CURRENT ISSUES AND CONTROVERSIES IN LIPID MANAGEMENT IN WOMEN

Thomas F. Whayne, Jr, MD, PhD, FACC Professor of Medicine (Cardiology) Gill Heart Institute University of Kentucky October, 2010 (no conflicts to disclose) Objectives: 1. Summarize basic data supporting the benefit of cholesterol reduction. 2. Discuss the latest concepts in the treatment of cholesterol, LDL, triglycerides and HDL plus emphasize the cholesterol treatment gap. 3. Identify problems with certain pharmaceuticals including what is innovative and of value versus what is marketing. 4. Interrelate the importance of inflammatory risk factors in coronary heart disease management. 5. Discuss future directions in coronary heart disease prevention. 6. Consider the nature and prevalence of the metabolic syndrome in the spectrum of coronary heart disease. 7. Consider specific characteristics of CHD in women. Mortality rates in US women

6500

4500 Heart disease Stroke 2500 1600 Colon cancer Endometrial cancer 1200 Breast cancer

800 Lung cancer

Mortality rate per 100,000 rateper Mortality 400

0 45-54 55-64 65-74 75-84 85+ Age (yrs) Howe et al. J Natl Cancer Inst 2001. Am Heart Assoc. Heart and Stroke Update 2001. ETHNIC DIFFERENCES

In the Heart and Estrogen/progestin Replacement Study (HERS) over 4.1 years†, events from CHD occurred approximately twofold in African American women compared with Caucasian women.

†Jha A et al. Circulation 2003;108:10898-1094. METABOLIC SYNDROME, SYNDROME X or CV DYSMETABOLIC SYNDROME HAVE AT LEAST 3 OF 5 MAJOR COMPONENTS†: TG  150 mg/dl. HDL < 40 mg/dl in men and < 50 mg/dl in women . BP  130/85 mm/Hg. Waist girth > 102 cm (men) and > 88 cm (women). Fasting glucose  100 mg/dl. OTHER COMPONENTS:  dense LDL, Insulin resistance, Hyperuricemia,  PAI-1,  hsCRP,  Tissue necrosis factor-α  Interleukin-6,  Resistin, and  Adiponectin. MUST TREAT EACH INDIVIDUAL MAJOR COMPONENT.

†Grundy SM, et al. Circulation 2005;112:2735-2752. Latest Overweight and Obesity Rates

The Economist, December 13-19, 2003. Metabolic Syndrome: Prevalence Increases with Age 47 million or 23% of US adults have the metabolic syndrome

Adapted from: Ford ES, et al. JAMA 2002;287:356-359. The Metabolic Syndrome (MS) Associates with CHD/Myocardial Infarction more than any Individual Component† but still not as much as Diabetes Mellitus. MS also markedly associated with PVD.

†Similar occurrence with stroke

Ninomiya JK, et al. (NHANES III). Circulation 2004;109:42-6. ASPIRIN AND PRIMARY PREVENTION IN WOMEN

Women’s Health Study* (WHS-39,876 women): 477 MACE with ASA over 10 years vs. 522 events with placebo (a nonsignificant 9% ↓ MACE). Stroke rate 19% lower with ASA (p=0.04). Small but insignificant increment in MI risk with ASA, not seen with placebo. Meta-analysis of ASA# in women and men: Composite of MACE decreased due to effect of ASA in decreasing ischemic stroke in women and MI in men.

*Ridker PM et al. N Engl J Med. 2005;352:1293-1304. # Berger JS et al. JAMA. 2006;295:306-313. ^Becker DM et al. JAMA. 2006;295:1420-1427. ACE INHIBITOR IN PREGNANCY

MAJOR CONGENITAL MALFORMATIONS HAVE NOW BEEN ASSOCIATED WITH EXPOSURE TO ACE INHIBITORS IN ALL THREE TRIMESTERS WHEREAS, PREVIOUSLY, IT WAS CONSIDERED ONLY A CONCERN AFTER THE 1st TRIMESTER†. Rx acceptable during pregnancy: Alphamethyldopa, Metoprolol tartrate and Labetalol.

