Preventing the Clinical Manifestations of CV Disease in Asia: Opportunities for Lipid Management Slides prepared and presented by Prof John JP Kastelein Academic Medical Centre Amsterdam, The Netherlands

The Burden of CVD in Asia: CHD Deaths by Country, 2002 Cardiovascular disease (CVD), including stroke and coronary heart disease (CHD), is a leading cause of mortality in the East Asia and Pacific region, according to 2002 World Health Organization (WHO) statistics. For example, in China, stroke was responsible for more than 1.5 million deaths and CHD led to more than 700,000 deaths in 2002 alone. WHO CVD Atlas. 2002. Deaths from stroke. http://www.who.int/ cardiovascular_diseases/en/cvd_atlas_16_death_from_stroke.pdf. Accessed March 7, 2011. WHO CVD Atlas. 2002. Deaths from coronary heart disease. http://www.who.int/ cardiovascular_diseases/en/cvd_atlas_14_deathHD.pdf. Accessed March 7, 2011. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442. doi:10.1371/journal.pmed.0030442. 2 WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002. 2

The Burden of CVD in Asia: Stroke Deaths by Country, 2002 Cardiovascular disease (CVD), including stroke and coronary heart disease (CHD), is a leading cause of mortality in the East Asia and Pacific region, according to 2002 World Health Organization (WHO) statistics. For example, in China, stroke was responsible for more than 1.5 million deaths and CHD led to more than 700,000 deaths in 2002 alone. WHO CVD Atlas. 2002. Deaths from stroke. http://www.who.int/ cardiovascular_diseases/en/cvd_atlas_16_death_from_stroke.pdf. Accessed March 7, 2011. WHO CVD Atlas. 2002. Deaths from coronary heart disease. http://www.who.int/ cardiovascular_diseases/en/cvd_atlas_14_deathHD.pdf. Accessed March 7, 2011. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med. 2006;3(11):e442. doi:10.1371/journal.pmed.0030442. WHO CVD Atlas. 2002. WHO Stroke Atlas. 2002. 3 3

Age-Standardized Stroke and CHD Death Rates by Country, 2002 Age-standardized mortality rates for stroke are elevated in East Asian Pacific countries and are generally higher than in Western countries. East Asian countries have lower CHD mortality rates than do Western countries, but South Asian and some Southeast Asian countries have age-standardized mortality rates for CHD that are comparable to or higher than those of Western countries. Ueshima H, Sekikawa A, Miura K, et al. Cardiovascular disease and risk factors in Asia: a selected review. Circulation. 2008;118:2702-2709. Ueshima H et al. Circulation. 2008;118:2702-2709. 4 4

Projected Stroke and CHD Increase to 2030 in China A computer model (CHD Policy-China, a Markov model of CVD in the adult Chinese population) was used to estimate annual CHD and stroke event rates in China from 2010 to 2030 using simulations based on aging and population growth alone and, in addition, based on projected changes in systolic blood pressure, total cholesterol, diabetes, and smoking. Demographic changes expected to occur in China from 2010 to 2030 are forecasted to cause a rise of greater than 50% in annual CHD and stroke events. Much of the projected increase is due to aging and population growth alone. Additional events are attributed to trends in systolic blood pressure, total cholesterol, diabetes, and smoking. Data for the model come from the International Collaborative Study of Cardiovascular Disease in Asia Study for risk-factor trends; various other Chinese studies for stroke incidence, mortality, and case-fatality rates; and the China Multiprovincial Cohort Study for stroke and CHD hazard ratios. Moran A, Gu D, Zhao D, et al. Future cardiovascular disease in China: Markov model and risk factor scenario projections from the Coronary Heart Disease Policy Model— China. Circ Cardiovasc Qual Outcomes. 2010;3:243-252. Moran et al. Circ Cardiovasc Qual Outcomes. 2010;3;243-252. 5 5

