Studies focused on Lp-PLA2 modulation are little explored in literature, despite of its possible manipulation. Regarding that Lp-PLA2 is associated with cholesterol and oxidized lipids in LDL and HDL, it is probable that drugs and environment factors, capable of modulating the lipid metabolism, may change the mass and the activity of this enzyme.
Gerra et al. showed that lovastatin was responsible for the simultaneous decrease of LDL-C level and Lp-PLA2 activity. Similary, Tsimihodimos et al. found reduced Lp-PLA2 activity in plasma of hypercholesterolemic patients under atorvastatin therapy, with a reduction in LDL-Lp-PLA2 activity; in contrast, there was no modification in HDL-Lp-PLA2 activity. The same authors, in an investigation of the effect of fenofibrate on hypercholesterolemic patients, observed a reduction in the LDL-Lp-PLA2 activity and an increase of the HDL-Lp-PLA2 activity . Schaefer et al., comparing the effect of atorvastatin with placebo in coronary heart disease patients observed a reduction of Lp-PLA2 under therapy.
Studying the effect of cholesterol feeding and simvastatin treatment on rabbits, Zhang et al. found that the LDL-Lp-PLA2 activity increased with cholesterol feeding and decreased after the treatment. In this way, O'Donoghue et al. found that an intensive statin therapy was responsible for 20% of reduction in LDL-Lp-PLA2 , in average. Likewise, Schaefer et al. observed that simvastatin determined a reduction of the Lp-PLA2 mass in 26%.
In the same way, atorvastatin or fenofibrate therapies can increase the ratio of HDL-Lp-PLA2 to plasma Lp-PLA2 (or to LDL-Lp-PLA2 ) . Also, the effect of gemfibrozil was monitored in men with low HDL-C, and it was verified that individuals in highest quartile of Lp-PLA2 showed reduction of cardiovascular events . The use of darapladib (oral Lp-PLA2 inhibitor) by coronary patients caused a reduction of 59% of the enzyme activity after 12 months of treatment; concomitantly, the placebo group presented a significant increase of necrotic core volume when compared to the therapy group . In a complementary study, the combined effect of atorvastatin and darapladib was evaluated in patients with coronary heart disease in the course of 12 weeks; the individuals under darapladib showed a reduction of approximately 54% in the Lp-PLA2 activity when compared with controls .
Investigating patients under low-fat-diet and orlistat treatment, fenofibrate or both drugs during six months, Filippatos et al. observed a significant reduction of Lp-PLA2 activity in all groups (14%, 22% and 35%, respectively) when compared to basal time. The results suggested the combination of the two treatments as the optimal therapy.
Hence, the direct influence of lipid metabolism on Lp-PLA2 was confirmed by the efficiency of hypocholesterolemic drugs. Nonetheless, a similar profile was not observed in patients under anti-hypertension treatment: Spirou et al. and Rizos et al. verified that anti-hypertensive was not able to change Lp-PLA2 activity.
Despite the positive effect on Lp-PLA2 demonstrated by application of drugs, many studies have also investigated the influence of diet and other environment factors on the enzyme. In this context, Pedersen et al. compared the effects of high (6.6 g), low (2.0 g) and control doses of n-3 polyunsaturated fatty acids in some metabolic parameters; they did not observe any effect on Lp-PLA2 activity. Recently, in a sub-sample (n = 150, follow up = 1 y) of PREDIMED study, the authors of the present work, comparing diets enhanced with a mix of nuts (30 g/d), olive oil (50 g/d) or with low concentration of saturated fat (< 7%), observed a reduction in Lp-PLA2 only in the nuts group [NRTD, personal communication].
The effect of selenium on Lp-PLA2 was recently evaluated  on rats, subject to three different diets (control, high fat and high fat enhanced with selenium). The results showed that the Lp-PLA2 levels in control group were lower than the other groups, and that the selenium did not affect this enzyme.
The Nurses' Health Study demonstrated that the replacement of energy from carbohydrates for proteins, as well as the alcohol consumption or use of cholesterol-lowering drugs, were associated with a reduction in the Lp-PLA2 activity. Smoking, overweight, aspirin use, hypercholesterolemia and age were, nevertheless, related to the elevation of Lp-PLA2 activity . In addition, obese and non-diabetic women submitted to a weight reduction program showed a significant reduction in Lp-PLA2 activity, directly associated with VLDL-C . The influence of the nutritional status on Lp-PLA2 activity was also evaluated in adolescents where it was positively associated with body mass index, waist circumference and fat mass percentage .
Finally, Chen et al. compared vegetarians with omnivores and observed that vegetarians presented lower Lp-PLA2 activity, with lower total cholesterol and LDL-cholesterol, but with increased chances of higher C-reactive protein.