Combined effects of ezetimibe and phytosterols on cholesterol metabolism: a randomized, controlled feeding study in humans

Abstract

Background: Both ezetimibe and phytosterols inhibit cholesterol absorption. We tested the hypothesis that the combination of ezetimibe and phytosterols is more effective than ezetimibe alone in altering cholesterol metabolism.

Methods and results: Twenty-one mildly hypercholesterolemic subjects completed a randomized, double-blind, placebo-controlled, triple-crossover study. Each subject received a phytosterol-controlled diet plus (1) ezetimibe placebo+phytosterol placebo, (2) 10 mg/d ezetimibe+phytosterol placebo, and (3) 10 mg/d ezetimibe+2.5 g phytosterols for 3 weeks each. All meals were prepared in a metabolic kitchen. Primary outcomes were intestinal cholesterol absorption, fecal cholesterol excretion, and low-density lipoprotein cholesterol levels. The combined treatment resulted in significantly lower intestinal cholesterol absorption (598 mg/d; 95% confidence interval [CI], 368 to 828) relative to control (2161 mg/d; 95% CI, 1112 to 3209) and ezetimibe alone (1054 mg/d; 95% CI, 546 to 1561; both P<0.0001). Fecal cholesterol excretion was significantly greater (P<0.0001) with combined treatment (962 mg/d; 95% CI, 757 to 1168) relative to control (505 mg/d; 95% CI, 386 to 625) and ezetimibe alone (794 mg/d; 95% CI, 615 to 973). Plasma low-density lipoprotein cholesterol values during treatment with control, ezetimibe alone, and ezetimibe+phytosterols averaged 129 mg/dL (95% CI, 116 to 142), 108 mg/dL (95% CI, 97 to 119), and 101 mg/dL (95% CI, 90 to 112; (P<0.0001 relative to control).

Conclusion: The addition of phytosterols to ezetimibe significantly enhanced the effects of ezetimibe on whole-body cholesterol metabolism and plasma low-density lipoprotein cholesterol. The large cumulative action of combined dietary and pharmacological treatment on cholesterol metabolism emphasizes the potential importance of dietary phytosterols as adjunctive therapy for the treatment of hypercholesterolemia.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00863265.

Figures

Figure 1. Consolidated Standards of Reporting Trials (CONSORT) flow diagram

Flow of subjects from enrollment to allocation was shown together with major reasons for exclusion. All completed subjects were analyzed. Notes: *drop out due to death in the family ˆ9 females; 13 males (1 female dropped out); All completed subjects were analyzed.

Figure 2. Effects of ezetimibe alone and in combination with phytosterol supplementation on (A) intestinal cholesterol absorption, (B) fecal cholesterol excretion, and (C) plasma LDL cholesterol

Each subject received a phytosterol-controlled diet (159 ± 4.9 mg/day) plus (1) ezetimibe placebo + phytosterol placebo (double placebo), (2) 10 mg ezetimibe/day + phytosterol placebo, and (3) 10 mg ezetimibe/day + phytosterol supplement (2.5 ± 0.1 g/day), for 3 weeks each using a triple crossover design. Values shown are individual results with means.