Increase in Age-Standardized Mean Total Cholesterol Levels in Asia 1980-2008 Men Women Global mean total cholesterol levels changed little between 1980 and 2008, decreasing by less than 0.1 mmol/L per decade in men and women. In contrast, in East and Southeast Asia and the Pacific region, mean total cholesterol levels in men (shown on the left) and women (shown on the right) were estimated to increase by 0.08 and 0.09 mmol/L per decade, respectively, from 1980 to 2008. Trends in mean serum cholesterol were determined in an analysis of data from published and unpublished health surveys and epidemiologic studies from 199 countries and territories in 21 subregions, which were grouped into 7 merged regions. Farzadfar F, Finucane MM, Danaei G, et al; on behalf of the Global Burden of Metabolic Risk Factors of Chronic Diseases Collaborating Group (Cholesterol). National, regional, and global trends in serum total cholesterol since 1980: systematic analysis of health examination surveys and epidemiological studies with 321 country-years and 3.0 million participants. Lancet. 2011;377:578-586. Southeast Asia: Cambodia, Indonesia, Lao People’s Democratic Republic, Malaysia, Maldives, Myanmar, Philippines, Sri Lanka, Thailand, Timor-Leste, Vietnam East Asia: China, Hong Kong (China), Macau (China), Democratic People’s Republic of Korea, Taiwan, Brunei, Darussalam, Japan, Republic of Korea, Singapore, islands of Oceania 6 Farzadfar et al. Lancet. 2011;377:578-586. 6

Statins raise LDL receptors in the liver Discovery of statins Discovery of LDL receptors Brown and Goldstein, 1974 Endo, 1976 Statins raise LDL receptors in the liver Plasma LDL is reduced

Clear Cardiovascular Benefits of Intensive Lipid-Lowering Therapy POSCH-PL 4S-PL Primary prevention trials 25 Secondary prevention trials POSCH-Rx 20 CARE-PL 4S-Rx HPS 15 LIPID-PL Statin trials % Patients with CHD Event TNT-10A CARE-Rx HPS-PL 10 LIPID-Rx WOSCOPS-PL non statin trials TNT-80A WOSCOPS-Rx HPS-Rx LRC-PL 5 ASCOT-PL LRC-Rx ASCOT-Rx AFCAPS-PL Populations with low cholesterol levels (150 mg/dL) and low LDL-C levels (70 mg/dL) have a low incidence of coronary artery disease. Epidemiological studies show that lowering plasma cholesterol levels results in a progressive decrease in cardiovascular events.1-4 Combined data from the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) and West of Scotland Coronary Prevention Study (WOSCOPS) trials suggest that reducing cholesterol levels from 285 mg/dL to 190 mg/dL decreases the incidence of CHD events from 170/1,000 patients in 10 years to 70/1,000 patients in 10 years.3,4 Physicians today are under increasing pressure to attain LDL-C goals below 100 mg/dL,5 and these targets could be reduced still further in the light of findings from ongoing clinical trials. Statins can achieve LDL-C reductions of up to 50–60% when used in high doses,6 however, statins in monotherapy are unable to reduce LDL-C levels beyond this level, leaving many hypercholesterolaemic patients at significant risk of coronary events. Strategies that combine lipid modifying agents with complementary mechanisms of action may further enhance the benefits of statin therapy.7 References 1. Castelli WP. Epidemiology of coronary heart disease: the Framingham study. Am J Med 1984; 76: 4–12. 2. Sacks FM, Pfeffer MA, Moye LA et al., for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9. 3. Shepherd J, Cobbe SM, Ford I et al., for the West of Scotland Coronary Prevention Study Group. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995; 333: 1301–7. 4. Downs JR, Clearfield M, Weis S et al., for the AFCAPS/TexCAPS Research Group. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. JAMA 1998; 279: 1615–22. 5. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486–97. 6. Grundy SM. Statin trials and goals of cholesterol-lowering therapy. Circulation 1998; 97: 1436–9. 7. Izzat NN, Deshazer ME, Loose-Mitchell DS. New molecular targets for cholesterol-lowering therapy. J Pharmacol Exp Ther 2000; 293: 315–20. AFCAPS-Rx 50 70 90 110 130 150 170 190 210 (mg/dL) 1.3 1.8 2.3 2.8 3.4 3.9 4.4 4.9 5.4 (mmol/L) LDL cholesterol

