1. The case for intensive lipid management: The opportunities and issues for cardiologists Prof. John Betteridge University College London Slide lecture prepared and held by: Master Class: Advanced CV Risk management in cardiology June 17-18, 2011, London Presentation topic

2. A Survey of 246 Suggested Coronary Risk Factors Paul N. Hopkins and Roger R. Williams Department of Internal Medicine, Cardiology Division, University of Utah Medical Center, Salt Lake City, UT 84132 (USA) Atherosclerosis 1981

3. BMJ 1975, 4 500-502

4. Down regulate HMGCoA reductase Reduce LDL receptor synthesis Esterified by ACAT (storage) The Fate of LDL PCSK9 prevents LDLR recycling LDLR

5. FH3: mutations in PCSK9 Proprotein convertase subtilisin/kexin type 9 PCSK9 is a protease which binds to LDL-R and directs them to lysosomes for degradation, rather than recycling to cell surface Loss of function (non-sense and some mis-sense) mutations lead to  LDL levels –2.6% of US blacks, LDL  28%, CHD  88% –3.2% of US whites, LDL  15%, CHD  47% (Cohen et al. NEJM 2006;354:1264) Rare gain of function (other mis-sense) mutations described which lead to severe FH –D374Y accounts for 2% of FH in UK –phenotype generally more severe than HeFH due to LDLR mutations –true homozygotes not described? Statins increase PCSK9 as well as LDLR activity – counterproductive Potential therapeutic target Tall, NEJM 2006;354:1310Horton et al. Trends Biochem Sci 2006;32:71Zhang et al. PNAS 2008;105:13045

6. Familial Hypercholesterolaemia Autosomal dominant inheritance Xanthomata Premature vascular disease Elevated low density lipoprotein levels Genetic defect at the LDL receptor

7. COHEN et al. New Engl J Med 354:1264, 2006 P=0.003 No Yes PCSK9 46L Coronary Heart Disease ( % ) 12840 Frequency ( % ) Plasma LDL Cholesterol in White Subjects ( mg/dL) No PCSK9 46L Allele ( n=9223 ) 3020100 3020100 0 50 100 150 200 250 300 50 th Percentile PCSK9 46L Allele ( n=301 ) LDL-C Distribution and CAD Incidence Presence or Absence of PCSK9 46L Allele Dallas Heart Study

8. LDL and Atherogenesis LDL and Atherogenesis Steinberg D et al. N Engl J Med 1989;320:915-924. Endothelium Vessel Lumen LDL LDL Readily Enter the Artery Wall Where They May be Modified LDL Intima Modified LDL Modified LDL are Pro inflammatory Modified LDL are Pro inflammatory Hydrolysis of Phosphatidylcholine to Lysophosphatidylcholine Other Chemical Modifications Oxidation of Lipids and ApoB Aggregation

9. LDL LDL Endothelium Vessel Lumen Monocyte Macrophage Adhesion Molecules Macrophages and Foam Cells Express Growth Factors and Proteinases Macrophages and Foam Cells Express Growth Factors and Proteinases Foam Cell Intima Modified LDL Cytokines Cell Proliferation Matrix Degradation Growth Factors Metalloproteinases Ross R. N Engl J Med 1999;340:115-126. MCP-1MCP-1

10. From Association to Cause Cholesterol and CHD strength dose response independent consistent plausible mechanism predictive reversible

11. Problems with Early Trials Available drugs of limited efficacy, poorly tolerated or both.Available drugs of limited efficacy, poorly tolerated or both. small differences between control and treated groups Clinical trial science poorly developed.Clinical trial science poorly developed. low end-point numbers poor data collection Lack of definitive outcomes: small reduction in CHD events (mainly non-fatal MI) no effect on overall mortality

12. Dietary cholesterol Biliary cholesterol Effects of Statins Intestinal pool LDL receptors Hepatic cholesterol Synthesis Plasma LDL Statins

