Efficacy and tolerability of fluvastatin extended-release delivery system: a pooled analysis.

BACKGROUND: At high doses, the pharmacokinetics of fluvastatin immediate-release (IR) are nonlinear, possibly due to saturation of hepatic uptake. Fluvastatin delivery to the liver in a slower but sustained fashion would be expected to avoid hepatic saturation without elevating systemic drug levels.

OBJECTIVE: This pooled analysis compared the efficacy and tolerability of extended-release (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowering low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) levels and raising high-density lipoprotein cholesterol (HDL-C) levels in patients with hypercholesterolemia.

METHODS: Data were pooled from 3 double-blind, randomized, active-controlled, multicenter, parallel-group studies that compared changes in lipid and apolipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged > or =18 years with primary hypercholesterolemia (consistently elevated LDL-C level [> or =160 mg/dL] and plasma TG levels < or =400 mg/dL). The primary efficacy variable was percent change in LDL-C from baseline.

RESULTS: The pooled analysis provided an intent-to-treat efficacy study population of 1674 patients. At 4 weeks, fluvastatin XL 80 mg HS reduced LDL-C levels by a mean of 36.3% (median 38%), significantly greater than a mean reduction of 25.9% (median 27%) seen with fluvastatin IR 40 mg HS, and an incremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 and 24 weeks, fluvastatin XL 80 mg HS provided an LDL-C reduction equivalent to fluvastatin IR 40 mg BID (P < 0.001 for noninferiority). Significant, dose-related changes in HDL-C, LDL-C:HDL-C ratio, total cholesterol, TG, and apolipoprotein A-I and apolipoprotein B levels also occurred. Mean HDL-C level increased by 8.7% and median TG level decreased by 19% with fluvastatin XL 80 mg HS (P < 0.001 and P < 0.05 vs fluvastatin IR 40 mg HS, respectively). Maximum mean increases in HDL-C level (21%) and median decreases in TG level (31%) with fluvastatin XL 80 mg HS occurred in patients with type IIb dyslipidemia and the highest baseline TG. Adverse events were mild, with similar frequency in all treatment groups.

CONCLUSIONS: Once-daily administration of fluvastatin XL 80 mg provides enhanced efficacy with an additional 10.4% reduction in LDL-C levels compared with fluvastatin IR 40 mg HS, and superior increases in HDL-C levels, particularly in patients with elevated TG levels (P < 0.05 vs fluvastatin IR 40 mg HS). Fluvastatin XL 80 mg HS has a good tolerability profile and is effective as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.