1. 04/16 CARD-1063303-0004 Date of preparation May 2014 LDL-Cholesterol – Lower is Better Reducing CHD in high risk patients

2. 04/16 CARD-1063303-0004 Date of preparation May 2014 Contents 1.Contents Slide 2.Presentation summary 3.Title slide: LDL-Cholesterol – Lower is Better: Reducing CHD in high risk patients 4.OPTIONAL SLIDE #1: Cardiovascular disease and cholesterol: Key facts 5.Identifying ‘higher risk’ patients 6.Why treat high risk patients? 7.The impact of lowering LDL-C: Lower is better – however you achieve it 8.Beneficial CV risk reduction with lowering LDL-C – however you achieve it 9.OPTIONAL SLIDE #2: What does NICE advise for high risk patients? 10.What are your options? 11.Title slide: Treatment options: What the trials say 12.OPTIONAL SLIDE #3: Trial overview 13.Lowering LDL-C: Treatment options 14.ALTERNATIVE VERSION TO SLIDE #12: Lowering LDL-C: Treatment options 15.Treating high risk patients: What are your choices? 16.NICE recommendations for treatment with ezetimibe 17.OPTIONAL SLIDE #4: Safety data for ezetimibe 18.What NICE says... Patients with Type 2 diabetes 19.What NICE says... Patients with Familial Hypercholesterolaemia 20.In summary: Treating higher risk patients 21.OPTIONAL SLIDE #5 Additional Slides

3. 04/16 CARD-1063303-0004 Date of preparation May 2014 Presentation summary 1.Cholesterol and CVD, leading cause of death and high cost 2.Reducing LDL-C levels significantly reduces the risk of CHD 3.Treatment strategies for the cohort of high risk patients 4.Review evidence, clinical trials, clinical practice and NICE Guidance to manage this difficult group of patients

4. 04/16 CARD-1063303-0004 Date of preparation May 2014 Cardiovascular disease and cholesterol: Key facts CVD is the leading cause of death in England and Wales 1 The annual cost of managing CVD exceeds £30 billion 2 Over 80% of premature CVD is avoidable 2,3 Reducing CVD risk by 1% over 10 years would prevent 25,000 new cases of CVD 4 Reducing total cholesterol levels by 5% would save the NHS £80 million per annum 4 LDL-C is a key modifiable CVD risk factor 1 NICE targets for secondary prevention of CVD (high risk patients): TC < 4 mmol/L or LDL-C < 2 mmol/L 1 More than 50% of patients will not achieve their target lipid levels on statin therapy alone 1 1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. British Heart Foundation. Modelling the UK burden of cardiovascular disease to 2020. September 2008. Available at: http://www.bhf.org.uk/plugins/PublicationsSearchResults/DownloadFile.aspx?docid=ad18e5a0-7da6-4c7c-8142-f68f27cde451 [Accessed on 21 January 2014], 3. WHO. Cardiovascular diseases. Available at: http://www.euro.who.int/en/what-we-do/health-topics/noncommunicable-diseases/cardiovascular-diseases/facts-and-figures [Accessed on 21 January 2014], 4. Barton P et al. BMJ 2011 Jul 28; 343:d4044.

5. 04/16 CARD-1063303-0004 Date of preparation: May 2014 Identifying ‘higher risk’ patients Who are the higher risk patients? There is a population of patients who are difficult to treat and at increased risk of CVD: – Patients with Type 2 diabetes and established CVD who need to achieve a total cholesterol or an LDL-C of < 4mmol/L and < 2mmol/L, respectively 2,3 – Those with familial hypercholesterolaemia requiring > 50% reduction in LDL-C 4 1. Trusler D. BMJ 2011; 343: d4350, 2. NICE Clinical Guideline 67. May 2008. Reissued March 2010, Reproduced with permission 3. NICE Clinical Guideline 87. May 2009. Reproduced with permission 4. NICE Clinical Guideline 71 August 2008. Reproduced with permission.

6. 04/16 CARD-1063303-0004 Date of preparation: May 2014 Why treat high risk patients? Patients with T2DM die from complications of their disease > 70% of patients with T2DM die from cardiovascular causes 1 Patients at high risk of cardiovascular disease have the most to gain from risk factor modification 2 Intensive LDL-C reduction results in significant reductions in cardiovascular morbidity and mortality 3 A 1 mmol/L reduction in LDL-C results in a 22% reduction in the risk of major vascular events 4 The opportunity to improve cardiovascular outcomes by treating atherogenic dyslipidaemia in diabetes (or diabetic patients) should not be missed 3 1. Laakso M. Diabetes Care 2010; 33(2): 442–449, 2. SIGN97. Feb 2007 Available at: http://www.sign.ac.uk/pdf/sign97.pdf [Accessed on 22 January 2014], 3. Nesto RW. Clinical Diabetes 2008; 26(1): 8–13, 4. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681.

