Lipid and dyslipidaemiaLipoprotein Metabolism

3. Lipoprotein Metabolism in insulin resistance and type 2 diabetes 4. Management of dyslipidaemia LIPIDLIPOPROTEIN METABOLISMAND THE MANAGEMENT OF DYSLIPIDAEMIA

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Lipid plasma tidak larut dalam airUntuk melarutkan perlu Apolipoprotein = Apoprotein = ApoKompleks lipid plasma apoprotein disebut lipoproteinLipoprotein = kolesterol, trigliserida, fosfolipid, dan apoproteinLIPOPROTEIN

+=LIPOPROTEIN

Apolipoprotein + Lipid = Lipoprotein APAKAH LIPOPROTEIN ?Feher MD, Richmond W. Lipids and Lipid Disorders Second ed. Bayer. 1996

JENIS LIPOPROTEINLipoprotein classRelative size, triglyceride and cholesterol contentMajor apoproteinsChylomicronsB48, E, CII

VLDLB100, E, CIIIDLB100, ELDLB100HDLAI,AII

TriglycerideCholesterol

THE METABOLIC PATHWAY OF LIPOPROTEINSEndogenous pathwayExogenous pathwayReverse cholesterol transport

Shepherd J. Eur Heart J Supplements 2001;3(suppl E):E2-E5Exogenous Lipoprotein Metabolism EndogenousRCTPRCTP = reverse cholesterol transport pathway

Liver

VLDL

VLDLMacrophageVLDL Cholesterol

Reverse cholesterol transport

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

TriglycerideCholesteryl ester

LDL Receptor Scavenger receptor-A / CD 36

ABC-1 transporter

SRB-1 receptor

THE METABOLIC PATHWAY OF LIPOPROTEIN IN TYPE 2 DIABETES MELLITUS AND METABOLIC SYNDROME

Lipoprotein Metabolism in Insulin ResistanceInsulinIRAdipocytes FFAPerlemakanhati(CETP)(CETP)

LDLteroksidasi(lipoprotein or Hepatic lipase i)ApoA1KidneyTGTGKwiterovich PO, Jr. The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: A current review. Am J Cardiol 2000;86:5L-10L VLDLlarge CEFFA : Free Fatty AcidCE : Cholesteryl EsterCETP : Cholesteryl Ester Transfer ProteinCE

DISLIPIDEMIADislipidemi diabetes tipe 2 / resistensi insulin

Resistensi insulin mengakibatkan FFA meningkat hati, menjadi sumber VLDL

VLDLLDL, pertukaran TG dan kolesterol LDL kecil padatApoA1 dikeluarkan oleh ginjal, sehingga HDL kolesterol rendah

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

Management of dyslipidaemia

All three lipid profiles

-kolesterol LDL, kolesterol HDL, dan trigliserid

play a role in the formation of atherosclerosis

Hubungan antara kadar serum kolesterol dan risiko penyakit arteri koronerDari penelitian Multiple Risk Factor Intervention Trial (MRFIT)Farnier M, Davignon J. Am J Cardiol. 1998;82:3J-10J

150100500PAK / 1000

10181722257355156< 130130 - 160160 - 190> 190Insiden PAK / 1000 orang dalam 4 tahun menurut kadar trigliserid dan LDL-kolesterol. LDL-kolesterol Assman G. Am J Cardiol 1992;70:10H-13H

Trigliserid < 200 mg/dlTrigliserid > 200 mg/dl

Insidens PAK (per 1.000 dalam 6 tahun)80

120< 3535 - 55> 55HDL-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).1006040200PROCAM Study

CLASSIFICATION OF LDL-cholesterol, Total-cholesterol, HDL-cholesterol and Triglycerides NCEP-ATP III

KLASIFIKASI TOTAL, LDL, HDL-KOLESTEROL, DAN TRIGLISERID MENURUT NCEP ATP IIIJAMA 2001;285:24862-497

Risk assessment: first step in the management of dyslipidaemia Langkah pertama menentukan risiko PKV seseorang adalah dengan menghitung berapa faktor risiko yang dimiliki penderita tersebut (risk assessment) Faktor risiko dikelompokkan atas tiga kelompok risiko rendah, risiko sedang, dan risiko tinggi

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

JAMA 2001;285:24862-497HDL cholesterol > 60 mg/dl counts as a negative risk factor,

its presence removes 1 risk factor from the total count

Three categories of risk that modify LDL cholesterol goalsJAMA 2001;285:24862-497Kelompok risikoSasaran LDL (mg/dl)Mereka dengan PAK atau yang disamakan (risiko tinggi)Faktor risiko multipel ( > 2) (risiko sedang)0 - 1 faktor risiko (risiko rendah)< 100

< 130

< 160

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

3,5%18,8%20,2%45,0%No DM, No MINo DM, MIDM, No MIDM, MI7-year incidence of MIType 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.

