PREVENTION OF CORONARY PATIENT WITH CHD HEART DISEASE • Obese male patient with previous angina, cardiac catheterization with placement of two stents and now stable. • Notable clinical characteristics: Thomas F . Wh ayne, J r, MD , PhD, FACC Triglycerides 354 mg/dl. Professor of Medicine (Cardiology) HDL 28 mg/dl in men. Gill Heart Institute BP 140/90 mm/Hg. University of Kentucky Fasting glucose 120 mg/dl. November, 2009 • Specific management?

Characteristics of Plaques Prone to HIGH SENSENSITIVITY Rupture From Inflammation and LDL CREACTIVE PROTEIN (hs-CRP) Fibrous cap Media • A MARKER OF INFLAMMATION: CRP AND

Lumen Lipid hsCRP ARE SAME PROTEIN Core • MAY BE ANOTHER RISK FACTOR AND PLAY A ROLE IN PLAQUE FORMATION “Vulnerable” plaque • MAY PREDICT HIGH RISK ACUTE CORONARY SYNDROME • MAY INDICATE PATIENTS MOST LIKELY TO Lumen RESPOND TO T lymphocyte Lipid • STATINS SHOWN TO REDUCE CRP Core Macrophage foam cell (tissue factor) “Activated” Intimal SMC (HLA-DR+) – ACCENTUATES THIS EFFECT* “Stable” plaque Normal medial SMC • NEED DOSE RESPONSE CURVE Libby P. Circulation. 1999; 91:284491:2844--2850.2850. *Sager PT, et al. Am J Cardiol. 2003;92:1414-1418.

Resultados Estudio VYTAL sobre PCR: Ezetimiba/Simvastatina vs. Atorvastatina en pts con DM II e Hipercolesterolemia (n=1229) CURRENT CLINICALLY USEFUL MARKERS OF INFLAMMATION Atorvastatina E/Simvas Atorvas E/S 10 mg 20 mg 10/20 40 mg 10/40 0 • LIPOPROTEIN-ASSOCIATED Ezetimiba/ --55 Simvastatina PHOSPHOLIPASE A2*. Atorvastatina ®

asales --1010 a Sensibilidad – PLAC TEST. t b --1515 --13.713.7 de Al --13.813.8 • HIGH SENSITIVITY C-REACTIVE --2020 # PCR PROTEIN (hsCRP) . --2525 --23.323.3 desde niveles

--3030 --28.628.6 • NEVERTHELESS, LDL REMAINS THE

% Cambio PCR --3535 --33.333.3 STANDARD MAJOR RISK FACTOR. *Brilakis ES. Eur Heart J. 2005;26:137-144. Goldberg RB. Mayo Clin Proc 2006;81:15792006;81:1579--8888 #Willcox BJ. CVR&R. 2004;25:66-69.

1 Key Statin Pleiotropic Effects* JUPITER Trial design: Apparently healthy patients with LDL cholesterol <130 mg/dl and hs- CRP ≥2 mg/dl were randomized to 20 mg daily or placebo. Clinical • Improved endothelial motor dysfunction. outcomes were compared at a median of 1.9 years.

• Increased fibrinolysis (via  PAI-1). Results (p < 0.00001) (p = 0.02) • Rosuvastatin associated with a significant ↓ in the • Favorable modulation of immune function. primary outcome of MI, stroke, unstable angina, revascularization, or cardiovascular death (HR 2 2 0.56, 95% CI 0.46-0.69, p < 0.00001)

• Antithrombotic properties-decreased platelet Yrs Yrs

- - • All-cause mortality ↓ with rosuvastatin (p = 0.02) aggregation. 1.36 • Serious adverse effects were similar (p = 0.60) 1.25 1 1.0 Conclusions • Decreased metalloproteinase activity with 0.77 1 decreased macrophage activity • Rosuvastatin was associated with a significant reduction in major cardiovascular events, including

