New advances in cholesterol management Taking the Lead New advances in cholesterol management Hervey Wilcox Consultant Chemical Pathologist Epsom and St Helier NHS Trust

Rimonabant (RIO Study) Weight (kg) Waist (cm) Triglycerides (%) HDL (%) Rimonabant (RIO Study)

CHD RISK FACTORS: attributable risk fractions in UK ~10% OTHER FACTORS: Exercise, Obesity, Diabetes, Poverty, Stress, Homocysteine, etc   Isles et al Lancet. 1992 Mar 21;339(8795):702-6.; Emberson et al Eur J Cardiovasc Prev Rehabil. 2004 Apr;11(2):125-34; Unal et al Circulation. 2004 Mar 9;109(9):1101-7 ~50% Cholesterol / Unhealthy Diet Isles et al Lancet. 1992 Mar 21;339(8795):702-6.; Emberson et al Eur J Cardiovasc Prev Rehabil. 2004 Apr;11(2):125-34; Unal et al Circulation. 2004 Mar 9;109(9):1101-7

X16 MAJOR MODIFIABLE CHD RISK FACTORS Smoking Hypertension Dyslipidaemia Three major risk factors for CHD identified by the InterHeart Study, when in isolation it can be reasonably straight forward to treat, however many people have them as a cluster and the next slide shows the multiplication of risk that is associated with a cluster of these three modifiable risk factors Poulter N, Sever P, Thom S (1993). Cardiovascular disease practical issues for prevention. St. Albans. Caroline Black.

The Framingham Study: Relationship Between Cholesterol and CHD Risk 150 125 100 CHD incidence per 1000 75 50 25 <5.3 5.3-6.1 6.1-6.8 6.8-7.6 >7.6 Serum total cholesterol, mmol/L Castelli WP. Am J Med. 1984;76:4-12

Event Rates Plotted Against LDL-C Levels (2o prevention trials) 30 25 20 15 10 5 Statin Placebo 4S TNT (80 mg of atorvastatin) TNT (10 mg of atorvastatin) 4S LIPID Event (%) LIPID CARE CARE HPS HPS No clear target – the lower the cholesterol the greater the benefit Targets and goals for total or LDL cholesterol reduction give the impression that there is a point where treated individuals realise the benefit of treatment. However all the data we have, such as this, indicates that in general the greater the cholesterol reduction achieved the greater the benefit realised in terms of reduction in cardiovascular risk. The Treatment to New Targets trial (TNT) extended the benefits of aggressive cholesterol lowering to include patients with stable coronary disease and it is clear from this trial that benefit is derived by achieving LDL levels of 2mmol/l. It remains unclear whether further benefits may be realised by even lower levels of LDLc, however this is a highly likely scenario, certainly in patients with ACS, LDLc levels of 1.6mmol/l in the PROVE-IT trial were shown to be associated with significantly favourable CV outcomes. 0.3 0.8 1.3 1.8 2.3 2.9 3.4 3.9 4.4 4.9 5.4 LDL-C (mmol/L) after LaRosa et al. NEJM 2005

Cardiovascular disease Mortality rate from CVD is disproportionate 3 times higher in unskilled workers than professionals therefore more common in deprived areas this differential has doubled in the last 20 years 40% higher for people from the Indian sub-continent than the rest of the population National Service Framework - CHD

Case Study Female 59 years old TC 7.4 mmol/l LDL 5.0 mmol/l HDL 1.2 mmol/l Trigs 2.5 mmol/l BP 158/92 mm Hg BMI 28 kg/m2 Smoker Family History: Positive family history of ischaemic heart disease and diabetes. Father died aged 70 after developing angina in his early 60s. Based on this profile, the 10 year CHD risk is 11-12%. In terms of family history, the history shown increases the risk by 50%.

