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Logo of jlrJournal of Lipid Research
J Lipid Res. 2012 September; 53(9): 1719–1721.
PMCID: PMC3413215

New lipid and lipoprotein targets for the treatment of cardiometabolic diseases

Stanley L. Hazen, Associate Editor1

Lifestyle and dietary efforts have known benefits for the prevention of cardiovascular disease (CVD) (1, 2). In addition, prescriptive approaches for cardiovascular risk reduction include treatment of elevated blood pressure and anti-platelet therapy with low dose aspirin, particularly within subjects at higher risk such as those with known CVD (3, 4). Beyond these interventions, our current pharmacopoeia for the prevention and treatment of CVD is in large part based upon manipulation of lipid and lipoprotein targets. The dose-dependent relationship between circulating levels of low density lipoprotein (LDL) cholesterol and incident CVD risks in population studies (5) and the unequivocal benefit of therapies that lower LDL (6, 7) have prompted its central role in the approach to risk prediction and preventive strategies. Yet, although high potency statin therapy has proven efficacy for both primary and secondary prevention subjects (68), many patients with established CVD have “normal” LDL levels, though likely above ideal (9), often without clear alternative risk factors. Although some experts feel the current LDL target goals are still too high, many subjects cannot even reach these goals, much less the lower treatment goals now being advocated with current agents. Thus, there is significant unmet need for additional agents to help subjects achieve appropriate therapeutic targets. Further, the polygenetic/causal nature of CVD suggests that there are additional factors that play contributory roles in the development and progression of CVD, which have yet to be appropriately leveraged as therapeutic targets. Indeed, subjects with CVD are already typically placed on poly-pharmacy, yet substantial residual risk still exists and few new agents have made it to use in the past decade in patient care for prevention of CVD and its complications. Cardiovascular therapeutics faces significant hurdles and the demonstration of a new drug with proven efficacy for reduction in hard endpoints (incident heart attack, stroke, and death) on top of high potency statin therapy has yet to be realized.

Despite these obstacles, the magnitude of the problem is staggering, and “the prize” for those who usher in the next generation of cardiovascular therapeutics cannot be underestimated. While mortality rates from CVD have reduced, the prevalence of major risk factors like obesity and diabetes are rising. Fully one in three individuals in industrialized societies will be affected by CVD and approximately one in three subjects will die from CVD (10). With CVD as the single largest cause of morbidity and mortality in industrial societies and the significant healthcare burden of obesity and diabetes, it is perhaps not too surprising that a multitude of novel therapeutic approaches are under investigation with many already undergoing early clinical trials in humans.

In this issue of the Journal of Lipid Research, we launch the first installment of a series of review articles for a new Thematic Review Series entitled “New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases”. In the first review, Bart Staels and colleagues (11) discuss “Bile acid receptors as targets for the treatment of dyslipidemia and cardiovascular diseases”. Bile acid sequestrants were among the first lipid lowering agents with proven efficacy in LDL lowering and CVD event risk reduction in use (12). By binding and facilitating gastrointestinal elimination of bile acids, a net reduction in bile acid pool size is achieved, prompting hepatic cholesterol consumption for increased bile acid synthesis. Accompanying increases in hepatic LDL receptor levels promote a net decrease in circulating LDL cholesterol levels. Although effective at lowering LDL cholesterol and CVD events, their clinical use has been somewhat limited by side effects (e.g., triglyceride elevations, gastrointestinal issues). Their widespread use demonstrated numerous additional metabolic effects, particularly in type 2 diabetic subjects, where reductions in fasting glucose and changes in energy metabolism are observed. The two receptors mediating these phenomena, the nuclear farnesoid X receptor (FXR) and the G-protein coupled receptor TGR5, have emerged as novel targets of glucose metabolism, weight loss, and regulation of inflammation. In their review, Dr. Staels and colleagues focus on recent advances in the understanding of bile acid metabolism as well as the role of FXR and TGR5 in lipid, glucose, and energy metabolism. Further, they review how both receptors are pharmacological targets under investigation for the treatment of atherosclerotic CVD, as well as a variety of metabolic disorders including cholestasis, hyperlipidemia, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, obesity, and type 2 diabetes mellitus. Up-to-date information is provided on the current state of preclinical and clinical studies with various FXR and TGR5 agonists as well as selective bile acid receptor modulators.

