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Purpose This article reviews therapies that affect HDLs. Findings Lipid-modifying agents in current use (including statins, fibrates, and niacin) increase the concentration of HDL cholesterol to some extent. However, these agents have additional effects (beyond raising HDL) with the potential to reduce atherosclerotic cardiovascular disease (ASCVD) risk, making it difficult to determine (one way or the other) whether an increase in HDL concentration affects risk. New investigational approaches targeting HDLs include infusions of reconstituted HDLs, reinfusion of selectively delipidated plasma in which the concentration of pre-β HDLs (the preferred acceptor of cell cholesterol) has been increased, and inhibitors of cholesteryl ester transfer protein (CETP). Positive results of the effects of reconstituted HDL infusions on coronary atheroma burden encourage further investigation of these agents. One small study on the effects of reinfusing selectively delipidated plasma has also provided results supporting additional development of this approach. CETP inhibitors are the most effective HDL-raising agents developed yet, with the ability to more than double the concentration of HDL cholesterol. They also reduce LDL cholesterol by up to 50%. Clinical outcome trials with the first 2 of these agents (torcetrapib and dalcetrapib) failed and, in the case of torcetrapib, treatment increased ASCVD events and increased both cardiovascular and noncardiovascular death. However, the subsequent discovery that torcetrapib had serious adverse effects unrelated to CETP inhibition meant that trials with this agent were unable to test the hypothesis that inhibiting CETP (or raising the level of HDL cholesterol) would translate into a reduction in ASCVD risk. The trial with dalcetrapib, a relatively weak inhibitor of CETP, was conducted in people soon after an acute coronary event when HDL functionality is impaired. The CETP inhibitor hypothesis will remain untested until completion of ongoing trials with CETP inhibitors that are more potent than dalcetrapib and that do not have the adverse effects of torcetrapib. Implications Positive trials with reconstituted HDL infusions and reinfusions of selectively delipidated plasma will establish HDLs as important therapeutic targets. However, although a positive result in the trials with CETP inhibitors will establish CETP inhibition as a valid strategy to reduce ASCVD risk, it will not be possible to determine with certainty whether the reduction in risk is the consequence of effects on the HDL fraction or whether it is the result of CETP inhibitor−mediated reductions in LDL cholesterol. [ABSTRACT FROM AUTHOR]