ATVB In Focus
Novel Approaches to the Treatment of Dyslipidemia
Disorders of plasma lipoprotein metabolism (“dyslipidemia”) play a major role in the initiation and progression of atherosclerotic cardiovascular disease (ASCVD). Low-density lipoproteins (LDL), as well as other atherogenic apoB-containing lipoproteins, are known to promote cholesterol accumulation in macrophages as well as inflammatory responses within the vessel wall, leading to atherosclerosis progression. In addition, high-density lipoproteins (HDL) and their major apolipoprotein, apoA-I, promote the efflux of cholesterol from macrophages, the first step in the process of reverse cholesterol transport, and have other antiinflammatory and antioxidant effects that may contribute to inhibition of atherosclerosis. Pharmacological treatment to reduce levels of atherogenic lipoproteins, particularly the use of 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase inhibitors, or statins, has been proven in multiple large clinical outcome trials to significantly reduce the risk of cardiovascular events, generally by about one-third over five years. Indeed, the reduction of cardiovascular risk with statin therapy has been one of the greatest advances in medicine over the last two decades, and the expanding use of statin therapy will undoubtedly contribute to an important reduction in atherosclerotic cardiovascular disease over the next several decades.
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However, the success of statin therapy has not eliminated the importance of continuing to develop new therapeutic approaches to the treatment of dyslipidemia. First, as the targets for lipid lowering therapy become ever more aggressive, it becomes more and more difficult for a substantial number of patients to achieve these aggressive targets using statins alone. Approximately only one-half of high risk patients with established coronary heart disease (CHD) or CHD risk equivalent status are able to reach the “optional” LDL cholesterol goal of <70 mg/dL using even the highest doses of the most potent statins. Therefore, there will continue to be a major need for drugs that can be used in combination with statins to allow patients to achieve aggressive LDL cholesterol and non-HDL cholesterol goals. Second, a substantial minority of individuals cannot tolerate statins or dose escalation of statins because of muscle pain. It is unclear what the true prevalence of this condition really is, but as the number of individuals who are candidates for statin therapy continues to expand well beyond 40 million individuals in the US alone, even a small percent of this number represents a substantial number of individuals intolerant to statins who require other pharmacological approaches to reducing atherogenic lipoproteins. Third, although statins are highly effective at reducing LDL cholesterol, many patients on statin therapy with well-controlled LDL cholesterol levels continue to have elevated triglycerides and non-HDL cholesterol levels and available evidence suggests that this presents an ongoing risk for these patients. There will be an increasing move toward using drugs in combination with statins that are more effective at reducing triglycerides and non-HDL cholesterol, particularly if atherosclerosis imaging and large outcome trials show that this approach further reduces cardiovascular risk. Fourth, low levels of HDL cholesterol continue to represent a major unmet medical need. Some data suggest that in patients treated with a statin, low HDL cholesterol is one of the most important risk factors for subsequent cardiovascular events. Therefore, new approaches to raise HDL cholesterol levels are needed. Finally, we must keep in mind that as effective as statins are at reducing cardiovascular risk, they reduce risk by only about one-third over five years. Therefore, we need to know more about what factors predict cardiovascular events in statin-treated patients. Undoubtedly, some of these factors will be related to other plasma lipid and lipoprotein fractions as noted above, and these will continue to be major targets for the development of new therapies.
Although some of the needs discussed above are met in part by existing non-statin therapies (such as bile acid sequestrants, cholesterol absorption inhibitors, fibrates, and niacin), unmet needs still exist. In light of this, there has been a renewed interest in academia and industry (both biotech and big pharma) in the development of novel approaches to the treatment of dyslipidemia for reduction in atherosclerosis and cardiovascular risk. The science around the molecular regulation of lipid and lipoprotein metabolism has advanced dramatically over the last two decades and has identified a variety of new molecular targets for the potential development of therapeutic approaches targeted toward lipid and lipoprotein metabolism. From a physiological standpoint, there are a variety of pathways that are of particular interest. The discovery of the cholesterol absorption inhibitor ezetimibe has substantially increased the role of the intestine in plasma lipoprotein metabolism and as a potential target for new pharmacological development. Much has been learned about the molecular regulation of hepatic VLDL assembly and secretion and, given that the majority of dyslipidemic individuals have overproduction of VLDL by the liver, this pathway presents an attractive target for the development of new therapeutic approaches. The complex pathways of HDL metabolism and reverse cholesterol transport present many potential attractive targets for the development of new therapeutic approaches; some involve the manipulation of HDL metabolism with the primary goal of raising plasma levels of HDL cholesterol, whereas others involve the manipulation of macrophage cholesterol and lipid efflux with the primary goal of promoting reverse cholesterol transport. The many enzymes that are carried on or interact with plasma lipoproteins are also attractive potential targets for the development of pharmacological inhibitors or promoters. Finally, the antiatherogenic effects of apolipoproteins such as apoA-I and apoE invite the concept of mimicking these effects through bioactive mimetic peptides.
Given the large amount of interest and activity in this broad area, the editors of Arteriosclerosis, Thrombosis, and Vascular Biology elected to launch a new series of brief reviews entitled “Novel Approaches to the Treatment of Dyslipidemia.” I am honored to have been asked to edit the series and am excited to introduce the series with the first of these brief reviews in this issue of ATVB. Hubert Chen and Bob Farese discuss the potential for DGAT1 as a target for pharmacological inhibition. Subsequent reviews in this series will cover a wide range of molecular approaches to dyslipidemia in development, including inhibition of cholesterol absorption, inhibition of hepatic VLDL assembly and secretion, influencing HDL metabolism, promoting reverse cholesterol transport, influencing lipoprotein-associated enzymes, and apolipoprotein mimetic peptides. We have invited world-class investigators in these areas to write timely, up-to-date reviews of these topics. We hope that this series will provide the readers of ATVB with a broad appreciation for the science and clinical potential underlying the dynamic area of novel approaches to the treatment of dyslipidemia.