13. High-risk CHD patients (high cholesterol) High-risk CHD patients (high cholesterol) Majority of CHD patients (broad range of cholesterol levels) Patients at high risk of CHD (high of CHD (high cholesterol) cholesterol) Patients at low Patients at low risk of CHD risk of CHD (low HDL-C) (low HDL-C) Primary prevention Secondary prevention Statins:The Evidence Base. WOSCOPS(pravastatin) AFCAPS/TexCAPS(lovastatin) 4S(simvastatin) CARE (pravastatin) LIPID (pravastatin) LIPID (pravastatin) Continuum of risk 22.6 12.9 8.44 7.9 2.8 Placebo MI rate per 100 subjects per 5 years HPS

14. CHD Risk Despite Statin Therapy CHD Risk Despite Statin Therapy Trial Statin treatment Clinical events* Risk reduction vs placebo WOSCOPS** (6595) Pravastatin 40 mg 31% AFCAPS/TexCAPS** (6605) Lovastatin 20 or 40 mg 40% ASCOT-LLA** (10,305) Atorvastatin 10 mg 38% 4S** (4444) Simvastatin 20 mg 26% CARE*** (4159) Pravastatin 40 mg 24% LIPID*** (9014) Pravastatin 40 mg 24% HPS*** (20,536) Simvastatin 40 mg 27% PROSPER*** (5804) Pravastatin 40 mg 24% *Nonfatal myocardial infarction and coronary death; **Primary prevention trial; ***Secondary prevention trial Remaining risk 69% 60% 62% 74% 76% 73% 76%

15. Early Primary and Secondary CVD Prevention Trials With CHD Event (%) ? 25 20 15 10 5 0 507090110130150170190210 Secondary prevention Primary prevention 4S-PI 4S-Rx Lipid-PI CARE-PI Lipid-Rx WOS-Rx WOS-PI AFCAPS-PI AFCAPS-Rx CARE-Rx LDL-cholesterol (mg/dl) ?

16. PROVE-IT Trial Intensive and Moderate Lipid-Lowering after Acute Coronary Syndromes Population: 4162 patients within 10 days of acute coronary syndrome Treatment: Standard: Pravastatin 40mg/day mean LDL 2.46mmol/l Intensive: Atorvastatin 80mg/day mean LDL 1.6mmol/l Primary endpoint: Death, MI, unstable angina requiring hospitalisation, revascularisation and stroke Follow-up: 18-36 months (mean 24 months) Cannon et al N Engl J Med April 8 th 2004 Pravastatin 40mg 26.3% 16% reduction p=0.005 p=0.005 CVD Endpoints 243018 Months Months 126 Atorvastatin 80mg 22.4%

17. Intensive Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease Treat to New Targets Trial (TNT) Population: 10,001 patients with CHD: previous MI, angina with objective evidence of atherosclerotic CHD, coronary revascularization. Protocol: 15464 CHD patients, LDL-C 130-250mg/dl (3.4-6.5mmol/l) 8 week run-in treatment with atorvastatin 10 mg/day. 5461 excluded. If LDL -C <130mg/dl randomised to either atorvastatin 10mg/dl or 80mg/day. Median follow-up 4.9yrs. Primary end point: Occurrence of first CVD event; CHD death, non- fatal, non procedure - related MI, resuscitation after cardiac arrest, fatal or non fatal stroke.. La Rosa et al NEJM March 2005

18. Treat to New Targets: Lipid Effects

19. Primary Efficacy Outcome Measure: First Major Cardiovascular Event* TNT *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke HR = 0.78 (95% CI 0.69, 0.89) P=0.0002 Proportion of patients experiencing major cardiovascular event 0 0.05 0.10 0.15 Atorvastatin 10 mg Atorvastatin 80 mg 0123456 Time (years) Relative risk reduction = 22% HR 0.78 (95%CI 0.69, 0.89) p=0.0002 Atorvastatin 10mg Atorvastatin 80mg Relative risk reduction 22%

20. Statin Therapy in Secondary Prevention Trials Event Rates Against LDL-C New Insights from TNT Statin trials show highly significant reductions in CHD events and stroke. The lower the LDL the better. Despite these dramatic effects there remains a significant residual risk. TNT has demonstrated that more intensive LDL lowering results in increased benefit La Rosa et al NEJM March 2005        Events (%) LDL cholesterol (mg/dl)