Events/100 Person Events/100 Person Events/100 death, in patients with LDL <130 mg/dl, but high hs- • Anti-inflammatory effects. 0 0 CRP (≥2.0 mg/dl) • May require revision of current guidelines • Increased nitric oxide. Primary outcome All-cause mortality Rosuvastatin Placebo Ridker PM, et al. NEJM 2008;359:2195-207 (n = 8,901) (n = 8,901) Presented by Dr. Paul Ridker at AHA 2008 *Davignon J. Curr Ath Reports. 2004;6:27-35

ASTEROID Atheroma Area OTHER IMPORTANT STUDY, 2006 10.16 mm2

POINTS WITH STATINS Baseline IVUS  SUDDEN STATIN WITHDRAWAL MAY Exam INCREASE EVENT RATES IN ACUTE Lumen Area CORONARY SYNDROME (ACS) (Spencer FA. 6.16 mm2 Arch Intern Med. 2004; 164:2162-2168) Atheroma A rea  EARLY STATIN USE MAY  EVENT RATES 5.81 mm2 IN ACS (BENEFIT QUESTIONED AT LOW Follow-up CHOLESTEROL LEVELS) IVUS  ADHERENCE IMPROVED BY STARTING 24 months STATINS DURING HOSPITALIZATION AND rosuvastatin Lumen Area MAY HELP STABILIZE PLAQUES (Fonarow G. 5.96 mm2 Am J Cardiol. 2001;87:819-822)

CHD Risk Is Increased With Sites of Action of ACEIs and AT1-Receptor Very High TG Levels# (500 mg/dL) Blockade Angiotensinogen TGs are independently associated with Renin premature familial CHD* 12 ACEI Angiotensin I Bradykinin 10 10.7 Chymase ACEACE--KininaseKininase II 8 Trypsin X X X Peptidase ds Ratio 6 BK IIII-- d AAitiIIngiotensin II ItiInactive receptor degradation 4 AT1 --receptorreceptor blocker products CHD O 2 2.8 1.7 1.0 1.2 1.1 X 0 Statins: AT --receptorreceptor NO <100 100-149 150-199 200-299 300-499 500+ AT 1 --receptorreceptor 2  reg. Serum Triglycerides (mg/dL) Vasoconstriction AntiAnti--proliferationproliferation Vasodilation *Triglyceride odds ratio adjusted for HDL-C; n=653 (FHx early CHD), n=1029 (control) Salt/water retention Cell differentiation NatriuNatriu--/diuresis/diuresis Remodeling Tissue repair AntiAnti--remodelingremodeling

#Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012. European Heart Journal 1999;20:9971999;20:997--1008.1008.

2 LDL LOWER THAN 70 mg/dl (TNT†) Log-Linear Relationship Between LDL-C FOR THE HIGH RISK CV PATIENT Levels and Relative Risk for CHD

• Stable CAD patients • This relationship is consistent 3.7 with a large body of • 80 mg/dl [Mean lowest LDL = 77] epidemiologic data and data 2.9 available from clinical trials of (REVERSAL: mean lowest LDL = 79, Relative Risk LDL-C–lowering therapy. for CHD, 2.2 PROVE-IT: mean lowest LDL = 62 and Log Scale • These data suggest that for 1.7 every 30-mg/dL change in ASTEROID: mean lowest LDL = 61) 1.3 LDL-C, the relative risk for 1.0 CHD is changed in proportion by about 30%. • Significant clinical benefit over 10 mg/dl • The relative risk is set at 1.0 for 40 70 100 130 160 190 LDL-C = 40 mg/dL. • No overall mortality advantage for 80 mg/dl LDL-C, mg/dL

• More elevated aminotransferase for 80 mg/dl LDL-C = low-density lipoprotein cholesterol; CHD = coronary heart disease.

Reprinted with permission from Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent †LaRosa JC, et al. New Engl J Med. 2005;352:1425-1435. clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239; http://lww.com.