†Cooper WO et al. N Engl J Med 2006;354:2443-2451. First Coronary Event* Women’s Survival Rates

1.00

Low hsCRP, Low LDL-C 0.99 Probability of Event-Free Low hsCRP, High LDL-C Survival 0.98 High hsCRP, Low LDL-C

0.97

0.96 High hsCRP, High LDL-C 0 2 4 6 6 10 Years of Follow-up

*Cushman M, Novel Risk Factors: C-Reactive Protein, p. 125. Women’s Health Study Data. First Coronary Event Asymptomatic Women’s Survival Rates by Calcium Score

1.00 Ca2+ score <10

0.96 Ca2+ score 11-100 Ca2+ score 101-400 Cumulative 0.92 Unadjusted All-Cause Ca2+ score 401-1000 Survival 0.88

0.84

N=4191 Ca2+ score >1000 0.80 0 1 2 3 4 5 Follow-up (years)

LJ Shaw and P Raggi, Diagnostic Procedures, p. 188. EBT Research Foundation Study Data. Cardiac Syndrome X ST-Segment Depression during Treadmill Exercise Stress Testing

Baseline BP 130/80

Peak BP 180/90 exercise Chest Pain

4 minute BP 138/90 recovery

JC Kaski, Cardiac Syndrome X, p. 206. LOW GRADE CHRONIC INFLAMMATION IN POLYCYSTIC OVARIAN SYNDROME (PCOS)† • PCOS ASSOCIATIONS: OLIGOMENORRHEA AND TESTOSTERONE. • WOMEN WITH PCOS: INSULIN RESISTANT, RISK FOR CHD AND RISK FOR TYPE 2 DIABETES. • WOMEN WITH PCOS: SIGNIFICANTLY C-REACTIVE PROTEIN LEVELS COMPARED TO WOMEN WITH NORMAL MENSES AND NORMAL ANDROGEN LEVELS

†Kelly CCJ, et al. J Clin Endocrinol Metab 2001;86:2453-2455. ESTROGEN REPLACEMENT • HDL, LDL, endothelial stabilization (good). • Increase in CRP; occasional marked increase in triglycerides; thrombogenesis [oral estrogens and not transdermal estrogens] (bad). • Heart Estrog/Prog Replacement Study (HERS)*. – Mean age 67. No CV benefit and in 1st year: ↑CHD, ↑MI. • Trend toward  CHD risk when estrogen started closer to menopause# and < age 60 as compared to  CHD risk in women more distant from menopause. • Decreased coronary calcified-plaque burden in a trial in women with estrogen+.

*Hully S, et al. JAMA 1998;280:605-613. #Rossouw JE, et al. JAMA 2007;297:1465-1477. +Manson JE, et al. N Engl J Med 2007;356: 2591-2602. WOMEN’S HEALTH INITIATIVE IN 2002 (WHI)† • Large randomized trial. • PremPro: 0.625 mg conjugated estrogens with 2.5 mg medroxyprogesterone acetate, did not prevent CV disease and may have increased MI and stroke. • No increased MI if less than 10 years postmenopausal but stroke risk still increased in this subgroup.

†Writing Gp, WHI Investigators. JAMA 2002;288:321-333. Estrogen Therapy and Coronary Artery Calcification

• Substudy of WHI†. • Estrogen only – Premarin 0.625 mg/d. • Ages 50-59. • Duration - over 7.4 yr of Estrogen, 8.7 yr later. • Coronary calcium score - significantly less in women on Estrogen.

†Manson JE. N Engl J Med 2007;356:2591-2602. CHD CHARACTERISTICS OF WOMEN • Women present older with first MI (68.6 vs 60.1 years).* – 28 day mortality higher for women (18.5 vs 8.3%). • CHD still occurs primarily after menopause when LDL increases and HDL decreases. • Women overall are less likely to die of CHD. – Female to male ratio is 1/(2.5-4.5). – Protection is less in diabetic women. • CHD is the major health problem in women. – 1 in 2 deaths due to CVD vs 1 in 29 deaths due to breast cancer. *JAMA. 1998;280:1405-1409. CHD CHARACTERISTICS OF WOMEN* • Once MI occurs, women do worse In hospital mortality of women < 50 is twice that of men (6.1 vs 2.9%). • CHD in the young woman appears to be in an especially malignant form. • Aggressive use and LDL lowering appear essential in the young woman with CHD.

