March 2004

Shire Health International

Crestor achieves results in tackling elevated LDL-C in patients with metabolic syndrome

New data confirm CRESTOR meets one of the key challenges of this silent epidemic

London, UK, Monday 8 March 2004. New data show CRESTORTM (rosuvastatin) has a more favourable effect on atherogenic dyslipidaemia in patients with elevated LDL-C and the metabolic syndrome, than other currently available statins.1 Today results from the STELLAR study were presented to delegates at the 53rd Annual Scientific Session of the American College of Cardiology (ACC) in New Orleans, USA, showing CRESTOR favourably reduces patients' LDL-cholesterol (LDL-C or 'bad' cholesterol) and non-HDL-C (a measure of all the atherogenic or 'bad' lipid particles) compared with other statins.1

People with the metabolic syndrome are nearly twice as likely to die from cardiovascular disease and their risk of heart attack and stroke is threefold.2 Affecting approximately one in five men, and nearly one in four women,3 this silent epidemic is predicted to increase greatly over the coming years due to a rise in obesity and an ageing population. 4 For these patients, the management of raised LDL-C levels remains a primary target of treatment, as highlighted in both the US NCEP ATP III guidelines5 and the recently revised European Guidelines on Cardiovascular Disease Prevention in Clinical Practice.6

These new CRESTOR data come from a sub-group analysis of 811 patients in the STELLAR study7 who had elevated LDL-C and three or more of the five risk factors associated with the metabolic syndrome. The results indicate that CRESTOR shows a favourable improvement in reducing LDL-C and atherogenic lipids when compared with other statins:
  • CRESTOR 10-40mg reduced LDL-C by 44-55% versus 37-50% with atorvastatin 10-80mg, 28-47% with simvastatin 10-80mg and 20-29% with pravastatin 10-40mg (ns)
  • CRESTOR 10-40mg reduced all the atherogenic lipids, as assessed by non-HDL-C, by 40-52% versus 34-46% with atorvastatin 10-80mg, 26-42% with simvastatin 10-80mg and 19-27% with pravastatin 10-40mg (ns)


Clinicians at the ACC welcomed the news that CRESTOR has a more favourable effect on atherogenic dyslipidaemia than other statins. Commenting on the data, lead investigator for this sub-group analysis of STELLAR, Dr Prakash Deedwania of the University of California, San Francisco, said, 'The increasing prevalence of the metabolic syndrome means that clinicians are having to meet new management challenges, and while it is important to focus on therapeutic lifestyle changes, we need a treatment that effectively targets the atherogenic dyslipidaemia seen in patients with this syndrome. These results are encouraging as they show that with CRESTOR, we have a treatment that is highly effective at helping to correct the underlying lipid abnormalities associated with the metabolic syndrome.'

Further results from this study show:
  • CRESTOR 10mg, the recommended start dose, reduced non-HDL-C by 40% compared to atorvastatin 10mg (34%, ns), simvastatin 10mg (26%, p<0.002) and pravastatin 10mg, 20mg and 40mg (19%, 21% and 27% respectively, p<0.002)
  • CRESTOR 20mg was significantly more effective (p<0.002) at reducing non-HDL-C (48%) than atorvastatin 20mg (38%), simvastatin 20mg and 40mg (35% and 36%) and pravastatin 20mg and 40mg (21% and 27%)
  • CRESTOR 40mg reduced non-HDL-C by 52% compared to 46% with both atorvastatin 40mg and 80mg (ns) and this was significantly more effective (p<0.002) than simvastatin 40mg and 80mg (36% and 42%) and pravastatin 40mg (27%)
  • CRESTOR 10-40mg reduced triglycerides by 22-34% versus 23-33% with atorvastatin 10-80mg, 15-23% with simvastatin 10-80mg and 12-15% with pravastatin 10-40mg (ns)


Professor Gunnar Olsson, Vice President and Head of the Cardiovascular Therapy Area at AstraZeneca said: 'These results add to the wealth of existing data on CRESTOR showing that CRESTOR is a highly effective treatment at lowering LDL-C in addition to its 10mg start dose efficacy, HDL-C raising benefits and ability to get patients to achieve treatment guideline goals. Whilst patients with the metabolic syndrome are burdened by several cardiovascular risk factors, a priority for physicians is to reduce their elevated LDL-C and CRESTOR has shown additional value in this area."

Previous results from MERCURY I demonstrate that in 1,342 patients with elevated LDL-C and the metabolic syndrome, CRESTOR 10mg was significantly more effective than atorvastatin 10mg, simvastatin 20mg and pravastatin 40mg at lowering patients' LDL-C levels (46.7% vs. 36.5%, 35.1% and 29.9% respectively, p<0.0001) and enabled significantly more patients to reach their European and US NCEP ATP III LDL-C goals. Additionally, CRESTOR 10mg lowered triglycerides by 23.4% and raised HDL-C by 9.4%, both important risk factors in patients with the metabolic syndrome.8

AstraZeneca is also exploring the benefits of CRESTOR in patients with elevated LDL-C and the metabolic syndrome in a prospectively designed study called COMETS.9 COMETS is investigating the effects of CRESTOR, compared to atorvastatin or placebo, on lipids and other risk factors associated with the metabolic syndrome.

