Curriculum vitaeCurriculum vitae• Nama : Em YunirNama : Em Yunir• Tempat/tanggal lahir : Jakarta/ 9 Juni 1962• Agama : Islam• Lulus Fakultas kedokteran Universitas Indonesia tahun 1988Lulus Fakultas kedokteran Universitas Indonesia tahun 1988• Lulus Spesialis Ilmu Penyakit Dalam FKUI tahun 2000• Program Konsultan Metabolik Endokrin tahan 2000• Staf Divisi Metabolik Endokrin Departemen Ilmu Penyakit Dalam Staf Divisi Metabolik Endokrin Departemen Ilmu Penyakit Dalam

Fakultas Kedokteran Universitas Indonesia• Poli klinik Diabetes Terpadu Rumah sakit Marzoeki Mahdi Bogor

Organisasi :• Sekjen Persadia Tahun 2005 -2008• PERKENI• PEDI• PAPDI

FAKTOR-FAKTOR RISIKO PENYAKIT JANTUNG DAN PEMBULUH DARAHPENYAKIT JANTUNG DAN PEMBULUH DARAH

EM YUNIREM YUNIRDIVISI METABOLIK DAN ENDOKRIN

FKUI/RSUPN CIPTOMANGUNKUSUMO FKUI/RSUPN CIPTOMANGUNKUSUMO

Penyakit Jantung Pembuluh DarahPenyakit Jantung Pembuluh DarahPenyakit Jantung Pembuluh DarahPenyakit Jantung Pembuluh Darah

ddJantung danpembuluh

Jantung danpembuluh Stroke Stroke

darah jantungdarah jantung

PADPAD

Penyakit jantung pembuluhdarah mempunyai risikodarah mempunyai risiko

kematian yang sama besard di b t litdengan diabetes melitus

7-Year Incidence of Fatal/Nonfatal MI

From the East-West Study

e of (%

)

Diabetic (n=1059)Nondiabetic (n=1373)

40

5045

45†

ence

Rat

enf

arct

ion

20

3025

35

18 8* 20.2

ear I

ncid

eoc

ardi

al In

10

20

5

15

3.5

18.8

7-ye

Myo 0

No DM, no MI No DM, MI DM, no MI DM, MI

5

* p<0.001 vs. nondiabetic, no MI† p<0.001 vs. diabetic, no MI

Haffner SM et al. N Engl J Med 1998;339:229-34.

Penyakit Jantung dan pembuluh d hdarah

Penyebab utama kematian di USPenyebab utama kematian di US

Penyebab 40 % angka kematian CVDy % g

1/3 diantaranya kematian premature

Suddent death usia 15-34 tahun

Angka kecacatan >>

CDCP 2007

Diabetes Melitus Diabetes Melitus

Meningkatkan risiko kematianMeningkatkan risiko kematianMeningkatkan risiko kematianMeningkatkan risiko kematian

Meningkatkan angka kesakitanMeningkatkan angka kesakitanMeningkatkan angka kesakitanMeningkatkan angka kesakitan

Komplikasi kronisKomplikasi kronispp

KecacatanKecacatan

Penurunan kwalitas hidupPenurunan kwalitas hidup

ADA 2008

Cardiometabolic RiskCardiometabolic Risk

Sekelompok faktor risiko terhadapl kit j t dmunculnya penyakit jantung dan

diabetes tipe 2 di kemudian hari

Beberapa faktor risiko dapatdimodifikasi untuk pencegahan

Faktor-faktor risiko kardiometabolik Faktor faktor risiko kardiometabolik

Dapat dimodifikasi Tidak dapat dimodifikasip p• Berat badan lebih/obesitas •Umur

• Gula darah diatas normal •Etnis/suku bangsa• Gula darah diatas normal •Etnis/suku bangsa• Dislipidemia :kolesterol LDL ,

HDL , Trigliserida•Jenis kelamin

• Tekanan darah tinggi •Keturunan• Hiperkoagulasi• InflamasiInflamasi• Merokok• Kurang aktivitas• Pola makan tidak sehat

Overweight / ObesityGeneticsAge

Abnormal lipid metabolismInsulin resistance syndrome

Insulin Resistance

•LDL ↑•Apo-B ↑•HDL-C ↓

?

su es sta ce sy d o e

↑Glucose↑

Lipids ↑BP•TG ↑

Cardiometabolic risk Age race

p

Cardiometabolic riskGlobal diabetes / CVD risk

Age, race, sex,

family history

Inflammation Smoking

Physical activity Inflammation Hypercoagulatio

nElevated blood pressure

Physical activity

Brunzell JD et al. Lipoprotein Management in Patients with Cardiometabolic Risk. J Am Coll Cardiol

2008;51:1512-24.

