Background/Objective:
Lapaquistat acetate (LAPA), a novel lipid-lowering agent, inhibits squalene synthase, an enzyme distal to HMG-CoA reductase in the cholesterol biosynthetic pathway. We evaluated the effects of LAPA on LDL-C, other plasma lipid variables, and high-sensitivity C-reactive protein (hs-CRP) levels when co-administered with a stable dose of the HMG-CoA reductase inhibitor, atorvastatin (ATV), in subjects with primary hypercholesterolemia already on ATV therapy.
Methods:
This multicenter, randomized, double-blind, placebo-controlled, Phase III trial was conducted at 79 centers in the US. After a 4-wk dietary run-in and ATV (10, 20, or 40 mg/d) stabilization, 448 subjects (LDL-C ≥100 mg/dL, TG ≤400 mg/dL) were randomized to 1 of 3 treatments: LAPA 50 mg, 100 mg, or placebo co-administered with ongoing ATV dosed once daily for 24 wks. The primary endpoint was percent (%) change from baseline in direct LDL-C at 24 wks; secondary endpoints included % changes in calculated LDL-C, total cholesterol (TC), non-HDL-C, Apo B, TG, HDL-C, VLDL-C, Apo A1, and hs-CRP levels. Safety was monitored using clinical and laboratory examinations.
Results:
Baseline clinical and lipid characteristics were comparable among the 3 treatment groups. Compared with placebo, LAPA treatment resulted in significant reductions (see Table
) in LDL-C, other lipid variables, and hs-CRP. The enhanced LDL-C-lowering effect was independent of ATV dose. LAPA co-administration was well tolerated. Overall, adverse event (AE) incidences were similar in the 3 treatment groups. Serious AEs in 12 subjects (5 in placebo, 3 in 50 mg LAPA, and 4 in 100 mg LAPA) were reported.
Conclusion:
Lapaquistat acetate, a novel squalene synthase inhibitor, was well tolerated and effective in reducing LDL-C, hs-CRP, and in improving the atherogenic lipid profile when co-administered with atorvastatin. This combination may prove to be a useful therapeutic option for patients with hypercholesterolemia.
Least Squares Mean % Change from Baseline (±SE)
3-Hydroxy-3-methylglutaryl-coenzyme A reductase in normal and dystrophic hamsters