More vs less intensive statin therapy Second CTT cycle: More vs less intensive statin therapy Study Treatment comparison N Target population Entry lipid criteria PROVE-IT A 80 vs. P 40 4162 ACS TC ≤240 mg/dL A to Z S 40 then S 80 vs. placebo then S 20 4497 TC ≤250 mg/dL TNT A 80 vs. A 10 10,001 Prior CHD LDL-C 130-250 mg/dL TG ≤600 mg/dL IDEAL A 80 vs. S 20-40 8888 SEARCH S 80 vs. S 20 12,064 TC ≥4.5 mmol/L or ≥3.5 if on statins 9

Proportional effects on MAJOR VASCULAR EVENTS per mmol/L reduction in LDL cholesterol No. of events (% pa) Statin/ Contr ol/ Relative risk (CI) More statin Less statin Nonfatal MI 3485 (1.0) 4593 (1.3) 0.73 (0.69 - 0.78) CHD death 1887 (0.5) 2281 (0.6) 0.80 (0.74 - 0.87) Any major coronary event 5105 (1.4) 6512 (1.9) 0.76 (0.73 - 0.78) CABG 1453 (0.4) 1857 (0.5) 0.75 (0.69 - 0.82) PTCA 1767 (0.5) 2283 (0.7) 0.72 (0.65 - 0.80) Unspecified 2133 (0.6) 2667 (0.8) 0.76 (0.70 - 0.82) Any coronary revascularisation 5353 (1.5) 6807 (2.0) 0.75 (0.72 - 0.78) Ischaemic stroke 1427 (0.4) 1751 (0.5) 0.79 (0.72 - 0.87) Haemorrhagic stroke Ungroup, rotate Ungroup fully Group all outcome rows Stretch height to 125% Group all Expand to 120% (locked aspect ratio), then move to 1.5cm horizontal Bump up font size 3 times Ungroup fully and sort out text problems Move left column left 4 clicks Move headers down 2 clicks Move MCE section up 3 clicks, CRV section up 1 and stroke section up 1 Move forest plot section right 2 clicks Unbold relative risks 257 (0.1) 220 (0.1) 1.12 (0.88 - 1.43) Unknown stroke 618 (0.2) 709 (0.2) 0.88 (0.76 - 1.01) Any stroke 2302 (0.6) 2680 (0.8) 0.84 (0.79 - 0.89) Any major vascular event 10973 (3.2) 13350 (4.0) 0.78 (0.76 - 0.80) 99% or 95% CI 0.4 0.6 0.8 1 1.2 1.4 Statin/more Control/less statin better statin better 10

Absolute effect of statin therapy on MAJOR VASCULAR EVENTS 20 Control 21% relative risk reduction per mmol/L Statin 15% relative risk reduction per 0.5 mmol/L More statin 15 Five year risk of a major vascular event, % 10 Combined evidence: ~33% relative risk reduction per 1.5 mmol/L 5 1 2 3 4 5 LDL cholesterol, mmol/L 11

ASAP: Atorvastatin Reduced CRP to a Greater Extent Than Simvastatin Baseline 1 year 2 years Additional Findings No correlation between CRP and LDL-C reduction Significant correlation between decrease in CRP and reduction in IMT (r =.13; P=.03) Patients in the highest tertile of change in CRP had the greatest mean reduction in IMT -50 -40 -30 -20 -10 14.0 19.7 Change (%) P<.001 P<.022 In ASAP, atorvastatin 80 mg reduced CRP significantly more than simvastatin 40 mg. At 1 year, the median percent change in CRP was 44.9% with atorvastatin and 14.0% with simvastatin (P<.001). By 2 years, the median percent change was 40.1% with atorvastatin and 19.7% with simvastatin (P<.022)1 There was no correlation between reductions in CRP and LDL-C. However, decreases in CRP were significantly correlated with reductions in IMT (r =.13; P=.03)1 Patients in the highest CRP tertile experienced the greatest mean reduction in IMT1 Reference: 1. van Wissen S, Trip MD, Smilde TJ, et al. Differential hs-CRP reduction in patients with familial hypercholesterolemia treated with aggressive or conventional statin therapy. Atherosclerosis. 2002;165:361-366. 40.1 44.9 Atorvastatin 80 mg Simvastatin 40 mg van Wissen S et al. Atherosclerosis. 2002;165:361-366.

Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): Study Design Patient population Men and women aged 40-79 years Untreated HTN (SBP 160 mm Hg, DBP 100 mm Hg, or both) Treated HTN (SBP 140 mm Hg, DBP 90 mm Hg, or both) TC 251.4 mg/dL At least 3 additional CVD risk factors Atorvastatin 10 mg (n=5168) 19,342 patients with HTN 10,305 patients with TC 251.4 mg/dL Placebo (n=5137) 5 years In the Anglo-Scandinavian cardiac outcomes trial—lipid lowering arm (ASCOT-LLA), men and women, 40 to 79 years of age, with treated or untreated hypertension, a mean LDL-C of 133 mg/dL, total cholesterol levels 251.4 mg/dL, and at least 3 other CVD risk factors were randomized to receive either atorvastatin 10 mg or placebo. Planned follow-up was 5 years and the primary end point of this study was nonfatal MI and fatal CHD1 Untreated hypertension was defined as systolic blood pressure 160 mm Hg and/or diastolic blood pressure of 100 mm Hg; treated hypertension was defined as systolic blood pressure 140 mm Hg and/or diastolic blood pressure  90 mm Hg. Additional CVD risk factors included left-ventricular hypertrophy or other specified abnormalities on electrocardiogram, type 2 diabetes, peripheral arterial disease, previous stroke or transient ischemic attack, male sex, age 55 years or older, microalbuminuria or proteinuria, smoking, plasma TC:HDL-C ratio of 6 or higher, and a family history of premature CHD1 At baseline, patients had mean LDL-C levels of 131 mg/dL and a mean blood pressure of 164/95 mm Hg. Concurrent treatment of hypertension over the course of the trial reduced blood pressure to 138/80 mm Hg1 Reference: 1. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. Trial stopped at 3.3 years, 2 years earlier than expected Primary efficacy end point Nonfatal MI, including silent MI, and fatal CHD HTN=hypertension; SBP=systolic blood pressure; DBP=diastolic blood pressure; TC=total cholesterol; CVD=cardiovascular disease. Sever PS et al. Lancet. 2003;361:1149-1158.

ASCOT-LLA: Atorvastatin Reduced the Occurrence of First Major CV Events 4 36% RRR in nonfatal MI and fatal CHD P=.0005 3 Placebo Patients with nonfatal MI and fatal CHD (%) 2 Atorvastatin (10 mg) 1 This graph depicts the cumulative incidence of nonfatal MI and fatal CHD at 6-month intervals during the first 3.5 years of the study. As highlighted, the benefit of atorvastatin therapy emerged in the first year of follow-up and after 3.5 years there was a significant 36% reduction in nonfatal MI and fatal CHD compared with placebo1 Due to a significant reduction in the primary end point and stroke, the trial was stopped after only 3.3 years, nearly 2 years earlier than expected1 Reference: 1. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158. 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years RRR=relative risk reduction. Adapted from Sever PS et al. Lancet. 2003;361:1149-1158.

PROVE IT: Study Design Patient population Men and women aged 18 years Hospitalized within 10 days of acute MI or high-risk unstable angina (UA) TC 240 mg/dL Stable condition, enrolled after percutaneous coronary intervention (PCI), if planned Atorvastatin 80 mg (n=2099) 4162 patients Pravastatin 40 mg (n=2063) The PROVE IT clinical trial (supported by Bristol-Myers Squibb and Sankyo) compared the effectiveness of high-dose, intensive therapy with atorvastatin (80 mg) with that of standard-dose pravastatin (40 mg) in reducing the incidence of death and major coronary events in patients who had been hospitalized for an ACS (acute MI with or without ST-segment elevation or high-risk unstable angina) within the preceding 10 days. Patients were required to have cholesterol levels 240 mg/dL and to be in stable condition enrolled after percutaneous revascularization, if planned. Median LDL-C at baseline was 106 mg/dL1 Eligible patients were randomly assigned to receive either high-dose atorvastatin (80 mg) or standard-dose pravastatin (40 mg) and then followed up for 18 to 36 months. The primary efficacy measure was the time from randomization until the occurrence of a first major cardiac event—death from any cause, MI, documented unstable angina requiring rehospitalization, revascularization, or stroke1 Reference: 1. Cannon CP, Braunwald E, McCabe CH, et al. Comparison of intensive and moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. 18 to 36 months Primary efficacy end point Composite of death from any cause, MI, documented UA requiring rehospitalization, revascularization, and stroke Cannon CP et al. N Engl J Med. 2004;350:1495-1504.

