Therapeutic Options to Reduce Lp-PLA2 Levels and the Potential Impact on Vascular Risk Reduction

Cerebrovascular Disease and Stroke (C Helgason and M Alberts, Section Editors)

Opinion statement

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme involved in the metabolism of Low-density lipoprotein (LDL) to pro-inflammatory mediators. Lp-PLA2 is highly expressed in the necrotic core of atherosclerotic plaques and has been associated with atherosclerotic plaque instability. Multiple studies have shown an association between elevated Lp-PLA2 levels and risk of both stroke and myocardial infarction, even after adjustment for standard vascular risk factors, and several professional organizations have recommended Lp-PLA2 as a potentially usefully tool to improve risk stratification for individual patients. Therapies directed at lowering Lp-PLA2 levels may represent a novel approach to reducing vascular risk, though direct clinical benefit from targeting treatment to Lp-PLA2 levels remains unproven. Statins appear to significantly lower Lp-PLA2 levels; fibrates and niacin may also lower Lp-PLA2 levels, though this is less well established. Darapladib, a potent, selective Lp-PLA2 inhibitor, is currently in phase III trials for prevention of recurrent vascular events in patients with coronary artery disease.

Keywords

Lp-PLA2 Stroke TIA Transient ischemic attack Cardiovascular disease Myocardial infarction Risk stratification Inflammatory biomarkers Atherosclerosis 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Garcia-Garcia HM, Serruys PW. Phospholipase A2 inhibitors. Curr Opin Lipidol. 2009;20(4):327–32.PubMedCrossRefGoogle Scholar
  2. 2.
    Wilensky RL et al. Inhibition of lipoprotein-associated phospholipase A2 reduces complex coronary atherosclerotic plaque development. Nat Med. 2008;14(10):1059–66.PubMedCrossRefGoogle Scholar
  3. 3.
    Mannheim D et al. Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke. 2008;39(5):1448–55.PubMedCrossRefGoogle Scholar
  4. 4.
    Kolodgie FD et al. Lipoprotein-associated phospholipase A2 protein expression in the natural progression of human coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 2006;26(11):2523–9.PubMedCrossRefGoogle Scholar
  5. 5.
    PLAC Test Package Insert. 2008, diaDexus, South San Francisco, CA.Google Scholar
  6. 6.
    Elkind, MS. et al. High-Sensitivity C-Reactive Protein and Lipoprotein-Associated Phospholipase A2 Stability Before and After Stroke and Myocardial Infarction. Stroke, 2009.Google Scholar
  7. 7.
    Ballantyne CM et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident ischemic stroke in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Arch Intern Med. 2005;165(21):2479–84.PubMedCrossRefGoogle Scholar
  8. 8.
    Wassertheil-Smoller S et al. Lipoprotein-associated phospholipase A2, hormone use, and the risk of ischemic stroke in postmenopausal women. Hypertension. 2008;51(4):1115–22.PubMedCrossRefGoogle Scholar
  9. 9.
    Elkind MS et al. High-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, and outcome after ischemic stroke. Arch Intern Med. 2006;166(19):2073–80.PubMedCrossRefGoogle Scholar
  10. 10.
    Oei HH et al. Lipoprotein-associated phospholipase A2 activity is associated with risk of coronary heart disease and ischemic stroke: the Rotterdam Study. Circulation. 2005;111(5):570–5.PubMedCrossRefGoogle Scholar
  11. 11.
    Elkind MS et al. Lipoprotein-associated phospholipase A2 activity and risk of recurrent stroke. Cerebrovasc Dis. 2009;27(1):42–50.PubMedCrossRefGoogle Scholar
  12. 12.
    Robins SJ et al. Cardiovascular events with increased lipoprotein-associated phospholipase A(2) and low high-density lipoprotein-cholesterol: the Veterans Affairs HDL Intervention Trial. Arterioscler Thromb Vasc Biol. 2008;28(6):1172–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Packard CJ et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. West of Scotland Coronary Prevention Study Group. N Engl J Med. 2000;343(16):1148–55.PubMedCrossRefGoogle Scholar
  14. 14.