*Ann Intern Med. 2001;134:173-181. CHD CHARACTERISTICS OF WOMEN • Arterial inflammation probably different. – High levels of TNF-alpha receptors significant only in women in Nurses’ Health Study vs men in Health Professionals Follow-up Study.† • Procedure problems in women. • Care delays in women.* – One third with no chest pain. – Family caregivers. – Can lead to less aggressive treatments. – Have  cardiac complications/mortality as a result. • Aggressive statin use and LDL lowering: – Essential in the young woman with CHD.

†Pai JK, et al. N Engl J Med 2004;351:2599-2610. *Canto J et al. JAMA 2000;283:3223-3229. PCI IN WOMEN†

• Benefit from an early invasive strategy is similar in women and men with further increased benefit in women with markers of increased CV risk. • This benefit occurs despite some unavoidable disadvantages such as anatomically smaller coronary arteries.

†Glaser R et al. JAMA 2002;288:3124-3129. Operative Mortality from CABG Gender Differences in Mortality Trends

5%

4% Female 3%

2% Male 1%

0% 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

FH Edwards, CABG Surgery, p. 276. Society of Thoracic Surgeons National Cardiac Surgery Database. Characteristics of Plaques Prone to Rupture From Inflammation and LDL

Fibrous cap Media

Lumen Lipid Core

“Vulnerable” plaque

Lumen T lymphocyte Lipid Core Macrophage foam cell (tissue factor) “Activated” Intimal SMC (HLA-DR+) “Stable” plaque Normal medial SMC

Libby P. Circulation. 1999; 91:2844-2850. HIGH SENSENSITIVITY CREACTIVE PROTEIN (hs-CRP) • A MARKER OF INFLAMMATION: CRP AND hsCRP ARE SAME PROTEIN. • MAY BE ANOTHER RISK FACTOR AND PLAY A ROLE IN PLAQUE FORMATION. • MAY PREDICT HIGH RISK ACUTE CORONARY SYNDROME. • MAY INDICATE PATIENTS MOST LIKELY TO RESPOND TO . • ASSOC. WITH ELEMENTS OF METAB. SYNDR. • STATINS SHOWN TO REDUCE CRP. – ACCENTUATES THIS EFFECT.* • NEED STATIN DOSE RESPONSE CURVE.

*Sager PT, et al. Am J Cardiol. 2003;92:1414-1418. CURRENT CLINICALLY USEFUL MARKERS OF INFLAMMATION

• LIPOPROTEIN-ASSOCIATED PHOSPHOLIPASE A2*. – PLAC® TEST. • HIGH SENSITIVITY C-REACTIVE PROTEIN (hsCRP)#. • NEVERTHELESS, LDL REMAINS THE STANDARD MAJOR RISK FACTOR (GOLD STANDARD OF TREATMENT).

*Brilakis ES. Eur Heart J. 2005;26:137-144. #Willcox BJ. CVR&R. 2004;25:66-69. LIPID RESEARCH CLINICS (LRC)

OVER 7.4 YEARS, MAJOR CORONARY EVENTS REDUCED BY 19% WITH P = 0.05.*

*Lipid Research Clinics. JAMA 1984;251:365-374. LDL-APHERESIS ATHEROSCLEROSIS REGRESSION STUDY (LAARS)*

• For 2 years, 42 men treated with biweekly LDL-apheresis plus 40 mg/d vs. simvastatin 40 mg/d alone. • LDL reduced 63% in apheresis group vs. reduced 47% with simvastatin alone. • Quantitative coronary angio endpoints. – On basis of coronary segment, mean percent stenosis of all lesions showed tendency to decrease. – Only in the apheresis group, more minor lesions disappeared in comparison to the medication group. • On bicycle exercise test, time to 0.1 mV increased significantly by 39% and the maximum level of ST depression decreased significantly by 0.07 mV in the apheresis group vs. no changes in the medication group.

