June 2003 - Doctors should routinely consider giving cholesterol-lowering statins to anyone with diabetes who has a substantial risk of a heart attack or a stroke, according to the authors of research published (Saturday 14 June) in The Lancet medical journal[1].
A UK multi-centre randomised trial of nearly 6,000 people with diabetes has provided the first definitive evidence that statins cut the risk of heart attacks, strokes or revascularisation operations by about a third in diabetic patients, irrespective of their cholesterol levels and whether or not they have existing arterial disease.
These results mean that guidelines for treating diabetes should be revamped, with more emphasis placed on reducing blood cholesterol levels in all people with diabetes. If the findings are acted on, around one million people with diabetes in the UK and 100 million worldwide[2] will be candidates for cholesterol-lowering treatment. This could prevent at least 10,000 heart attacks, strokes and revascularisation operations each year in the UK, and about one million worldwide.
The research, involving 69 UK hospitals, was coordinated by the Clinical Trial Service Unit of Oxford University. The 6,000 diabetic patients were among 20,000 volunteers at high risk of heart attacks and strokes who took part in the Medical Research Council/British Heart Foundation Heart Protection Study (HPS), the overall results of which were published last year (6 July) in The Lancet. The new report extends and amplifies the analyses of the large group who had diabetes.
Of the nearly 6,000 patients with known diabetes in the study, 90% had Type 2 diabetes and 10% had Type 1 diabetes[3]. About 2,000 had pre-existing coronary disease, 1,000 had other occlusive arterial disease and 3,000 had no evidence of either condition. Lowering cholesterol with 40mg daily of simvastatin (the study statin) was effective in all types of diabetic patient, and was similarly effective whatever the patient's age, sex or cholesterol level.
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Lead researcher Professor Rory Collins said: "There are estimated to be more than one million people in the UK with diabetes mellitus and about 150 million worldwide, and those figures are expected to double by 2025. People with diabetes have a higher risk of heart attacks and strokes than the general population, and most of their deaths are due to cardiovascular disease. So, these new results are extremely important, not only for the very many people who have diabetes but also for the health systems that have to cope with this increasing global problem."
Overall in the study, about 25% of patients who were allocated placebo (dummy) tablets experienced at least one major vascular event (heart attack, stroke or revascularisation procedure) during 5 years of treatment. Allocation to 40mg daily simvastatin produced an average reduction in "bad" LDL-cholesterol of 1mmol/L during the study, and reduced this rate of major vascular events by about one quarter. Diabetic patients who did not have any diagnosed occlusive arterial disease had a major vascular event rate of about 15% in the placebo group, but simvastatin still reduced this somewhat lower event rate by about one quarter .
Even among those diabetic patients whose "bad" LDL cholesterol would have been considered relatively low (below 3.0 mmol/L), there was a reduction in risk of about one quarter. The proportional risk reduction was also about a quarter among various other categories of diabetic patient � including those with different duration, type or control of diabetes, the over 65s, those with raised blood pressure and those with total cholesterol below 5.0mmol/L. In addition, among those who had a first major event after entering the study, being allocated simvastatin reduced the rate of subsequent events during the 5-year treatment period.[4]
The clinical co-ordinator of the study, Dr Jane Armitage, said: "When we make allowances for those volunteers who did not comply fully with their study treatments, daily use of 40mg simvastatin would probably reduce the rate of first vascular events by about one-third. So, five years of treatment in diabetic patients without any occlusive arterial disease would prevent around 45 out of every 1,000 people with diabetes from suffering at least one major vascular event, and would prevent about 70 first or subsequent events among these 45 individuals."
Professor Collins said that it is now imperative for diabetes treatment guidelines to be re-examined. "Our finding that lowering blood cholesterol levels with statin therapy produces substantial reductions in the risk of heart attacks and strokes in diabetic patients � together with the findings in two other studies[5] that blood pressure lowering treatment can do likewise � has important implications for avoiding the vascular complications of diabetes. In particular, these results support a renewed emphasis on controlling blood cholesterol and other vascular risk factors, in addition to controlling hyperglycaemia, among people with diabetes."
He added: "As drug patents expire on different brands of statins, these drugs are becoming much cheaper and will be affordable in many more countries around the world."[6]
Professor Sir Charles George, Medical Director at the British Heart Foundation, said: "It's very exciting that this huge study � which the BHF helped to launch � was able to focus on around 3,000 people with diabetes but no previous evidence of coronary heart disease or other diagnosed arterial disease. The finding that simvastatin was effective in all types of diabetic person has important implications for statin treatment, which must now be considered in all diabetic people with an additional risk factor for coronary heart disease."
Sir George Radda, Chief Executive of the MRC, said: "This is excellent news, another important finding from the Heart Protection Study, this time for those with diabetes. It's very timely as the recent Department of Health/MRC Review into diabetes research outlined the need to define the most appropriate and cost effective therapies in relation to cardiovascular disease in diabetics."
Simon O'Neill, Head of Care Developments, Diabetes UK, said: "This research proves that statins can offer real benefits to many people with diabetes, helping them to avoid some of the life threatening complications of diabetes - heart attack and stroke. We hope that all health care professionals will take this research into account when treating people with diabetes. Many people could benefit greatly if offered statins as an integral part of their diabetes care programme."
The Heart Protection Study was funded by the UK Medical Research Council, the British Heart Foundation,[7] Merck & Co (makers of simvastatin) and Roche Vitamins. The study was designed, conducted and analysed entirely independently of all funding sources by the Clinical Trial Service Unit.
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Notes:
- MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. The Lancet. 14 June 2003. Vol 361. No. 9374 Pp 2005-16
- King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025. Diabetes Care 1998; 21: 1414-31
- Diabetes Mellitus: a condition characterised by a raised concentration of glucose in the blood because of a deficiency in the production and/or action of insulin. Type 1 (juvenile onset diabetes) involves a severe deficiency or absence of insulin production. Type 2 (maturity onset diabetes) involves reduced insulin production and usually starts after the age of 40.
- Results in more detail available from Wednesday 11 June on web site: www.hpsinfo.org Copy of full paper available from Margaret Willson
- UK Prospective Diabetes Study Group (UKPDS). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. BMJ 1998; 317: 703�13. The Heart Outcomes Prevention Evaluation Study Investigators (HOPE). Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000:342: 145�53
- Simvastatin is now out of patent in the UK and some other European countries, although it remains under patent in the USA until 2005. Currently, 40mg daily simvastatin (Zocor) has a list price in the UK of �1.06 per day, but generic simvastatin is anticipated to cost only about 10-25 pence per day (i.e. one-tenth to one-quarter of current prices).
- More information can be obtained about MRC at www.mrc.ac.uk and about BHF at www.bhf.org.uk
Source: Clinical Trial Service Unit
