title: Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial.
abstract: BACKGROUND
  Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins.
  
  
  OBJECTIVE
  To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia.
  
  
  METHODS
  Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe.
  
  
  METHODS
  Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks.
  
  
  METHODS
  The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment.
  
  
  RESULTS
  The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed.
  
  
  CONCLUSIONS
  Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01105975.
authors.affiliation: Cleveland Clinic Coordinating Center for Clinical Research, Cleveland Clinic, Cleveland, OH 44195, USA. nichols1@ccf.org
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Nicholls
authors.forename: H Bryan
authors.initials: HB
authors.lastname: Brewer
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Krueger
authors.forename: Ming-Dauh
authors.initials: MD
authors.lastname: Wang
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Shao
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Ellen
authors.initials: E
authors.lastname: McErlean
authors.forename: Steven E
authors.initials: SE
authors.lastname: Nissen
mesh_terms: D000368:Aged; D000069059:Atorvastatin; D001569:Benzodiazepines / Q000008:administration & dosage* / Q000494:pharmacology; D002318:Cardiovascular Diseases / Q000517:prevention & control; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors*; D008076:Cholesterol, HDL / Q000187:drug effects*; D008078:Cholesterol, LDL / Q000187:drug effects*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D050171:Dyslipidemias / Q000188:drug therapy*; D005260:Female; D005464:Fluorobenzenes / Q000008:administration & dosage; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D000068718:Rosuvastatin Calcium; D019821:Simvastatin / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D001569:Benzodiazepines; C568301:evacetrapib; D000068718:Rosuvastatin Calcium; D000069059:Atorvastatin; D019821:Simvastatin