Dyslipidemia 울산의대서울아산병원심장병원심장내과이철환

Dyslipidemia 울산의대서울아산병원심장병원심장내과이철환

Presentation General LDL cholesterol HDL cholesterol Future Summary

A top healthcare priority 사망 / 인구 10 만 Causes of Death Worldwide, 2008 140 120 2008 년 한국인 5 대사망원인 100 80 60 40 20 0 암뇌혈관심장질환당뇨사고

50/M, chest pain for 1 hour 50% of patients with CAD presented with AMI or SCD.

Question 1. 급성관동맥증후군을유발하는가장흔한병태생리학적 (pathophysiology) 기전은? 1) Progressive coronary atherosclerosis 2) Coronary artery spasm 3) Coronary artery plaque rupture 4) Embolization to coronary artery 5) Coronary artery plaque erosion 3

Question 2. 다음중 Framingham risk score 계산시구성요소에해당하지않는것은? 1) Age 2) Systolic blood pressure 3) Total cholesterol 4) HDL cholesterol 5) Family history of coronary artery disease 5

Heart Attack and Brain Attack Axis of Evil Arterial wall side - LDL cholesterol - inflammation Arterial lumen side - platelet - coagulation

Subclinical plaque rupture increase plaque burden. Plaque Burden (%) # of prior ruptures at healed rupture site # of prior ruptures at acute rupture site Burke et al. Circulation 2001;103:934-40

The misconception: Coronary intervention of a coronary stenosis is prevent an impending heart attack Therapeutic Approach Revascularization - stenting/bypass surgery Infarct prevention - medical treatment

Restenosis rate (%) Thinking the unthinkable. Quantum Advance! DES POBA (1977) BMS (1986) 50 40 30 20 DES (1999) 10 0 POBA BMS DES

The Rationale for PCI Role of Percutaneous Coronary Intervention Symptoms (ischemia) Prognosis (death/mi) Stable CAD Yes No (except, left main disease) ACS Yes Yes * PCI vs Medical Therapy: not competitive but complementary. * PCI: ischemia producing lesion, suitable for angioplasty, risk area>10% of left ventricle As with most other therapeutic interventions in medicine, the relief of symptoms remains a noble task of physicians caring for patients with stable CAD.

PCI/CABG I Fixed You? The Wall Disease, Not Lumen.. RESOLUTE All Comers Trial (n=2292) (death/mi/revascularization) Atherosclerosis is a diffuse process. (CV death/target vessel MI/TLR) Lack of luminal obstruction does not mean a lack Target-vessel MI: 4.6% of atherosclerosis Non-target-vessel MI: 0.65% Beginning of the road Lancet2011;377:1241

Question 3. Very high risk group 과관련이없는것은? 1) Acute coronary syndrome 2) Coronary artery disease with smoking 3) Coronary artery disease with metabolic syndrome 4) Coronary artery disease with diabetes 5) Target goal of LDL cholesterol <100mg/dl 5

Updated ATP III LDL-C Goals LDL-C (mg/dl) Risk Category Goal Initiation Level for TLC Consideration Level for Drug Therapy High risk: CHD or CHD risk equivalents (10-yr risk >20%) <100 (optional: <70) 100 100 (<100: consider drug options) Moderately high risk: 2+ risk factors (10-yr risk 10 20%) <130 (optional: <100) 130 130 (100 129: consider drug options) Moderate risk: 2+ risk factors (10-yr risk <10%) Lower risk: 0 1 risk factor <130 130 160 <160 160 190 (160 189: LDL-C lowering drug optional) Circulation 2004;110:227-239

No Clear Threshold MRFIT; 361,662 men, 6 year follow-up ATP III Classification LDL-C < 100mg/dl optimal T-Chol < 200mg/dl desirable HDL-C < 40mg/dl low The relation between LDL-C levels and CHD risk is continuous over a broad range of LDL levels from low to high

Mean annual citations The initial road to cholesterol treatments was rather bumpy. BMJ 1992;305:15-19 100 Cholesterol Lowering Trials before Statin Era 10 1 Lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. Unsupportive trials Supportive trials

Proportion of patients dead Lancet 1994;344:1383 Revolution Pre-S & S Era 4S Quantum advance in atherosclerosis 15 10 5 Statins Miracle drug! Best placebo selling product simvastatin 30% risk reduction p = 0.0003 0 0 1 2 3 4 5 6 Years since randomization

Lancet 2002:360:7 Heart Protection Study Baseline STATIN PLACEBO Risk ratio and 95% CI Feature (10269) (10267) STATIN better STATIN worse LDL (mg/dl) < 100 (2.6 mmol/l) 285 360 n=20,536 40-80 y Every patients with atherosclerosis has 100 < 130 670 881 130 LDL-C (3.4 mmol/l) that 1087 is too 1365 high for him or her. ALL PATIENTS 2042 (19.9%) 2606 (25.4%) 0.4 0.6 0.8 1.0 1.2 1.4

Landmark Statin Trials Anti-atherosclerosis Drug High risk CAD Moderate risk CAD Low risk CAD Secondary Prevention High risk normal Moderate risk normal Primary Prevention Low risk normal JUPITER A paradigm changing trial

JUPITER Trial A home run for the public health!

