PMID- 19576325
OWN - NLM
STAT- MEDLINE
DCOM- 20090724
LR  - 20211203
IS  - 1879-1913 (Electronic)
IS  - 0002-9149 (Linking)
VI  - 104
IP  - 1
DP  - 2009 Jul 1
TI  - Safety and tolerability of dalcetrapib.
PG  - 82-91
LID - 10.1016/j.amjcard.2009.02.061 [doi]
AB  - Efficacy and safety data for dalcetrapib (RO4607381/JTT-705) are presented, 
      following a report of increased mortality and cardiac events with another 
      cholesteryl ester transfer protein inhibitor, torcetrapib, associated with 
      off-target adverse effects (hypertension and the activation of the 
      renin-angiotensin-aldosterone system). The efficacy and clinical safety of 
      dalcetrapib 300, 600, and 900 mg or placebo were assessed (n = 838) in 4 pooled 
      4-week phase IIa trials (1 monotherapy, n = 193; 3 statin combination, n = 353) 
      and 1 12-week phase IIb trial (with pravastatin, n = 292). Nonclinical safety, 
      assessed by the induction of aldosterone production and aldosterone synthase 
      (cytochrome P450 11B2) messenger ribonucleic acid, was measured in human 
      adrenocarcinoma (H295R) cells exposed to dalcetrapib or torcetrapib. Dalcetrapib 
      increased high-density lipoprotein cholesterol by up to 36% and apolipoprotein 
      A-I by up to 16%. The incidence of adverse events (AEs) was similar between 
      placebo (42%) and dalcetrapib 300 mg (50%) and 600 mg (42%), with more events 
      with dalcetrapib 900 mg (58%) (p <0.05, pooled 4-week studies). Six serious AEs 
      (3 with placebo, 1 with dalcetrapib 300 mg, and 2 with dalcetrapib 600 mg) were 
      considered "unrelated" to treatment. Cardiovascular AEs were similar across 
      treatment groups, with no dose-related trends and no clinically relevant changes 
      in blood pressure or electrocardiographic results. Findings were similar in the 
      12-week study. In vitro, torcetrapib but not dalcetrapib increased aldosterone 
      production and cytochrome P450 11B2 messenger ribonucleic acid levels. In 
      conclusion, dalcetrapib alone or in combination with statins was effective at 
      increasing high-density lipoprotein cholesterol and was well tolerated, without 
      clinically relevant changes in blood pressure or cardiovascular AEs and no 
      effects on aldosterone production as assessed nonclinically.
FAU - Stein, Evan A
AU  - Stein EA
AD  - Metabolic and Atherosclerosis Research Center, Cincinnati, OH, USA. 
      esteinmrl@aol.com
FAU - Stroes, Erik S G
AU  - Stroes ES
FAU - Steiner, George
AU  - Steiner G
FAU - Buckley, Brendan M
AU  - Buckley BM
FAU - Capponi, Alessandro M
AU  - Capponi AM
FAU - Burgess, Tracy
AU  - Burgess T
FAU - Niesor, Eric J
AU  - Niesor EJ
FAU - Kallend, David
AU  - Kallend D
FAU - Kastelein, John J P
AU  - Kastelein JJ
LA  - eng
SI  - ClinicalTrials.gov/NCT00658515
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Cardiol
JT  - The American journal of cardiology
JID - 0207277
RN  - 0 (Amides)
RN  - 0 (Anticholesteremic Agents)
RN  - 0 (Cholesterol Ester Transfer Proteins)
RN  - 0 (Esters)
RN  - 0 (Quinolines)
RN  - 0 (Sulfhydryl Compounds)
RN  - 3D050LIQ3H (dalcetrapib)
RN  - 4N4457MV2U (torcetrapib)
SB  - IM
MH  - Amides
MH  - Anticholesteremic Agents/*adverse effects/therapeutic use
MH  - Cholesterol Ester Transfer Proteins/antagonists & inhibitors
MH  - Coronary Artery Disease/*drug therapy
MH  - Double-Blind Method
MH  - Dyslipidemias/*drug therapy
MH  - Esters
MH  - Female
MH  - Humans
MH  - Incidence
MH  - Male
MH  - Middle Aged
MH  - Quinolines/adverse effects/therapeutic use
MH  - Risk Assessment
MH  - Risk Factors
MH  - Sulfhydryl Compounds/*adverse effects/therapeutic use
EDAT- 2009/07/07 09:00
MHDA- 2009/07/25 09:00
CRDT- 2009/07/07 09:00
PHST- 2008/11/26 00:00 [received]
PHST- 2009/02/17 00:00 [revised]
PHST- 2009/02/17 00:00 [accepted]
PHST- 2009/07/07 09:00 [entrez]
PHST- 2009/07/07 09:00 [pubmed]
PHST- 2009/07/25 09:00 [medline]
AID - S0002-9149(09)00670-5 [pii]
AID - 10.1016/j.amjcard.2009.02.061 [doi]
PST - ppublish
SO  - Am J Cardiol. 2009 Jul 1;104(1):82-91. doi: 10.1016/j.amjcard.2009.02.061.