The overwhelming case for LDL-C lowering Prof Kausik Ray, BSc (hons), MBChB, FRCP, MD, MPhil (Cantab), FACC, FESC Professor of Cardiovascular Disease Prevention St Georges University of London Honorary Consultant Cardiologist St Georges Hospital

Years Since Randomization 4S Primary Endpoint: Total Mortality 1.00 Simvastatin 0.95 30% Risk Reduction (P=0.0003) 0.90 Placebo Proportion Alive 0.85 0.80 0.00 1 2 3 4 5 6 Years Since Randomization Scandinavian Simvastatin Survival Study Group. Lancet. 1994 ;344:1383-1389.

Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22. HPS: Effects of Simvastatin on First Major Vascular Event According to Baseline LDL-C Risk ratio and 95% CI STATIN PLACEBO (n=10269) (n=10267) LDL-C (mg/dL) < 116 598/3389 756/3404 484/2549 646/2514 116 - 139 139 951/4331 1183/4349 24% reduction p<0.0001 ALL PATIENTS 2033 2585 (19.8%) (25.2%) 0.4 0.6 0.8 1.0 1.2 1.4 STATIN better STATIN worse Heart Protection Study Collaborative Group. Lancet 2002; 360:7-22.

ASCOT-LLA: Primary Prevention in HTN Nonfatal MI and Fatal CHD Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 4 Baseline LDL 132 mg/dl 3.0% 36% reduction 3 Cumulative Incidence (%) 2 1.9% LLA: Primary Endpoint: Nonfatal MI and Fatal CHD The primary endpoint of non-fatal myocardial infarction, including silent myocardial infarction, and fatal CHD was significantly lower by 36% (hazard ratio 0·64 [95% CI 0·50–0·83], p=0·0005) in the atorvastatin group than in the placebo group 1 HR = 0.64 (0.50-0.83) p=0.0005 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 Years Sever PS et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58.

CARDS-Cumulative Hazard for Primary Endpoint Relative Risk -37% (95% CI: -52, -17) 15 P=0.001 Placebo 127 events 10 Cumulative Hazard (%) Atorvastatin 10mg 83 events 5 1 2 3 4 4.75 Years Placebo 1410 1351 1306 1022 651 305 Atorva 1428 1392 1361 1074 694 328

CTT Collaboration Effects on Major Coronary Events per mmol/L LDL Cholesterol Reduction Subdivided by Baseline Lipid Values Groups (mmol/L) Events (%) RR & CI Heterogeneity/trend p-value Treatment Control (Treatment : Control) Total cholesterol: ≤5.2 748 (6·9) 940 (8·6) 5.2-6.5 1678 (7·0) 2246 (9·4) p = 0·7 >6.5 896 (8·8) 1220 (12·1) LDL cholesterol: ≤3.5 1130 (6·8) 1443 (8·7) 3.5-4.5 1374 (7·3) 1814 (9·6) p = 0·5 >4.5 801 (9·3) 1120 (12·9) HDL cholesterol: ≤0.9 1167 (9·3) 1538 (12·1) 0.9-1.1 939 (7·4) 1270 (10·2) p = 0·8 >1.1 1207 (6·2) 1595 (8·1) Triglycerides: ≤1.4 1162 (7·3) 1521 (9·6) 1.4-2.0 937 (7·1) 1304 (9·8) p = 0·6 >2.0 1217 (7·9) 1564 (10·2) 0·77 (0·74 – 0·80) Overall 3337 (7·4) 4420 (9·8) p < 0·00001 0·5 1·0 1·5 Treatment Control better better CTT Collaborators. Lancet. 2005; 366:1267-78

Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials 50% 40% 30% 20% 10% 0% -10% Major Vascular Events Proportional Reduction in Event Rate (SE) Relation between proportional reduction in incidence of major coronary events and major vascular events and mean absolute LDL cholesterol reduction at 1 year Square represents a single trial plotted against mean absolute LDL cholesterol reduction at 1 year, with vertical lines above and below corresponding to one SE of unweighted event rate reduction. Trials are plotted in order of magnitude of difference in LDL cholesterol difference at 1 year (webtable 1). For each outcome, regression line (which is forced to pass through the origin) represents weighted event rate reduction per mmol/L LDL cholesterol reduction. 0.5 1.0 1.5 2.0 Reduction in LDL Cholesterol (mmol/L) Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

Only high dose statins have been tested immediately after ACS 16 ACS 4S CARE LIPID/ HPS/IDEAL 12 Death/ Nonfatal MI (%) 8 PROVE IT-TIMI 22/ A to Z/ IDEAL 4 Stable CAD 2 4 6 4 5 6 Months Of Follow-Up Years

All-Cause Death or Major CV Events in All Randomized Subjects 30 Pravastatin 40mg (26.3%) 25 20 % with Event Atorvastatin 80mg (22.4%) 15 10 16% RR (P = 0.005) 5 3 18 21 24 27 30 6 9 12 15 Months of Follow-up Cannon CP, et al. NEJM 2004;350:1495-504.