7. 04/16 CARD-1063303-0004 Date of preparation: May 2014 The impact of lowering LDL-C: Lower is better – however you achieve it For every 1 mmol/L reduction in LDL-C there is a 22% reduction in the risk of major vascular events at 1 year 1 There is a proportional relationship between lowering LDL-C and reducing 5-year non-fatal MI and CHD death risk – irrespective of how LDL-C is lowered 2 1 mmol/L 22% 1. Cholesterol Treatment Trialists’ (CTT) Collaboration. The Lancet 2010; 376(9753): 1670–1681, 2. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.

8. 04/16 CARD-1063303-0004 Date of preparation: May 2014 POSCH 4S WOSCOPS CARE LIPID AF/TexCAPS 100 80 60 40 20 0 -20 152025304035 LDL-C reduction (%) Nonfatal myocardial infarction and CHD death Estimated relative risk reduction (%) Oslo MRC Los Angeles Upjohn LRC NHLBI HPS ALERT PROSPER ASCOT-LLA CARDS The London and Sydney trials are not shown, but were included in the analysis Relative risk reduction 95% probability interval Slope=1 Adapted from Robinson JG et al. J Am Coll Cardiol 2005;46(10):1855–1862 Meta-analysis of data from 19 trials with 81,859 participants 1 Beneficial CV risk reduction with lowering LDL-C – however you achieve it Data from 5 diet, 3 bile acid sequestrant and 10 statin trials Data from 1 surgery trial 1. Robinson JG et al. J Am Coll Cardiol 2005; 46(10): 1855–1862.

9. 04/16 CARD-1063303-0004 Date of preparation: May 2014 What guidance is available for lowering cholesterol? – Diabetes NICE CG87 1, FH NICE CG71 2, Lipids NICE CG67 3 Which of these guidelines relate to high risk patients? – Diabetes NICE CG87 Initiate simvastatin 40 mg, increasing to 80 mg* unless TC < 4mmol/L or LDL-C < 2mmol/L Consider intensifying therapy with statin or ezetimibe if existing or new CVD or increased albumin excretion rate – FH NICE CG71 High intensity statin to achieve a recommended LDL-C reduction of 50% from baseline. Ezetimibe co-administered with a statin (if) target lipid levels are not controlled after dose titration of initial statin, or because titration is limited by intolerance to initial statin What does NICE advise for high risk patients? NICE Recommended Levels: LDL-C: 2.0 mmol/L or TC: 4.0 mmol/L *MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.” 4 1. NICE Clinical Guideline 87. May 2009. Reproduced with permission. 2. NICE Clinical Guideline 71. August 2008 Reproduced with permission. 3. NICE Clinical Guideline 67. May 2008. Reissued March 2010. Reproduced with permission. 4. MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014]. Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated

10. 04/16 CARD-1063303-0004 Date of preparation May 2014 What are your options? Lifestyle Statin Fibrate Resin, fish oil, nicotinic acid* Cholesterol absorption inhibitor *No longer available as a modified release medicine in the EU. Instant release available as a supplement in health shops.

11. 04/16 CARD-1063303-0004 Date of preparation May 2014 Treatment options What the trials say

12. 04/16 CARD-1063303-0004 Date of preparation: May 2014 *MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.” 4 Therapy5 mg10 mg20 mg40 mg80 mg Rosuvastatin 38-45% in LDL-C. 1,2 43-52% in LDL-C. 1,2,3 48-55% in LDL-C. 1,2,3 53-63% in LDL-C. 1,2,3 Atorvastatin 37% in LDL-C. 1,3 43% in LDL-C. 1,3 48-49% in LDL-C. 1,3 51-55% in LDL-C. 1,3 Simvastatin 27-30% in LDL-C. 1,3,4 32-38% in LDL-C. 1,3,4 37-41% in LDL-C. 1,3,4 42-47% in LDL-C. 1,3,4 Pravastatin 20 % in LDL-C. 1,3 23-24 % in LDL-C. 1,3,5 29-34% in LDL-C. 1,3,6 Statin + ezetimibe 31% in LDL-C eze 10 + atorva 20 mg vs. 11% in LDL-C atorva 40 mg. 7 27% in LDL-C eze 10 + atorva 40 mg vs. 11% in LDL-C atorva 80 mg. 8 46% in LDL-C eze 10 + simva 10 mg vs. 35% in LDL-C simva 20 mg. 9 51% in LDL-C eze 10 + simva 20 mg vs. 42% in LDL-C simva 40 mg. 9 55% in LDL-C eze 10 + simva 40 mg vs. 46% in LDL-C simva 80 mg*. 9 61% in LDL-C eze 10 + simva 80 mg* vs. 46% in LDL-C simva 80 mg*. 9 Statin + Anion exchange resin 42% in LDL-C colesevelam 3.8 mg + simva 10 mg vs. 26% in LDL-C simva 10 mg vs. 16% in LDL-C colesevelam 3.8 mg. 10 42% in LDL-C colesevelam 2.3 mg + simva 20 mg vs. 34% in LDL-C simva 20 mg vs. 8% in LDL-C colesevelam 2.3 g. 10 1. Law MR et al. BMJ 2003; 326(7404); 1423–1427, 2. Crestor Summary of Product Characteristics, 3. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 4. Zocor Summary of Product Characteristics, 5. Lipostat Summary of Product Characteristics, 6. Shepherd J et al. The Lancet 2002; 360(9346): 1623–1630, 7. Conard SE et al. Am J Cardiol 2008; 102: 1489–1494, 8. Leiter LA et al. Am J Cardiol 2008; 102(11): 1495–1501, 9. Goldberg AC et al. Mayo Clin Proc. 2004; 79: 620–629, 10.Knapp HH et al. Am J Med 2001; 110(5): 352–360. All reductions are from baseline as specified in the relevant studies. LDL-C lowering efficacy of lipid lowering therapies

13. 04/16 CARD-1063303-0004 Date of preparation May 2014 Treatment option % LDL-C reduction from treated baseline Doubling statin Switching statin Adding ezetimibe Lowering LDL-C: Treatment options 6% 1,2 8% 1 23.2% 1 1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.

14. 04/16 CARD-1063303-0004 Date of preparation May 2014 Lowering LDL-C: Treatment options Treatment option 5 0 -5 -10 -15 -20 -25 Treated baseline % LDL-C reduction from baseline Graphical version of previous slide Doubling statin Switching statin Adding ezetimibe % LDL-C reduction from treated baseline 6% 1,2 8% 1 23.2% 1 1. NICE Technology Appraisal Guidance 132, November 2007, 2. Knopp RH. N Engl J Med 1999; 341: 498–511.

15. 04/16 CARD-1063303-0004 Date of preparation: May 2014 *MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.” 4 Risk factorsNICE-recommended treatment Type 2 diabetes (T2DM) 1,2 Initiate patient on simvastatin 40 mg T2DM, 1–3 months after initiation, if on assessment LDL-C > 2 mmol/L or total cholesterol > 4 mmol/L, or other CVD risk factors develop 2 Intensify statin therapy to simvastatin 80 mg* T2DM: If there is existing CVD, increased albumin excretion or inadequate lipid level control 2 Intensify statin therapy; or consider statin + ezetimibe Secondary prevention of CVD 1 Initiate simvastatin 40 mg (or a lower dose if potential drug interactions or 40 mg is contraindicated) Secondary prevention CVD if lipid levels are LDL-C > 2 mmol/L or total cholesterol > 4 mmol/L 1 Intensify statin therapy to simvastatin 80 mg* (or switch to drug of similar efficacy) if lipid targets not met Acute Coronary Syndrome (ACS) 1 Treat with higher intensity statin Familial Hypercholesterolaemia 3 Combined statin + ezetimibe Ezetimibe monotherapy if patient cannot tolerate statins Treating high-risk patients: What are your choices? 1. NICE Clinical Guideline 67. May 2008. Reissued March 2010, 2. NICE Clinical Guideline 87. May 2009, 3. NICE Clinical Guideline 71. August 2008, 4.MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2013]. Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated

16. 04/16 CARD-1063303-0004 Date of preparation: May 2014 Ezetimibe is recommended, as an option, in combination with a statin, when: – Serum total or LDL-C concentration is not appropriately controlled either after appropriate dose titration of initial statin or because dose titration is limited by intolerance to the initial statin therapy – You are considering switching from the initial statin therapy Ezetimibe monotherapy is recommended, as an option, in adults with primary hypercholesterolaemia – who are intolerant to statins, or who are contraindicated for statin therapy NICE recommendations for treatment with ezetimibe 1 “The Committee agreed that there is sufficient evidence to link reductions in LDL cholesterol concentrations induced by treatment with ezetimibe with future reductions in cardiovascular events.”* 1 1. NICE Technology Appraisal Guidance 132. November 2007. Reproduced with permission. *Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated

17. 04/16 CARD-1063303-0004 Date of preparation: May 2014 Safety data for ezetimibe 1 AEs in clinical studies of up to 112 weeks duration Ezetimibe monotherapy (n=2,396) vs. placebo (n=1,159) Ezetimibe co- administered with a statin (n=11,308) vs. statin alone (n=9,361) Common (≥ 1/100 to < 1/10) Abdominal pain, diarrhoea, flatulence, fatigue ALT and/or AST increased, headache, myalgia Uncommon (≥ 1/1,000 to < 1/100) ALT and/or AST increased, blood CPK increased, GGT increased, liver function test abnormal, cough, dyspepsia, gastro- oesophageal reflux disease, nausea, arthralgia, muscle spasms, neck pain, decreased appetite, hot flush, hypertension, chest pain, pain Paraesthesia, dry mouth, gastritis, pruritus, rash, urticaria, back pain, muscular weakness, pain in extremity, asthenia, oedema peripheral ALT, alanine aminotransferase; AST, aspartate aminotransferase; CPK, creatine phosphokinase; GGT, gamma-glutamyltransferase Importantly, evidence from 13 randomised, blinded clinical trials in which ezetimibe and simvastatin were administered in combination either as separate or combined tablets (n=4,558) suggests that ezetimibe does not enhance nor aggravate the known muscle effects of simvastatin when compared to simvastatin monotherapy (n=2,563). 2 1. Ezetrol 10 mg Tablets Summary of Product Characteristics, 2. Davidson MH et al. Am J Cardiol 2006; 97(2): 223–228.

18. 04/16 CARD-1063303-0004 Date of preparation: May 2014 What NICE says… Patients with Type 2 Diabetes “Consider intensifying cholesterol-lowering therapy (with a more effective statin or ezetimibe in line with NICE guidance) if there is existing or newly diagnosed cardiovascular disease, or if there is an increased albumin excretion rate, to achieve a total cholesterol level below 4.0 mmol/litre (and HDL cholesterol not exceeding 1.4 mmol/litre) or an LDL cholesterol level below 2.0 mmol/litre.” National Institute for Health and Care Excellence. Type 2 Diabetes. Clinical Guideline 87 July 2011. London:NICE. Available from http://guidance.nice.org.uk/CG87. Reproduced with permission

19. 04/16 CARD-1063303-0004 Date of preparation: May 2014 What NICE says…Patients with Familial Hypercholesterolaemia “Ezetimibe, co-administered with initial statin therapy, is recommended as an option for the treatment of adults with heterozygous-familial hypercholesterolaemia who have been initiated on statin therapy when: Serum total or LDL-C concentration is not appropriately controlled either after appropriate dose titration of initial statin therapy or because dose titration is limited by intolerance to the initial statin therapy; and Consideration is being given to changing from initial statin therapy to an alternative statin.” National Institute for Health and Care Excellence. FH. Clinical Guideline 71 August 2008. London: NICE. Available from http://guidance.nice.org.uk/CG71. Reproduced with permission

20. 04/16 CARD-1063303-0004 Date of preparation: May 2014 In summary: Treating higher risk patients In secondary prevention patients NICE recommends to consider increasing the statin to simvastatin 80mg, or a drug of similar efficacy and acquisition cost, if TC <4mmol/L or LDL-C<2mmol/L is not attained 1 The evidence indicates that a greater reduction in baseline LDL-C can be achieved by adding ezetimibe to a statin, than by increasing the statin dose, 2 or by switching from simvastatin to atorvastatin 3 In patients with CVD, NICE recommends intensified treatment for hypercholesterolaemia. 1 In these patients, ezetimibe added to a statin can help more patients achieve NICE-recommended lipid management levels Reduction in LDL-C, irrespective of how it is achieved, reduces the risk of CVD. 4 NICE have accepted there is sufficient evidence to link LDL-C reduction via ezetimibe use with a reduction in future CV events* 5 1. NICE Clinical Guideline 67. May 2008. Reissued March 2010. Reproduced with permission. 2. Conard SE et al. Am J Cardiol 2008; 102(11): 1489–1494, 3. McCormack T et al. Int J Clin Prac 2010; 64(8): 1052–1061, 4. Robinson JG, et al. J Am Coll Cardiol 2005; 46(10): 1855–1862, 5. NICE Technology Appraisal Guidance 132, November 2007. Reproduced with permission. *Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated

21. 04/16 CARD-1063303-0004 Date of preparation May 2014 Additional Slides

22. 04/16 CARD-1063303-0004 Date of preparation May 2014 Leiter LA et al. Efficacy and safety of ezetimibe added on to atorvastatin (40 mg) compared with up-titration of atorvastatin (to 80 mg) in hypercholesterolemic patients at high risk of coronary heart disease. Am J Cardiol 2008; 102 (11): 1495–1501.

