How much should LDL cholesterol be lowered in secondary prevention? Clinical efficacy and safety in the era of PCSK9 inhibitors

There is a strong evidence that more marked lowering of low-density lipoprotein cholesterol (LDL-C) leads to progressively lower risk of cardiovascular disease (CVD) events. The evidence on validity of this hypothesis comes from epidemiological, genetic and clinical studies. The hypothesis "the lower the better" has been recently strongly supported by the results of secondary prevention trials with PCSK9 inhibitors. The combination of PCSK9 inhibitors and statins has resulted in achieving extremely low LDL-C levels with additional reduction of CVD events in secondary prevention. However, despite large clinical benefits, the safety of aggressive LDL-C lowering should be always taken into consideration, and there is still an ongoing discussion on whether very low LDL-C might result in some non-CVD adverse events. However, based on the available knowledge, so far the serious adverse events associated with achieving of very low LDL-C levels or intensive drug therapy have not been noted. These positive clinical effects were reflected in current ESC/EAS Guidelines (2019) for dyslipidaemia management. The experts strongly recommended the LDL-C lowering to levels that have been achieved in trials of PCSK9 inhibitors. In this state of the art review, we aimed to finally justify the critical need for LDL-C reduction to very low levels in secondary prevention patients in order to be as low as possible, as early as possible, and preferably lifelong.