*Kroon A. Circulation 1996;93:1826-1835. PROGRAM ON THE SURGICAL CONTROL OF THE HYPERLIPIDEMIAS (POSCH)* • Between 1975 and 1983, 838 survivors of single MI entered into study which ended in 1990.* – 417 patients to Rx/diet/control group. – 421 patients to diet/partial ileal bypass intervention group. • Apparent zero surgical mortality in the first 57 patients.† • All POSCH post 5 yr. mort./ath. endpts. favorable.* – Mort. from CHD/nonfatal MI: 157 vs. 105 (P<0.001). – Nonfatal MI: 109 vs. 68 (P<0.001). – CABG or PTCA: 201 vs. 106 (P<0.001). – Onset of PVD: 93 vs. 68 (P=0.02). • POSCH: LDL 37.7% lower and HDL 4.3% higher.*

*Buchwald H. Arch Intern Med 1998;158:1253-1261. †Buchwald H. Ann Surg 1990;212:318-329.

Key Statin Pleiotropic Effects*

• Improved endothelial motor dysfunction. • Increased fibrinolysis (via  PAI-1). • Favorable modulation of immune function. • Antithrombotic properties-decreased platelet aggregation. • Decreased metalloproteinase activity with decreased macrophage activity • Anti-inflammatory effects. • Increased nitric oxide.

*Davignon J. Curr Ath Reports. 2004;6:27-35 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 outcomes were compared at a median of 1.9 years.

Results (p < 0.00001) (p = 0.02) • Rosuvastatin associated with a significant ↓ in the 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)

Yrs Yrs - - • All-cause mortality ↓ with rosuvastatin (p = 0.02) 1.36 • Serious adverse effects were similar (p = 0.60) 1.25 1.0 1 Conclusions 0.77 1 • Rosuvastatin was associated with a significant

reduction in major cardiovascular events, including Events/100 Events/100 Person Events/100 Events/100 Person death, in patients with LDL <130 mg/dl, but high hs- 0 0 CRP (≥2.0 mg/dl) • May require revision of current guidelines 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 JUPITER: ASTRONOMICAL SCIENCE OR ASTRONOMICAL MARKETING* • Critical reappraisal of JUPITER:† – Primary end point a soft potpourri of MI, stroke arterial revasc. (a decision), hospitalization for unstable angina (a decision) or CV death. – Stopped too soon (fewer than 2 years) with only 240 total hard endpoints (MI, stroke, confirmed CV death) out of total of 17,802 patients (8,901 each group) even though 83 for rosuvastatin and 157 for placebo seems impressive. – After dissecting the data by subtracting “nonfatal MI” from “any MI”: • Rosuvastatin: 9 fatal MI’s • Placebo: 6 fatal MI’s • Troubling concerns about this and other commercially sponsored trials.† – In JUPITER, per the methods, the sponsor collected the trial data and monitored the study sites. – Risk of poor quality. – Bias. • hsCRP is not recommended by guidelines as a target of Rx based on lack of clinical trial evidence to support clinical benefit.#

*Whayne T. Clinical Geriatrics 2009;17:36. †deLorgeril M. Arch Intern Med 2010;170:1032-1036. #Kaul S. Arch Intern Med 1010;170:1073-1077. OTHER IMPORTANT POINTS WITH STATINS  SUDDEN STATIN WITHDRAWAL MAY INCREASE EVENT RATES IN ACUTE CORONARY SYNDROME (ACS).*  EARLY STATIN USE MAY  EVENT RATES IN ACS (BENEFIT QUESTIONED AT LOW CHOLESTEROL LEVELS).  ADHERENCE IMPROVED BY STARTING STATINS DURING HOSPITALIZATION AND MAY HELP STABILIZE PLAQUES.†

*Spencer F. Arch Intern Med 2004; 164:2162-2168. †Fonarow G. Am J Cardiol 2001;87:819-822. ASTEROID Atheroma Area STUDY, 2006 10.16 mm2