FURTHER SUPPORT OF HIGH DOSE STATINS IN ACS LOWER IS BETTER PROVE-IT STUDY (2004)+: Decreased ACS problems with Atorvastatin (A) 80 mg vs (P) 40 mg; hsCRP  almost SUBSTUDY OF PROVE-IT SHOWED the same: from 12.3 to 1.3 (A) vs. 2.1(P). THAT SUBGROUPS OF LDL < 40 [Mean lowest LDL 62] . MG/DL AND LDL 40-60 MG/DL HAD MIRACL STUDY (ACS)*: FEWER MAJOR CARDIAC EVENTS†. Atorvastatin 80 mg/d  ischemic events and rehospitalizations in the first 16wks

†Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411-1416. +Cannon et al. N Engl J Med. 2004;350:1495-1504. *Schwartz et al. JAMA. 2001;285:1711-1718.

ADVERSE EVENTS WITH HIGH Statins and Fatal Rhabdomyolysis* DOSE STATINS STATIN FATALITIES No./MILLION Rx • No increase reported in REVERSAL and 31 3.16 PROVE-IT with Atorvastatin 80 mg/d. 19 0.19 • Evaluations prior to release of any statin have 14 0.12 shown more myos itis and li ver i nfl ammati on with higher doses. Atorvastatin 6 0.04 • IDEAL Study* (previous MI): Primary endpoint Pravastatin 3 0.04 of major coronary events failed and there were 0 0.00 more myalgias with Atorvastatin 80 mg/d vs. *NEJM 2002;346:539-40. Simvastatin 20 mg/d. Occasionally, can see histopathologic changes of myopathy with *Pedersen TR et al. JAMA. 2005;294:2437-2445. statins despite normal CPK (Ann Intern Med. 2002;137:581-585).

3 AORTIC STENOSIS (AS) STROKE ALSO REDUCED BY STATINS • Heart Protection Study (HPS) showed decreased EXACERBATION BY  LDL. strokes with simvastatin 40 mg, except with pre- EXACERBATION BY  Lp(a). existing cerebrovascular disease.* STATINS (2002) MAY  DEVEL.* OF AS. • CARDS Study showed decreased strokes with A SMALL RANDOMIZED 2005 STUDY SHOWED # FAILURE OF ATORVASTATIN TO DECREASE atorvastatin 10 mg in Type 2 Diabetes patients. PROGRESSION# OF AS. • SPARCL Study showed decreased strokes with A 2005 STUDY WITH ROSUVASTATIN+ atorvastatin 80 mg in patients with recent stroke MARKEDLY SLOWED PROGRESSION OF AS. or TIA and no known CHD. There was a slight NO  IN AS IN SEAS TRIAL WITH increase in hemorrhagic stroke.+ EZETIMIBE/SIMVASTATIN^.

*Clin. Cardiol 2002;25:201-202. +J Am Coll Cardiol 2007;49:554-561. *The Lancet 2004;363:757-767. # #N Engl J Med 2005;352:2389-2397. ^SEAS Trial, Medpage Today 2008, July 21. The Lancet 2004;364:685-696. +N Engl J Med 2006;355:549-559.

THE ENHANCE STUDY: RESULTS* Residual Cardiovascular Risk Despite LDL-C Lowering • Group-1 (eze/sim): Significant decrease in LDL (58% vs. Therapies based on LDL-C lowering reduce the risks of CAD 41% in Group-2 (sim); p < 0.01). 4S CARE WOSCOPS LIPID AFCAPS HPS PROSPER CARDS ASCOT • Group-1: Slightly more progression in carotid intima- 0 media thickness but very insignificant. 10 20 15% • Group-1 vs. Group-2: No significant differences in CV 30 24% 24% 24% tion (%) 29% outcomes (the study was designed as an imaging only). c 40 34% 36% 37% 37% + 50 • Next step: an outcomes study: Improve-It . 60 • Lipid Research Clinics#: Men with upper 5% CV risk 70

80 using cholestyramine required 7.4 years with only LDL Relative risk redu Relative 90 lowering to show decreased cardiovascular events and 100 Despite the benefits of LDL lowering, this can be expected to apply to ezetimibe alone. 60-70% residual risk remains *Kastelein JJP, et al. N Engl J Med 2008;358:1431-1443. 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; WOSCOPS=West of Scotland Coronary Prevention Study; +The Wall Street Journal Jan. 17, 2008: D-1, D-3. LIPID=Long-term Intervention with Pravastatin in Ischemic Disease; AFCAPS=Air Force/Texas Coronary Atherosclerosis Prevention Study; HPS=Heart-Protection Study; PROSPER=Prospective Study of Pravastatin in Elderly at RISK; CARDS=Collaborative Atorvastatin Diabetes Study; #The Lipid Res. Clinics. JAMA 1984;251:351-364. ASCOT-LLA=Anglo-Scand. Cardiac Outcomes Trial.

THE ENHANCE STUDY: CONCERN REGARDING EZETIMIBE, SCIENTIFIC ISSUES LOW LDL AND CANCER • LDL is most specific lipoprotein associated with CHD (the gold standard of CV risk factors)* with goal < 70◊ • SEAS Trial: New onset cancer in 101 patients and no special claim for high dose statin except in ACS. in active-Rx vs. 65 in control group†. • Each doubling of the statin dose only decreases LDL • SEAS + ONGOING SHARP AND another 6%+ and the same with hsCRP. IMPROVE-IT: NO CREDIBLE EVIDENCE • The higher the statin dose, the higher the incidence of ON ADVERSE EFFECT OF EZETIMIBE myalgia (1-5% in labeling info# and reported up to 9%†) ON CANCER RATE†. and of liver inflammation. • NO ASSOCIATION OF CANCER AND • Altered sleep patterns with simvastatin. LDL LOWERING EVER ESTABLISHED. *SytKowski P. N Engl J Med 1990;322:1635-1641. ◊LaRosa JC. N Engl J Med 2005;352:1425-1435. Cannon CP. N Engl J Med 2004;350:1495-1504. +Jones PH. Am J Cardiol 2003;92:152-160. #Thompson P. JAMA 2003;289:1681-1690. †Peto R, et al. N Engl J Med 2008;359:1357-1366. †de Sauvage Nolting PRW. Am J Cardiol2002;90:181-184.

4 The Majority of Statin Monotherapy LDL Reduction Is Seen With the Initial Dose

Pravastatin Simvastatin Atorvastatin Rosuvastatin

–5

–15 –20% –28% 10 mg

eline, % –37% LDL-C ,† 20 mg s –4% –46%* –25 –6% 40 mg –7% 80 mg –35 –4% –6% –7%

Mean change in change Mean –45 –5% from untreated ba –3% –6% –55 –3%

*P<0.001 vs atorvastatin 10 mg; simvastatin 20 mg and 40 mg; and pravastatin 10 mg, 20 mg, and 40 mg. †P=0.026 vs atorvastatin 20 mg

Jones PH et al. Am J Cardiol. 2003;92:152.

Adding ZETIA® (ezetimibe) to Atorvastatin Low HDL-C and High LDL-C 10 or 20 mg: Dramatically More LDL-C Increase Coronary Artery Disease Risk; Reduction Than Double the Usual Doses† Elevated HDL Appears Protective ZETIA + ZETIA + Atorvastatin Atorvastatin alone Atorvastatin Atorvastatin Alone 10 mg 10 mg 20 mg 20 mg 20 mg 40 mg Framingham Heart Study (n=65) (n=60) (n=60) (n=62) (n=60) (n=66) 0 0 Relative Risk 3.0 of CAD After eline eline

n LDL-C n LDL-C 2.5 s s 4 Years -20 -20 2.0

1.5

-40 -37% -40 1.0 -42% -42% -45% 0.5 From Untreated Ba Untreated From Ba Untreated From -53% -54% 25 -60 -60 0.0 45 Mean Percent Change i Percent Mean Change i Percent Mean Change 100 65 P<0.01 P<0.01 160 220 LDL-C, mg/dL 85

†Ballantyne CM et al. Circulation. 2003;107:2409–2415. CAD=coronary artery disease. This information was adapted from The Canadian Journal of Cardiology1988;4(Suppl A):5A–10A.