1. Diabetes

Risk of CVD in people with diabetes 2-4 times more likely than in those without diabetes more likely than in those without diabetes

Up to 12% of CVD deaths in the Asia-Pacific pregion due to diabetes

India – more than 150,000 CVD deaths due to diabetes

China – 70,000 CVD deaths from diabetes

Natural History of Type 2 Diabetesy yp

Genetic b k d f

Age0-15+ 15-40+ 15-60+ 25-70+

background for:– Insulin sensitivity– Insulin secretion– Complications

Environmental

Microvascular complications

Environmental factors:

– Nutrition– Obesity– Physical inactivity

Postprandial Fasting D th

Disability

– Insulin resistance

IGT Postprandial hyperglycemia

Fasting hyperglycemia Death

– Pseudo-normal – Hypoinsulinemia– Hyperinsulinemia– ↓ HDL cholesterol– ↑ Triglycerides– Hypertension– Accelerated

insulin– Retinopathy– Nephropathy– Neuropathy

– Blindness– Renal failure– Amputation– IHD– StrokeAccelerated

atherosclerosisStroke

Macrovascular complicationsDisability

Manifestsi klinik pre-diabetes Manifestsi klinik pre diabetes

1. Impaired fasting glucose ( IFG )1. Impaired fasting glucose ( IFG )

GD puasa : 100 mg/dl – 125 mg/dlGD puasa : 100 mg/dl – 125 mg/dl

2. Impaired glucose tolerance ( IGT )2. Impaired glucose tolerance ( IGT )

GD 2 jam PP 140 – 199 mg/dl ( OGTT ) GD 2 jam PP 140 – 199 mg/dl ( OGTT )

Abnormalities of the CV system specific to y pdiabetes

Microangiopathy Autonomic Neuropathy Other Blood Vessel Damage

What is it? Damage to small blood vessels and capillary circulation

Damage to nerve supply of internal organs

Damage to inner/outer lining of blood vessels

Clinical Outcome

– Retinopathy– Nephropathy– Neuropathy

– Problems with pulse rate– Postural fall in BP– Foot ulcers

– Impaired regularity of blood flow

– Weakened vessel walls– Diabetic foot – Impotence

– Gastrointestinal dysfunction– Aggravated microangiopathy– Atherosclerosis/

macroangiopathy

International Diabetes Federation, 2006.

Does improved glycemic control reduce CVD risk?

• Improved glycemic control can prevent onset or progression of microvascular complications

•BUT: d t i l t t ll f th – We need to aggressively treat all of the

commonly associated features of diabetes in order to effectively reduce diabetes in order to effectively reduce patient CVD risk

Marks J. Clin Diab 2003;21:99-100.

Lowering HbA1C Reduces Risk of Complicationss o Co p ca o sIn intensively treated patients, HbA1C was 7.0% compared with 7.9% in conventionally treated patients. This 0.9% decrease in HbA1C is associated with a reduction in risk for diabetic complications.

MIBorderline significance-16Retinopathy

Cataract extractionBorderline significance

Significant-21

-24Microvascular endpoint

Albuminuria at 12 yearsSignificant

Significant

-25

-34Any diabetes-related

endpointSignificant-120 -10 -20 -30 -40

-50

UK Prospective Diabetes Study (UKPDS) Group (33). Lancet 1998;352:837-53.

50

Recommendations for glycemic, blood pressure, and lipid control for adults with diabetes

A1C <7.0%Blood pressure 130/80 mmHgLipids

– LDL-C <100 mg/dL (2.6 mmol/L)*

* In patients with overt CVD treatment with a statin to lower LDL C to <70 In patients with overt CVD, treatment with a statin to lower LDL-C to <70 mg/dL (<1.8 mmol/L) is an option.

American Diabetes Association. Diabetes Care 2008;31(1):S12-S54.

