New Challenges for HDL-Modifying Therapies as a Strategy to Lower Cardiovascular Disease Events in Statin-Treated Patients

High density lipoproteins (HDL) represent diverse subpopulations of particles that are heterogeneous in their physicochemical composition and functionality [1–3]. The cholesterol content of HDL particles, HDL cholesterol, has been used as a biomarker of atherosclerotic cardiovascular disease risk, and a target for pharmaceutical intervention [4]. Sincemany of these clinical trials were initiated, there have been transformational changes in our understanding of HDL biology and function such that increasing the cholesterol content of HDL is a failed therapeutic strategy [3, 4]. Among high-risk individuals treated with high-intensity statin therapy, low HDL-C has not been a consistent biomarker of cardiovascular events [5, 6]. In the Treating to New Targets (TNT) trial, atorvastatin-treated patients who achieved low density lipoprotein (LDL) cholesterol levels less than 70 mg/dL, recurrent cardiovascular events were higher among subgroups with low HDL cholesterol levels [7]. However, this association may have been confounded by the higher apolipoprotein B, the major protein on atherogenic lipoproteins, in the subgroups of patients with low HDL cholesterol levels. Low HDL cholesterol is also considered a biomarker of elevated triglyceride-rich lipoproteins as shown in Mendelian randomization studies [9]. In contrast to HDL cholesterol, HDL particle number is more strongly associated with increased cardiovascular risk in statin-treated individuals [6]. In JUPITER, a primary prevention trial of individuals at high risk for an initial cardiovascular event, on-trial levels of HDL cholesterol were not associated with cardiovascular risk in rosuvastatin-treated individuals [10]. In contrast, low ontrial levels of HDL particles were predictive of cardiovascular events. Cholesteryl ester transfer protein (CETP) is a plasma protein that facilitates exchange of neutral lipid between lipoprotein particles resulting in lower concentrations of VLDL and LDL particles without necessarily changing HDL particle concentration with the exception of dalcetrapib that had modest effects of increasing HDL particle concentration [10]. In a Mendelian randomization study that included 16,503 cases and 46,576 controls, the CETP polymorphism rs3764261 on chromosome 16q13 were associated with higher levels of HDL cholesterol (3.86 mg/dL per allele) and lower levels of LDL cholesterol (-1.16 mg/dL per allele) [8]. Carriers of the rs3764261 trait had a 4 % lower risk of myocardial infarction than non-carriers. Thus, CETP inhibition is a potential strategy for lowering cardiovascular events based on pharmacogenomics. Two clinical outcomes trials have been completed with CETP inhibitors [11, 12]. The ILLUSTRATE trial investigated the efficacy of the CETP inhibitor torcetrapib as a strategy to reduce the risk of recurrent events in atorvastatin-treated patients with stable coronary heart disease [11]. As compared with baseline values, torcetrapib increased HDL cholesterol by 72.1 %, and lowered LDL cholesterol and triglycerides by 24.9 and 9 %, respectively. Due to a higher mortality rate R. S. Rosenson (*) Mount Sinai Heart, Mount Sinai Icahn School of Medicine, New York, NY, USA e-mail: robert.rosenson@mssm.edu