STELLAR, MERCURY I and COMETS are part of AstraZeneca's extensive GALAXY Programme� investigating the effects of CRESTOR on cardiovascular risk reduction and patient outcomes.

CRESTOR has now received regulatory approvals in more than 45 countries across five continents and has been launched in over 35 countries worldwide, including 13 European markets, the US and Canada. Over one million patients have been treated with CRESTOR. The post marketing experience supports the favourable benefit:risk profile of CRESTOR and confirms that the safety profile is comparable to other currently marketed statins. CRESTOR 10mg is the usual recommended start dose for both patients new to statin treatment and those switching to CRESTOR from other statins.

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the top five pharmaceutical companies in the world with healthcare sales of over $18.8 billion and leading positions in sales of gastrointestinal, oncology, cardiovascular, neuroscience and respiratory products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global and European) as well as the FTSE4Good Index. AstraZeneca has more than 40 years experience in cardiovascular medicine and aims to increase lifespan and improve quality of life by reducing the risk, prevalence and impact of cardiovascular disease. AstraZeneca has a comprehensive cardiovascular portfolio including CRESTOR�, Atacand�, ZESTRIL�, TENORMIN�, SELOKEN� ZOK /TOPROL-XL� and Plendil�. This heritage is complemented by an innovative pipeline including the first oral direct thrombin inhibitor, ExantaTM, and a novel treatment for type 2 diabetes / metabolic syndrome, GALIDA�



For further information please visit: www.AstraZenecaPressOffice.com or contact:

Julia Walker, Global PR Manager, Cardiovascular Therapy Area, AstraZeneca
Tel: 44-162-551-0866
Mobile: 44-771-880-1984
Email: [email protected]
or
Ellie Goss, Shire Health International
Tel: 44-207-471-1519
Mobile : 44-774-780-3217
Email: [email protected]

Notes to editors:
The CRESTOR GALAXY Programme
The GALAXY Programme is a large, comprehensive, long-term, and evolving global research initiative sponsored by AstraZeneca to investigate cardiovascular risk reduction and patient outcomes with CRESTOR. Please refer to the GALAXY media backgrounders for more information on the GALAXY Programme and each of the individual GALAXY Programme studies.

The Metabolic Syndrome
The term 'the metabolic syndrome' is used to describe a number of risk factors that are clustered together in some people. This clustering of risk factors is associated with an increased risk of heart attack, stroke, type 2 diabetes and death.2-4 Currently there is no globally accepted definition of the metabolic syndrome. The World Health Organisation (WHO) and the US National Cholesterol Education Programme's Adult Treatment Panel III (NCEP ATP III) have both defined the metabolic syndrome. The NCEP ATP III guidelines state that patients with three or more of the following risk factors are clinically identified as having the metabolic syndrome:5 Risk Factor Defining Level Abdominal obesity Men (Women) Waist circumference: >102cm (>40 inches) >88cm (>35 inches) Triglycerides >150mg/dL (170mmol/L) HDL-cholesterol Men (Women) <40mg/dL (0.9mmol/L)<50mg/dL (1.3mmol/L) Blood pressure >130/>85mmHg Fasting glucose �110mg/dL (6.11mmol/L)




Alone, each risk factor conveys increased cardiovascular disease risk, but in combination they enhance the patient's risk.10 Presence of the metabolic syndrome significantly increases the risk of heart attack, type 2 diabetes and death.2,4

Non-HDL-C
Non-HDL-C is calculated routinely as the amount of total cholesterol (TC) minus the amount of HDL-C. Therefore, non-HDL-C is important as it refers to all the atherogenic lipoproteins fractions.11 High levels of these are an important factor in the development of atherosclerosis.

