Relationship of Lipoprotein-Associated Phospholipase A2 Mass and Activity with Incident Vascular Events among Primary Prevention Patients Allocated to Placebo or to Statin Therapy: An Analysis from the JUPITER Trial

Abstract

BACKGROUND Although lipoprotein-associated phospholipase A2 (Lp-PLA2) levels are associated with cardiovascular events, Lp-PLA2 is physically linked to LDL cholesterol (LDL-C). Whether measures of Lp-PLA2 mass or activity continue to predict risk after LDL-C reduction by statin therapy is uncertain. METHODS Lp-PLA2 mass concentration and activity were evaluated at baseline and after treatment in the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial comparing rosuvastatin 20 mg to placebo among 17 802 men and women without cardiovascular disease or diabetes at study entry. The relationships of Lp-PLA2 mass and activity with risk of future vascular events were evaluated in the placebo and rosuvastatin groups. RESULTS Before randomization, levels of Lp-PLA2 mass and activity correlated moderately with each other and with LDL-C. The magnitude of these correlations increased after statin therapy. Rosuvastatin reduced Lp-PLA2 mass by 33.8%, Lp-PLA2 activity by 33.2%, and LDL-C by 48.7% (all P < 0.0001). Among those study participants allocated to placebo, increasing quartiles of Lp-PLA2 activity (Ptrend = 0.04) but not Lp-PLA2 mass (Ptrend = 0.92) were associated with incident cardiovascular events after adjustment for LDL-C and conventional risk factors. Comparable analyses conducted among those allocated to rosuvastatin revealed no significant relationship between Lp-PLA2 levels and subsequent vascular events. The ability of rosuvastatin to reduce vascular events was not significantly modified by baseline Lp-PLA2 level. CONCLUSIONS Among JUPITER trial participants allocated to placebo, levels of Lp-PLA2 activity, but not mass, were associated with cardiovascular risk. However, Lp-PLA2 no longer predicted risk or modified clinical outcomes when participants were treated with rosuvastatin.

Lipoprotein‐Associated Phospholipase A 2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

“…Prior to the current study, several lines of evidence supported Lp‐PLA 2 activity as a risk indicator of adverse outcomes both in patients with stable CHD and in the general population in addition to being potentially involved in the development of atherosclerosis and vulnerable plaque at the tissue level 6, 7, 8, 9, 22, 23, 24, 25, 26, 27. Furthermore, in 2 case–control studies, natural deficiency of Lp‐PLA 2 activity due to carriage of the V279F‐null allele in the Lp‐PLA 2 gene was associated with a lower risk of developing CHD 30.…”

Association between the Lipoprotein-Associated Phospholipase A2 Activity and the Progression of Subclinical Atherosclerosis

“…Therefore, it is unlikely that failure to include these participants altered the results. Additionally, it has been reported that treatment with statins significantly lowers the Lp-PLA2 level 29) . In the current analysis, 11.8% of the subjects were receiving antidyslipidemic drugs, including statins, fibrates and traditional Chinese medicines for dyslipidemia.…”

Darapladib for Preventing Ischemic Events in Stable Coronary Heart Disease

“…[19][20][21] In addition, in the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) study, among patients with stable chronic coronary heart disease, more than half the treatment effect of pravastatin in reducing rates of death from coronary heart disease or myocardial infarction was estimated to be due to an asso ciation with a reduction in levels of lipoprotein-associated phospholipase A 2 . 22 Incremental benefits of inhibiting lipoprotein-associated phospholipase A 2 activity, if present, could be less in patients treated with statins.…”