23. 04/16 CARD-1063303-0004 Date of preparation May 2014 Efficacy of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg Randomised, multi-centre, double-blind study Criteria – hypercholesterolaemia and high risk of CHD LDL-C ≥1.8mmol/L and ≤4.1mmol/L Run-in – atorvastatin 40mg for at least 4 weeks Treatment – up-titration to atorvastatin 80mg or addition of ezetimibe 10mg to atorvastatin 40mg for 6 weeks Leiter LA et al. Efficacy and Safety of Ezetimibe Added on to Atorvastatin (40mg) Compared with Uptitration of Atorvastatin (to 80mg) in Hypercholesterolemic Patients at High Risk of Coronary Heart Disease Am J Cardiol 2008; 102: 1495–1501.

24. 04/16 CARD-1063303-0004 Date of preparation May 2014 Efficacy of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg 0 -5 -10 -15 -20 -25 -30 Baseline % change in LDL-C from treated baseline at week 6 Baseline LDL-C 2.3mmol/L p<0.001 for treatment difference between arms -11% -27% Atorvastatin 80mg (n=279) Atorvastatin/ezetimibe 40/10mg (n=277) Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501. Note: A beneficial effect of EZETROL on cardiovascular morbidity and mortality has not yet been demonstrated

25. 04/16 CARD-1063303-0004 Date of preparation May 2014 Tolerability of adding ezetimibe to atorvastatin 40mg vs. up-titrating to atorvastatin 80mg Tolerability profiles of both treatments generally similar and consistent with previous studies of similar duration Serious adverse event incidence low – None considered drug-related No myopathy or rhabdomyolysis No significant differences in pre-specified AEs between groups Leiter LA et al. Am J Cardiol 2008; 102: 1495–1501.

26. 04/16 CARD-1063303-0004 Date of preparation May 2014 Jones PH et al. STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin and pravastatin across doses. Am J cardiol 2003; 93: 152–160.

27. 04/16 CARD-1063303-0004 Date of preparation May 2014 Comparison of the efficacy and safety of rosuvastatin vs. atorvastatin, simvastatin and pravastatin across doses (STELLAR trial) 1 Randomised, multi-centre, parallel group, open-label (n = 2431) Patient criteria – hypercholesterolaemia i.e. LDL-C between  4.10 and < 6.42 mmol/l (  160 and < 250 mg/dl) Treatment duration – 6 weeks Randomised treatments: – rosuvastatin 10, 20, 40 or 80 mg* – atorvastatin 10, 20, 40 or 80 mg – simvastatin 10, 20, 40 or 80 mg† – pravastatin 10, 20, or 40 mg 1. Jones PH et al. Am J Cardiol 2003; 93: 152–160, 2. MHRA. Drug Safety Update. May 2010. Available at: http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 [Accessed on 21 January 2014]. * Rosuvastatin 80 mg is not licensed † MHRA (May 2010) reported increased risk of myopathy with high-dose (80 mg) simvastatin and advised: “Consider only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks.” 2

28. 04/16 CARD-1063303-0004 Date of preparation May 2014 Pooled-dose analyses: rosuvastatin reduced mean LDL-C at 6 weeks more than atorvastatin, simvastatin and pravastatin 0 -5 -10 -15 -20 -25 -30 Baseline Increased mean % reductions in LDL-C from baseline at Week 6 with rosuvastatin vs. comparator statins p <0.001 (for all 3 comparisons) -8.2% -12 to -18% Reduction compared with atorvastatin 10–80 mg Reduction compared with simvastatin 10 to 80 mg -26% Reduction compared with pravastatin 10 to 40 mg Adapted from Jones PH et al. Am J Cardiol 2003; 93: 152–160

29. 04/16 CARD-1063303-0004 Date of preparation May 2014 Safety: rosuvastatin vs. atorvastatin, simvastatin and pravastatin Drug tolerability was similar across treatments Percentage of patients reporting AEs ranged from 40 – 56% across treatments; most mild to moderate in intensity and dose-related Most common AEs: pain (6%), pharyngitis (5%), myalgia (4%), headache (4%) 29 serious adverse events reported 2 patients died (1 received simvastatin 10 mg, 1 atorvastatin 40 mg); both deaths due to CV disease – unrelated to treatment Jones PH et al. Am J Cardiol 2003; 93: 152–160