Cardiovascular Disease
The term cardiovascular disease (CVD) refers to a wide range of disorders affecting the heart and blood vessels. CVD can be sub-divided into the following diseases:
  • coronary heart disease (CHD) (e.g. heart attacks and angina)
  • cerebrovascular disease (e.g. strokes and transient ischaemic attacks)
  • peripheral vascular disease (e.g intermittent claudication)

    CVD is estimated to account for approximately a third of all deaths globally and is the leading cause of mortality in Europe and the US. Over 16.7 million deaths each year are due to CVD (more than 45,000 deaths every day, and almost 32 deaths each minute).12 In Europe, about half of all deaths from CVD are from CHD and nearly one-third are from stroke.13

    For more information please refer to the media backgrounders, 'The metabolic syndrome', 'STELLAR study', 'GALAXY Programme' and 'GALAXY Programme studies', which can be found on: www.AstraZenecaPressOffice.com

    Additional data at ACC
    AstraZeneca will be presenting important new data for EXANTA and ATACAND during the ACC 2004:
  • EXANTA SPORTIF III and V Studies, Monday 8 March, 16.00 - 17.30, Oral Presentation, MCC Convention Center, Room 265: B Olsson, Efficacy and Safety of Ximelagatran Compared with Well-Controlled Warfarin in Elderly Patients with Nonvalvular Atrial Fibrillation: Observations from the SPORTIF Trials. J Halperin, Efficacy and Safety of Ximelagatran Compared with Well-Controlled Warfarin in Women and Men with Nonvalvular Atrial Fibrillation in the SPORTIF Trials: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
  • ATACAND CHARM Study, Monday 8 March, Morning Session, Poster Session, MCC Convention Center: Scott Solomon et al., Cause of Death Across Full Spectrum of Ventricular Function in Patients with Heart Failure: The CHARM Study: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
  • Monday 8 March, 11.00 - 12.15, Oral Presentation, Session Number 810, MCC Convention Center: Salim Yusuf et al., Impact of the Angiotensin-Receptor Blocker Candesartan in Preventing Diabetes in Patients With Heart Failure: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
  • Monday 8 March, 15.00 - 17.00, Poster Session, Session Number 1108, MCC Convention Center: John McMurray et al., Low Hemoglobin is an Independent Predictor of Adverse Fatal and Non Fatal outcomes in Both Reduced and Preserved Systolic Function Chronic Heart Failure: findings from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity Programme (CHARM): 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
  • Tuesday 9 March, 08.30 - 10.00, Oral Presentation, Session Number 835, MCC Convention Center: John McMurray et al., Candesartan Improves Functional Class Across a Broad Spectrum of Patients With Chronic Heart Failure: Results of the Candesartan in Heart Failure- Assessment of Reduction in Mortality and Morbidity Programme (CHARM): 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.
  • Tuesday 9 March, 12.00 - 14.00, Poster Session, Session Number 1145, MCC Convention Center: Karl Swedberg et al., Prevention of AF in Symptomatic Chronic Heart Failure by Candesartan - Results From CHARM: 53rd Annual Scientific Session of the American College of Cardiology, New Orleans, USA, March 2004.

    New CRESTOR data at the European Atherosclerosis Society Congress
    New CRESTOR data looking at its effect on patients with type 2 diabetes will be presented at the European Atherosclerosis Society Congress in Seville, from 17-20 April 2004. For more information about AstraZeneca media activities at this congress please contact: Ellie Goss on 44-207-471-1519 or email [email protected].

    References:

    1. Deedwania P & Hunninghake D. Comparative Effects of Statins on Atherogenic Dyslipidemia in Patients With the Metabolic Syndrome. 53rd American College of Cardiology (ACC) Congress in New Orleans, USA, March 2004

    2. Isomaa B, et al. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 2001;24:683-9

    3. Ford ES, et al. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. Journal of the American Medical Association 2002;287:356-9

    4. Meigs JB. Epidemiology of the metabolic syndrome. American Journal of Managed Care 2002;8:S282-92

    5. 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;285:2486-2497. Also available on-line: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3_rpt.htm

    6. de Backer G, Ambrosioni E, Borch-Johnsen K et al. European guidelines on cardiovascular disease prevention in clinical practice. European Heart Journal 2003;24:1601-10

    7. Jones P, Davidson M, Stein E et al. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses. American Journal of Cardiology 2003;92:152-160

    8. Stender S, Schuster H, Barter P et al. Comparing the Effects of Statins on Cholesterol Goal Achievement and Plasma Lipids in Hypercholesterolaemic Patients with and those without the Metabolic Syndrome: Results from the MERCURY I Trial. Diabetes Metab 2003;29 (Suppl):4S138 Abstract 1833

    9. Stalenhoef AFH, Ballantyne CM, Sarti C et al. A COmparative study with rosuvastatin in subjects with METabolic Syndrome: rationale and design of the COMETS study. Diabetes Metab 2003;29(Suppl):4S318 Abstract 2559

    10. Kaplan NM. The deadly quartet: upper body adiposity, glucose intolerance, hypertrigylceridaemia and hypertension. Archives of Internal Medicine 1989;149:1514-20

    11. Cui Y, et al. Non-high-density lipoprotein cholesterol level predictor of cardiovascular disease mortality. Archives of Internal Medicine 2001;161:1413-9

    12. World Health Report 2003. World Health Organization. http://www.who.int.

    13. European Cardiovascular Disease Statistics, 2000 Edition, British Heart Foundation. http://www.bhf.org.uk


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