Fling to JUPITER No doubt, it is definitively positive! N=17,802 1.9 years follow-up Primary endpoint Secondary endpoints CV Death/MI/Stroke Total death Myocardial infarction Stroke Relative Risk 44% 47% 20% 54% 48% A home run for the public health! LDL 50% CRP 37%

Statin Benefits, Why? King of CV Medicine

Question 4. 다음중 HDL cholesterol 기능이아닌것은? 1) Reverse cholesterol transport 2) Anti-inflammatory effects 3) Anti-oxidant effects 4) Anti-restenotic effects 5) Anti-thrombotic effects 4

Residual Clinical Risk in Statin Trials

Red Flag Sign A Death Knell for the HDL Hypothesis? HDL: not predictive of residual vascular risk - JUPITER: Lancet2010;376:333 - TNT: NEJM2007; 357: 1301 - PROVEIT: ATVB2009; 29: 424

The Story So Far HDL-Targeted Therapies Futile Strategies? Estrogen ( 15%): WHI trial Fibrates ( 15%): ACCORD Lipid trial We have reached the limit of what we can do by lowering LDL-C?. Nicotinic acids ( 20%) Extended release niacin: AIM-HIGH trial Tredaptive (nicotinic acid/laropiprant) : HPS-2 trial high-risk project CETP inhibitors ( 30%-140%) Torcetrapib: Illuminate trial ( death: discarded) Anacetrapib: Define trial (safe), HPS-3 (REVEAL) trial Dalcetrapib: Dal-Plaque (promising), Dal-Outcomes trial

New Targets A Potential Game Changer Biologic Wows for LDL-C Lowering PCSK9: a key regulator of the LDL receptor Gain-of-function mutations result in hypercholesterolemia Loss-of-function mutations associated with low LDL-C & low prevalence of CHD events SAR236553/REGN727 is a highly specific, fully human monoclonal antibody (mab) to PCSK9

LDL Receptor Function and Life Cycle

The Role of PCSK9 in the Regulation of LDL Receptor Expression

Impact of an PCSK9 mab on LDL Receptor Expression

LDL-C Mean ( SE) % Change from Baseline Adjunct to Statin Monoclonal Antibody to PCSK9, SAR236553/REGN727, in Patients with Primary Hypercholesterolemia 0-10 BASELINE WEEK 2 WEEK 4 WEEK 6 WEEK 8 WEEK 10 WEEK 12-5.1% -20-30 -40-50 - 39.6% - 43.2% - 47.7% -60-70 -80 Placebo SAR236553 50 mg Q2W SAR236553 100 mg Q2W SAR236553 200 mg Q4W SAR236553 300 mg Q4W SAR236553 150 mg Q2W - 64.2% - 72.4% It was generally safe & well tolerated. SQ every two weeks dropped LDL by 40% to 72% There is some risk of immunity with an agent like this & we need longer-term outcome studies.

Question 5. 다음중혈관질환예방에서 Level A evidence 에해당하지않는약물은? 1) Aspirin 2) Clopidogrel 3) Statins 4) Anti-hypertensive drugs 5) Fibrate 5

lost its shine but not its worth. Things May Not Be as They Seem Here today, gone tomorrow! ACEI Estrogen Fibrate Folate/B6,12 Glitazone Omega-3* Vitamin C/E Without Statin Yes No No No No Probable No With Statin No - No No No No No *Statin: GISSI-Prevention (5%, Lancet 1995;354:447), -Omega trial (85%, NEJM 2010 on line)

the only proven medicine Statin is Anti-atherosclerotic Drug! Landmark Statin Trials So Luxurious Clinical End-Point Trials: The Only One_Statin Trials AFCAPS/TexCaps, WOSCOPS, ALLHAT, CARE, LIPID, PROSPER, 4S, HPS, A-to-Z, MIRACL, CARDS, PROVE-IT, ALLIANCE, 4D, ASCOT-LLA, IDEAL, TNT, SPARCL, AURORA, CORONA, GISSI-HF, JUPITER, SEAS, SHARP, IMPROVE-IT (ongoing). Save life!: The only proven medicine in 1 & 2 prevention

Take action, The Power save lives! of Evidence-Based Practice AMI in USA Statin Message Atherosclerosis will become history! Interventionists/surgeons, get a new day job! NEJM2010;362:2155 62%

Prevention is better than cure! Death So Sweet What s Happy Life? Rectangularizing life s journey 2030 년?