This paradox was explained by putative off-target effects not related to CETP inhibition that were specific to torcetrapib. human arterial imaging results that tended to look favorable. However, the dalcetrapib development program was recently terminated, presumably because interim analysis of a large CVD outcome trial indicated no benefit. These events raise important questions regarding the validity of the mechanism of CETP inhibition and the broader issue of whether pharmacological raising of high-density lipoprotein cholesterol itself is usually a useful strategy for CVD risk reduction. 0.04) in the progression of plaque in the dalcetrapib group compared to the placebo group as assessed by MRI. Although a 7% reduction in the most diseased carotid segment was seen in the dalcetrapib group, no significant difference (= 0.08) in the wall thickness of the right and left carotid arteries or the ascending thoracic aorta was found when measured by PET/CT. Overall, dal-PLAQUE found that dalcetrapib was safe and possibly led to regression of carotid lesions and reduction of vessel inflammation.56 These mild changes observed must be interpreted in context, as the patients were concurrently on effective statin therapy, illustrating that this plaque benefit was incremental to that of statins.17 Interestingly, these benefits correlated with the degree of HDL cholesterol increase. The dalcetrapib group also showed a 7% reduction in LDL cholesterol beyond that accounted for by their statin treatment. Although not powered statistically to look at CVD events, in dal-PLAQUE there were fewer CVD events in the dalcetrapib group than in the placebo group (3% vs 11%, respectively). In the recent dal-VESSEL trial,57 patients with CVD or comparative and low HDL cholesterol were treated with dalcetrapib 600 mg or placebo for 36 weeks. Here, the primary endpoints evaluated were the change in brachial FMD after 12 and 36 weeks. Similar to prior studies, dalcetrapib treatment led to Ginsenoside Rh3 a 50% reduction in CETP activity and a 31% increase in HDL cholesterol. Levels of apo A-I were also increased, but there was no change to LDL cholesterol. Despite these favorable biochemical changes, no significant differences were observed for FMD at any point of the study. Ambulatory 24-hour systolic and diastolic blood pressures at 4, 12, and 36 weeks were not altered in the dalcetrapib arm, and there were no increases in nitric oxide-dependent endothelial function or markers of oxidative stress and inflammation.57 Unpublished studies in the dalcetrapib clinical program include dal-PLAQUE2, dal-ACUTE, and dal-OUTCOMES. Dal-PLAQUE2 was designed to evaluate dalcetrapibs effect on atherosclerosis by measuring coronary plaque in 900 patients by intravascular carotid B-mode ultrasound imaging and coronary angioplasty.61 Dal-ACUTE (“type”:”clinical-trial”,”attrs”:”text”:”NCT01323153″,”term_id”:”NCT01323153″NCT01323153) evaluated the use of dalcetrapib in 300 patients after acute coronary syndrome.59 The largest study, namely dal-OUTCOMES, was a multicenter, randomized, double-blinded, placebo-controlled Phase III trial60 that randomized 15,600 patients to either dalcetrapib or placebo 4 to 12 weeks after acute coronary syndrome. Patients were monitored for major cardiovascular events, including coronary artery disease death, acute MI, unstable angina requiring hospital admission, cardiac arrest, or stroke. In May 2012, Roche announced that it was terminating the dal-OUTCOMES trial 2 years early due to its lack of efficacy, and was simultaneously terminating the entire dalcetrapib program. Implications of termination of the dalcetrapib development program The CVD prevention community has been left somewhat shell-shocked after the recent turn of events related to dalcetrapib, which, to say the least, were unexpected and surprising. Dalcetrapib lacked the known off-target effects of torcetrapib. Further, dalcetrapibs contribution to the reduction of atherosclerotic progression and vascular inflammation without adversely affecting blood pressure or aldosterone56 seemed encouraging. But despite these encouraging safety and efficacy signals from the early-phase clinical trials, and the evidence favoring the unique mechanism of CETP modulation, the Phase III dal-OUTCOMES trial was terminated prematurely.62 Full details surrounding this termination should emerge soon, and hopefully there will be full publication of them. However, the termination appears to have been due to lack of efficacy rather than to increased risk of harm or deleterious effects.63 Considering the prior failures of ILLUMINATE and AIM-HIGH, dal-OUTCOMES adds further evidence that targeting HDL does not improve CVD risk. But is the HDL hypothesis wrong? Or does the way in which HDL is usually raised matter? Perhaps CETP inhibition Rabbit Polyclonal to KAL1 is not the best way to raise HDL. Further evidence that HDL itself may simply be a biomarker rather than a causal factor for CVD came from recent genetic studies performed in tens of thousands of patients, which found (1) an inverse association of CHD risk in patients with genetically reduced CETP function64.Comparable to prior studies, dalcetrapib treatment led to a 50% reduction in CETP activity and a 31% increase in HDL cholesterol. the dalcetrapib group compared to the placebo group as assessed by MRI. Although a 7% reduction in the most diseased carotid segment was seen in the dalcetrapib group, no significant difference (= 0.08) in the wall thickness of the right and left carotid arteries or the ascending thoracic aorta was found when measured by PET/CT. Overall, dal-PLAQUE found that dalcetrapib was safe and possibly led to regression of carotid lesions and reduction of vessel inflammation.56 These Ginsenoside Rh3 mild changes observed must be interpreted in context, as the patients were concurrently on effective statin therapy, illustrating that this plaque benefit was incremental to that of statins.17 Interestingly, these benefits correlated with the degree of HDL cholesterol increase. The dalcetrapib group also showed a 7% reduction in LDL cholesterol beyond that accounted for by their statin treatment. Although not powered statistically to look at CVD events, in dal-PLAQUE there were fewer CVD events in the dalcetrapib group than in the placebo group (3% vs 11%, respectively). In the recent dal-VESSEL trial,57 patients with CVD or comparative and low HDL cholesterol were treated with dalcetrapib 600 mg or placebo for 36 weeks. Here, the primary endpoints evaluated were the change in brachial FMD after 12 and 36 weeks. Similar to prior studies, dalcetrapib treatment led to a 50% reduction in CETP activity and a 31% increase in HDL cholesterol. Levels of apo A-I were also increased, but there was no change to LDL cholesterol. Despite these favorable biochemical changes, no significant differences were observed for FMD at any point of the study. Ambulatory 24-hour systolic and diastolic blood pressures at 4, 12, and 36 weeks were not altered in the dalcetrapib arm, and there were no increases in nitric oxide-dependent endothelial function or markers of oxidative stress and inflammation.57 Unpublished studies in the dalcetrapib clinical program include dal-PLAQUE2, dal-ACUTE, and dal-OUTCOMES. Dal-PLAQUE2 was designed to evaluate dalcetrapibs effect on atherosclerosis by measuring coronary plaque in 900 patients by intravascular carotid B-mode ultrasound imaging and coronary angioplasty.61 Dal-ACUTE (“type”:”clinical-trial”,”attrs”:”text”:”NCT01323153″,”term_id”:”NCT01323153″NCT01323153) evaluated the use of dalcetrapib in 300 patients after acute coronary syndrome.59 The largest study, namely dal-OUTCOMES, was a multicenter, randomized, double-blinded, placebo-controlled Phase III trial60 that randomized 15,600 patients to either dalcetrapib or placebo 4 to 12 Ginsenoside Rh3 weeks after acute coronary syndrome. Patients were monitored for major cardiovascular events, including coronary artery disease death, acute MI, unstable angina requiring hospital admission, cardiac arrest, or stroke. In May 2012, Roche announced that it was terminating the dal-OUTCOMES trial 2 years early due to its lack of efficacy, and was simultaneously terminating the entire dalcetrapib program. Implications of termination of the dalcetrapib development program The CVD prevention community has been left somewhat shell-shocked after the recent turn of events related to dalcetrapib, which, to say the least, were unexpected and surprising. Dalcetrapib lacked the known off-target effects of torcetrapib. Further, dalcetrapibs contribution to the reduction of atherosclerotic progression and vascular inflammation without adversely affecting blood pressure or aldosterone56 seemed encouraging. But despite these encouraging safety and efficacy signals from the early-phase clinical trials, and the evidence favoring the unique mechanism of CETP modulation, the Phase III dal-OUTCOMES trial was terminated prematurely.62 Full details surrounding this termination should emerge soon, and hopefully there will be full publication of them. However, the termination appears to have been due to lack of Ginsenoside Rh3 efficacy rather than to increased risk of harm Ginsenoside Rh3 or deleterious effects.63 Considering the prior failures of ILLUMINATE and AIM-HIGH, dal-OUTCOMES adds further evidence that targeting HDL does not improve CVD risk. But is the HDL hypothesis wrong? Or does the way in which HDL is raised matter? Perhaps CETP inhibition is not the best way to raise HDL. Further evidence that HDL itself may simply be a biomarker rather than a causal factor for CVD came from recent genetic studies performed in tens of thousands of patients, which found (1) an inverse association of CHD risk in patients with genetically reduced CETP function64 and (2) that certain genetic variants that raise HDL over a lifetime do not lower risk of myocardial infarction.65 Although these results seem to further undermine the importance of HDL, it may.