Is there benefit from an LDL of 2 mmol/L vs 2.6mmol/L in stable CAD? IDEAL TNT -13% RRR 15 16 Atorvastatin 10 mg Simvastatin 20/40 Atorvastatin 80 mg Atorvastatin 80 -22% RRR 12 10 Major CV Event* (%) MCVE Cumulative Hazard (%) 8 5 4 HR = 0.78, P<.001 HR = 0.87, P=.02 0 1 2 3 4 5 6 Time (years) 1 2 3 4 5 Years Since Randomization *CHD death, nonfatal non-procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke. LaRosa JC, et al. NEJM. 2005; 352:1425-1435 Pedersen TR, et al. JAMA. 2005; 294:2437-2445

Cholesterol Trialist Collaboration Meta-Analysis of Dyslipidemia Trials 50% 40% 30% 20% 10% 0% -10% Major Vascular Events TNT Proportional Reduction in Event Rate (SE) IDEAL Relation between proportional reduction in incidence of major coronary events and major vascular events and mean absolute LDL cholesterol reduction at 1 year Square represents a single trial plotted against mean absolute LDL cholesterol reduction at 1 year, with vertical lines above and below corresponding to one SE of unweighted event rate reduction. Trials are plotted in order of magnitude of difference in LDL cholesterol difference at 1 year (webtable 1). For each outcome, regression line (which is forced to pass through the origin) represents weighted event rate reduction per mmol/L LDL cholesterol reduction. 0.5 1.0 1.5 2.0 Reduction in LDL Cholesterol (mmol/L) Adapted from CTT Collaborators. Lancet. 2005; 366:1267-78

Meta-Analysis of Intensive Statin Therapy LDL Cholesterol by Trial Patients n Prior Statin Use ACS Stable CAD Pooled 4162 4497 10001 8888 27548 25.2% 0% 75.5% 28.2% 160 140 120  Baseline   LDL-C (mg/dL)  .   100 Standard   Intensive   80   60 40 LDL-C PROVE IT- A-to-Z TNT IDEAL Pooled TIMI 22 Baseline* 108.4 112.9 152 121.5 129.6 (3.32) Standard* 97.1 101 104 101.4 (2.6) Intensive* 65.5 69.1 77 81 75.4 (1.93) Cannon CP, et al. JACC 2006; 48: 438 - 445.

Meta-Analysis of Intensive Statin Therapy - All Endpoints Odds Reduction Event Rates No./Total (%) High Dose Std Dose -16% 3972/13798 (28.8) 4445/13750 (32.3) 1097/13798 (8.0) 1288/13750 (9.4) -12% 462/13798 (3.3) 520/13750 (3.8) +3% 340/13798 (2.5) 331/13750 (2.4) -6% 808/13798 (5.9) 857/13750 (6.2) -18% 316/13798 (2.3) 381/13750 (2.8) Odds Ratio (95% CI) Coronary Death or Any Cardiovascular Event Coronary Death or MI Cardiovascular Death Non-Cardiovascular Death Total Mortality Stroke OR, 0.84 95% CI, 0.80-0.89 P=.0000000000006 OR, 0.84 95% CI, 0.77-0.91 p=0.00003 OR, 0.88 95% CI, 0.78-1.00 p=.054 OR, 1.03 95% CI, 0.88-1.20 p=0.73 OR, 0.94 95% CI, 0.85-1.04 P=0.20 OR 0.82 95% CI, 0.71-0.96 p=0.012 0.5 1 2.5 High-dose statin better High-dose statin worse Cannon CP, et al. JACC 2006; 48: 438 - 445.

