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• W2069700293 abstract "The benefits of cholesterol-lowering therapy in patients with a prior history of a vascular event or diabetes are well established, but there is still considerable uncertainty about when to commence treatment and about the intensity of treatment in people with no prior history of vascular disease or diabetes [1]. Recognition that levels of blood pressure [2] and LDL cholesterol, irrespective of age [3, 4], are each continuously related to cardiovascular disease prompted a shift in preventive strategies to treatment of people at ‘high-risk’ rather than of people at high levels of individual cardiovascular risk factors. The Prospective Studies Collaboration (PSC) meta-analysis of 61 prospective studies, involving 55 000 vascular deaths amongst 900 000 adults with no previous vascular disease, demonstrated that higher total cholesterol levels were associated with higher risks of coronary heart disease (CHD), with no lower threshold below which there is not a lower risk of CHD throughout the main range of cholesterol studied in developed countries [4].The associations were log-linear, which implies that greater absolute reductions in LDL cholesterol levels should be associated with greater proportional reductions in risk of coronary heart disease. These observations are also important because they imply that strategies to lower cholesterol levels should be effective irrespective of the starting LDL cholesterol level. The meta-analysis of the observational studies indicated that 1 mmol L−1 (38.7 mg dL−1) lower level of total cholesterol was associated with a lower risk of CHD mortality of one-half, one-third and one-sixth in both sexes, respectively, at ages 40–49, 50–69 and 70–89 years [4]. The Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis of 14 randomized trials of statin therapy involving 90 000 participants, demonstrated that the benefits of statin therapy were proportional to the differences in LDL cholesterol achieved in the individual trials [5]. The mean LDL cholesterol differences at 1 year were 1.09 mmol L−1 (42.2 mg dL−1) and ranged from 0.35 mmol L−1 (13.5 mg dL−1) to 1.77 mmol L (68.5 mg dL−1). There was an approximately linear relationship between the absolute reduction in LDL cholesterol level achieved in the individual trials and the proportional reduction in the incidence of coronary heart disease and other major vascular events. The reduction in risk of vascular events was observed within 1 year of starting statin therapy, but was smaller in the first year compared with that observed in the subsequent years. During the first year, the risk of a major coronary event was reduced by about 14% per mmol L−1 lower LDL cholesterol, whilst it was 20–30% per mmol L−1 lower LDL in every subsequent year thereafter [5]. Similarly, the risk of major vascular events was reduced by about 10% per mmol L−1 lower LDL cholesterol during the first year, whilst in every subsequent year, it was reduced by 25%. This meta-analysis predicted that a reduction in LDL cholesterol of 1.5 mmol L−1 (58 mg dL−1) lower LDL cholesterol would be expected to reduce the incidence of major vascular events by about one-third [5]. Statin therapy is remarkably well tolerated and the adverse effects, such as myopathy or rhabdomylosis are rare at standard doses [6]. The introduction of more potent statins, such as rosuvastatin, and the use of combinations of statins with ezetimibe achieve greater reductions in LDL cholesterol levels than those achieved by standard doses of statins [7]. The METEOR trial, recently published in the Journal of Internal Medicine, demonstrated the speed with which the effects of intensive lipid-lowering therapy are achieved using rosuvastatin. The trial assessed carotid intimal thickness (CIMT) using B-mode ultrasound in 984 asymptomatic individuals with a 10-year risk of CHD of <10% [8]. All participants in the METEOR trial had some evidence of carotid artery atherosclerosis. Importantly, participants had moderately elevated pretreatment levels of LDL cholesterol between 3.1 and 4.9 mmol L−1 (120 and190 mg dL−1) and only participants who had not used lipid-lowering therapy within the previous 12 months were included [8, 9]. The ultrasound measurements of the carotid arteries were made every 6 months for up to 2 years using a state of the art methodology [8, 9]. A daily dose of 40 mg of rosuvastatin was associated with a substantial absolute reduction of LDL cholesterol of 1.99 mmol L−1 (77.0 mg dL−1), which is twice the mean difference in LDL cholesterol achieved in all the previous statin trials included in the first cycle of the CTT meta-analysis. Moreover, the METEOR trial demonstrated that this 1.99 