Reduction of remnant lipoprotein cholesterol concentrations by cilostazol in patients with intermittent claudication

Background: Elevated triglyceride-rich lipoproteins and reduced high-density lipoproteins (HDL) are associated with the development of intermittent claudication (IC), a life-limiting symptom of peripheral arterial disease. Cilostazol, a potent platelet inhibitor and vasodilator, lowers triglycerides and increases HDL concentrations in addition to increasing walking distance in patients with intermittent claudication. However, the association of remnant lipoproteins (a more atherogenic subset of triglyceride-rich lipoproteins) and peripheral arterial disease and the effects of cilostazol on remnant lipoproteins have not been studied. Methods and results: We quantified plasma remnant lipoprotein concentrations using the remnant lipoprotein-cholesterol assay (RLP-C). Patients with intermittent claudication (n=415) had significantly higher remnant lipoprotein concentrations compared to reference subjects (n=874; 0.31±0.32 versus 0.24±0.17 mmol/l, P<0.001) in addition to elevated total triglyceride (2.67±1.92 versus 1.92±1.24 mmol/l, P<0.001) and reduced high-density lipoprotein (HDL) cholesterol concentrations (1.06±0.31 versus 1.22±0.36 mmol/l, P<0.001). Cilostazol treatment (100 mg, b.i.d.) in patients with intermittent claudication (n=56) for 6 months resulted in 20% reduction of remnant lipoprotein-cholesterol (from 0.27±0.21 to 0.22±0.09 mmol/l, P<0.05) versus no significant change (from 0.26±0.17 to 0.27±0.12 mmol/l) in the placebo group (n=67). Cilostazol also reduced triglyceride concentrations significantly (from 2.32±1.46 to 1.79±0.72 mmol/l, P<0.01, in the cilostazol group versus 2.38±1.39 to 2.25±1.19 mmol/l in the placebo group) and increased HDL cholesterol concentrations (from 1.06±0.23 to 1.24±0.34 mmol/l, P<0.001) in the cilostazol group versus no significant change (1.06±0.34 to 1.09±0.36 mmol/l) in the placebo group. Pentoxifylline (400 mg, t.i.d.) did not have any significant effects on lipid variables (n=66). Conclusions: Remnant lipoprotein concentrations are significantly elevated in patients with intermittent claudication and can be reduced by cilostazol. Reduction of remnant lipoproteins may provide a long-term benefit to the patients with symptomatic peripheral arterial disease.