Baseline IVUS Exam

Lumen Area 6.16 mm2

Atheroma Area 5.81 mm2

Follow-up IVUS 24 months rosuvastatin

Lumen Area 5.96 mm2 CHD Risk Is Increased With Very High TG Levels# (500 mg/dL) TGs are independently associated with premature familial CHD* 12

10 10.7

8

6

4

CHD Odds CHD Ratio 2 2.8 1.7 1.0 1.2 1.1 0 <100 100-149 150-199 200-299 300-499 500+ Serum Triglycerides (mg/dL)

*Triglyceride odds ratio adjusted for HDL-C; n=653 (FHx early CHD), n=1029 (control)

#Hopkins PN et al. J Am Coll Cardiol. 2005;45:1003-1012. Sites of Action of ACEIs and AT1-Receptor Blockade

Angiotensinogen Renin ACEI Angiotensin I Bradykinin Chymase Trypsin X ACE-Kininase IIX X Peptidase BK II- Angiotensin II Inactive receptor degradation AT1 -receptor blocker products X NO Statins: AT 1 -receptor AT 2 -receptor  reg.

Vasoconstriction Anti-proliferation Vasodilation Salt/water retention Cell differentiation Natriu-/diuresis Remodeling Tissue repair Anti-remodeling

European Heart Journal 1999;20:997-1008. Log-Linear Relationship Between LDL Levels and Relative Risk for CHD • This relationship is consistent with a large body of 3.7 epidemiologic data and data available from clinical trials of 2.9 LDL-C–lowering therapy. Goal Relative Risk for high CV risk is LDL < 70 for CHD, 2.2 mg/dl. Log Scale 1.7 • These data suggest that for 1.3 every 30 mg/dL change in LDL, 1.0 the relative risk for CHD is changed in proportion by about 30%. 40 70 100 130 160 190 • The relative risk is set at 1.0 for LDL-C, mg/dL LDL = 40 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 clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227–239; http://lww.com. FURTHER SUPPORT OF LOWER IS BETTER

SUBSTUDY OF PROVE-IT SHOWED THAT SUBGROUPS OF LDL < 40 MG/DL AND LDL 40-60 MG/DL HAD FEWER MAJOR CARDIAC EVENTS†.

†Wiviott SD, et al. J Am Coll Cardiol 2005;46:1411-1416. HIGH DOSE STATINS IN ACS

PROVE-IT STUDY (2004)+: Decreased ACS problems with (A) 80 mg vs (P) 40 mg; hsCRP  almost the same: from 12.3 to 1.3 (A) vs. 2.1(P). [Mean lowest LDL 62]. MIRACL STUDY (ACS)*: Atorvastatin 80 mg/d  ischemic events and rehospitalizations in the first 16wks

+Cannon et al. N Engl J Med. 2004;350:1495-1504. *Schwartz et al. JAMA. 2001;285:1711-1718. Statins and Fatal Rhabdomyolysis*

STATIN FATALITIES No./MILLION Rx 31 3.16 19 0.19 Simvastatin 14 0.12 Atorvastatin 6 0.04 Pravastatin 3 0.04 0 0.00

*New Engl J Med. 2002;346:539-40. Data for rosuvastatin and not available in 2002.

Occasionally, can see histopathologic changes of myopathy with statins despite normal CPK (Ann Intern Med. 2002;137:581-585). AORTIC STENOSIS (AS)

EXACERBATION BY  LDL. EXACERBATION BY  Lp(a). STATINS (2002) MAY  DEVEL.* OF AS. A SMALL RANDOMIZED 2005 STUDY SHOWED FAILURE OF ATORVASTATIN TO DECREASE PROGRESSION# OF AS. A 2005 STUDY WITH ROSUVASTATIN+ MARKEDLY SLOWED PROGRESSION OF AS. NO  IN AS IN SEAS TRIAL WITH EZETIMIBE/SIMVASTATIN^.