The complex world of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists is elegantly summarized by Gregory Schwartz and colleagues (13) in their review entitled ” PPAR-γ as a therapeutic target in cardiovascular disease: evidence and uncertainty”. Both fundamental basic science aspects of PPAR-γ functions in multiple cell types and pathways are discussed along with results of seminal clinical trials for different agents within this class of drugs. The varied biological effects of distinct full PPAR-γ agonists are described with summaries of major clinical trials using these agents in diabetes subjects and among subjects with CVD. Ongoing pivotal clinical trials with PPAR-γ activators in patients with CVD are also summarized. In addition, some new PPAR-γ activators under development are reviewed, including both dual PPAR-α/γ agonists and selective partial PPAR-γ agonists, in the hope that these latter agents provide the established beneficial insulin sensitizing effects of this class of drugs but without the adverse effects observed.

Philip Barter and Kerry Anne Rye (14) extensively review the rapidly evolving world of cholesterol ester transfer protein inhibitors in their article entitled “Cholesterol ester transfer protein inhibition as a strategy to reduce cardiovascular risk”. In addition to an extensive review of the mechanism and biological function of CETP in lipoprotein metabolism, Drs. Barter and Rye detail the impact of CETP on lipoprotein composition, concentration, and structure, and genetic and clinical evidence linking CETP to atherosclerosis in animals and humans. Drs. Barter and Rye then extensively review the current state of the field with various small molecule CETP inhibitors including recent results of clinical trials. They start with the seminal clinical outcomes trials with torcetrapib and a thorough discussion of on and off target effects of the drug. They next review the recent results of trials with dalcetrapib and then discuss ongoing and potential planned clinical trials with other CETP inhibitors including anacetrapib and evacetrapib. Finally, controversies and unanswered questions related to CETP inhibition are discussed.

Robert Rosenson and Diana Stafforini (15) provide a thorough review of a novel therapeutic target in phase III clinical studies in humans in their paper entitled “Modulation of oxidative stress, inflammation, and atherosclerosis by lipoprotein-associated phospholipase A2”. They begin by reviewing evidence demonstrating lipoprotein-associated phospholipase A2 (Lp-PLA2) as both a novel diagnostic marker for CVD risks and a potential therapeutic target for atherosclerotic CVD. The biology, structure, cellular sources, and regulation of Lp-PLA2 are initially reviewed along with the multitude of clinical studies examining Lp-PLA2 mass and activity in various clinical cohorts of subjects across the spectrum of CVD. Genetic studies of Lp-PLA2 in animal models and humans are then reviewed. Finally, the current state of preclinical studies and past and ongoing clinical trial data with darapladib, the first Lp-PLA2 inhibitor to be tested in humans, is extensively reviewed and discussed.

Lecithin:cholesterol acyltransferase (LCAT) is the focus of the review by Sandra Kunnan and Miranda van Eck (16) entitled “Lecithin:cholesterol acyltransferase: old friend or foe in atherosclerosis?”. Over half a century ago, Glomset (17) identified LCAT as the key protein mediating cholesterol esterification and “plasma fatty acid trasferase” activity. Over the ensuing 50 years, numerous studies have focused on LCAT as a pivotal enzyme in HDL maturation and remodeling, yet its role in reverse cholesterol transport and atherosclerotic CVD remains in debate. In this review, the structure, function, and role of LCAT in atherosclerosis in multiple animal models and humans are extensively discussed. In addition, insights into the role of LCAT in CVD and other processes through genetic studies are discussed. Finally, efforts to increase LCAT levels by a variety of strategies as a novel CVD therapeutic are reviewed.

These are exciting times in the cardiometabolic pharmacology arena, with a large number of novel therapeutic targets under investigation. We hope that the readers of the JLR enjoy the present and future review articles that will be forthcoming in the Thematic Review Series “New Lipid and Lipoprotein Targets for the Treatment of Cardiometabolic Diseases”.


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Articles from Journal of Lipid Research are provided here courtesy of American Society for Biochemistry and Molecular Biology