mmol L−1 (77.0 mg dL−1) difference in plasma levels of LDL cholesterol was associated with a significant difference in the rates of CIMT progression at 12 months (0.0032 mm year−1 vs. 0.133 mm year−1, P = 0.049) and these differences were even more extreme at 18 (P < 0.001) and 24 months (P < 0.001) respectively. Further support for the effectiveness of more intensive lipid-lowering therapy in patients with no prior vascular disease with rosuvastatin therapy was provided by the JUPITER trial [10]. About 18 000 patients with an LDL cholesterol level <3.4 mmol L−1 (130 mg dL−1) and a C-reactive protein level of 2 mg L−1 or higher were randomized to rosuvastatin or placebo. In the JUPITER trial, a daily dose of 20 mg of rosuvastatin (which was half the dose of rosuvastatin used in the METEOR trial) was associated with a mean difference in LDL cholesterol levels of 1.2 mmol L−1 (47 mg dL−1) at 12 months between the treatment groups. The trial was stopped prematurely (possibly exaggerating its effect) after 1.9 years when this difference in LDL cholesterol was associated with a 44% reduction in the primary end-point of nonfatal or fatal cardiovascular events and arterial revascularization events. Thus, both the METEOR and the JUPITER trials demonstrated the effectiveness of intensive lipid-lowering therapy in patients with no prior history of vascular disease and moderately elevated levels of LDL cholesterol. The results of both trials of rosuvastatin therapy illustrate the potential benefits for risk of cardiovascular disease of greater absolute reductions in LDL cholesterol levels and these effects were observed within 1 year of starting treatment in both trials. The METEOR trial also indicated that CIMT can be used to assess the effectiveness of therapy administered for 12 months, given an appropriate sample size, high precision of measurements and a large treatment effect. The METEOR trial was well designed and its success may be attributed to the use of a potent statin, the accuracy of CIMT measurements in addition to the types of patient included. The unexpected null results of the ENHANCE trial that also used CIMT as an end-point caused a controversy about the role of CIMT as a valid end-point to assess cardiovascular risk [11, 12]. The ENHANCE trial compared the effects of daily therapy with 80 mg simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia treated for a 2-year period. Combined treatment with simvastatin and ezetimibe resulted in a 1.33 mmol L−1 (51.4 mg dL−1) difference in LDL cholesterol levels in this setting. However, this difference in LDL cholesterol did not result in any significant difference in CIMT after 2 years of treatment in the 720 participants. The null results of the ENHANCE trial prompted some experts to question the value of using CIMT in further trials to address such questions [12]. However, the METEOR trial [8, 9] differed from the ENHANCE [10] trial in several important respects: (i) METEOR involved a larger number of participants (984 vs. 720); (ii) METEOR achieved a greater difference in LDL cholesterol (1.99 vs. 1.33 mmol L−1; 77.0 vs. 51.4 mg dL−1); (iii) participants in METEOR had more extensive disease in their carotid arteries than ENHANCE (CIMT eligibility criteria of between 1.20–3.50 mm vs. mean of 0.695 mm in ENHANCE); (iv) participants in METEOR did not use lipid-lowering therapy for 12 months prior to enrolment, whereas all participants in ENHANCE were enrolled regardless of their previous treatment with lipid-lowering therapy. One of the main requirements for reliability for trials is size. A large number of participants at sufficient risk of events is required to have adequate statistical power to reliably assess the effects of treatments associated with moderate benefits. Both METEOR and JUPITER trials demonstrate the value of achieving large absolute reductions in LDL cholesterol levels. The METEOR trial illustrates elegantly what can be achieved by using CIMT to assess the effects of novel lipid-lowering therapy provided that the trials are carefully designed to take account of the experience of previous trials in this field. Importantly, the use of CIMT in such trials can also help select which agents should be tested in large-scale trials using vascular disease end-points. Both authors declare that they have no conflict of interest. RC and JA are supported by grants from the British Heart Foundation and the Medical Research Council of the United Kingdom." @default.
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• W2069700293 title "Greater absolute reductions in LDL cholesterol should yield greater proportional reductions in risk of cardiovascular disease" @default.
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