*Clin. Cardiol 2002;25:201-202. +J Am Coll Cardiol 2007;49:554-561. #N Engl J Med 2005;352:2389-2397. ^SEAS Trial, Medpage Today 2008, July 21. STROKE ALSO REDUCED BY STATINS • Heart Protection Study (HPS) showed decreased strokes with simvastatin 40 mg, except with pre- existing cerebrovascular disease.* • CARDS Study showed decreased strokes with atorvastatin 10 mg in Type 2 Diabetes patients.# • SPARCL Study showed decreased strokes with atorvastatin 80 mg in patients with recent stroke or TIA and no known CHD. There was a slight increase in hemorrhagic stroke.+

*The Lancet 2004;363:757-767. #The Lancet 2004;364:685-696. +N Engl J Med 2006;355:549-559. Residual Cardiovascular Risk Despite LDL-C Lowering

Therapies based on LDL-C lowering reduce the risks of CAD 4S CARE WOSCOPS LIPID AFCAPS HPS PROSPER CARDS ASCOT 0

10

20 15%

30 24% 24% 24% 29% 34% 40 37% 37% 36%

50

60

70

80 Relative risk Relative reduction (%) 90

100 Despite the benefits of LDL lowering, 60-70% residual risk remains 4S=Scandinavian Simvastatin Survival Study; CARE=Cholesterol and Recurrent Events; WOSCOPS=West of Scotland Coronary Prevention Study; 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; ASCOT-LLA=Anglo-Scand. Cardiac Outcomes Trial. USE OF STATINS WITH OTHER MEDS. AND IN SPECIAL SITUATIONS • : – : Never use with a statin due to inhib. of glucuronidase essen. for statin metab. – : Can use with a statin with care. • NICOTINIC ACID (Niaspan® or other new sustained release form® preferred): Can be used with a statin with care. • STATINS OVER THE COUNTER?* • DECREASED DOSING FREQUENCY OF STATINS? – Atorvastatin and Rosuvastatin.#^

*Whayne TF. Am J Cardiol 2008;101:745. #Backes JM. World Congress on Hrt Dis. Intern Med News Aug 2008;41:1. ^Gadarla M. Am J Cardiol 2008;101:1747-1748. THE ENHANCE STUDY: RESULTS* • Group-1 (eze/sim): Significant decrease in LDL (58% vs. 41% in Group-2 (sim); p < 0.01). • Group-1: Slightly more progression in carotid intima- media thickness but very insignificant. • Group-1 vs. Group-2: No significant differences in CV outcomes (the study was designed as an imaging only). • Next step: an outcomes study: Improve-It+. • Lipid Research Clinics#: Men with upper 5% CV risk using cholestyramine required 7.4 years with only LDL lowering to show decreased cardiovascular events and this can be expected to apply to ezetimibe alone.

*Kastelein JJP, et al. N Engl J Med 2008;358:1431-1443. +The Wall Street Journal Jan. 17, 2008: D-1, D-3. #The Lipid Res. Clinics. JAMA 1984;251:351-364. ENHANCE STUDY: RELEVANT CLINICAL ISSUES AND VALUE OF EZETIMIBE • LDL is most specific lipoprotein associated with CHD (the gold standard of CV risk factors)* with goal < 70 and no special claim for high dose statin except in ACS. • Each doubling of the statin dose only decreases LDL another 6%+ and the same with hsCRP. • The higher the statin dose, the higher the incidence of liver inflammation/myalgia. Myalgia described as 1-5% in labeling information# and reported in clinical studies up to 10.5%† (clin. trials run in eliminates many pts.). Do not need CPK increase to have significant myopathy.¶ • Ezetimibe is valuable in attaining LDL gold standard by adding approximately another 25% LDL reduction to statin Rx. *SytKowski P et al. N Engl J Med 1990;322:1635-1641. ◊LaRosa JC et al. N Engl J Med 2005;352:1425-1435. Cannon CP et al. N Engl J Med 2004;350:1495-1504. +Jones PH et al. Am J Cardiol 2003;92:152-160. #Thompson P et al. JAMA 2003;289:1681-1690. †Bruckert E et al. Cardiovasc Drugs Ther 2005;19:403-414. ¶Phillips PS et al. Ann Intern Med 2002;137:581-585. CONCERN REGARDING EZETIMIBE, LOW LDL AND CANCER • SEAS Trial: New onset cancer in 101 patients in active-Rx vs. 65 in control group†. • SEAS + ONGOING SHARP AND IMPROVE-IT: NO CREDIBLE EVIDENCE FOR ADVERSE EFFECT OF EZETIMIBE ON CANCER RATE†. • NO ASSOCIATION OF CANCER AND LDL LOWERING EVER ESTABLISHED.