APO A-1 MILANO*

• A VERY PROTECTIVE HDL Apo A-1 VARIANT IN RURAL ITALY NEAR MILAN IN WHICH HDL LEVELS ARE LOW BUT THERE IS  CV RISK. • IV INFUSION OF RECOMBINANT ApoA-1 MILANO-PHOSPHOLIPID COMPLEXES HAS BEEN SHOWN TO RESULT IN CORONARY ATHEROSCLEROSIS REGRESSION AS DEMONSTRATED BY IVUS.

*P < 0.05 vs atorvastatin *Nissen SE et al. JAMA. 2003;290:2292-2300.

5 Multiple Actions of HDL-C as a Potential Basis for Antiatherosclerotic Activity Niaspan Efficacy Combined Data from Pivotal Studies

HDL Antioxidant Anti-inflammatory 30% 29% 30 HDL-C 21% 24% Antithrombotic Profibrinolytic 20 16% • Antiplatelet 10%

• Protein C Baseline 10 activation --3%3% --8%8% 0 --5%5% --12%12% --13%13% -10 --16%16% Enhanced reverse --17%17% --21%21% --14%14% --22%22% cholesterol transport -20 LDL --21%21% --25%25% --26%26% (RCT) -30 --30%30% --32%32% Lp(a) Change from -40 --39%39% Antiatherothrombotic --44%44% TG effect -50 500 mg 1000 1500 2000 2500 3000

Kashyap ML, et al. J Am Coll Cardiol 2000;35(SupplA):326A. Reproduced with permission from Shah PK et al. Circulation. 2001;104:2376–2383. Gotto AM. Am J Cardiol 1998;81:492.

*CORDAPTIVE® (/ER ): Mechanism of Niacin-Induced Reduced Percent of Patients Discontinued Due to Flushing*. Flushing by Prostagalandin D2 Smooth muscle cell or other 25 EP2 or EP4 cell type

PGE2 20 p<0.001 vs. Dermal macrophages PGD2 Selective ients t ER Niacin DP1 DP1 Receptor Undesirable effects 15 Nicotinic Antagonist Acid–Induced Flush Laropiprant 10 Arachidonic acid Markedly reduces COX-1 Niacin Flush in mice

PGE2 PGD2 and humans 5 Percent of Pa Cutaneous vasodilation and 0 burning sensation on face and ER Niacin/ ER Niacin Placebo upper body laropiprant *The ER Niacin component is a new formulation. The name is being changed to Tredaptive®. Adapted from Pike NB. J Clin Invest. 2005;115:3400-3403.

CETP Inhibitors: Percent Change from Baseline in Apo B 1. Cholesterol Ester Transferase Protein Inhibitor. (similar to LDL) [DALM 2007]

2. New investigational pharmaceutical class that will be Monotherapy Co-administration most effective medication yet for elevating the HDL. 10 10 3. Unfortunately, testing and marketing 0 0 was planned only in combination with Atorvastatin -10 -10 instead of also being available alone to be combined as -20 -20 ge from Baseline ge from Baseline Apo B Apo B n n -30 -30 indi cat ed with o ther s ta tins an d w ith o ther in in medications.* Extensive clinician protest then forced -40 -40 -50 -50 Percent Cha individual availability. However, CV complications Percent Cha -60 -60 048048 (BP, MI’s, Deaths) later forced withdrawal. Weeks on Treatment Weeks on Treatment

