EDITORIAL COMMENT
Treating Residual Cardiovascular RiskWill Lipoprotein-Associated Phospholipase A2 Inhibition Live Up to Its Promise?*
Wolfgang Koenig, MD, FRCP, FESC, FAHA, FACC*
Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Ulm, Germany.
* Reprint requests and correspondence: Dr. Wolfgang Koenig, Department of Internal Medicine II–Cardiology, University of Ulm Medical Center, Robert-Koch Str. 8, D-89081 Ulm, Germany. (Email: wolfgang.koenig{at}uniklinik-ulm.de).
Cardiovascular diseases (CVDs), including coronary heart disease (CHD) as the largest contributor, represent the major cause of death worldwide and will continue to increase in the future, owing to aging of the population, the epidemic of obesity and the metabolic syndrome including type 2 diabetes mellitus, and the rapid transition of developing countries into industrialized nations and their acquisition of cardiovascular risk factors. Such a perspective will become reality despite an enormous advancement in our understanding of the pathophysiology of atherothrombosis, identification of treatable risk factors, and the development of an armamentarium of potent drugs to combat this widespread disease, including statins, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and antiplatelet drugs. Nevertheless, between 1980 and 2000, a remarkable reduction of CHD deaths primarily in the elderly has been observed in several countries, including the U.S., where deaths were reduced by approximately 50% (1). About 40% of the total reduction in CHD deaths has been attributed to various therapeutic strategies like aggressive treatment in secondary prevention after myocardial infarction (MI), initial revascularization for acute MI, and treatment of heart failure, and more than 50% was related to reduction in risk factors (of which reduction in cholesterol and blood pressure accounted for 24% and 20%, respectively, and another 20% by reduction in smoking and increase in physical activity). However, these positive trends might level off soon, in particular in younger age groups, owing to the counteracting developments just described.
Statins have been proven most efficacious in numerous randomized controlled clinical trials, resulting in a profound reduction of relative risk (RRR) for a first MI or a recurrent MI between 19% and 38% (2). A recent meta-analysis investigating the effects of 2 ACE inhibitors, ramipril and perindopril, found a 27% RRR in the group already aggressively pre-treated with revascularization, anti-platelets, lipid-lowering drugs, and beta-blockers (3). Similar results have been obtained for aspirin and thienopyridines like clopidogrel. However, in diabetic patients, even intensive treatment including lifestyle changes and control of glucose, blood pressure, and lipids was still associated with a 19% CVD event rate over 5 years compared with even 32% in the conventionally treated group (4). Unfortunately, the individual risk reductions achieved by each drug group do not add up, leaving us with an RRR of 30% to 40% at best, even in populations receiving aggressive polypharmacy. Conversely, this means that 60% to 70% of patients do experience an event despite the best available medical treatment.
Such data clearly raise the question: how to improve the current situation? One point certainly relates to an improvement in the control of risk factors through lifestyle changes and the achievement of better compliance of patients in primary prevention in whom drug therapy is indicated. An alternative strategy might consist in the development of new drugs that would be complementary to the presently available compounds. Because modification of the lipid profile has been proven to be the most effective intervention to reduce CHD events, great efforts are being undertaken by the pharmaceutical industry to develop new candidates in this area or to improve pharmacokinetics and side effects of older compounds, such as drugs to further modify low-density lipoprotein cholesterol (LDL-C) or high-density lipoprotein cholesterol (HDL-C). In addition, basic and clinical research have convincingly demonstrated that atherosclerosis carries several typical features of a local and systemic inflammatory process (5). Thus, intervening with various modulators of plaque biology that are directly involved in inflammatory and destabilizing processes in the plaque might also be promising. Lipoprotein-associated phospholipase A2 (Lp-PLA2) might be such a candidate that could represent a link between lipid metabolism and the inflammatory response.