†Peto R, et al. N Engl J Med 2008;359:1357-1366. The Majority of Statin Monotherapy LDL Reduction Is Seen With the Initial Dose

Pravastatin Simvastatin Atorvastatin Rosuvastatin

–5 C - –15 –20% –28% 10 mg –37% 20 mg –4% –46%*,† –25 –6% 40 mg –7% 80 mg –35 –4% –6% –7%

Mean change in LDL in change Mean –45 –5% from untreated baseline, % baseline, untreated from –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.

EZETIMIBE AND OXIDIZED LDL*

• Ezetimibe decreased ox-LDL in association with reductions in total LDL and in large buoyant LDL. • This change in ox-LDL by ezetimibe was not associated with any significant change is small dense LDL, HDL or VLDL. • Increasing statin dose did not decrease ox-LDL further. • Further investigation warranted due to strong association between ox-LDL and atherosclerosis.

*Azar R. Am J Cardiol 2010;106:193-197. Low HDL-C and High LDL-C Increase Coronary Artery Disease Risk; Elevated HDL Appears Protective

Framingham Heart Study

Relative Risk 3.0 of CHD After 4 Years 2.5 2.0

1.5

1.0

0.5

25 0.0 45 100 65 160 220 LDL-C, mg/dL 85

CHD=coronary heart disease. This information was adapted from The Canadian Journal of Cardiology1988;4(Suppl A):5A–10A. *P < 0.05 vs atorvastatin Multiple Actions of HDL-C as a Potential Basis for Antiatherosclerotic Activity

Antioxidant Anti-inflammatory HDL-C Antithrombotic Profibrinolytic • Antiplatelet • Protein C activation

Enhanced reverse cholesterol transport (RCT)

Antiatherothrombotic effect

Reproduced with permission from Shah PK et al. Circulation. 2001;104:2376–2383. Niaspan Efficacy Combined Data from Pivotal Studies

HDL

30% 29% 30 21% 24% 20 16% 10% 10 -3% -8% 0 -5% -12% -13% -10 -16% -17% -21% -14% -22% -20 LDL -21% -25% -26% -30 -30%

-32% Lp(a) Change from Baselinefrom Change -40 -39% -44% TG -50 500 mg 1000 1500 2000 2500 3000

Kashyap ML, et al. J Am Coll Cardiol 2000;35(SupplA):326A. Gotto AM. Am J Cardiol 1998;81:492. Mechanism of -Induced Flushing by Prostagalandin D2

Smooth muscle cell or other EP or EP 2 4 cell type

PGE2

Dermal macrophages PGD2 Selective DP1 DP1 Receptor Undesirable effects Nicotinic Antagonist Acid–Induced Flush Arachidonic acid Markedly reduces COX-1 Niacin Flush in mice

PGE2 PGD2 and humans

Cutaneous vasodilation and burning sensation on face and upper body

Adapted from Pike NB. J Clin Invest. 2005;115:3400-3403. CETP Inhibitors: 1. Cholesterol Ester Transferase Protein Inhibitor. 2. New investigational pharmaceutical class that will be most effective medication yet for elevating the HDL. 3. Unfortunately, testing and marketing was planned only in combination with Atorvastatin instead of also being available alone to be combined as indicated with other statins and with other medications.* Extensive clinician protest then forced individual availability. However, CV complications (BP, MI’s, Deaths) later forced withdrawal. 4. Other CETP inhibitors are on the horizon (Anacetrapib-Merck, -Roche/Japan Tobacco), reportedly without BP/CV problems.