    Koenig W et al. Lipoprotein-associated phospholipase A2 predicts future cardiovascular events in patients with coronary heart disease independently of traditional risk factors, markers of inflammation, renal function, and hemodynamic stress. Arterioscler Thromb Vasc Biol. 2006;26(7):1586–93.PubMedCrossRefGoogle Scholar
  15. 15.
    Cucchiara BL et al. Lipoprotein-associated phospholipase A2 and C-reactive protein for risk-stratification of patients with TIA. Stroke. 2009;40(7):2332–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Delgado P et al. Lipoprotein-associated phospholipase A(2) activity is associated with large-artery atherosclerotic etiology and recurrent stroke in TIA patients. Cerebrovasc Dis. 2012;33(2):150–8.PubMedCrossRefGoogle Scholar
  17. 17.••
    The Lp-PLA2 Studies Collaboration. Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies. Lancet. 2010;375(9725):1536–44. This is the largest pooled analysis of the predictive value of Lp-PLA2. It incorporates 32 separate prospective studies involving 79,036 subjects with 17,722 outcome events and examines the predictive value of both Lp-PLA2 mass and activity for coronary heart disease, stroke, and mortality. The large sample size allows for adjustment for multiple potential confounders, and facilitates analysis in multiple particular patient subgroups.CrossRefGoogle Scholar
  18. 18.
    Heart Protection Study Collaborative, G. Lipoprotein-associated phospholipase A(2) activity and mass in relation to vascular disease and nonvascular mortality. J Intern Med. 2010;268(4):348–58.CrossRefGoogle Scholar
  19. 19.
    Saougos VG et al. Differential effect of hypolipidemic drugs on lipoprotein-associated phospholipase A2. Arterioscler Thromb Vasc Biol. 2007;27(10):2236–43.PubMedCrossRefGoogle Scholar
  20. 20.
    Albert MA et al. The effect of statin therapy on lipoprotein associated phospholipase A2 levels. Atherosclerosis. 2005;182(1):193–8.PubMedCrossRefGoogle Scholar
  21. 21.••
    Ridker PM et al. Relationship of lipoprotein-associated phospholipase A(2) mass and activity with incident vascular events among primary prevention patients allocated to placebo or to statin therapy: an analysis from the JUPITER trial. Clin Chem. 2012;58(5):877–86. This study presents a post-hoc analysis of Lp-PLA2 in the large, randomized JUPITER trial comparing rosuvastatin to placebo in 17,000 patients with elevated CRP but no history of vascular disease. At baseline, levels of Lp-PLA2 mass and activity had a moderate correlation both with each other and LDL. In study participants assigned placebo, Lp-PLA2 activity (p=0.04) but not mass (p=0.92) was associated with vascular events after adjustment for LDL and standard vascular risk factors. In the rosuvastatin treated group, there was no association between Lp-PLA2 levels and vascular events. Rosuvastatin significantly reduced Lp-PLA2 mass by 33.8 % and Lp-PLA2 activity by 33.2 % compared to an 11.7 % and 1.7 % reduction, respectively, in the placebo group (both comparisons p < 0.0001). Rosuvastatin was associated with a significant reduction in vascular events, but this was not modified by baseline Lp-PLA2 levels.PubMedCrossRefGoogle Scholar
  22. 22.
    Greenland P et al. ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2010;56(25):e50–e103.PubMedCrossRefGoogle Scholar
  23. 23.
    Goldstein LB et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(2):517–84.PubMedCrossRefGoogle Scholar
  24. 24.
    Jellinger PS et al. American Association of Clinical Endocrinologists' Guidelines for Management of Dyslipidemia and Prevention of Atherosclerosis. Endocr Pract. 2012;18 Suppl 1:1–78.PubMedCrossRefGoogle Scholar
  25. 25.
