High concentrations of low-density lipoprotein (LDL) cholesterol produce changes in arterial walls that can be seen on carotid and femoral artery ultrasonography. Techniques for measuring intimal media thickness (IMT) have been standardized, and this measure has been demonstrated to be predictive of coronary artery disease. Patients with familial hypercholesterolemia have an accelerated process of arterial damage, and treatment with a statin drug such as simvastatin is recommended to lower LDL cholesterol concentrations, but compliance with therapy tends to be poor. In most hypercholesterolemic patients, simvastatin can reduce LDL cholesterol concentrations by 30 to 40 percent. A new agent, atorvastatin, can lower LDL cholesterol levels in patients with primary hyperlipidemia by over 60 percent over the 10- to 80-mg range. Smilde and colleagues designed a study to see if aggressive LDL cholesterol lowering with atorvastatin would slow atherosclerosis progression, as measured by carotid IMT.
They enrolled more than 300 patients with demonstrated familial hypercholesterolemia in a randomized, double-blind trial comparing conventional therapy using simvastatin to aggressive therapy using atorvastatin. Patients began treatment with 40 mg of atorvastatin or 20 mg of simvastatin daily with matching placebo. After four weeks, daily dosages were increased to 80 mg of atorvastatin and 40 mg of simvastatin, and this regimen was sustained for two years. Patients were monitored every 12 weeks during the trial at clinic visits that included a physical examination, pill counts, dietary reviews, laboratory screenings and IMT measurements of the common carotid and internal carotid arteries.
The patients in the two treatment groups were comparable at the beginning of the study in all significant variables, including lipid and lipoprotein concentrations. Of the 160 patients treated with atorvastatin, 141 completed two years of treatment. Similarly, 139 of 165 patients completed two years of treatment with simvastatin. Compliance was greater than 80 percent in both groups. In the atorvastatin group, the mean total cholesterol level fell by 41.8 percent and the LDL cholesterol level fell by 50.5 percent; high-density lipoprotein (HDL) cholesterol levels increased by 13.2 percent. In patients treated with simvastatin, the total cholesterol level fell by 33.6 percent, the LDL cholesterol level fell by 41.2 percent, and the HDL cholesterol level increased by 13.4 percent. The number of adverse effects was comparable in the groups, and both drugs were well tolerated. Significant differences in IMT were found in the two treatment groups. The carotid IMT regressed in 66 percent of patients treated with atorvastatin compared with 42 percent in those treated with simvastatin. The mean decrease in IMT of -0.031 mm in the atorvastatin group was significantly better than the mean increase of 0.036 mm in the simvastatin group. The change in arterial IMT correlated with baseline IMT, percentage of LDL cholesterol reduction and age, but not with smoking, cardiovascular history or gender.
The authors conclude that aggressive LDL cholesterol reduction with atorvastatin was associated with demonstrable regression of IMT. Although simvastatin therapy lowered LDL cholesterol, it did not lead to changes in the arterial wall, perhaps because, as suggested by previous studies, a threshold effect of at least 45 percent reduction must occur before measurable changes are found in the arterial wall. Reduction in triglycerides could also be important in IMT reduction. Triglyceride-rich LDL cholesterol may be more atherogenic. Although patients with familial hypercholesterolemia tend to have normal levels of triglycerides, their triglyceride levels were lowered to a greater extent with atorvastatin than with simvastatin.
editor's note: Familial hypercholesterolemia is not as rare as is generally believed. The heterozygous form may affect one in 500 persons—or three to four patients in the practice population of an average family physician. One half of men and 15 percent of women with this condition die before age 60 if untreated. In the Netherlands and Great Britain, searching for cases by testing family members of index cases is believed to be cost-effective, and one Dutch group discovered over 2,000 undiagnosed cases in two years using this method. As shown in this study, aggressive appropriate treatment normalizes laboratory values and produces measurable changes in the arterial wall. The direct link to reduction in mortality and morbidity has not yet been made, but the pathophysiologic changes are impressive. The caveat appears to be that significant reductions in LDL cholesterol levels are necessary before physical changes occur in the arterial wall. Projected to the larger populations of patients with elevated cholesterol levels and other cardiac risk factors, the message unfortunately may be that, like smoking, “cutting down is not enough.” To change arterial wall characteristics, LDL cholesterol and triglyceride levels must be dramatically reduced and the reductions sustained with diet, exercise and appropriate medications.—a.d.w.