Lipoprotein-associated phospholipase A2, a 45.4 kDa protein, is a calcium-independent member of the phospholipase A2 family (reviewed in [6]) that is mainly produced by monocytes, macrophages, T-lymphocytes, and mast cells. In the bloodstream, two-thirds of the Lp-PLA2 circulates primarily bound to LDL-C; the other one-third is distributed between HDL-C and very-low-density lipoproteins. Furthermore, Lp-PLA2 has been detected in both rabbit and human atherosclerotic lesions. Moreover, in investigating Lp-PLA2 expression in coronary segments from sudden coronary death patients, a strong expression of this enzyme within the fibrous cap of coronary lesions prone to rupture was found, whereas in less advanced lesions, Lp-PLA2 expression was relatively low or even absent. The Lp-PLA2 might act pro-atherogenic by its ability to promote oxidation of LDL-C. After LDL oxidation within the arterial wall, Lp-PLA2 cleaves an oxidized phosphatidylcholine component of the lipoprotein particle, generating 2 potent pro-inflammatory and pro-atherogenic mediators, namely lysophosphatidylcholine (LysoPC) and oxidized fatty acid. Pro-inflammatory actions of LysoPC as well as those of oxidized fatty acid trigger a cascade of events that might directly promote atherogenesis. The LysoPC is a potent chemoattractant for T-cells and monocytes, promotes endothelial cell dysfunction, stimulates macrophage proliferation, and induces apoptosis in smooth muscle cells and macrophages. Thus, Lp-PLA2 might represent an important "missing link" between the oxidative modification of low-density lipoprotein in the arterial vascular wall and local inflammatory processes within the atherosclerotic plaque.
Over the last 7 years, a large body of evidence has been accumulated that demonstrates that increased circulating concentrations of Lp-PLA2 mass or elevated activity of the enzyme are positively associated with various cardiovascular end points. Such results have been reported in initially healthy subjects from representative population-based studies as well as in patients with manifest CHD (6), although the association was not stronger than that for other emerging biomarkers, such as C-reactive protein (CRP), but rather showed an additive value in conjunction with this molecule. There were some controversial results concerning the association of Lp-PLA2 with subclinical atherosclerotic disease, but a recent report (7) demonstrated that Lp-PLA2 was independently associated with coronary artery endothelial dysfunction, an established precursor of manifest atherosclerosis, and was a strong predictor of endothelial dysfunction in humans. In addition, the same group (8) showed local production of Lp-PLA2 in early atherosclerosis and that LysoPC, the active product of Lp-PLA2, was associated with endothelial dysfunction. Thus, evidence on various scientific levels argues for a direct involvement of Lp-PLA2 in the atherosclerotic process.
The Lp-PLA2 could also represent an attractive novel therapeutic target, because azetidinones, a new class of compounds acting as acylating inhibitors of the enzymatic activity of Lp-PLA2, have shown the ability to interfere with the biological (toxic) sequelae of oxidized LDL, namely chemoattraction of monocytes and apoptosis in macrophages (6). Decreased accumulation of LysoPC and oxidized fatty acid contents were also seen with this compound. Moreover, experimental studies in Watanabe heritable hyperlipidemic rabbits have shown a 95% inhibition of Lp-PLA2 in atherosclerotic plaque and a reduction of atherosclerotic lesion formation (6). In addition, oral administration of an Lp-PLA2 inhibitor to healthy volunteers in a phase I clinical trial demonstrated almost the same dose-dependent reduction in Lp-PLA2 activity of up to 95%, thereby identifying this compound as a very potent Lp-PLA2 inhibitor with a suitable profile for evaluation in humans (6). Furthermore, results from an early phase II trial showed that administration of 40 and 80 mg of SB-480848 (darapladib) to patients for 14 days before carotid endarterectomy resulted in the inhibition of Lp-PLA2 plasma activity by 52% and 81%, respectively, and the inhibition of Lp-PLA2 plaque activity by 52% and 80%, respectively, compared with placebo (6).
