Effects of fluvastatin extended-release (80 mg) alone and in combination with ezetimibe (10 mg) on low-density lipoprotein cholesterol and inflammatory parameters in patients with primary hypercholesterolemia: a 12-week, multicenter, randomized, open-label, parallel-group study.
BACKGROUND
Combining lipid-lowering agents with complementary mechanisms of action can provide greater cholesterol reductions than using either agent alone, improving achievement of target low-density lipoprotein cholesterol (LDL-C) levels.


OBJECTIVE
The aim of this study was to assess the effects of fluvastatin extended-release (XL) 80 mg/d administered alone or combined with ezetimibe 10 mg/d on plasma lipid levels and inflammatory parameters in patients with primary hypercholesterolemia. The tolerability of both regimens was also evaluated.


METHODS
In this multicenter, randomized, open-label, parallel-group study, patients with hypercholesterolemia were randomized in a 1:1 ratio to receive fluvastatin XL 80 mg/d alone or in combination with ezetimibe 10 mg/d for 12 weeks. The primary end point was the percentage change from baseline to week 12 in LDL-C level with fluvastatin XL + ezetimibe combination therapy compared with fluvastatin XL alone. Plasma concentrations of inflammatory biomarkers were measured at baseline and week 12. Proportions of patients who achieved National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) LDL-C goals were calculated. Tolerability was assessed by the monitoring and recording of all adverse events (AEs) and laboratory values.


RESULTS
A total of 82 patients were enrolled (mean [SD] age, 50.0 [12.0] years; 44% male; 100% white; mean [SD] weight, 73.5 [14.9] kg; combination group, 38 patients; monotherapy group, 44). Fluvastatin XL + ezetimibe and fluvastatin XL monotherapy were associated with significant decreases from baseline in mean LDL-C level (by 49.9% and 35.2%, respectively; between-group difference, P < 0.001). Fluvastatin XL + ezetimibe was associated with significantly greater reductions from baseline than fluvastatin XL monotherapy in total cholesterol (38.2% vs 27.5% P < 0.001), triglycerides (21% vs 3.8% P = 0.02) and apolipoprotein B (34.8% vs 22.5% P < 0.001). NCEP ATP III LDL-C goals were achieved by 87% of patients receiving fluvastatin XL + ezetimibe and 67% of patients receiving fluvastatin XL monotherapy (between-group difference, P = 0.042). The combination was associated with significantly lowered high-sensitivity C-reactive protein (hs-CRP) levels in patients with high baseline hs-CRP (>2 mg/L; P < 0.02), >1 cardiovascular risk factor (P < 0.05), or hypertension (P = 0.015); both regimens were associated with significantly reduced plasma levels of interleukin-1B. No significant between-group differences in the incidences of AEs were found. Most AEs were mild or moderate in intensity. Headache was the most common AE, occurring in 5/44 (11.4%) patients in the fluvastatin XL group and 2/38 (5.3%) patients in the fluvastatin XL + ezetimibe group. One serious AE (convulsive crisis) occurred in a patient receiving fluvastatin XL + ezetimibe, but was not suspected to be related to study medication.


CONCLUSIONS
Fluvastatin XL in combination with ezetimibe was found to be well-tolerated and effective, allowing the majority (87%) of these patients with primary hypercholesterolemia to achieve current treatment goals, and reduced hs-CRP levels in patients at higher cardiovascular risk.
Alvarez-Sala
Luis A
LA
Lipids Unit, Hospital Universitario Gregorio Marañón, Madrid, Spain. lalvarezsalaw@medynet.com
Cachofeiro
Victoria
V
Masana
Luis
L
Suarez
Carmen
C
Pinilla
Blanca
B
Plana
Nuria
N
Trias
Ferran
F
Moreno
Miguel Angel
MA
Gambus
Gemma
G
Lahera
Vicente
V
Pintó
Xavier
X
D000924:Anticholesteremic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001055:Apolipoproteins B / Q000097:blood; D001384:Azetidines / Q000008:administration & dosage* / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000032:analysis; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood*; D003692:Delayed-Action Preparations; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005229:Fatty Acids, Monounsaturated / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006937:Hypercholesterolemia / Q000188:drug therapy*; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D053583:Interleukin-1beta / Q000097:blood; D008297:Male; D008875:Middle Aged; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D001055:Apolipoproteins B; D001384:Azetidines; D015415:Biomarkers; D008078:Cholesterol, LDL; D003692:Delayed-Action Preparations; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D053583:Interleukin-1beta; D014280:Triglycerides; D000077340:Fluvastatin; D002097:C-Reactive Protein; D002784:Cholesterol; D000069438:Ezetimibe