diet - Aterosklerosis
DISLIPIDEMI
Dislipidemia Metabolisme C H Statin -CHD
LIPID LDL -SNH
Fibrat
HDL
-CHD
WC
CH Exercise - Hipertensi
- Dislipidemia
SINDROMA
KUMPULAN GEJALA
YANG DISEBABKAN LDL Diet -DM
Sindrom Metabolik OLEH KARENA
RESISTENSI INSULIN. HDL Metformin -SNH
METABOLIK
( Pre Sakit )
DAN...........
RESISTENSI INSULIN TG Glitazone - PCOS, Gout
KARENA
AU - Gallstone
( pre sakit ) OBESITAS SENTRAL
GDP Statin - NAFL
Alb - Acanthosis
nigricans
Closing Remark

Exercise

Diet

Orlistat

Sibutramine

Statin

Metformin The NEJM, Vol. 342 : 145-153, Jan

2000
50