Lipid-altering efficacy and safety of simvastatin 80 mg/day: Long-term experience in a large group of patients with hypercholesterolemia

Background: Elevated levels of low-density lipoprotein (LDL) cholesterol pr omote the development of atherosclerosis and coronary heart disease. Hypothesis: Simvastatin 80 mg/day will be more effective than simvastatin 4 0 mg/day at reducing LDL cholesterol and will be well tolerated. Methods: Two similar, randomized, multicenter, controlled, double-blind, pa rallel-group, 48-week studies were performed to evaluate the long-term lipi d-altering efficacy and safety of simvastatin 80 mg/day in patients with hy percholesterolemia. One study conducted in the US enrolled patients meeting the National Cholesterol Education Program (NCEP) LDL cholesterol criteria for pharmacologic treatment. In the other multinational study, patients wi th LDL cholesterol levels greater than or equal to 4.2 mmol/l were enrolled . At 20 centers in the US and 19 countries world-wide, 1,105 hypercholester olemic patients, while on a lipid-lowering diet, were randomly assigned at a ratio of 2:3 to receive simvastatin 40 mg (n = 436) or 80 mg (n = 669) on ce daily for 24 weeks. Those patients completing an initial 24-week base st udy were enrolled in a 24-week blinded extension. Patients who had started on the 80 mg dose in the base study continued on the same dose in the exten sion, while those who had started on the 40 mg dose were rerandomized at a 1:1 ratio to simvastatin 40 or 80 mg in the extension. Results: There was a significant advantage in the LDL cholesterol-lowering effect of the 80 mg dose compared with that of the 40 mg dose, which was ma intained over the 48 weeks of treatment. The mean percentage reductions (95 % confidence intervals) from baseline in LDL cholesterol for the 40 and 80 mg groups were 41% (42, 39) and 47% (48, 46), respectively, for the 24-week base study, and 41% (43, 39) and 46% (47, 45), respectively, after 48 week s of treatment (p < 0.001 between groups). Larger reductions in total chole sterol and triglycerides were also observed with the 80 mg dose compared wi th the 40 mg dose at Weeks 24 and 48. Both doses were well tolerated, with close to 95% of patients enrolled completing the entire 48 weeks of treatme nt. Myopathy (muscle symptoms plus creatine kinase increase > 10 fold upper Limit of normal) and clinically significant hepatic transaminase increases (> 3 times the upper Limit of normal) occurred infrequently with both dose s. There was no significant difference between the groups in the number of patients with such increases, although there were more cases for both with the 80 mg dose. Conclusions: Compared with the 40 mg dose, simvastatin 80 mg produced great er reductions in LDL cholesterol, total cholesterol, and triglycerides. Bot h doses were well tolerated.