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Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
by Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH,Lancet.
Article Abstract:
BACKGROUND: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld.
How do we know that reducing cholesterol levels in the blood is beneficial
By: Anonymous - Wed 2/14/2007 AMAfter 7 years of follow up the results showed that those who took cholestyramine had a reduced risk of cardiovascular disease.
In 1987 the Helsinki Heart Study was published in the New England Journal of Medicine (NEJM Nov. 12, 1987). This study demonstated the cardiovascular benefit of prescribing Gemfibrosil for patients with elevated non-HDL cholesterol levels. Over 4000 men between 40 and 55 years of age were studied. The study group received Gemfibrosil 600mg twice daily and the control group received placebo. Those who took Gemfibrosil showed a significant reduction in cardiovascular events from the second year of therapy onwards.
In 1995 the results of the West of Scotland Coronary Prevention Study (WOSCOPS) was published in the New England Journal of Medicine (Vol. 333). This was a large primary prevention study involving over 6500 men, between the ages of 45 and 64, who had elevated LDL cholesterol levels. Some of them had pre-existing vascular disease or hypertension while others did not. None of them had suffered from myocardial infarction or stroke. The study group was given Pravastatin 40 mg daily while the control group received placebo. After five years of follow-up the results showed that those who took Pravastatin had a significantly reduced cardiovascular risk.
The Scandinavian Simvastatin Survival Study, or the 4S study, published in the Lancet in 1994 (Vol. 344), showed us that correcting lipid abnormalities with simvastatin produced a significant reduction in cardiovascular events in those with established coronary heart disease (previous myocardial infarction or angina). In this study 4444 patients (most of them males) with elevated total cholesterol levels were studied. Half of them received simavastatin - 20mg or 40mg per day - in order to bring their total cholesterol levels to below 5.2mmol/L.
The 4S study lasted five years. At the end of it, all the 4444 patients enrolled in the study were followed up for a further period of five years. During this follow-up period, most of the patients were on simvastatin 20mg per day. At the end of 10 years, it was seen that the original simvastatin group (2222 patients) continued to enjoy a lower cardiovascular mortality than the original placebo group. It was also seen that there was no increased incidence of cancer or cancer-related deaths because of simvastatin. These follow-up results were published in the Lancet, August 28, 2004.
The 4S study described above showed that recurrent coronary events were fewer in those who took simastatin. The question was then asked: Does statin therapy reduced mortality as well? To answer this question, the Long term Intervention with Pravastain in Ischemic Disease (LIPID) study was done. This study, published in the New England Journal of Medicine, November 5, 1998 treated over 9000 patients who had suffered a coronary event with either Pravastatin 40mg per day or placebo. The study found that deaths from coronary heart disease occurred significantly less often in those treated with Pravastatin.
In an extended follow up of the LIPID study, researchers found that the long term use of Pravastatin did not have any significant adverse effects and that continuing Pravastatin for 8 years was useful in lowering mortality from cardiovascular diseases. This follow up study was published in the Lancet, April 20, 2002.
The Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), published in the Lancet (November 23, 2002), studied whether people above the age of 70 years benefited from reduction of cholesterol. Here, about 5800 patients (most of them women) between 70 and 82 years of age, with either pre-existing vascular disease or at increased cardiovascular risk, were randomised to receive either Pravastatin 40mg daily or placebo. The patients were followed up for three years. The results showed that Pravastatin reduced the risk of coronary events (but not of stroke).
The Heart Protection Study (HPS) published in the Lancet, July 6, 2002, showed evidence that reducing cholesterol in patients with diabetes, strokes and peripheral vascular disease was as beneficial as in those with coronary artery disease. In this study over 20000 people between 40 and 80 years of age from the United Kingdom were randomly allocated to either 40mg per day of simvastatin or placebo. The study also found that people at increased risk for cardiovascular disease benefited from simvastatin even if their cholesterol levels were within the normal range to begin with. Patients more than 70 years of age also benefited from simvastatin.
A study called the Anglo Scandanavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA) looked at the value of reducing cholesterol in patients who had hypertension and other cardiovascular risk factors. Over 19000 such patients were randomised to receive either Atorvastatin 10mg daily or placebo. This study, published in the Lancet, April 5, 2003 showed a significant benefit with Atorvastatin within a year of starting treatment.
The Collaborative Atorvastatin Diabetes Study (CARDS) published in the Lancet, August 21, 2004, looked at the value of lowering cholesterol in diabetic patients without a prior history of cardiovascular disease. About 2800 patients from England and Ireland with type 2 diabetes and an additional risk factor like retinopathy, proteinuria, hypertension or smoking were randomised to receive either 10mg of Atorvastatin per day or placebo. The results showed a very significant benefit of Atorvastatin in reducing the risk of myocardial infarction and stroke in these patients even if their initial cholesterol levels were not high.