Case Study Male 50 years old TC 5.5 mmol/l HDL 0.7 mmol/l Trigs 5.7 mmol/l BP 148/84 mm Hg BMI 28 kg/m2 Non-Smoker Family history of ischaemic heart disease and diabetes. Based on this profile, the 10 year CHD risk is 11-12%. In terms of family history, the history shown increases the risk by 50%.

STATINS STABILIZE PLAQUES lipid core adventitia STATIN THERAPY lipid core Many individuals who develop vascular disease do not have particularly elevated cholesterol Trials have demonstrated statin benefits on increased regression and reduced progression of atheromatous plaques Meta analysis of 14 trials has shown a 19% reduction in progression of plaques with statins. LDL Targets significantly lower to achieve favourable plaque modulation (LDL reduction >45%) adventitia

Reduce total cholesterol by 25% or LDL-C by 30% BHS 2004 Guidelines13 New guidelines published in 2004 by British Hypertension Society13 In patients with hypertension, optimal cholesterol levels: Reduce total cholesterol by 25% or LDL-C by 30% Total cholesterol of <4 mmol/l LDL-C of <2 mmol/l More recent studies – Heart Protection Study (HPS)4 and PROVE-IT11 indicate that an intensive cholesterol-lowering regimen provides maximum clinical benefit (see slide 4). Guidelines issued by the British Hypertension Society (BHS)13 in 2004 recommend lower target levels of <4 mmol/l for total cholesterol and <2 mmol/l for LDL-C, reflective of the growing evidence that lower is better. The guidelines recommend lipid-lowering therapy for all people with high blood pressure complicated by CVD, irrespective of baseline total-cholesterol or LDL-C. The guidelines recommend that treatment is guided by CVD risk (see next slide). 13. Williams B, Poulter NR, Brown MJ et al. J Human Hypertens 2004;18:139-185.

Cholesterol Targets Past, Present & Future Guideline Year published LDL-C target (mmol/l) TC target (mmol/l) Joint British Societies 1998 <3.0 <5.0 NSF for CHD 2000 <3.0 & >30% ↓ <5.0 & >25% ↓ EAS 2003 <2.5 in high risk <4.5 in high risk BHS IV 2004 <2.0 in high risk <4.0 in high risk December 2005 <2.0 >30% ↓ In high risk <4.0 >25% ↓ Guidelines JBS = Joint British Societies1 EAS = European Atherosclerosis Society (1998)2 , (1998)3 NSF for CHD = National Service Framework for Coronary Heart Disease4 BHS IV = British Hypertension Society (Part Four)5 The soon to be launched new JBS targets are likely to mirror those from BHS IV References Wood D. Joint British recommendations on the prevention of coronary heart disease in clinical practice. British Cardiac Society, British Hyperlipidaemia Association, British Hypertension Society, endorsed by the British Diabetic Association. Heart 1998; 80 (supplement 2): S1-S29 Wood D et al. Prevention of coronary heart disease in clinical practice. Recommendations of the second joint task force of European and other societies on coronary prevention. European Heart Journal 1998, 19:1434-1503. De Backer D et al. European guidelines on cardiovascular disease prevention in clinical practice. Third joint taskforce of European and other societies on cardiovascular disease prevention in clinical practice. European Heart Journal 2003, 24:1601-1610 Department of Health. National Service Framework for Coronary Heart Disease. March 2000. Visit www.doh.gov.uk/nsf/coronarynsf2.htm Williams B et al. British Hypertension Society guidelines. Guidelines for management of hypertension: report of the fourth working party of the British Hypertension Society, 2004 - BHS IV. J Human Hypertension 2004 (18): 139-185.

