title: Effects of ezetimibe added to statin therapy on markers of cholesterol absorption and synthesis and LDL-C lowering in hyperlipidemic patients.
abstract: OBJECTIVE
  Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers.
  
  
  METHODS
  Hypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively).
  
  
  RESULTS
  The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p < 0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group.
  
  
  CONCLUSIONS
  Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed.
authors.affiliation: Lipid Metabolism Laboratory, Human Nutrition Research Center on Aging at Tufts University, 711 Washington Street, Boston, MA 02111, USA. nuntakorn.thongtang@tufts.edu
authors.forename: Nuntakorn
authors.initials: N
authors.lastname: Thongtang
authors.forename: Jianxin
authors.initials: J
authors.lastname: Lin
authors.forename: Ernst J
authors.initials: EJ
authors.lastname: Schaefer
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lowe
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Tomassini
authors.forename: Arvind K
authors.initials: AK
authors.lastname: Shah
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Tershakovec
mesh_terms: D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001053:Apolipoproteins / Q000097:blood; D001384:Azetidines / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis / Q000097:blood*; D008078:Cholesterol, LDL / Q000097:blood*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy*; D007408:Intestinal Absorption / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012855:Sitosterols / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States
chemical_list: D000924:Anticholesteremic Agents; D001053:Apolipoproteins; D001384:Azetidines; D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D012855:Sitosterols; C025473:gamma-sitosterol; C001521:lathosterol; D002097:C-Reactive Protein; D002784:Cholesterol; D000069438:Ezetimibe