In this issue of the Journal, Mohler et al. (9) present data from a large multicenter, randomized double-blind placebo-controlled trial investigating the effect of darapladib (SB-480848), a selective Lp-PLA2 inhibitor, on Lp-PLA2 activity and a panel of biomarkers reflecting different pathways of the pathophysiology of atherosclerosis. The study population comprised of 959 patients with stable CHD or CHD risk equivalents; all were on a polypharmacy regimen and treated with 3 different doses of darapladib (40, 80, and 160 mg) over 12 weeks against a background of atorvastatin 20 and 80 mg. Most importantly, no safety concerns were noted. Darapladib inhibited Lp-PLA2 activity in a dose-dependent manner in both statin groups at different LDL-C levels but did not affect LDL-C levels. At 12 weeks, darapladib in the highest dose significantly decreased interleukin-6 and showed a trend to decreased CRP concentrations. There were no effects on myeloperoxidase and matrix metalloproteinase-9, which might have been owing to analytic problems, and no alteration of markers of platelet function was seen.
What do these data tell us? First, it is reassuring that no safety issues were reported in almost 1,000 high-risk patients, although the treatment period was only 3 months. Thus, we do not know whether there is a potential for adverse effects long-term. Second, this study investigated blood biomarkers as surrogates of atherosclerosis risk, and although the effects were not dramatic and seen only with the highest dose, they point in the right direction. However, even if there was no signal of harm in the biomarker profile, it has to be kept in mind that recent experience from several trials has painfully demonstrated the limitations of surrogate markers in the assessment of drug efficacy. Third, this study does not provide information on what is going on inside the vessel wall itself after inhibition of Lp-PLA2 activity. This issue is presently addressed in the IBIS-2 (Integrated Biomarker and Imaging Study) using intravascular ultrasound grey scale information, virtual histology, and palpography in 330 patients with stable CHD or acute coronary syndrome, treated with darapladib for 12 months (9).
In summary, the study by Mohler et al. (10) shows that darapladib substantially inhibits plasma Lp-PLA2 activity and suggests a modulation of the systemic inflammatory response in the presence of intensive statin therapy. Because inflammation plays a pivotal role in atherothrombosis and its clinical complications, inhibition of Lp-PLA2 might have promise as a suitable strategy to combat residual cardiovascular risk in carefully selected patients.
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Footnotes
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The author has received honoraria for lectures from GlaxoSmithKline, the manufacturer of darapladib, and has been a member of an advisory board to GlaxoSmithKline.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980–2000 N Engl J Med 2007;356:2388-2398.[Abstract/Free Full Text]2. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction J Am Coll Cardiol 2005;46:1225-1228.[Abstract/Free Full Text] 3. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-converting-enzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials Lancet 2006;368:581-588.[CrossRef][Web of Science][Medline] 4. Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes N Engl J Med 2003;348:383-393.[Abstract/Free Full Text] 5. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease N Engl J Med 2005;352:1685-1695.[Free Full Text] 6. Khuseyinova N, Koenig W. Predicting the risk of cardiovascular disease: where does lipoprotein-associated phospholipase A2 fit in? Mol Diagn Ther 2007;11:203-217.[Web of Science][Medline] 7. Yang EH, McConnell JP, Lennon RJ, et al. Lipoprotein-associated phospholipase A2 is an independent marker for coronary endothelial dysfunction in humans Arterioscler Thromb Vasc Biol 2006;26:106-111.[Abstract/Free Full Text] 8. Lavi S, McConnell JP, Rihal CS, et al. Local production of lipoprotein-associated phospholipase A2 and lysophosphatidylcholine in the coronary circulation: association with early coronary atherosclerosis and endothelial dysfunction in humans Circulation 2007;115:2715-2721.[Abstract/Free Full Text] 9. ClinicalTrials.gov Integrated Biomarker and Imaging Study–2 (NCT00268996)http://www.clinicaltrials.gov/ct2/show/NCT00268996?term=NCT00268996&rank=1 2007Accessed March 21, 2008. 10. Mohler III ER, Ballantyne CM, Davidson MH, et al. for the Darapladib Investigators The effect of darapladib on plasma lipoprotein-associated phospholipase A2 activity and cardiovascular biomarkers in patients with stable coronary heart disease or coronary heart disease risk equivalent: the results of a multicenter, randomized, double-blind, placebo-controlled study J Am Coll Cardiol 2008;51:1632-1642.[Abstract/Free Full Text]
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