JBS 2: Targets in High Risk Individuals BP < 140 mm Hg systolic and < 85 mm Hg diastolic Total Cholesterol < 4.0 mmol/l (LDL Cholesterol < 2.0 mmol/l) Or a 25% reduction in TC and 30% reduction in LDL-C, whichever is greater Diabetes mellitus optimally controlled HbAIC < 6.5 % BP <130 mm/Hg systolic and < 80 mm Hg diastolic

JBS 2 CVD Risk Prediction Charts NON-DIABETIC MAN NON-DIABETIC WOMAN Figure 1: Joint British Societies’ cardiovascular disease (CVD) risk prediction chart: non-diabetic men Figure 2: Joint British Societies’ cardiovascular disease (CVD) risk prediction chart: non-diabetic women Heart: December 2005 Vol 91 Supplement V (Inside Covers) Reproduced with permission from the BMJ Publishing Group

How cholesterol links to CHD risk 1% increase in HDL-C reduces CHD risk by 2-3% 1% decrease in LDL-C reduces CHD risk by 1% Get the LDL lower and the HDL higher Maximum benefit is gained only by targeting the whole lipid profile. A wealth of RCT’s provide compelling evidence that lowering LDLc prevents CV events, the evidence for HDL raising is currently based on epidemiological data. In the USA, the NCEP Expert Panel have estimated, based on data from epidemiology studies as well as intervention studies, that each 1% decrease in LDL-C equates to a 1% reduction in CHD risk. In addition, every 1% increase in HDL-C equates to a 2-3% reduction in CHD risk. Reference 1. Third Report of the NCEP Expert Panel (2002). NIH Publication No. 02-5213. Website: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf Third Report of the NCEP Expert Panel (2002). NIH Publication No. 02-5213 http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf

LDL-C: % Change from Baseline Statin dose (mg) 10 20 40 80 –10 –20 pravastatin LDL mean % change from baseline –30 simvastatin atorvastatin –40 This is a build slide which will allow you to demonstrate the advances in LDL-C lowering efficacy that have been made with different agents. The maximum LDL-C lowering benefits are observed at the lowest dose thereafter there is a approximately 6% increase with every doubling of dose study This slide shows the percentage change from baseline in LDL-C at week 6 at each dose across respective dose ranges. STELLAR: 6 wk, open label study, n=2431, pts with hypercholesterolaemia, baseline LDL >160<250 or 4.1-6.5 mmol/l, pairwise comparisons made – largest study conducted across statin full dose ranges. Reference Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160 Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. 2. Blasetto JW, Stein EA, Brown WV et al. Am J Cardiol 2003; 91(Suppl): 3C–10C. rosuvastatin –50 –60 Adapted from Jones et al. Am J Cardiol 2003