    Rimm EB et al. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ. 1999;319(7224):1523–8.PubMedCrossRefGoogle Scholar
  26. 26.
    O'Donnell MJ et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case–control study. Lancet. 2010;376(9735):112–23.PubMedCrossRefGoogle Scholar
  27. 27.
    Reynolds K et al. Alcohol consumption and risk of stroke: a meta-analysis. JAMA. 2003;289(5):579–88.PubMedCrossRefGoogle Scholar
  28. 28.
    Davies MJ et al. Effects of moderate alcohol intake on fasting insulin and glucose concentrations and insulin sensitivity in postmenopausal women: a randomized controlled trial. JAMA. 2002;287(19):2559–62.PubMedCrossRefGoogle Scholar
  29. 29.
    Beulens JWJ et al. Moderate alcohol consumption and lipoprotein-associated phospholipase A2 activity. Nutr Metab Cardiovasc Dis. 2008;18:539–44.PubMedCrossRefGoogle Scholar
  30. 30.
    Hatoum IJ et al. Dietary, lifestyle, and clinical predictors of lipoprotein-associated phospholipase A2 activity in individuals without coronary artery disease. Am J Clin Nutr. 2010;91(3):786–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Nelson TL, Hokanson JE, Hickey MS. Omega-3 fatty acids and lipoprotein associated phospholipase A(2) in healthy older adult males and females. Eur J Nutr. 2011;50(3):185–93.PubMedCrossRefGoogle Scholar
  32. 32.
    Maki KC, Bays H, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Tselepis AD et al. Smoking induces lipoprotein-associated phospholipase A2 in cardiovascular disease free adults: the ATTICA Study. Atherosclerosis. 2009;206(1):303–8.PubMedCrossRefGoogle Scholar
  34. 34.
    Ballantyne CM et al. Lipoprotein-associated phospholipase A2, high-sensitivity C-reactive protein, and risk for incident coronary heart disease in middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 2004;109(7):837–42.PubMedCrossRefGoogle Scholar
  35. 35.
    Persson M et al. The epidemiology of Lp-PLA(2): distribution and correlation with cardiovascular risk factors in a population-based cohort. Atherosclerosis. 2007;190(2):388–96.PubMedCrossRefGoogle Scholar
  36. 36.
    Cucchiara B, Kasner SE. Use of statins in CNS disorders. J Neurol Sci. 2001;187(1–2):81–9.PubMedCrossRefGoogle Scholar
  37. 37.
    White H et al. Changes in Lp-PLA2 Activity in Secondary Prevention Predict Coronary Events and Treatment Effect by Pravastatin in the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) Trial. Circulation. 2011;124:A14857. abstract.CrossRefGoogle Scholar
  38. 38.•
    Ryu SK et al. Phospholipase A2 enzymes, high-dose atorvastatin, and prediction of ischemic events after acute coronary syndromes. Circulation. 2012;125(6):757–66. In this study, Lp-PLA2 and sPLA2 levels in 2500 subjects with acute coronary syndromes enrolled in the MIRACL trial and randomized to atorvastatin or placebo were analyzed. Baseline levels of Lp-pLA2 activity and mass were not associated with the primary study outcome (death, myocardial infarction, or unstable angina at 4 months), nor were levels of sPLA2. In the overall cohort, baseline sPLA2 mass was associated with mortality in multivariate analysis (p=0.004); this association was driven the the placebo group, as when analyzed separately no association was seen in the atorvastatin group. Atorvastatin significantly reduced sPLA2 mass compared to placebo (−32.1 vs. -23.1 %), as well as sPLA2 activity (−29.5 vs. -19.2 %) and Lp-PLA2 mass (−35.8 vs. -6.2 %) and activity (−24.3 vs. 5.4 %), (p<0.001 for all comparisons). The authors conclude that by modulating sPLA2 levels, atorvastatin reduced the risk of death by about 50 %.PubMedCrossRefGoogle Scholar
  39. 39.
