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

Background: At high doses, the pharmacokinetics of fluvastatin immediate-re lease (IR) are nonlinear, possibly due to saturation of hepatic uptake. Flu vastatin delivery to the liver in a slower but sustained fashion would be e xpected to avoid hepatic saturation without elevating systemic drug levels. Objective: This pooled analysis compared the efficacy and tolerability of e xtended-release (XL) 80-mg and IR 40-mg formulations of fluvastatin in lowe ring low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) leve ls and raising high-density lipoprotein cholesterol (HDL-C) levels in patie nts with hypercholesterolemia. Methods: Data were pooled from 3 double-blind, randomized, active-controlle d. multicenter, parallel-group studies that compared changes in lipid and a polipoprotein levels with fluvastatin XL 80 mg at bedtime (HS) with changes in fluvastatin IR 40 mg HS or BID in patients aged greater than or equal t o 18 years with primary hypercholesterolemia (consistently elevated LDL-C l evel [greater than or equal to 160 mg/dL] and plasma TG levels less than or equal to 400 mg/dL). The primary efficacy variable was percent change in L DL-C from baseline. Results: The pooled analysis provided an intent-to-treat efficacy study pop ulation 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 i ncremental additional mean reduction in LDL-C of 10.4% (P < 0.001). At 4 an d 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, do se-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 le velincreased 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, respectivel y). 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 s imilar frequency in all treatment groups. Conclusions: Once-daily administration of fluvastatin XL 80 mg provides enh anced 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, parti cularly 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 effe ctive as starting and maintenance lipid-lowering treatment in patients with type II hypercholesterolemia.