4. Other CETP inhibitors are on the horizon Placebo Atorva 20 mg Anacetrapib 10 mg Anacetrapib 10 mg + Atorva 20 mg (Anacetrapib-Merck, R1658-Roche/Japan Tobacco), Anacetrapib 40 mg Anacetrapib 40 mg + Atorva 20 mg Anacetrapib 150 mg Anacetrapib 150 mg + Atorva 20 mg reportedly without BP/CV problems. Anacetrapib 300 mg Anacetrapib 300 mg + Atorva 20 mg 1.Merck Research Laboratories, Rahway, NJ. Daniel Bloomfield,1; Gary L. Carlson,1; Aditi Sapre,1; Diane Tribble,2; 2.Isis Pharmaceuticals, Carlsbad, CA. James M. McKenney,3; Thomas W. Littlejohn III,4; Christine McCrary 3.Virginia Commonwealth University & National Clinical Research, Inc. *Avorn J. N Engl J Med 2005;352:2573-2576. Sisk,1; Yale Mitchel,1; Richard C. Pasternak,1. 4.Piedmont Medical Research Associates, Winston-Salem, NC.

6 Percent Change from Baseline in BP Results with Anacetrapib [DALM 2007]; Apo A-I (similar to HDL; DALM 2007) (Results contrast with BP with Torcetrapi) 10 Monotherapy Co-administration Systolic Diastolic 50 50

40 40 5

30 30

20 po A-I 20 0 ge from Baseline ge from Baseline ge from Baseline (±SE) Apo A-I A n n n in In 10 10

0 0 -5 Percent Cha Percent Cha -10 -10 048048

Weeks on Treatment Weeks on Treatment LS Mean % Cha -10 Placebo Atorva 20 mg Anacetrapib 10 mg Anacetrapib 10 mg + Atorva 20 mg Anacetrapib 40 mg Anacetrapib 40 mg + Atorva 20 mg Anacetrapib 150 mg Anacetrapib 150 mg + Atorva 20 mg Anacetrapib 300 mg Anacetrapib 300 mg + Atorva 20 mg 1.Merck Research Laboratories, Rahway, NJ. Daniel Bloomfield,1; Gary L. Carlson,1; Aditi Sapre,1; Diane 1.Merck Research Laboratories, Rahway, NJ. 2.Isis Pharmaceuticals, Carlsbad, CA. Tribble,2; James M. McKenney,3; Thomas W. Littlejohn III,4; Daniel Bloomfield,1; Gary L. Carlson,1; Aditi Sapre,1; Diane 2.Isis Pharmaceuticals, Carlsbad, CA. 3.Virginia Commonwealth University & National Clinical Research, Inc. Christine McCrary Sisk,1; Yale Mitchel,1; Richard C. Pasternak,1. Tribble,2; James M. McKenney,3; Thomas W. Littlejohn III,4; 3.Virginia Commonwealth University & National Clinical Research, Inc. 4.Piedmont Medical Research Associates, Winston-Salem, NC. Christine McCrary Sisk,1; Yale Mitchel,1; Richard C. Pasternak,1. 4.Piedmont Medical Research Associates, Winston-Salem, NC.

USE OF STATINS WITH OTHER MEDS. LIPOPROTEIN (a); [from DALM 2007] AND IN SPECIAL SITUATIONS

40 Monotherapy Co-administration • : 20 – : Never use with a statin due to inhib. of

0 glucuronidase essen. for statin metab. – : Can use with a statin with care. -20 from Baseline (95% CI) • NICOTINIC ACID (Niaspan® or other new sustained ® -40 release form preferred): Can be used with a statin with care. -60 • STATINS OVER THE COUNTER?* Median % Median Change -80 • DECREASED DOSING FREQUENCY OF STATINS? – Atorvastatin and Rosuvastatin.#

*Whayne TF. Am J Cardiol 2008;101:745. Daniel Bloomfield,1; Gary L. Carlson,1; Aditi Sapre,1; Diane 1.Merck Research Laboratories, Rahway, NJ. # Tribble,2; James M. McKenney,3; Thomas W. Littlejohn III,4; 2.Isis Pharmaceuticals, Carlsbad, CA. Backes JM. World Congress on Hrt Dis. Intern Med News Aug 2008;41:1. 3.Virginia Commonwealth University & National Clinical Research, Inc. Christine McCrary Sisk,1; Yale Mitchel,1; Richard C. Pasternak,1. 4.Piedmont Medical Research Associates, Winston-Salem, NC.

ESTROGEN REPLACEMENT CAD CHARACTERISTICS OF • HDL, LDL, endothelial stabilization (good). WOMEN • Increase in CRP, thrombogenesis (bad). • Once MI occurs, women do worse (Ann • Heart Estrog/Prog Replacement Study (HERS)*. Intern Med. 2001;134:173-181). • Trend toward  CHD risk when estrogen started • In hospital mortality of women < 50 is twice cltloser to menopause# and60d < age 60 as comparedtd to that of men (6.1 vs 2.9%).  CHD risk in women more distant from • CAD in the young woman appears to be in menopause. an especially malignant form. • Decreased coronary calcified-plaque burden in a • Aggressive statin use and LDL lowering + trial in women with estrogen . appear essential in the young woman with *Hully S, et al. JAMA 1998;280:605-613. #Rossouw JE, et al. JAMA 2007;297:1465-1477. CAD. +Manson JE, et al. N Engl J Med 2007;356: 2591-2602.

7 ALTERNATIVE MEDICATIONS COENZYME Q-10 + • Some are of definite value. (uncertain benefit/risk)* • Unfortunately, due to the lack of financial incentive, • MITOCHONDRIAL ENERGY TRANSDUCTION there is no pharmaceutical company support for large • FUNCTIONAL ELEMENT IN ALL CELL placebo controlled trials to guide the clinician and bring MEMBRANES effective alternative medications into clinical practice – ANTIOXIDANT ACTION while incentinggp ph ysicians/ patients not to use ineffective/ – REGENERATION OF REDOX CAPACITY dangerous Rx. Also, the NIH has not supported trials. • CONTROL OF MEMBRANE CHANNELS • Dangerous and of no value: Chelation therapy. • BIOSYNTHESIS IN MITOCHONDRIA AND • Questionable value: Folic acid/B-12/B-6 combination for ENDOPLASMIC RETICULUM elevated serum homocysteine. • BIOSYNTHESIS INHIBITED BY STATINS • Alternative Rx with apparent value:  Aspirin, Coenzyme Q, Nuts, Olive Oil, Omega Fatty Acids, • DOSE: 200 mg once daily (to  risk of statin myositis) Plant Sterols (Stanols), , Red Wine, Red Yeast *Crane F. J Am Col Nutr 2001;20:591-598. Rice, Soluble Dietary Fiber, Soy. Kelly P. Amer Col Cardiol Sci Sessions 2005 (used 100 mg once daily). +Caso G. Am J Cardiol 2007;99:1409-1412.

RED WINE CONCLUSION

• BENEFIT FROM ALCOHOL  The hsCRP appears to be the most clinically used – ALCOHOL MAY DECREASE INSULIN RESISTANCE* marker of inflammation but Phospholipase A2 – ALCOHOL HAS AN ANTI-PLATELET EFFECT# avoids nonarterial inflammatory etiologies. • BENEFIT FROM POLYPHENOLS# • LDL is still the gold standard of CV risk factors • BENEFIT FROM  NITRIC OXIDE (ONE and it should be targeted aggressively. SUGGESTED POLYPHENOL EFFECT)# • BENEFIT FROM FLAVONOIDS WHICH INHIBIT • Ezetimibe has been subjected to ENHANCEd LDL OXIDATION+ hype. RED WINE, DARK CHOCOLATE, GREEN TEA ARE • Treatment of HDL may be the next basic focus to MAIN SOURCES OF FLAVONOIDS decrease CV risk. • Failure to treat LDL in a patient with high CV *Howard A et al. Ann Intern Med. 2004;140:211-219 #Wallerath T et al. J Am Col Cardiol. 2003;41:471-478 risk, without specific reasons, is malpractice. +Maron D. Curr Ath Reports. 2004;6:7378

8