title: Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial.
abstract: OBJECTIVE
  High-density lipoprotein cholesterol (HDL-C) is inversely associated with cardiovascular (CV) events and thus an attractive therapeutic target. However, in spite of marked elevations in HDL-C, the first cholesterol transport protein (CETP) inhibitor torcetrapib raised blood pressure (BP), impaired endothelial function, and increased CV mortality and morbidity. Dalcetrapib is a novel molecule acting on CETP with a different chemical structure to torcetrapib. As HDL stimulates nitric oxide (NO), suppresses inflammation, and exerts protective CV effects, we investigated the effects of dalcetrapib on endothelial function, blood pressure, inflammatory markers, and lipids in patients with, or at risk of, coronary heart disease (CHD) in a double-blind randomized placebo-controlled trial (clinicaltrials.gov number NCT00655538).
  
  
  RESULTS
  Patients with target low-density lipoprotein cholesterol (LDL-C) levels received dalcetrapib 600 mg/day or placebo for 36 weeks on top of standard therapy (including statins). The primary outcome measures were the change from baseline of flow-mediated dilatation (%FMD) of the right brachial artery after 5 min of cuff occlusion at 12 weeks and the 24 h ambulatory blood pressure monitoring (ABPM) at week 4. Secondary outcomes included change from baseline in FMD after 36 weeks and the change in ABPM at 12 and 36 weeks, changes in HDL-C, LDL-C, triglycerides, CETP activity, as well as standard safety parameters. Four hundred seventy-six patients were randomized. Baseline FMD was 4.1 ± 2.2 and 4.0 ± 2.4% with placebo or dalcetrapib, respectively and did not change significantly from placebo after 12 and 36 weeks (P = 0.1764 and 0.9515, respectively). After 4, 24, and 36 weeks of treatment with dalcetrapib, CETP activity decreased by 51, 53, and 56% (placebo corrected, all P < 0.0001), while at weeks 4, 12, and 36 HDL-C increased by 25, 27, and 31% (placebo corrected, all P < 0.0001). Low-density lipoprotein cholesterol levels did not change. At baseline, ABPM was 125 ± 12/74 ± 8mmHg in the placebo and 128 ± 11/75 ± 7mmHg in the dalcetrapib group (P = 0.3372 and 0.1248, respectively, placebo-corrected change from baseline) and did not change for up to 36 weeks. Biomarkers of inflammation, oxidative stress, and coagulation did not change during follow-up except for Lp-PLA(2) mass levels which increased by 17% (placebo corrected). Overall 7 patients given dalcetrapib and 8 patients given placebo experienced at least one pre-specified adjudicated event (11 events with dalcetrapib and 12 events with placebo).
  
  
  CONCLUSIONS
  The dal-VESSEL trial has established the tolerability and safety of CETP-inhibition with dalcetrapib in patients with or at risk of CHD. Dalcetrapib reduced CETP activity and increased HDL-C levels without affecting NO-dependent endothelial function, blood pressure, or markers of inflammation and oxidative stress. The dal-OUTCOMES trial (NCT00658515) will show whether dalcetrapib improves outcomes in spite of a lack of effect on endothelial function.
authors.affiliation: Department of Cardiology, Cardiovascular Centre, University of Zurich, 8091 Zurich, Switzerland. cardiotfl@gmx.ch
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Stefano
authors.initials: S
authors.lastname: Taddei
authors.forename: Juan-Carlos
authors.initials: JC
authors.lastname: Kaski
authors.forename: J Wouter
authors.initials: JW
authors.lastname: Jukema
authors.forename: David
authors.initials: D
authors.lastname: Kallend
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: John E
authors.initials: JE
authors.lastname: Deanfield
mesh_terms: D000368:Aged; D000577:Amides; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001916:Brachial Artery / Q000502:physiology; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors; D008076:Cholesterol, HDL / Q000378:metabolism; D008078:Cholesterol, LDL / Q000378:metabolism; D003327:Coronary Disease / Q000503:physiopathology / Q000517:prevention & control*; D004311:Double-Blind Method; D004730:Endothelium, Vascular / Q000187:drug effects; D004952:Esters; D005260:Female; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D013438:Sulfhydryl Compounds / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome; D014280:Triglycerides / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000577:Amides; D000924:Anticholesteremic Agents; D015415:Biomarkers; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004952:Esters; D013438:Sulfhydryl Compounds; D014280:Triglycerides; C411602:dalcetrapib