Statin efficacy across the dose range: change in HDL-C Change in HDL-C from baseline (%) 2 4 6 8 10 12 Rosuvastatin † 9.5 ‡ 9.6 * 7.7 Atorvastatin Simvastatin Pravastatin 5.3 6.0 5.2 6.8 5.7 4.8 4.4 2.1 3.2 4.4 5.6 The HDL-C raising efficacy of rosuvastatin also compares very favourably with that of simvastatin and pravastatin. Rosuvastatin resulted in a statistically significant greater increase in HDL-C compared with atorvastatin for rosuvastatin 20-mg and 40-mg-dose comparisons (p<0.002). rosuvastatin 10 mg raised HDL-C statistically significantly more than pravastatin 10 mg (p<0.002). rosuvastatin 20 mg raised HDL-C statistically significantly more than atorvastatin 20, 40 and 80 mg, simvastatin 40 mg, and pravastatin 20, 40 mg (p<0.002). rosuvastatin 40 mg raised HDL-C statistically significantly more than atorvastatin 40 and 80 mg, simvastatin 40 mg, and pravastatin 40 mg (p<0.002). Mean baseline HDL-C for rosuvastatin group: 51 mg/dL. (1.3mmol/l) Reference 1. Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial). Am J Cardiol 2003;92:152–160 Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Dose (mg) *p<0.002 vs pravastatin 10 mg †p<0.002 vs atorvastatin 20, 40, 80 mg; simvastatin 40 mg; pravastatin 20, 40 mg ‡p<0.002 vs atorvastatin 40, 80 mg; simvastatin 40 mg; pravastatin 40 mg Observed data in ITT population Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Statin efficacy across the dose range: change in Triglycerides Rosuvastatin Atorvastatin Simvastatin Pravastatin Dose (mg) 10 20 40 10 20 40 80 10 20 40 80 10 20 40 Change in TG from baseline (%) –5 –7.7 –10 –8.2 –11.9 –15 –13.2 –14.8 –17.6 –20 –18.2 –19.8 * –20.0 –22.6 –25 –23.7 † FASTING Triglycerides Looking across the whole lipid range, this slide looks at STELLAR data for triglycerides. Dose for dose, there were no significant differences in reductions in TG levels from baseline between rosuvastatin and atorvastatin; however, rosuvastatin resulted in a statistically significant greater reduction in TG compared with simvastatin or pravastatin (p<0.002). rosuvastatin 10 mg decreased triglycerides statistically significantly more than pravastatin 10 and 20 mg (p<0.002). rosuvastatin 20 mg decreased triglycerides statistically significantly more than simvastatin 40 mg, pravastatin 20 and 40 mg (p<0.002). rosuvastatin 40 mg decreased triglycerides statistically significantly more than simvastatin 40 mg and pravastatin 40 mg (p<0.002). Mean baseline TG for rosuvastatin group: 179 mg/dL. Reference 1. Jones PH et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR Trial) Am J Cardiol 2003;92:152–160 Adapted from Am J Cardiol 2003;92:152-160 with permission from Excerpta Medica Inc. –26.1 ‡ –26.8 –30 –28.2 *p<0.002 vs pravastatin 10, 20 mg †p<0.002 vs simvastatin 40 mg; pravastatin 20, 40 mg ‡p<0.002 vs simvastatin 40 mg; pravastatin 40 mg Adapted from Jones PH et al. Am J Cardiol 2003;92:152–160

Using statins safely Get the right dose for the right patient In certain circumstances, prescribe statins with caution* e.g. Elderly patients (Age >70 years) Patients with history of muscle disorders, renal or hepatic impairment and hypothyroidism and patients of Asian orgin Combination with other drugs/ foods; Cyclosporin, erythromycin, amiodarone, fibrates, warfarin, grapefruit juice Using statins safely This slide is a mandatory inclusion in the presentation to reinforce the appropriate prescribing message. It highlights the importance of tailoring statin therapy to individual patients and should be delivered in the context of the lowest effective dose offering the most favourable benefit to risk profile. The tolerability of rosuvastatin is consistent with other available statins. Statin SmPCs have been updated to include common risk factors that predispose patients to myopathy. These include;Renal impairment,  hypothyroidism, personal or familial history of hereditary muscular disorders, previous history of muscular toxicity with a statin or fibrate, previous history of liver disease and/or where substantial quantities of alcohol are consumed, in elderly (age > 70 years). The recommended start dose for CRESTOR is 5 or 10mg. The choice should take into account the individual patient’s cholesterol level and future cardiovascular risk as well as the potential risk for adverse reactions. 5mg start dose is recommended for Asian patients and those with pre-disposing risk factors for myopathy. 10mg remains the appropriate start dose for the majority of patients. You should discuss that 20mg is the top dose for rosuvastatin in patients with risk factors for myopathy and Asian patients. Specialist supervision is recommended when titrating up to the 40mg dose, which should only be considered for the minority of patients with severe hypercholesterolaemia at high CV risk. *See individual SmPCs for details

