Diabetes Volume 65, July 2016 1767 Changting Xiao,1 Satya Dash,1 Cecilia Morgantini,1 Robert A. Hegele,2 and Gary F. Lewis1 Pharmacological Targeting of the Atherogenic Dyslipidemia Complex: The Next Frontier in CVD Prevention Beyond Lowering LDL Cholesterol Diabetes 2016;65:1767–1778 | DOI: 10.2337/db16-0046 Notwithstanding the effectiveness of lowering LDL cho- has been the primary goal of dyslipidemia management, lesterol, residual CVD risk remains in high-risk popula- with statins as the treatment of choice for CVD prevention. tions, including patients with diabetes, likely contributed Large-scale, randomized, clinical trials of LDL-lowering PERSPECTIVES IN DIABETES to by non-LDL lipid abnormalities. In this Perspectives therapies have demonstrated significant reduction in CVD in Diabetes article, we emphasize that changing demo- events over a wide range of baseline LDL-C levels (2,3). graphics and lifestyles over the past few decades have However, even with LDL-C levels lowered substantially or “ resulted in an epidemic of the atherogenic dyslipidemia at treatment goals with statin therapy, CVD risks are not ” complex, the main features of which include hypertrigly- eliminated and there remains significant “residual risk.” In- ceridemia, low HDL cholesterol levels, qualitative changes tensifying statin therapy may provide additional benefits in LDL particles, accumulation of remnant lipoproteins, (4,5); this approach, however, has limited potential, owing and postprandial hyperlipidemia. We brieflyreviewthe to tolerability, side effects, and finite efficacy. Further LDL-C underlying pathophysiology of this form of dyslipidemia, lowering may also be achieved with the use of nonstatin in particular its association with insulin resistance, obe- sity, and type 2 diabetes, and the marked atherogenicity agents, such as cholesterol absorption inhibitors and PCSK9 of this condition. We explain the failure of existing classes inhibitors, added to statin therapy. In patients with acute of therapeutic agents such as fibrates, niacin, and cho- coronary syndrome, ezetimibe, when added to statin ther- fi lesteryl ester transfer protein inhibitors that are known to apy, signi cantly improved CVD outcomes, in which im- modify components of the atherogenic dyslipidemia com- provement was proportional to LDL-C reduction (6). plex. Finally, we discuss targeted repurposing of existing Additional benefits of PCSK9 inhibitors on CVD outcomes therapies and review promising new therapeutic strate- are anticipated, considering their efficacy in further low- gies to modify the atherogenic dyslipidemia complex. We ering LDL-C levels when added to statin therapy (7). How- postulate that targeting the central abnormality of the ath- ever, it remains to be established to what extent LDL-C can erogenic dyslipidemia complex, the elevation of triglyceride- be safely reduced and whether earlier treatment or extreme rich lipoprotein particles, represents a new frontier in CVD LDL-C lowering alone is sufficient for CVD risk reduction. prevention and is likely to prove the most effective strategy The intent of this Perspective is to highlight an additional in correcting most aspects of the atherogenic dyslipidemia form of highly prevalent dyslipidemia, the atherogenic complex, thereby preventing CVD events. dyslipidemia complex, which represents a promising therapeu- tic target for further prevention of atherosclerotic CVD beyond LDL-C lowering. We fully acknowledge that lifestyle modifi- Epidemiological, genetic, and animal studies and random- cation (e.g., body weight reduction in overweight or obese ized, controlled clinical trials support a central role for LDL individuals and an increase in physical activity), if successfully cholesterol (LDL-C) in the development of atherosclerotic implemented, remains the cornerstone of therapy for the cardiovascular disease (CVD) events (1). LDL-C lowering atherogenic dyslipidemia complex. Other nonlipid CVD risk 1Departments of Medicine and Physiology and the Banting & Best Diabetes Received 10 January 2016 and accepted 23 March 2016. Centre, University of Toronto, Toronto, Ontario, Canada © 2016 by the American Diabetes Association. Readers may use this article as 2 Robarts Research Institute, Schulich School of Medicine and Dentistry, Western long as the work is properly cited, the use is educational and not for profit, and University, London, Ontario, Canada the work is not altered. Corresponding author: Gary F. Lewis, [email protected]. 