The inverse relationship between high-density lipoprotein cholesterol (HDL‑C) levels and coronary heart disease (CHD) has stimulated interest in pharmacological agents that elevate plasma HDL. However, the recent unexpected association of torcetrapib — an agent that increases plasma HDL‑C — with increased cardiovas‑ cular mortality has led to the discontinuation of further trials involving this drug 1 . Furthermore, imaging trials using surrogate endpoints of atherosclerosis did not demonstrate any benefits attributable to torcetrapib 2–4 . As a result of these findings, questions regarding the effi‑ cacy and safety of HDL elevation as a strategy for CHD prevention have been raised. For a systematic review of all trials evaluating HDL‑C levels and atherosclerotic outcomes we refer the reader to a recently published article by Ansell and colleagues 5 . Here, we will discuss the importance of HDL in atherosclerosis, potential reasons for the failure of torcetrapib and future HDL‑ based strategies that might reduce or delay cardiovascular endpoints. The HDL particle: structure and function HDL structure. HDL particles are heterogeneous in shape, density, size and anti‑atherogenic properties. Their shape can range from discoidal to spherical with densities ranging between 1.063 and 1.21 g/mL. In addi‑ tion to a high protein content — approximately 50% by weight — HDL particles are composed of approximately 30% phospholipids, 25% cholesterol (of which about 70% is esterified) and 5% triglyceride. The larger spherical HDL particles contain a hydrophobic core of cholesteryl ester (CE) and triglyceride, whereas small discoidal HDL particles contain primarily apolipoprotein A-1 (APOA1) in a lipid monolayer that is composed of phospholipids and free cholesterol 6 . APOA1 and APOA2 are the major structural apolipo‑ proteins of HDL. APOA1 is present on most HDL particles and accounts for almost 70% of their protein content. Another 20% of HDL protein is contributed by APOA2, which is present on two‑thirds of HDL par‑ ticles 7 . Minor HDL protein components include other apolipoproteins (APOA4, APOA5, APOC1, APOC2, APOC3, APOD and APOE), enzymes involved in lipid metabolism or with possible antioxidant activities — such as lecithin–cholesterol acyltransferase (LCAT), lipoprotein‑associated phospholipase A 2 (also called platelet‑activating factor‑acetyl hydrolase, PAF‑AH), paraoxonase 1 (PON1) and glutathione selenoperoxi‑ dase (GPX) — as well as other proteins, such as serum amyloid A, α‑1‑antitrypsin and amyloid‑β 6 . HDL subclassifications and relationship to function. Plasma HDL‑C level is currently the most accessible laboratory measurement of HDL. However, HDL‑C simply quantifies the amount of cholesterol contained within the HDL lipoprotein fraction and does not neces‑ sarily correlate with the number of particles or with their net anti‑atherogenic properties. In research laboratories, HDL particles can be subclassified according to their size or density using two‑dimensional gel electrophoresis or density gradient ultracentrifugation, respectively, or by their apolipoprotein composition using immunological methods. Some evidence suggests that these subcategories define specific functional properties of HDL. Robarts Research Institute and Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada, N6A 5K8 Correspondence to R.A.H. e‑mail: hegele@robarts.ca doi:10.1038/nrd2489 High-density lipoprotein (HDL). A class of cholesterol- rich lipoprotein particles that drive the return of cholesterol from the periphery back to the liver; cholesterol carried by these particles is colloquially referred to as ‘good cholesterol’. Atherosclerosis A complex, multifactorial disease process that results in the development of arterial wall plaques, which can eventually occlude the arterial lumen and compromise blood flow, resulting in a heart attack or stroke depending on the affected arterial bed. Plasma lipids — especially cholesterol —in circulating lipoprotein particles have a key role at several stages of atherosclerosis. Is raising HDL a futile strategy for atheroprotection? Tisha Joy and Robert A. Hegele Abstract | The dramatic failure of clinical trials evaluating the cholesterol ester transfer protein inhibitor torcetrapib has led to considerable doubt about the value of raising high-density lipoprotein cholesterol (HDL-C) as a treatment for cardiovascular disease. These results have underscored the intricacy of HDL metabolism, with functional quality perhaps being a more important consideration than the circulating quantity of HDL. As a result, HDL-based therapeutics that maintain or enhance HDL functionality warrant closer investigation. In this article, we review the complexity of HDL metabolism, discuss clinical-trial data for HDL-raising agents, including possible reasons for the failure of torcetrapib, and consider the potential for future HDL-based therapies. REVIEWS NATURE REVIEWS | DRUG DISCOVERY VOLUME 7 | FEBRUARY 2008 | 143 © 2008 Nature Publishing Group