Consensus statement: How to identify anti-inflammatory effects of lipid-lowering therapy?
The working group on atherosclerosis and vascular biology of the European Society of Cardiology published a position paper, which provides an overview of anti-inflammatory effects of lipid-lowering drugs and consensus statements on how to identify these effects.
It remains topic of debate whether the anti-inflammatory effects of lipid-lowering therapy in atherosclerosis are independent of a decrease in LDL-c. The recent introduction of PCSK9 inhibitors gave new insights into the role of lipids on the immune and inflammatory responses in atherosclerosis. These findings, along with the results with IL-1β blockade have led to a debate on whether personalized medicine can be based on lipid levels and inflammatory biomarkers in response to lipid-lowering and/or anti-inflammatory therapies.
To conclude on possible mechanisms behind these observations, the working group critically interpreted and integrated results obtained in both experimental and clinical studies on anti-inflammatory actions of lipid-lowering therapy and established a consensus statement on how to identify the anti-inflammatory response to lipid-lowering treatment.
While the causal effect of elevated LDL-c levels on inflammation in atherosclerosis is well-recognized, it is less well known that immune cells also affect lipid metabolism in atherogenesis. On the one hand, lipid metabolism has profound effects on both innate and adaptive immunity via multiple mechanisms. On the other hand, both innate and adaptive immune processes regulate lipid metabolism, leading to a vicious circle that promotes atherogenesis. Studies on the effect of anti-inflammatory therapies have shown contradictory results. Together, they point to the importance of monitoring lipid levels in anti-inflammation studies in CV prevention.
Current therapy in secondary prevention of atherosclerosis consists of statins, which, according to experimental and clinical data, have both anti-inflammatory and immunomodulatory properties. It remains unknown whether the actions of statins could, at least in part, be independent of their lipid-lowering effects, since oral statins hardly affect plaque inflammation in humans. Non-statin lipid-lowering drugs have been shown to have anti-inflammatory effects (for instance with PCSK9 inhibitors), supporting the relationship between lipids and inflammation. The position paper discusses the available evidence on this relationship in more detail.
Based on the reviewed evidence, the working group composed the following consensus statements:
1. Despite cholesterol-lowering effects through different mechanisms, most lipid-lowering treatments, including dietary interventions, share anti-inflammatory and immunomodulatory properties, which may be of clinical importance to predict the effect of therapy.
2. Using surrogates for both lipid metabolism and inflammation as biomarkers or vascular inflammation imaging in future studies may lead to a better understanding of the relative importance of different underlying mechanisms.
3. Comparative studies of further lipid lowering, anti-inflammation and a combination of both will be crucial to identify effects that are specific or shared for each treatment strategy.