Residual cardiovascular risk

Residual cardiovascular risk is often associated with lipid abnormalities, such as atherogenic dyslipidaemia (AD). Dyslipidaemias are one of the determinants of the risk of developing atherosclerotic cardiovascular disease. In addition to low-density lipoprotein (LDL) particles, which are the most atherogenic lipoproteins, other apolipoprotein B-containing lipoproteins [e.g. triglyceride (TG)-rich lipoproteins and their remnants] contribute to intimal cholesterol deposition and to the development of atherosclerosis. Lipoprotein size is a key determinant of atherogenesis, with remnants being able to penetrate the arterial intima and bind to and be retained by connective matrix tissue, thus directly contributing to plaque formation and progression. This is particularly relevant to patients with AD, and provides the rationale that supports the use of additional treatment targeting AD, in combination with statins, for the modulation of residual cardiovascular (CV) risk. One such example is fenofibrate, which has been shown to improve the lipoprotein profile and reduce the risk of CV events in subgroups of patients with AD from randomized clinical trials.

The use of a single parameter, e.g. non-high-density lipoprotein cholesterol (non-HDL-c), may be particularly useful, as it is easy to measure and already recognized by international guidelines. It is recommended as a secondary target for patients with high TGs and diabetes mellitus (DM), metabolic syndrome, or chronic kidney disease by the European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias. Of note, non-HDL-c is recommended as a primary treatment target in all patients by the National Institute for Health and Care Excellence Lipid modification guidelines.

Patient adherence to chronic therapies (and, in particular, to lipid-lowering therapies) is not optimal, especially in primary prevention. Adherence is crucial in secondary prevention, and adherence to CV drugs has been shown to result in a reduction in the rates of CV events. Fixed-dose combination therapy may be key for improving patient adherence, as experienced in the field of hypertension and type 2 DM.

While lipid abnormalities such as AD (that can be present even in statin-treated patients at LDL-c goals) carry a residual CV risk, awareness of this condition is not optimal and can jeopardize efforts to reduce CV risk. In addition to building awareness of AD and its associated residual CV risk, the identification of clear markers and goals for treatment also needs to be considered to make sure that residual CV risk associated with TG/HDL-c abnormalities is appropriately treated.

With the recent advances in the field of CV prevention, and notably with the results from studies evaluating combination therapy of statins with non-statin drugs (e.g. ezetimibe in the IMPROVE-IT trial) or alternative LDL-lowering therapy with PCSK9 inhibitors, the current statin-based approach to CV disease prevention is likely to change. The remaining role of other lipid disturbances under these circumstances therefore needs to be addressed.

We report here on the results of a meeting of European experts who gathered to address the question as to whether residual CV risk linked to lipoproteins other than LDL is relevant clinically, and how we can reduce the CV burden related to these forms of dyslipidaemia.