PROVE IT: Significant Clinical Benefit With Atorvastatin Occurred as Early as 30 Days Composite end point of death, MI, or urgent revascularization 4 2 1 3 Pravastatin (40 mg) 33% RRR P=.043 Death, MI, urgent revascularization (%) Atorvastatin (80 mg) A separate post hoc analysis evaluated the reduction in the primary composite end point and rate of death, MI, or urgent revascularization experienced by each treatment group during the first 30 days of therapy. There was a steady increase in the protective benefits of intensive atorvastatin therapy, demonstrated by a 33% reduction in death, MI, or urgent revascularization relative to standard pravastatin treatment by day 30, suggesting an early benefit to treatment with atorvastatin 80 mg versus pravastatin 40 mg1 Reference: 1. Cannon CP, Ray KK, McCabe CH, et al. Two windows of cardioprotection: the early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes. Results from the PROVE IT-TIMI 22 trial [abstract 2341]. Circulation. 2004;110(suppl III):III-499. 10 5 15 20 30 25 Time after entry to trial (days) Adapted from Cannon CP et al. Circulation. 2004;110(suppl III);III-499.

Atorvastatin Is the Only Statin With an Active HMG CoA Reductase Inhibitor Metabolite Atorvastatin parent molecule CH3 CH3 O CH O OH - .. NHC N Active ortho-hydroxy-atorvastatin metabolite F 70% of the activity of atorvastatin is attributed to active metabolites Site* H H H3C Atorvastatin is a synthetic lipid-lowering agent that is administered as the calcium salt of the active hydroxy acid (parent molecule).1 After administration, atorvastatin is rapidly absorbed and metabolized to the active hydroxylated metabolites, and peak plasma concentrations occur in 1 to 2 hours. Approximately 70% of atorvastatin’s activity is attributed to the active metabolites The o-hydroxy group, which is unique to the active atorvastatin metabolite, has been shown to protect LDL-C from oxidation1 Reference: 1. Walter MF, Jacob RF, Weng Y, Mason RP. Active hydroxy metabolite of atorvastatin increases resistance of human low-density lipoproteins to oxidative modification [abstract 882-4]. J Am Coll Cardiol. 2004;43(5 pt A):529A. O O CH3 OH O . . O N N H *Unique to ortho-hydroxy metabolite. Data on file (RP Mason). Pfizer Inc., New York, NY. F

What Accounts for the Added Benefits of Atorvastatin? Endothelial effects Anti-inflammatory effects Antioxidant effects Reduction in plaque progression Plaque stabilization + Reduction of lipids In addition to reducing LDL-C concentrations, atorvastatin may delay the development of atherosclerosis via endothelial, anti-inflammatory, or antioxidant effects, or by reducing plaque progression or promoting plaque stabilization Wassmann S, Nickenig G. Endothelium. 2003;10:23-33.

Statin Safety in Perspective Number needed to treat for 1 year to: Cause a GI Bleed1 Cause a Fatal GI Bleed1 Aspirin Cause Severe Myositis2 Cause Fatal Myositis2 Statins 248 2066 100,000 1,000,000 1Derry S, Loke YK. 2000 2Thompson PD, et al. 2003

Safety of Atorvastatin 80 mg in Clinical Trials Cannon, p 6, col 1 Follow-up Patients ALT/AST >3x ULN* CK >10x ULN* Newman et al† variable 4798 26 (0.6%) 2 (0.06%) PROVE-IT 2 years 2099 69 (3.3%) NA TNT 4.9 years 4995 60 (1.2%) IDEAL 4.8 years 4439 61 (1.38%) SPARCL 2365 51 (2.2%) 2 (0.08%) Total 18,696 267 (1.43%) 4 (0.021%) Newman, p 66, table 2 LaRosa, p 8 Pedersen, p 2442 Amarenco, p 557, table 3 Atorvastatin 80 mg has been studied in >18,000 patients in clinical trials1-5 that documented a low incidence of myopathy and liver enzyme elevation. Newman C, Tsai J, Szarek M, Luo D, Gibson E. Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials of 14,236 patients. Am J Cardiol. 2006;97:61-67. Cannon CP, Braunwald E, McCabe CH, et al; for the PROVE-IT Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504. LaRosa JC, Grundy, Waters DD, et al; for the Treating to New Targets (TNT) Investigators. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005;352:1425-1435. Pedersen TR, Faergeman O, Kastelein JJP, et al; for the Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction. The IDEAL Study: a randomised controlled trial. JAMA. 2005;294:2437-2445. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559. *Consecutive measurements. †Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC, et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al; for the IDEAL Study Group. JAMA. 2005;294:2437-2445; Amarenco P et al. N Engl J Med. 2006;355:549-559. 20 20

