Simvastatin with or without Ezetimibe in Familial Hypercholesterolemia Did Not Result In A Difference I In Intima–Media Thickness

A reduction in levels of low-density lipoprotein (LDL) cholesterol constitutes one of the cornerstones in the prevention of cardiovascular disease. In recent trials comparing various statins or the same statin at various doses, aggressive therapy to lower LDL cholesterol levels was associated with a reduction in rates of cardiovascular events.1,2,3,4 However, administration of the highest approved statin dose offers only limited additional lowering of LDL cholesterol at the expense of an increased incidence of side effects.5 Therefore, novel compounds that further reduce LDL cholesterol levels when added to statin therapy are of interest. A recently introduced compound, ezetimibe, selectively inhibits cholesterol absorption by binding to the Niemann–Pick C1-like 1 (NPC1L1) protein. The latter is located at the brush-border membrane of the enterocyte, where it contributes substantially to the intestinal uptake and cellular transport of cholesterols and noncholesterol sterols.6,7 Combined therapy with ezetimibe and a statin provides an incremental reduction in LDL cholesterol levels of 12 to 19%.8,9

In this study, we sought to determine whether the daily administration of 10 mg of ezetimibe in combination with 80 mg of simvastatin could reduce the progression of atherosclerosis in patients with familial hypercholesterolemia, as assessed by measurement of arterial intima–media thickness. The rationale for studying patients with familial hypercholesterolemia is that such patients have a greatly increased risk of premature coronary artery disease10 and an increased rate of progression of intima–media thickness starting in childhood.11 In our study, called the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial, we used B-mode ultrasonographic imaging of the intima–media thickness in the carotid and femoral arteries as a surrogate measure to assess the progression of atherosclerosis

The results of our study showed that the addition of ezetimibe to the highest recommended dose of simvastatin did not reduce the intima–media thickness of the carotid-artery wall in this cohort of patients with familial hypercholesterolemia, despite significant incremental reductions in levels of both LDL cholesterol and C-reactive protein. The primary outcome, the change in the mean intima–media thickness, did not differ significantly between the two study groups, nor did the secondary outcome measures.

There are at least three possible explanations for the absence of an incremental reduction in the intima–media thickness in patients receiving ezetimibe: the lack of vascular benefit conferred by ezetimibe despite the observed reduction in LDL cholesterol level, the inability of the measurement technique to accurately reflect changes in atherosclerotic burden, and the possibility that the study population had too low a risk, which would limit our ability to detect a differential response to the two interventions.

The first explanation to consider is that the lowering of LDL cholesterol levels by a drug other than a statin might be ineffective for slowing atherosclerosis. Thus, the fact that ezetimibe-induced lowering of LDL cholesterol levels was not associated with an incremental effect on carotid-artery intima–media thickness could be due to the different mechanisms of action of ezetimibe, as compared with those of statins. In addition to the capacity of statins to lower LDL cholesterol levels, the inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase also leads to a plethora of lipid-independent effects involving antiinflammatory action and improvement in endothelial function.15 A direct comparison between ezetimibe and statins revealed differential effects on endothelial function favoring statin therapy despite similar reductions in LDL cholesterol,16,17 although this finding has not been consistent in all studies.18 Also, dose intensification of statins in patients with familial hypercholesterolemia resulted in a further reduction in the progression of intima–media thickness in the carotid artery.19 Thus, it can be argued that certain lipid-independent effects of statins that are not shared by ezetimibe are involved in the production of a vascular benefit.

However, several facts argue against the concept that ezetimibe-induced lowering of LDL cholesterol levels does not produce additional vascular benefit beyond that of statins. First, a recent regression meta-analysis showed that the lipid-independent effects of statins did not confer an additional risk reduction beyond that expected from the degree of the lowering of the LDL cholesterol level.20 Second, data from the Program on Surgical Control of the Hyperlipidemias (POSCH) trial showed that reductions in levels of LDL cholesterol after ileocecal bypass were associated with significant reductions in cardiovascular mortality and event rates similar to those observed in statin-prevention trials.21,22 In view of the controversy regarding the lipid-independent effects of statins, the results of ongoing clinical trials comparing statins with combined therapy with ezetimibe and a statin are eagerly awaited to resolve this issue.

