A comparison of simvastatin and atorvastatin up to maximal recommended doses in a large multicenter randomized clinical trial.
OBJECTIVE
At higher doses, simvastatin has been shown to produce significantly greater increases in high-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I than atorvastatin. To extend and confirm these findings, a 36-week, randomized, double-blind, dose-titration study was performed in 826 hypercholesterolemic patients to compare the effects of simvastatin and atorvastatin on HDL cholesterol, apo A-I, and clinical and laboratory safety. PRIMARY HYPOTHESIS: Simvastatin, across a range of doses, will be more effective than atorvastatin at raising HDL cholesterol and apo A-I levels.


METHODS
A total of 826 hypercholesterolemic patients were enrolled in this double-blind, randomized, parallel, 36-week, dose-escalation study. Patients randomized to simvastatin received 40 mg/day for the first 6 weeks, 80 mg/day for the next 6 weeks, and remained on 80 mg/day for the final 24 weeks. Patients randomized to atorvastatin received 20 mg/day for the first 6 weeks, 40 mg/day for the next 6 weeks, and 80 mg/day for the remaining 24 weeks.


RESULTS
During the first 12 weeks of the study, simvastatin increased HDL cholesterol and apo A-I more than the comparative doses of atorvastatin, while producing slightly lower reductions in low-density lipoprotein (LDL) cholesterol and triglycerides. At the maximal dose comparison, simvastatin 80 mg and atorvastatin 80 mg, the HDL cholesterol and apo A-I differences favoring simvastatin were larger than at the lower doses. In addition, at the maximal dose comparison, the incidence of drug-related clinical adverse experiences was approximately two-fold higher with atorvastatin 80 mg than with simvastatin 80 mg (23 versus 12%, p < 0.001), due predominantly to a greater incidence of gastrointestinal symptoms with atorvastatin (10 versus 3%, p < 0.001). The incidence of clinically significant alanine aminotransferase elevations was also higher with atorvastatin 80 mg than with simvastatin 80 mg (3.8 versus 0.5%, p < 0.010), especially in women (6.0 versus 0.6%).


CONCLUSIONS
At the doses compared in this study, simvastatin led to greater increases in HDL cholesterol and apo A-I levels than atorvastatin. At the maximum dose comparison, there were fewer drug-related gastrointestinal symptoms and clinically significant aminotransferase elevations with simvastatin.
Illingworth
D R
DR
Division of Endocrinology, Diabetes, & Clinical Nutrition (L465), Oregon Health Sciences University, 3181 S.W. Sam Jackson Park Road, Portland, Oregon 97201, USA. illingwo@ohsu.edu
Crouse
J R
JR
Hunninghake
D B
DB
Davidson
M H
MH
Escobar
I D
ID
Stalenhoef
A F
AF
Paragh
G
G
Ma
P T
PT
Liu
M
M
Melino
M R
MR
O'Grady
L
L
Mercuri
M
M
Mitchel
Y B
YB
D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000097:blood; D000069059:Atorvastatin; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004311:Double-Blind Method; D005260:Female; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D008055:Lipids / Q000097:blood*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019821:Simvastatin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014481:United States
D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin