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Cholesteryl ester transfer protein (CETP) plays an important role in reverse cholesterol transport and the maintenance of cholesterol homeostasis. The consequences of CETP activity are influenced by triglyceride (TG) levels. When TG levels are increased, CETP promotes transfer of cholesteryl esters to VLDL and the generation of atherogenic dyslipidemia. Combined activities of CETP and hepatic lipase in the presence of TG-rich lipoproteins generate small, dense HDL and LDL particles. Inhibition of CETP may reduce the risk of atherosclerosis in patients with dyslipidemia. Decreasing CETP activity has consistently inhibited atherosclerosis in animal models. Three small-molecule CETP inhibitors, dalcetrapib, torcetrapib, and anacetrapib, have been or are being tested in phase 3 clinical studies. All three demonstrated potentially beneficial effects on the lipid profile in patients with dyslipidemia. Imaging studies with torcetrapib failed to show an effect on atherosclerosis in humans, probably because of the off-target effect on the RAAS. Preclinical evidence suggests that dalcetrapib seems to lack the off-target adverse effects on the RAAS that potentially caused the clinical development of torcetrapib to be halted. The lack of adverse effects on the RAAS remains to be confirmed in phase 3 studies with dalcetrapib. CETP inhibition as a therapeutic strategy remains a valid option to be tested with a CETP inhibitor that does not share torcetrapib's off-target effects.

Background Although low-density lipoprotein cholesterol (LDL-C) traditionally has been the focus of treatment guidelines and clinical trials of lipid therapy, patients continue to have cardiovascular disease (CVD) events despite effective lowering of their LDL-C levels, suggesting the influence of other risk factors. High-density lipoprotein cholesterol (HDL-C) levels have been shown to be inversely associated with CVD risk in epidemiological studies. Methods Meta-analyses and clinical trials that reported on the potential relation between HDL-C and CVD were reviewed. Results Low HDL-C level is associated with increased CVD risk. Statins reduce CVD events in patients with low HDL-C, and fibrates benefit patients with low HDL-C and high triglyceride levels. The benefit of statins on event reduction may be related to their effects on HDL-C. However, not all therapies that increase HDL-C reduce CVD events. Imaging trials have provided evidence of the combined influence of HDL-C and LDL-C on surrogate end points. Conclusion Drugs in the same class may have different effects on HDL-C, and these different lipid effects may translate into different effects on atherosclerosis and CVD events. A new class of agents, cholesteryl ester transfer protein inhibitors, is being examined in ongoing trials to determine whether dalcetrapib may have different effects than torcetrapib, which increased levels of HDL-C but was associated with increased adverse events. In addition, ongoing trials are examining whether targeting both HDL-C and LDL-C, by combining a second agent such as niacin with a statin, leads to greater benefit on CVD and clinical events.

Synopsis: Statins reduce cardiovascular events; however, limitations to therapy include poor adherence and persistence, cost, and adverse events. An alternative and more flexible dosing strategy, such as a once-weekly (Qwk) regimen, may potentially limit these common barriers. Purpose: We hypothesized a high-dose Qwk statin regimen would produce comparable lipid changes and safety measures as standard daily dosing. Methods: Participants were randomized to either rosuvastatin 80mgQwk (n5 10) or atorvastatin 10mgdaily (n5 10) in an 8-week double-blind pilot study. Lipid profiles, high-sensitivity C-reactive protein, hepatic panels, and creatinine kinase were assessed at baseline, and 1-4 and 5-8 days after last dose. Results: Both treatments produced significant reductions (P, .05) in total cholesterol and LDL-C from baseline to 1-4 and 5-8 days after last dose (Table). No significant differences were noted between the two groups for changes in HDL-C, triglycerides, and high-sensitivity C-reactive protein. Each treatment was well tolerated with no serious adverse events.

Results: Fifty-eight patients were randomized (39MIPO, 19 PBO) at 26 clinical centers in 6 countries. Forty-five (78%) patients completed the treatment period. Twelve (31%) MIPO and 1 (5%) PBO patient(s) withdrew (8 of the MIPO and the 1 PBO withdrawals were caused by an adverse event [AE]). LDL-C was reduced by 36% from a mean baseline level of 276 mg/dL in the MIPO group vs. an increase of 13% from a BL of 249 mg/dL in the PBO group (p , 0.001). This represents a 101 mg/dL mean reduction of LDL-C in theMIPOgroup. Similarly,MIPOproduced highly significant (P , .001) reductions in other atherogenic lipoproteins, eg, ApoB and Lp(a), there was no change in HDL-C. The most common on-treatment AEs were injection site reactions (90%MIPO, 32% PBO) and flu-like symptoms (46% MIPO, 21% PBO). Six (15%) MIPO patients and no PBO patients had ALT $3!ULN on consecutive measures at least 7 days apart. One MIPO patient had a transient ALT $10! ULN. ALT elevations were not associated with clinically significant increases in bilirubin. Conclusions: MIPO treatment significantly reduced LDL-C and ApoB in patients with severe hypercholesterolemia. The data support the potential utility of MIPO as a pharmacologic option for additional LDL C lowering in patients with heterozygous hypercholesterolemia not adequately controlled under existing LLTs.