Statin Benefit : Risk CK >10 X ULN: Frequency by % LDL-C Reduction Rosuvastatin (5- 40 mg) Atorvastatin (10 - 80 mg) 3.0 Simvastatin (40 - 80 mg) 2.5 Pravastatin (40 - 80 mg) 2.0 % CK > 10 × ULN 1.5 1.0 0.5 Shows the muscle effects – CK >10x ULN. Rise of CK linked to dose, not efficacy (RSV on right –greatest LDL reduction but not the highest rise). ALTs – same pattern The relationship between benefit and risk is a key consideration when assessing any drug. This slide shows available doses for the available statins, expressing percent LDL-C reduction vs percent of patients showing persistent CK elevation. This data taken from a publication by Brewer show that the effect of rosuvastatin on CK levels is certainly no worse than other statins up to 40 mg, and is combined with better effects on LDL-C reduction. (Rosuvastatin data are from the rosuvastatin clinical development programme and data for the other statins are from independent sources). The higher the dose the higher the risk of muscle side-effects. This slide is not specific to start doses. However it does support the point that for each statin its risk of causing myopathy increases with dose. The data for rosuvastatin is from clinical trials, whilst that for other statins is taken from US post-marking experience. Therefore they are not directly comparable and this slide should just be used to illustrate the trend within the dose range of the individual statins. All statins appear to have a dose above which the rate of muscle side-effects becomes unacceptable. For instance simvastatin has been investigated at a 160mg dose. The 80mg dose of rosuvastatin was also investigated but not marketed. Despite rosuvastatin’s superior LDL-C lowering efficacy, the percentage rise in CK to > 10 x ULN is no greater than with other currently marketed statins. 0.0 20 30 40 50 60 70 % LDL-C reduction 34 Adapted from Brewer HB. Am J Cardiol 2003;92(Suppl):23K–29K

Cholesterol metabolism16 Two main sources of plasma cholesterol Absorption of cholesterol from the intestine Production of cholesterol in the liver Two main sources of plasma cholesterol in the body exist (see next slide): Absorption of cholesterol from the intestine. Cholesterol is absorbed in the intestine from dietary sources and bile. Cholesterol is emulsified in the intestinal lumen by bile acids to form micelles, which are then absorbed into epithelial cells. After absorption, free cholesterol is esterified and is packaged, together with other lipids, into chylomicrons, which are secreted into the lymph and subsequently enter the blood16. Production of cholesterol: cholesterol is synthesised in the liver and extra-hepatic tissues. Cholesterol is secreted into the plasma either as free cholesterol or esterifed as lipoproteins (VLDL and LDL) or secreted into the bile as biliary cholesterol16. Shepherd J. Eur Heart J Supplements 2001;3:E2-E5.

Cholesterol production Liver Production 900 mg/day Cholesterol in the circulation Remnants (blood) Biliary cholesterol 1,000 mg/day Chylomicrons (lymph) 750 mg/day Dietary cholesterol 300-700 mg/day Absorption Faecal loss 750 mg/day Intestine Shepherd J. Eur Heart J Supplements 2001;3:E2-E5. Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

x x Dual Inhibition Inhibit cholesterol production using statins Liver 900 mg/day Reduced cholesterol in the circulation Remnants (blood) Biliary cholesterol 1,000 mg/day Chylomicrons (lymph) Inhibit cholesterol absorption using ezetimibe x Dual Inhibition of both cholesterol absorption and cholesterol production will lower plasma cholesterol levels more than either agent alone16. Reduce absorption from the intestine Ezetimibe is a cholesterol absorption inhibitor, which selectively inhibits the intestinal absorption from dietary and biliary sources16. Reduce cholesterol production Statins reduce the production of cholesterol by inhibiting the rate-limiting enzyme in the hepatic production of cholesterol: HMG-CoA reductase. By reducing the primary production of cholesterol, there is a homeostatic up-regulation of LDL-C receptors with a consequent reduction in circulating LDL levels16. Dietary cholesterol 300-700 mg/day Absorption Increased faecal loss Intestine Shepherd J. Eur Heart J Supplements 2001;3:E2-E5. Bays H. Expert Opin Invest Drugs 2002;11:1587-1604.

Cholesterol absorption site within small bowel brush border As discussed in the previous slide, there is a specific cholesterol uptake mechanism in the small bowel brush border. This slide illustrates the use of a fluorescent cholesterol analogue which occupies the receptor site, and shows up as a glowing point19. Uptake of a fluorescent cholesterol analogue in hamster small intestine Sparrow CP, Patel S, Baffic J et al. J Lipid Res 1999; 10:1747-1757.