PROVE IT-TIMI 22: Relationship Between Month 4 LDL and Long-Term Risk of Death or Major CV Event Hazard Ratio Referent >2.05 – 2.56 0.80 (0.59, 1.07) >1.54 – 2.05 > 1.03 -1.54 0.67 (0.50, 0.92) <1.03 0.61 (0.40, 0.91) 1 2 Lower Better Higher Better *Adjusted for age, gender, DM, prior MI, baseline LDL Wiviott SD, Cannon, Ray et al. JACC. 2005

TNT: Incidence of First Major Cardiovascular Events Across Quintiles P < 0.0001* P < 0.0001* % patients P < 0.05* P < 0.01* *P-value for trend across LDL-C LaRosa JC. AJC. 2007, 100, 747-52

Event rates by achieved LDL-C in trials Optimal standard Minimum audit standard ATP III JBS2 ESC GMS 2° Prevention Stable CHD 30 25 20 % with CHD event 15 1° Prevention 10 5 1.8 2.3 2.8 3.3 3.8 4.4 Mean LDL-C level at follow-up (mmol/L) Ray IJCP 2007, 61, 1608-11

PROVE IT Safety Results: Side Effects Atorvastatin 80 mg LDL (mmmol/L) p value Event* 2.07-2.59 1.55-2.07 1.04-1.55 <1.04 Myositis or Myalgia (AE) 1.6 3.1 3.2 2.8 NS CK > 3x ULN 2.3 0.7 1.9 1.0 CK > 10x ULN 0.3 Rhabdomyolysis ALT > 3X ULN 3.0 3.6 Wiviott, et al. JACC. 2005

Adverse Event Profiles Across Quintiles- TNT Number (%) of patients Quintile 1 <64 mg/dL (114/1722)* Quintile 2 64-<77 mg/dL (529/1403)* Quintile 3 77-<90 mg/dL (1019/968)* Quintile 4 90-<106 mg/dL (1515/515)* Quintile 5 ≥106 mg/dL (1718/266)* Withdrawals due to treatment-associated AEs 122 (6.6) 107 (5.5) 100 (5.0) 106 (5.2) 143 (7.2) Treatment-associated myalgia 84 (4.6) 85 (4.4) 93 (4.7) 96 (4.7) 104 (5.2) Persistent† CPK >10  ULN Persistent† ALT and/or AST >3  ULN 20 (1.1) 15 (0.8) 18 (0.9) 8 (0.4) 10 (0.5) Patients in both treatment groups were well matched for age, gender, race, cardiovascular risk factors and cardiovascular history. A little over half of the patients had a history of hypertension, and 15% were diabetic in each group. All had histories of coronary heart disease. *Number of patients: Atorvastatin 10 mg/atorvastatin 80 mg †Occurring twice within 4-10 days

CTT Lancet 2012

Statins increase risk of Dysglycaemia Sattar N, ……Ray. Lancet 2010; 375: 735-42

Statins and DYSGLYCAEMIA vs CVD Risk Preiss .... Ray. JAMA 2011;305:2556-64

Prognosis of Patients with New-Onset T2DM TNT, IDEAL and SPARCL TNT, IDEAL and SPARCL Atorvastatin 80 mg groups With new-onset T2DM Without new- onset T2DM Diabetes at baseline* Incidence of MCVE n / N (%) 157 / 1,387 (11.3%) 1,884/ 17,472 (10.8%) 832 / 4,761 (17.5%) 76 / 756 (10.1%) 867 / 8,684 (10.0%) 358 / 2,359 (15.2%) Univariate analysis** (HR=1.03, 95% CI 0.78-1.35, p=0.83) – (HR=0.90, 95% CI 0.60-1.34, p=0.59) Multivariate analysis** (HR=1.02, 95% CI 0.77-1.35, p=0.69) (HR=0.87, 95% CI 0.58-1.30, p=0.49) *Patients were excluded from the new-onset T2DM study **MCVEs in patients with and without new-onset T2DM were assessed with an extensive time-dependent Cox proportional hazard analysis Waters DD et al. JACC. 2011;

The Evidence for Clinical Benefit of Statin Therapy for the prevention of CAD ACS Pravastatin L-CAD PACT Simvastatin A to Z Atorvastatin MIRACL PROVE IT-TIMI 22 Primary Prev Pravastatin WOSCOPS PROSPER Simvastatin HPS Atorvastatin ASCOT CARDS Rosuvastatin JUPITER Lovastatin TEXCAPS/AFCAPS Secondary Prev Pravastatin CARE LIPID PROSPER Simvastatin 4S HPS SEARCH Atorvastatin AVERT TNT IDEAL

Summary LDL-C lowering offers similar proportional reductions among those with and without vascular disease The magnitude of benefit is related to the degree of LDL-C reduction LDL-C lowering is safe in general The greatest benefit are in those with the greatest absolute risk