Large epidemiologic studies have provided strong associations between intima–media thickness and stroke, angina pectoris, and myocardial infarction.10,11 In the Atherosclerosis Risk in Communities (ARIC) study involving 15,800 adults, an increase of 0.2 mm in the mean carotid-artery intima–media thickness was associated with an increase in relative risk for myocardial infarction and stroke of 33% and 28%, respectively.23 This close relationship between intima–media thickness and cardiovascular risk has subsequently been corroborated in several other studies.24

One of the principal determinants of atherosclerosis progression has proved to be LDL cholesterol levels, as confirmed by the linear relationship between the level of LDL cholesterol and intima–media thickness.25 This finding is further supported by the observation that progression in intima–media thickness is significantly attenuated in statin intervention studies in both adult and pediatric patients with familial hypercholesterolemia.11,19,26,27,28,29,30,31,32 On the basis of this information, the measurement of intima–media thickness can be considered as a validated surrogate marker for atherosclerotic vascular disease. Also, in view of the precision of the measurements in our study, as exemplified by the high intraclass correlation coefficient and the small standard deviations, it seems unlikely that we were unable to detect a truly significant change in arterial-wall measures using our measurement technique.

Patients with familial hypercholesterolemia are known to be at greatly increased risk for premature coronary artery disease,10 accompanied by accelerated progression of intima–media thickness starting in childhood.11 However, the treatment of patients with familial hypercholesterolemia has witnessed profound changes. Currently, the majority of patients with familial hypercholesterolemia are treated with high-dose statins starting at an early age. Such therapy can be expected to attenuate the progression of intima–media thickness, as was shown in the Atorvastatin versus Simvastatin on Atherosclerosis Progression (ASAP) study.19 Thus, it is not unexpected that the baseline carotid intima–media thickness in our study was lower than that observed in earlier trials involving patients with familial hypercholesterolemia33 and in most other previous lipid-modifying trials,26,27,31 with the exception of the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 1 (ARBITER-1) study.31 Among patients who received 80 mg of simvastatin only in our study, the progression of intima–media thickness was 0.0029 mm per year, as compared with 0.018 mm per year in patients with familial hypercholesterolemia who received 40 mg of simvastatin in the ASAP study — a reduction by a factor of 6 among patients receiving the higher dose. In further support of the influence of previous statin therapy, progression of intima–media thickness in the carotid artery decreased to 0.005 mm per year during long-term daily therapy with 80 mg of atorvastatin in the ASAP extension study,34 a finding that contrasts with the substantial reductions in intima–media thickness seen during the first 2 years of the trial. In the Rating Atherosclerotic Disease Change by Imaging with a New CETP [Cholesteryl Ester Transfer Protein] Inhibitor (RADIANCE 1) study,35 the most recent study involving a similar group of patients with familial hypercholesterolemia, the pattern of change in intima–media thickness after a mean daily dose of 57 mg of atorvastatin was very similar to that observed in both groups in our study. These data raise the possibility that there may be limits to the extent to which the lowering of LDL cholesterol levels can result in a further decrease in the progression of intima–media thickness in the context of previous statin therapy and a modest baseline intima–media thickness.

In conclusion, the reduction of LDL cholesterol by the addition of ezetimibe to simvastatin did not reduce intima–media thickness of the carotid-artery wall in patients with familial hypercholesterolemia in our study. The reason for the failure to observe an incremental effect on intima–media thickness despite a reduction in levels of LDL cholesterol remains unknown.

Supported by Merck and Schering-Plough.