Reductions of CRP with Ezetimibe/Simvastatin vs Simvastatin Alone EZE + S10 EZE + S20 EZE + S40 EZE + S80 S10 S20 S40 S80 Median Change in CRP (%) Reductions of CRP with ezetimibe/simvastatin vs simvastatin alone The study illustrated here examined the effects of ezetimibe and simvastatin combined in a single pill (Vytorin). Ezetimibe/simvastatin reduced CRP compared with the corresponding dose of simvastatin alone. Reference: Sager PT, Melani L, Lipka L, Strony J, Yang B, Suresh R, Veltri E, for the Ezetimibe Study Group. Effect of coadministration of ezetimibe and simvastatin on high-sensitivity C-reactive protein. Am J Cardiol 2003;92:1414-1418. Simvastatin (pooled n=443) Ezetimibe/simvastatin (pooled n=443) Sager PT et al. Am J Cardiol 2003;92:1414-1418.

Rationale for therapy with combination ezetimibe + statin39 20 mg 6% 40 mg 6% 80 mg 6% Three-step titration Statin 10 mg + Ezetimibe 10 mg 18% One-step co-administration Statin 10 mg The co-administration studies demonstrate that the effect of ezetimibe when added to a 10 mg dose of statin is equivalent to the 80 mg dose of the statin alone (or a three-fold dose titration)33,34. However, when using statins to lower cholesterol, the majority of the reduction in LDL-C is achieved at the starting dose38, and doubling the dose yields a relatively small additional reduction in LDL-C of approximately 6%. Therefore, a three-step doubling of the dose – i.e. increasing the dose from 10 mg to 80 mg, is required to produce an approximate 18% reduction in LDL-C. 10 20 30 40 50 60 % reduction in LDL-C Stein E. Eur Heart J Supplements 2001:3(Suppl E):E11-E16.

The Fenofibrate Intervention and Event Lowering in Diabetes

FIELD To assess whether early intervention with fenofibrate could prevent cardiovascular events in type 2 diabetics who had relatively normal lipid levels.

Study Design Randomised, double blind, placebo controlled, parallel group trial 63 centres: Australia, New Zealand, Finland 9795 middle-aged to elderly people with type 2 diabetes, considered to be at increased risk of CHD The First and Largest Study of Its Kind. The FIELD study is unique for several reasons, as outlined in this slide. Reference The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005. The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Adjustment for Statin Use Primary End Point: CHD Events Secondary End Point: Total CVD Risk Adjustment for Statin Use. After adjustment for statin use, fenofibrate was associated with a significant improvement in the primary end point (19% reduction in CHD events, P=.01). Adjustment for statin use also revealed a pronounced reduction of total CVD events. Reference The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005. P=.16 P=.01 P=.035 P=.004 Abbreviations: Adj, adjusted for statin use; Nonadj, nonadjusted risk The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Primary Prevention P=.014 P=.004 (n = 7664) (n = 7664) Effects on CHD Events and Total CVD Risk in Patients With No Prior CVD. Fenofibrate treatment had a particularly beneficial effect in patients that had no prior CVD. In this primary prevention population (78% of the total population), fenofibrate reduced the incidence of the primary end point (CHD events) by 25% (P=.014) and the incidence of total CVD events by 19% (P=.004). Reference The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005. P=.014 P=.004 (n = 7664) (n = 7664) The FIELD Study Investigators. Lancet [Early Online Publication]. November 14, 2005.

Improved Quality of Life: Reductions in Macro and Microvascular Disease Tertiary End Point Data - presented at AHA - 2005 Laser Treatment for Retinopathy* Hospitalisation for Angina Pectoris Progression of Albuminuria* Amputation These effects cannot be explained by changes in HbA1C or concomitant medications, or by the minor reduction in blood pressure in the Supralip group * FIELD Study Investigators. Lancet 2005, e-publication November 14