1768 Atherogenic Dyslipidemia Complex and CVD Diabetes Volume 65, July 2016 factor modifications, such as smoking cessation and antihy- world. The presence of high TG and low HDL-C levels, pertensive, antiplatelet, and anti-inflammatory therapies, have concurrent with high LDL-C levels, increased CVD risks in also been shown to effectively reduce the risk of CVD. A the Scandinavian Simvastatin Survival Study (16) and in review of nonlipid CVD risk factor modifications is beyond the the Helsinki Heart Study (17). Likewise, TG levels were scope of this Perspective, which focuses instead on pharma- strongly and independently associated with coronary cological modulation of the atherogenic dyslipidemia complex. heart disease risk in a meta-analysis of 29 prospective studies (18). Nonfasting TG level, which may reflect the THE ATHEROGENIC DYSLIPIDEMIA COMPLEX atherogenic capacity of TRL remnants, is a stronger pre- AND ITS RELATION TO ATHEROSCLEROTIC dictor of CVD events than fasting TG levels (19,20). Be- DISEASE cause most people are in the postprandial state for many The fourth quarter of the 20th century heralded the onset hours each day, changes in postprandial lipid levels may of a worldwide epidemic of obesity, metabolic syndrome, have an important impact on atherosclerosis development. and type 2 diabetes (T2D). These conditions are associ- Atherogenic properties have been assigned to athero- ated with a cluster of lipid and lipoprotein abnormalities, genic dyslipidemia complex components, as has been the presence of which has increased in parallel with these reviewed for TRL levels (21), remnant lipoprotein levels conditions (8). Such lipid and lipoprotein abnormalities (22), postprandial lipemia (23), nonfasting TG levels (24), have been referred to as the “atherogenic lipoprotein phe- sdLDL particles (25), and the antiatherosclerotic proper- notype” (9) or “atherogenic dyslipidemia” (10), which im- ties of HDL (26). Epidemiological or observational ap- ply a causal relationship between the phenotype and proaches are not suited to unravel causality, hence the atherosclerosis. As discussed below, atherogenicity can ongoing debate as to which individual component or com- only be attributed to the collective lipid/lipoprotein ab- ponents play a direct role in atherosclerosis. One should normality as a whole complex, but not to a specific fea- also bear in mind that the associated chronic inflamma- ture. Also, as discussed below, the features of this cluster tion, increased levels of prothrombotic factors, perturbed of lipid/lipoprotein abnormalities intertwine in their me- tissue factors, insulin resistance, and hyperglycemia play tabolism converging on triglyceride (TG)-rich lipoproteins important roles in promoting atherosclerosis. The inabil- (TRLs). This atherogenic dyslipidemia complex is charac- ity to disentangle individual components of the athero- terized by the presence of the following cluster of abnor- genic dyslipidemia complex and clearly implicate direct malities: hypertriglyceridemia (HTG; indicative of an roles of each in atherogenesis suggests that the phenotype elevation of TRLs), low HDL cholesterol (HDL-C) levels, is likely multidimensional and that continued efforts to high small dense LDL (sdLDL) levels, elevated levels of reduce causality to a single component might be mis- remnant lipoproteins, and postprandial hyperlipidemia. guided. Indeed, individual components of the atherogenic There is currently no uniformly accepted definition of dyslipidemia complex seldom exist in isolation; instead, the atherogenic dyslipidemia complex or its component they often present as a cluster because of their interrelated parts, nor would a strict definition necessarily add clarity, as metabolism and etiology (see below). In addition, most ther- was evidenced by a much criticized attempt to propose a apies aimed primarily at correcting a certain lipid moiety, as working definition of the metabolic syndrome (11). Further- well as lifestyle modification, improve multiple components more, certain characteristic abnormalities of the atherogenic of the atherogenic dyslipidemia complex simultaneously. dyslipidemia complex, such as postprandial hyperlipid- In contrast with elevated LDL-C or apoB levels, simple emia, sdLDL particles, and remnant lipoproteins, have biomarkers to assess the atherogenicity of the atherogenic not typically been measured in large-scale population stud- dyslipidemia complex are not well defined. Aside from plasma ies.Asaresult,thetrueprevalenceofthecomplexiscur- levels of TG, HDL-C, non-HDL-C, and ratios of these lipid rently unknown. Nevertheless, because several features of parameters, various methodologies besides standard assays of the atherogenic dyslipidemia complex are integral compo- plasma lipids are available for the assessment of atherogenic nents of the metabolic syndrome (12), and metabolic syn- dyslipidemia complex components. Specialized analyses, such drome affects nearly 35% of all adults and 50% of those .60 as gradient gel electrophoresis, vertical