*Avorn J. N Engl J Med 2005;352:2573-2576. Percent Change from Baseline in Apo A-I (similar to HDL; DALM 2007) Monotherapy Co-administration 50 50

40 40 I

30 I 30

- -

20 20 in Apo A Apo in In Apo A Apo In 10 10

0 0 Percent Change from Baseline Change Percent Percent Change from Change Percent Baseline -10 -10 0 4 8 0 4 8 Weeks on Treatment Weeks on Treatment

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 2.Isis Pharmaceuticals, Carlsbad, CA. Tribble,2; James M. McKenney,3; Thomas W. Littlejohn III,4; 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. LIPOPROTEIN (a); [from DALM 2007]

40 Monotherapy Co-administration

20

0

-20

-40

-60 Median % Median Change Baseline from (95% CI) -80

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. 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. NEGATIVE META-ANALYSIS OF STATIN BENEFIT* • Meta-analysis of 11 trials (total participants 65,229) including JUPITER, ALLHAT, ASCOT, MEGA, AFCAPS/TexCAPS, WOSCOPS, PROSPER, CARDS, ASPEN, PREVEND IT, HYRIM. • No evidence for benefit of statin therapy on all- cause mortality over average of 3.7 years was found in what was considered a high-risk primary prevention population. • More research, free of incentives, is essential.†

*Kausik K. Arch Intern Med 2010;170:1024-1031. †Green L. Arch Intern Med 2010;170:1007-1008. ALTERNATIVE MEDICATIONS • Some are of definite value. • Unfortunately, due to the lack of financial incentive, there is no pharmaceutical company support for large placebo controlled trials to guide the clinician and bring effective alternative medications into clinical practice while incenting physicians/patients not to use ineffective/ dangerous Rx. Also, the NIH has not supported trials. • Dangerous and of no value: Chelation therapy. • Questionable value: Folic acid/B-12/B-6 combination for elevated serum homocysteine. • Alternative Rx with apparent value: Aspirin, Coenzyme Q, Nuts, Olive Oil, Omega Fatty Acids, Plant Sterols (Stanols), , Red Wine, Red Yeast Rice, Soluble Dietary Fiber, Soy. COENZYME Q-10 (uncertain benefit/risk)*+ • MITOCHONDRIAL ENERGY TRANSDUCTION • FUNCTIONAL ELEMENT IN ALL CELL MEMBRANES – ANTIOXIDANT ACTION – REGENERATION OF REDOX CAPACITY • CONTROL OF MEMBRANE CHANNELS • BIOSYNTHESIS IN MITOCHONDRIA AND ENDOPLASMIC RETICULUM • BIOSYNTHESIS INHIBITED BY STATINS • DOSE: 200 mg once daily (to  risk of statin myositis) *Crane F. J Am Col Nutr 2001;20:591-598. Kelly P. Amer Col Cardiol Sci Sessions 2005 (used 100 mg once daily). +Caso G. Am J Cardiol 2007;99:1409-1412. RED WINE • BENEFIT FROM ALCOHOL – ALCOHOL MAY DECREASE INSULIN RESISTANCE* – ALCOHOL HAS AN ANTI-PLATELET EFFECT# • BENEFIT FROM POLYPHENOLS# • BENEFIT FROM  NITRIC OXIDE (ONE SUGGESTED POLYPHENOL EFFECT)# • BENEFIT FROM FLAVONOIDS WHICH INHIBIT LDL OXIDATION+ RED WINE, DARK CHOCOLATE, GREEN TEA ARE MAIN SOURCES OF FLAVONOIDS

*Howard A. Ann Intern Med. 2004;140:211-219 #Wallerath T. J Am Col Cardiol. 2003;41:471-478 +Maron D. Curr Ath Reports. 2004;6:7378 CONCLUSION

 hsCRP appears to be the most clinically used marker of inflammation but Phospholipase A2 avoids nonarterial inflammatory etiologies. • LDL is still the gold standard of CV risk factors and it should be targeted aggressively. • Ezetimibe has been subjected to ENHANCEd hype. • Treatment of HDL may be the next basic focus to decrease CV risk. • Failure to treat LDL in a patient with high CV risk, without specific reasons, is malpractice. • Women have significant risk from CHD, especially if developed less than age 50.