2. Complications of Hypertension in Patients with Diabetesin Patients with Diabetes

Microvascular MacrovascularR l di C di diRenal disease Cardiac disease

Autonomic neuropathy Cerebrovascular disease

Eye disease (glaucoma, retinopathy with potential

Reduced survival and recovery rates from stroke

blindness)Peripheral vascular disease

UKPDS Blood Pressure Study:Tight vs. Less Tight Controlg g• 1148 Type 2 patients

– Intensive BP group: 144/82 mmHgIntensive BP group: 144/82 mmHg – Controls: 154/87 mmHg

Endpoint Risk Reduction (%) p-valueAny diabetes-related endpoint

24 0.0046

Diabetes-related deaths

32 0.019

Heart failure 56 0.0043

Stroke 44 0.013

Myocardial infarction 21 NS

UK Prospective Diabetes Study Group. BMJ 1998;317:703-13.

Microvascular disease 37 0.0092

3. Overweight and Obesity Based on BMI Waist Circumference (WC)Based on BMI, Waist Circumference (WC), and Associated Disease Risk*

BMI (kg/m2)

Obesity Class

Disease Risk*(Relative to Normal

Weight and WC)Weight and WC)Men <40 in (<102 cm) >40 in ( >102 cm)Women <35 in (<88 cm) >35 in ( >88 cm)

UnderweightNormal**OverweightObesity

<18.518.5-24.925.0-29.930.0-34.0 I

--

IncreasedHigh

--

HighVery high

Extreme obesity35.0-39.9

>40IIIII

Very highExtremely high

Very highExtremely high

* Disease risk for type 2 diabetes, hypertension, and CVD** Increased WC can also be a marker for increased risk, even in people of normal weight

NHLBI Obesity Education Initiative, 2000.

Risiko kematian berdasarkan Index Masa Tubuh ( IMT )

Men3.0

Index Masa Tubuh ( IMT )of

Dea

th

Men

Women2.2

2.6

ive

Ris

k o

1.4

1.8

Rel

ati

Lean Overweight Obese1.0

1.4

<18.5 18.5–

20.4

20.5–

21.9

22.0–

23.4

23.5–

24.9

25.0–

26.4

26.5–

27.9

28.0–

29.9

30.0–

31.9

32.0–

34.9

35.0–

39.9

>40.0

g0.6

Body Mass indexThe Obesity Society, 2008.

Calle EE et al. N Engl J Med 1999;341:1097-105.

Abdominal Obesity and Increased Risk of CHDIncreased Risk of CHD

Waist circumference independently associated with increased age-adjusted risk of CHD, even after adjusting for BMI and other CV risk factors , j g

2 5

3.02.44

1 5

2.0

2.52.06

2.31 2.44p for trend = 0.007

e R

isk

0 5

1.0

1.5 1.27

Rel

ativ

e

0.0

0.5

<69.8 69.8-<74.2 74.2-<79.2 79.2-<86.3 86.3-<139.7

Quintiles of Waist Circumference (cm)

CVD Risk Associated with WC Even in Normal Weight Individualse o a e g d dua s

n=69,409 men p<0.01 for all

201%

21%

10

15

ency

(%)

13%

21%6%

1%3%

5

10

≥25 - 30

≥30

Freq

ue

26%9%

1%

0<90 ≥90 - <101 ≥101

<25

Waist Circumference Tertile (cm)

Balkau B et al. Circulation 2007;116(17):1942-51.

Multiple Factors Associated with Obesity Give Rise to Increased Risk of CVD

Primarymetabolic

disturbance

Intermediate vascular disease

risk factor Intravascular

pathologyClinicalevent

y

Hypertension

Insulin resistance

Dyslipidemia

Hyperglycemia Atherosclerosis

Overnutrition Hyperinsulinemia

Hyperglycemia• Coronary arteries• Carotid arteries• Cerebral arteries• Aorta• Peripheral arteries

CVDInflammation

Impairedfibrinolysis

Hypercoagulability

• Peripheral arteries

Endothelial dysfunction

Metabolic/Vascular Benefits f 10% W i ht L

• In diabetes:

of 10% Weight Loss

– Up to 50% ↓ in fasting glucose for newly diagnosed type 2 patient

At i k f di b t• At risk for diabetes:>30% ↓ in fasting insulin>30% in insulin sensitivity

• Mortality:>20% ↓ all-cause mortality>30% ↓ in diabetes-related deaths>40% ↓ in obesity-related deaths

Haslam D et al. BMJ 2006;333:640-2.

