Dalcetrapib (Roche) modulates cholesteryl ester transfer protein activity; however, the dal-PLAQUE study published online Sept. 12 in the Lancet, showed no evidence of a pathological effect related to the arterial wall over 24 months duration. While the trial found that dalcetrapib may have long standing vascular effects, including a reduction in vessel enlargement over 24 months, researchers said that more data are necessary to understand the long-term safety of the molecule.
To evaluate whether dalcetrapib increased atherosclerotic plaque progression, Zahi A. Fayad, MD, of the Mount Sinai School of Medicine in New York City, and colleagues randomized 66 patients to placebo and 64 patients to receive 600 mg/day of dalcetrapib for 24 months. The study used a non-invasive multimodality imaging approach to assess the structural and inflammatory characteristics of atherosclerosis.
Patients were at a high-risk for coronary heart disease and the researchers used MRI and PET/CT results as the study's co-primary endpoint.
For patients administered dalcetrapib, HDL-cholesterol increased 31 percent; apolipoprotein A1 increased by 10 percent. The percent change from baseline for dalcetrapib compared with placebo was an increase of 26.9 percent for HDL-cholesterol and 6.8 percent for apolipoprotein A1. Patients administered dalcetrapib saw median high reactive C-reactive protein increase by 33 percent after 24 months. This number remained unchanged with placebo.
While Lp-PLA 2 mass decreased with placebo at 24 months, it increased with dalcetrapib. The researchers noted that PET/CT showed no evidence of increased vascular inflammation with dalcetrapib compared to placebo after six months.
“The primary endpoints for dal-PLAQUE showed dalcetrapib did not increase plaque progression over 24 months or inflammation in the vessel wall over six months compared with placebo,” Fayad and colleagues wrote. “These data suggest dalcetrapib might be associated with favorable vascular changes.”
Fayad and colleagues said that dalcetrapib has the potential to reduce adverse structural changes within the blood vessels by a mechanism to reduce vascular inflammation and increase HDL-cholesterol.
“In light of the ongoing debate about the proatherogenicity or anti-atherogenicity of CETP [cholesteryl ester transfer protein] activity, the multimodality imaging techniques used in dal-PLAQUE were deemed a useful biomarker approach to increase confidence that CETP modulation with dalcetrapib does not cause short-term harm while results from larger outcomes trials were pending,” the authors noted.
While the researchers found positive outcomes in terms of how dalcetrapib reduced vessel enlargement, they noted that long-term safety and clinical outcomes of dalcetrapib will need to be evaluated in future clinical studies. Fayad et al noted that two studies, dal-PLAQUE 2 and dal-OUTCOMES, will assess both atherosclerotic disease progression via coronary intravascular ultrasound and carotid intemia-media thickness and cardiovascular morbidity, respectively.