21. Meta-Analysis Cardiovascular Outcomes Intensive vs Moderate Statin Therapy Population: 27,548 patients with stable CVD in TNT and IDEAL or acute coronary syndrome, PROVE-IT- TIMI-22, and A-to-Z 27,548 patients with stable CVD in TNT and IDEAL or acute coronary syndrome, PROVE-IT- TIMI-22, and A-to-ZResults: 16% odds reduction in coronary death or myocardial infarction, p<0.0001. 16% odds reduction in coronary death or myocardial infarction, p<0.0001. No difference in total or non-cardiovascular mortality. No difference in total or non-cardiovascular mortality. Cannon et al J Am Coll Cardiol, 2006; 48: 438-445 INTENSIVE MODERATE PROVE IT-TIMI 22 A-TO-Z TNT IDEAL Total Odds Ratio (95% CI) OR, 0.84 95% CI, 0.77-0.91 p=0.00003.6611.34

22. Implications of Recent Trials Adult Treatment Panel III Guidelines Implications of Recent Trials Adult Treatment Panel III Guidelines High Risk CVD: High Risk CVD: Initiate statin therapy regardless of Initiate statin therapy regardless of baseline LDL-C; baseline LDL-C; LDL goal <70mg/dl (1.8mmol/L) LDL goal <70mg/dl (1.8mmol/L) Circulation 2004;110 227

23. Statins and Stroke Reduction A Meta-Analysis Amarenco et al. Stroke. 2004;35:2902-2909. ASCOT-LLA ALLHAT-LLT PROSPER HPS GREACE MIRACL GISSI LIPID AFCAPS/TexCAPS Post-CABG CARE WOSCOPS 4S SMALL TRIALS OVERALL (95% confidence interval)0.79 (0.73-0.85) Odds Ratios (95% CI) Trials 0.20.40.60.81.01.21.4 Across 26 trials, statins reduced stroke by 21% (P<.0001), with no evidence of heterogeneity between trials Statin betterControl better

24. Heart Protection Study Stroke Outcomes HPS Collaborative Group. Lancet. 2004;363:757-767. HPS Collaborative Group. Lancet. 2004;363:757-767. *P<.05. * SimvastatinPlacebo 10.4 4.8 3.2 10.3 0 2 4 6 8 10 12 Prior cerebrovascular disease n=3280 No prior cerebrovascular disease n=17,256 Incidence of stroke (%) 169 275 170 415

25. SPARCL: Does Robust Lipid Lowering Reduce the Occurrence of Stroke in Patients without CHD? Patient population Stroke/TIA 1-6 months prior Stroke/TIA 1-6 months prior LDL 100-190 mg/dL LDL 100-190 mg/dL (2.6-4.9 mmol/L) (2.6-4.9 mmol/L) Exclusions: Exclusions: Age <18 years Age <18 years Hx of CAD Hx of CAD Endarterectomy in prior month Endarterectomy in prior month Subarachnoid hemorrhage Subarachnoid hemorrhage 4200 patients Primary endpoint: Primary endpoint: Time to first fatal Time to first fatal or non fatal stroke or non fatal stroke 5 years Welch KMA, et al. 26th International Stroke Conference; February 14-16, 2001, Ft Lauderdale, Fl, USA. Double-blind placebo Atorvastatin 80 mg

26. High-Dose Atorvastatin after Stroke or Transient Ischaemic Attack The SPARCL Trial Population: 4731 patients with stroke or TIA one to six months before study entry. LDL-C 2.6-4.9mmol/l and no known CHD 4731 patients with stroke or TIA one to six months before study entry. LDL-C 2.6-4.9mmol/l and no known CHDDesign: Randomised, double-blind, placebo- controlled trial comparing atorvastatin 80mg/day to placebo. Median follow-up 4.9years. Randomised, double-blind, placebo- controlled trial comparing atorvastatin 80mg/day to placebo. Median follow-up 4.9years. Primary endpoint: Time to first nonfatal or fatal stroke Time to first nonfatal or fatal strokeResults: 11.2% patients (265) on drug and 13.1% (311) on placebo had an event HR, 0.84 (95%CI 0.71-0.99) p=0.03. 5 year absolute risk reduction 2.2% 11.2% patients (265) on drug and 13.1% (311) on placebo had an event HR, 0.84 (95%CI 0.71-0.99) p=0.03. 5 year absolute risk reduction 2.2% Years % Patients SPARCL Investigators NEJM 2006; 355: 549-559