    O'Donoghue M et al. Lipoprotein-associated phospholipase A2 and its association with cardiovascular outcomes in patients with acute coronary syndromes in the PROVE IT-TIMI 22 (PRavastatin Or atorVastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction) trial. Circulation. 2006;113(14):1745–52.PubMedCrossRefGoogle Scholar
  40. 40.
    Keating GM, Ormrod D. Micronised fenofibrate: an updated review of its clinical efficacy in the management of dyslipidaemia. Drugs. 2002;62(13):1909–44.PubMedCrossRefGoogle Scholar
  41. 41.
    Staels B et al. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98(19):2088–93.PubMedCrossRefGoogle Scholar
  42. 42.
    Filippatos TD et al. The effect of orlistat and fenofibrate, alone or in combination, on small dense LDL and lipoprotein-associated phospholipase A2 in obese patients with metabolic syndrome. Atherosclerosis. 2007;193(2):428–37.PubMedCrossRefGoogle Scholar
  43. 43.
    Muhlestein JB et al. The reduction of inflammatory biomarkers by statin, fibrate, and combination therapy among diabetic patients with mixed dyslipidemia: the DIACOR (Diabetes and Combined Lipid Therapy Regimen) study. J Am Coll Cardiol. 2006;48(2):396–401.PubMedCrossRefGoogle Scholar
  44. 44.
    Rosenson RS. Fenofibrate reduces lipoprotein associated phospholipase A2 mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome. Am Heart J. 2008;155(3):499. e9–16.PubMedCrossRefGoogle Scholar
  45. 45.
    Wagner AM et al. Effect of statin and fibrate treatment on inflammation in type 2 diabetes. A randomized, cross-over study. Diabetes Res Clin Pract. 2011;93(1):e25–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Kuvin JT et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 2006;98(6):743–5.PubMedCrossRefGoogle Scholar
  47. 47.
    Mohler 3rd ER et al. 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(17):1632–41.PubMedCrossRefGoogle Scholar
  48. 48.
    Serruys PW et al. Effects of the direct lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coronary atherosclerotic plaque. Circulation. 2008;118(11):1172–82.PubMedCrossRefGoogle Scholar
  49. 49.•
    White H et al. Study design and rationale for the clinical outcomes of the STABILITY Trial (STabilization of Atherosclerotic plaque By Initiation of darapLadIb TherapY) comparing darapladib versus placebo in patients with coronary heart disease. Am Heart J. 2010;160(4):655–61. This study describes the design of rationale for a large, randomized, double-blind, placebo-controlled trial comparing the Lp-PLA2 inhibitor darapladib to placebo in patients with chronic coronary heart disease. The primary end point is a composite of major adverse cardiovascular events (cardiovascular death, nonfatal stroke). Results of this study will be critical to determining the specific role of Lp-PLA2 as a treatment target.PubMedCrossRefGoogle Scholar
  50. 50.•
    O'Donoghue ML et al. Study design and rationale for the Stabilization of pLaques usIng Darapladib-Thrombolysis in Myocardial Infarction (SOLID-TIMI 52) trial in patients after an acute coronary syndrome. Am Heart J. 2011;162(4):613–619 e1. This study describes the design of a large, randomized, double-blind, placebo-controlled trial (SOLID-TIMI 52) assessing the efficacy of the Lp-PLA2 inhibitor darapladib in patients within 30 days of hospitalization with an acute coronary syndrome. Results of this study will be critical to determining the specific role of Lp-PLA2 as a treatment target.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.1University of Pennsylvania Medical CenterPhiladelphiaUSA
  2. 2.Department of NeurologyUniversity of Pennsylvania School of MedicinePhiladelphiaUSA

Personalised recommendations