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【medical-news】依替米贝:能否增强我们对降脂的治
N Engl J Med 2008;358:1507–8.
The Ezetimibe and Simvastatin in Hypercholesterolaemia Enhances Atherosclerosis Regression (ENHANCE) trial was a prospective double-blind, active-comparator, multicentre study which assessed whether the daily administration of ezetimibe 10 mg in combination with 80 mg of simvastatin could reduce the progression of atherosclerosis in patients with familial hypercholesterolaemia (FH) as assessed by measurement of arterial intima-media thickness (a commonly used risk surrogate for vascular disease) using B-mode ultrasonography. Patients with FH have a greatly increased risk of premature coronary artery disease and an increased rate of intima-media thickness which starts in childhood.
Men and women aged 30–75 years were eligible to participate if FH had been diagnosed either by genetic testing or if they met the diagnostic criteria outlined by the World Health Organisation. Enrolment was independent of previous lipid treatment. Untreated levels of low-density lipoprotein (LDL) cholesterol had to be 210 mg/dl (5.43 mmol/l). Patients receiving lipid-lowering treatment who had an LDL cholesterol level <210 mg/dl were able to undergo randomisation if after the initial run-through period their LDL level was >210 mg/dl. The study consisted of three periods: a screening phase, a single-blind run-in period of 6 weeks and a double-blind study period of 24 months. The primary outcome measure was the change in mean carotid artery intima-media thickness. Seven hundred and twenty patients underwent randomisation—357 were assigned to combination therapy (simvastatin + ezetimibe), 363 were assigned to simvastatin + placebo.
The primary outcome, the mean (SE) change in the carotid artery intima-media thickness was 0.0058 (0.0037) mm in the simvastatin group and 0.0111 (0.0038) mm in the combination therapy group (p = 0.29). Secondary outcomes did not differ significantly between the two groups (these consisted of other variables relating to intima-media thickness of the carotid and femoral arteries). At the end of the study period the mean (SD) LDL cholesterol was 192.7 (60.3) mg/dl (4.98 (1.56) mmol/l) in the simvastatin group and 141.3 (52.6) mg/dl (3.65 (1.36) mmol/l) in the combined therapy group (a between-group difference of 16.5%, p<0.01). The differences between the two groups in reduction in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined therapy group (p<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups.
The results of this trial are contrary to our current understanding of lipid metabolism—why did patients with a lower LDL cholesterol level show no evidence of improvement in carotid intima-media thickness? Although the rate of change in carotid intima-media thickness has previously been used to demonstrate the efficacy of lipid-lowering drugs, pretreatment with statins in the patient group studied meant that the baseline carotid intima-media thickness level here was lower than in previous clinical trials. As a result, demonstration of any net benefit from the drug would have been harder to show. On the other hand, the benefits of lowering LDL cholesterol may not depend solely on "how low you go" but also on "how you get there"; ezetimibe does not share the pleiotropic effects of statins.
The key question now is whether ezetimibe either in addition to statin treatment or as monotherapy can provide any clinical benefit. The results of other trials which are currently underway will hopefully answer this and shed further light on the ability of surrogate imaging markers to predict future clinical outcomes. [标签:content1][标签:content2]
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作者:admin@医学,生命科学 2011-08-13 17:14
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