Non diabetic

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

PENGERTIAN YANG DISAMAKANJAMA 2001;285:24862-497 Penyakit aterosklerotik lain seperti penyakit

arteri perifer, aneurisma aorta abdominalis, dan penyakit arteri karotis simptomatik Diabetes melitus terutama tipe 2 Mereka dengan faktor risiko multipel yang

dalam waktu 10 tahun mempunyai risiko PAK > 20 % Secara praktis : diabetes melitus, strok, penyakit arteri perifer

ADULT TREATMENT PANEL REPORTSATP III update 2004Since 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)

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PREVENTION OF CORONARY HEART DISEASE IN TYPE 2 DIABETES MELLITUS Heart Protection Study with Simvastatin 40 mgRESULTS Lowering LDL-cholesterol from < 116 mg/dl to < 77 mg/dlThe lower the better ?

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Baseline LDL-C (mg/dl)Statin (n =10,269)Placebo (n =10,267)< 100100 129> 130All patients282 (16.4%)668 (18.9%)1,083 (21.6%)2,033 (19.8%)358 (21.0%)871 (24.7%)1,356 (26.9%)2,585 (25.2%)Event Rate RatioStatin Better0.40.60.81.01.21.4

Statin Worse0.76 (0.72 0.81) p

PREVENTION OF CORONARY HEART DISEASE IN TYPE 2 DIABETES MELLITUS Heart Protection Study with SimvastatinConclusionsThe 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 concentrationsStatin therapy should now be considered routinely for all diabetic patients at sufficiently high risk of major vascular events, irrespective of their initial cholesterol concentrations

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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

PROVE - IT

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C-REACTIVE PROTEIN LEVELS AND OUTCOMES AFTER STATIN THERAPYRidker PM, et al. N Engl J Med 2005; 352: 20 28Background and aims

Statins lower LDL-cholesterol levels and C-reactive protein. Do lowering C-reactive protein affects clinical outcomes- recurrent myocardial infarction and death from coronary causes - ?

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From the PROVE IT studyDivided 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? Subjects and methods

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RATIONAL FOR OPTIMAL VERY LOW LDL-CHOLESTEROL GOAL (< 70mg/dl)Lesson from HPSLesson 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?

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Circulation. July, 2004;110:227-239

WHAT ARE NEW?

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THE VERY HIGH RISK PATIENTSEstablished CVD plus:Multiple major risk factors (especially diabetes)Severe and poorly controlled risk factors (especially continued cigarette smoking)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/dlOn the basis of PROVE IT, patients with acute coronary syndromes

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

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PENATALAKSANAANPerubahan gaya hidup (therapeutic lifestyle changes ) Perencanaan makan (diet) Olahraga Berhenti merokok Batasi alkohol

Obat penurun lipid

OLAHRAGA TERATUR

OBAT PENURUN LIPID * bezafibrat, cipofibrat dan fenofibrat menurunkan LDL-kolesterol lebih banyak daripada gemfibrozil Persentasi penurunan LDL-kolesterol dan trigliserid, serta kenaikan HDL-kolesterolObatLDL-KHDL-KTGStatin

Resin

Fibrat*

Asam nikotinik

Ezetimibel 18 - 55%

15 - 30%

5 - 25%*

5 - 25%

10 - 15% 5 - 15%

3 - 5%

10 - 20%*

15 - 35%

- 7 - 30%

- /

20 - 50%*

20 - 50%

-

SASARAN LDL - KOLESTEROL PENGOBATAN PERUBAHAN GAYA HIDUP (DIET, OLAHRAGA), DAN PENGOBATAN STATINJAMA 2001;285:2487-2497Kelas risikoSasaran LDL (mg/dl)Kadar LDL dimana dimulai diet - olahraga (mg/dl)Kadar LDLdimana dimulai obat (mg/dl)PAK atau yangdisamakan> 2 faktor risiko0 - 1 faktor risiko< 100< 130< 160> 100> 130> 160> 130(100-129 dapat dipertimbangkan obat)> 160> 190

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 baikIa membawa hasil laboratorium sbb: pemeriksaan rutin baik, GDP 124 mg/dl, total -kol 198 mg/dl, LDL- kol 138 mgdl, HDL 50 mg/dl, TG 156 mg/dl.Diagnosa? Berapa sasaran LDL-kol?CONTOH KASUS (1)

Wanita umur 56 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 65 kg, TD 150/90 mmHg. Pemeriksaan fisik lain baikIa 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?CONTOH KASUS (2)

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