Safety and tolerability of dalcetrapib (RO4607381/JTT-705): results from a 48-week trial

Abstract

AimsCo-primary objectives were to evaluate dalcetrapib (JTT-705/RO4607381), which targets cholesteryl ester transfer protein (CETP), effects on high-density lipoprotein cholesterol (HDL-C) in participants with coronary heart disease or risk equivalents and to evaluate potential changes in mesenteric lymph nodes.Methods and resultsDouble-blind trial with participants randomized (2:1) to dalcetrapib 900 mg/day (higher than 600 mg phase III dose) or placebo, both with atorvastatin, for 24 weeks (n = 135; one without post-baseline efficacy data was excluded from intent-to-treat population); a subset continued for 24-week extension (n = 77). Lipid changes and safety parameters were assessed. Mesenteric lymph nodes were evaluated by magnetic resonance imaging. Dalcetrapib increased HDL-C (33.4%, Week 24; 33.8%, Week 48), decreased CETP activity (–53.5%, Week 24; –56.5%, Week 48), and increased apolipoprotein A-I (11.4%, Week 24; 16.4%, Week 48). Dalcetrapib showed no clinically relevant differences vs. placebo in adverse events, laboratory parameters including aldosterone, electrocardiograms, and vital signs including blood pressure (BP). Dalcetrapib had no measurable, clinically relevant effect on lymph node size.ConclusionDalcetrapib 900 mg administered for up to 48 weeks showed no clinically relevant changes in lymph nodes, BP, or other safety parameters. Dalcetrapib effectively increased HDL-C over 48 weeks of treatment.

32 Triglyceride-Rich Lipoproteins and High-Density Lipoprotein Cholesterol in Patients at High Risk of Cardiovascular Disease: Evidence and Guidance for Management

“…elevated TRL and their remnants combined with low HDL-C Insufficient evidence for TRL and their remnants alone Insufficient evidence for low HDL-C alone a For an interpretation of causality given the data available in 2010, all five types of evidence should favour causality and all three types of human studies (epidemiology, genetics, and intervention trials) must be consistent; this is clearly the case for elevated LDL-C. the off-target effects associated with torcetrapib, as indicated by recent studies. 235,236 Clinical outcome data from ongoing or planned studies (dal-OUTCOMES with dalcetrapib and REVEAL with anacetrapib) are awaited.…”

Crystal Structures of Cholesteryl Ester Transfer Protein in Complex with Inhibitors

“…The other CETP inhibitors named in Fig. 1 are being actively tested in later stage clinical trials (23)(24)(25); their effects on disease outcome remain unknown (26 -29).…”

HDL-C: Does it matter? An update on novel HDL-directed pharmaco-therapeutic strategies

“…Among patients with type II dyslipidemia receiving 40 mg of pravastatin daily and whose baseline levels of HDL-C and LDL-C were 48 mg/dl and 120 mg/dl, respectively, the addition of 600 mg of dalcetrapib daily increased HDL-cholesterol levels by 28% and decreased LDL-cholesterol levels by 7% compared with placebo administration, after 4 weeks of treatment (89). After 24 weeks of therapy with 900 mg of dalcetrapib daily, HDL-C levels increased by 33% (mean baseline level of 42 mg/dl) in patients at high risk of coronary heart disease events who were treated with 10-80 mg of atorvastatin daily, when compared with HDL levels in participants receiving placebo plus atorvastatin (90). LDL-C levels, however, did not differ in the two patient groups (mean baseline level of 74 mg/dl).…”