Impact of Weight Loss on Risk Factors

~5%Weight Loss

5%-10%Weight Lossg g

HbA1c ↓ ↓

Bl d ↓1

2

1

2↓Blood pressure ↓

Total cholesterol

2

3

2

3↓

↓

↓

HDL cholesterol

T i l id

33 3

4↓↑ ↑

Triglycerides

The Obesity Society, 2008.Wing RR et al Arch Intern Med 1987;147:1749 53

4↓

Wing RR et al. Arch Intern Med 1987;147:1749-53.Mertens IL, Van Gaal LF. Obes Res 2000;8:270-8.

Blackburn G. Obes Res 1995;3(Suppl 2):211S-16S.Ditschunheit HH et al. Eur J Clin Nutr 2002;56:264-70.

4 Dislipidemia 4. Dislipidemia

• Kolesterol total LDL HDL rendah Kolesterol total, LDL, HDL rendah , ipertrigliseridemia

• Prediktor CVD• Prediktor CVD• 25 % penduduk US• Penurunan 10 % kolesterlol total dapat

menurunkan risiko CVD 30 %

Risk of CHD by Triglyceride Level:The Framingham Heart Study

3

M W

Ris

k

n=5127

2

2.5Men Women

Rel

ativ

e

1

1.5

0.5

1

050

(0.6)100(1.1)

150(1.7)

200(2.3)

250(2.8)

300(3.4)

350(4.0)

400(4.5)

Faktor risiko dislipidemiaFaktor risiko dislipidemia

•Rokok•Tekanan darah tinggi•HDL rendah ( < 40 mg/dl )•Riwayat keluarga

i ( i ≥ 4 h i ≥ h )•Usia ( pria ≥ 45 tahun wanita ≥ 55 tahun )

5 Insulin Resisten 5. Insulin Resisten • Gangguan kemampuan insulin untuk Gangguan kemampuan insulin untuk

menstimulasi penggunaan glukosa di jaringan perifer dan menekan produksi glukosa hati.

Dipengaruhi oleh :p g1. berat badan berlebih 4. aktivitas fisik2. Umur 5. pengobatan. U u 5. pe goba a3. genetik 6. puber/kehamilan

Efek Resistensi Insulin

Glucose uptake ↓pGlucose oxidation ↓

Insulin i t

Lipolysis ↑F f tt id ↑

HyperinsulinemiaHyperglycemiaresistance Free fatty acid ↑ HyperglycemiaDyslipidemia

Glucose uptake ↓Glucose production ↑p

VLDL synthesis ↑ Cardiovascular disease

Insulin Resistance and PAD

9

p trend = 0.037

6

7

8

ce (%

)

4

5

6

Pre

vale

nc

1

2

3

PAD

1 Q1<1.08

Q21.08-1.86

Q31.86-3.34

Q4>3.34

HOMA IR Q til

Pande RL et al. Circulation 2008;118:33-41.

HOMA-IR Quartiles

6 Inflamasi6. Inflamasi

• Peningkatan reaksi inflamasi akibat Peningkatan reaksi inflamasi akibat injuri

• Mayor komponen dari atherosklerosis• Mayor komponen dari atherosklerosis• Marker : C Ractive Protein• Protrombic state• Risiko CVD 1,5 – 4 kali ,

Faktor risiko inflamasi Faktor risiko inflamasi

1 Merokok1. Merokok2. Obesitas

3 Di li id i3. Dislipidemia4. Hipertensi5. Diabetes

Pencegahan : aspirin

Kesimpulan Kesimpulan • Penyakit jantung pembuluh darah mempunyai risiko y j g p p y

mortalitas CVD yang sama diabetes Melitus• Faktor risiko kardiometabolik merupakan faktor

i ik b t h d ti b l kit risiko bersama terhadap timbulnya penyakit jantung dan diabetes

• Penyakit jantung dan diabetes akan menghadapi hal sama thd mortalitas

• Intervensi faktor risiko kardiometabolik dapat mengurangi resiko kejadian diabetes dan CVD dengan berbagai komplikasinya dengan berbagai komplikasinya