Is Current LDL Reduction Enough? 700 placebo 600 30.6% reduction treated 500 400 CV events 31.0% reduction 300 200 100 4S 2º prevention trial with simvastatin WOSCOPS 1º prevention trial with pravastatin

The Future of Best Practice “Normal” plasma cholesterol 700 (18.0) - Physiologic level for plasma LDL-cholesterol as predicted from receptor studies 25 mg/dL (0.65 mmol/L) FH homozygotes 300 (7.7) - FH heterozygotes 200 (5.2) Plasma cholesterol level mg/dL (mmol/L) - Guinea pig Cow Rabbit 150 (3.9) - Sheep Camel Pig Rat Normal adults 100 (2.6) - 50 (1.3) - Newborns

REVERSAL: Benefit of Intensive LDL-C Lowering on Plaque Progression 3 Progression (P=0.001) pravastatin 40 mg atorvastatin 80 mg 2 Percent change in atheroma volume 1 P=0.02 between treatment groups No change (P=0.98) -1 Nissen SE et al. JAMA 2004;291:1071–1080 23

REVERSAL Comparison of % LDL Cholesterol Reduction and Change in Atheroma Volume 20 15 10 Change in Atheroma Volume, mm3 5 -5 50% LDL-C reduction -10 -15 -80 -70 -60 -50 -40 -30 -20 -10 10 20 % Change in LDL Cholesterol

REVERSAL: Intensive Lipid Lowering With Atorvastatin Halted Plaque Progression After 18 Months 20 15 10 Pravastatin (40 mg) 5 Change in atheroma volume (mm3) Atorvastatin (80 mg) -5 -10 -15 As one would expect, results from the REVERSAL trial demonstrated an inverse relationship between reduction in LDL-C and change in atheroma volume. Pravastatin and atorvastatin produced parallel regression lines. However, for any degree of reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin. The investigators suggested that this added benefit with atorvastatin was equivalent to an additional 20% reduction in LDL-C. Data such as these suggest that, although LDL-C plays a central role in the progression of atherosclerosis, improved outcomes with atorvastatin are not due to intensive LDL-C lowering alone1 Reference: 1. Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291:1071-1080. -80 -70 -60 -50 -40 -30 -20 -10 0 10 20 For any degree reduction in LDL-C, the progression rate was lower with atorvastatin than with pravastatin Change in LDL-C (%) Nissen SE et al. JAMA. 2004;291:1071-1080.

Relationship Between Estimated GFR (eGFR) and Clinical Outcomes Death from Any Cause Total Events = 51,424 Cardiovascular Events Total Events = 139,011 Any Hospitalization Total Events = 554,651 Age-Standardized Event Rate (per 100 Person-Yr) The slide shows the longitudinal glomerular filtration rate (GFR) in a study of 1,120,295 adults in the Northern California Kaiser Permanente healthcare system. Patients were included if their serum creatinine had been measured between 1996 and 2000. Age-standardized rates of death from any cause, cardiovascular events, and hospitalization are shown here according to corresponding estimated GFR. A cardiovascular event was defined as hospitalization for coronary heart disease, heart failure, ischemic stroke, or peripheral arterial disease. eGFR (mL/min/1.73 m2) Go AS, et al. N Engl J Med. 2004;351:1296-305. 26

Proportion of Patients With Decline or Improvement From Baseline eGFR Treating to New Targets (TNT) Study Proportion of Patients With Decline or Improvement From Baseline eGFR P<0.0001 45.6% 37.8% P<0.0001 9.2% 6.6% (n=3324) (n=3225) (n=1505) (n=1602) eGFR decline from eGFR improvement from ≥60 mL/min/1.73 m2 <60 mL/min/1.73 m2 Slide 27