Risks and benefits of very low levels of low-density lipoprotein cholesterol. When less is not necessarily more

A mainstream in lipid management is to counteract the dose response association of elevated low-density lipoprotein cholesterol (LDL-C) andmajor cardiovascular (CV) events in primary and secondary prevention [1]. As CV risk increases, the different guidelines recommend lower LDL-C targets in very high-risk patients, but despite these evidences, there is still a gap between LDL-C targets and LDL-C levels, with frequent suboptimal lipid management even in very high-risk populations [2]. It is still debated which is the optimal threshold for LDL-C in primary prevention, while an evident benefit of an aggressive LDL-C lowering management has been proved effective in patients who have already experienced a CV event (Fig. 1) [3,4]. Nowadays, with the pharmacological arrows in our quiver, such as the proprotein convertase subtilisin/kexin 9 activity (PCSK9) inhibitors, an additional 50–70% decrease in LDL-C values not previously achievable in most cases using statins and/or ezetimibe can be obtained, reaching even extremely low values of LDL-C, similar to those seen in newborns [5]. Certainly the association of extremely low LDL-C levels and adverse events has been less commonly evaluated than the risk of having an extremely high LDL-C levels. The question if extremely low LDL-C levels per se may cause adverse events now arises. In a post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), the authors failed to demonstrate that a specific LDL-C threshold, even LDL-C level b 70 mg/dl (1.8 mmol L−1) or high LDL-C levels were more associated with CV events in hypertensive patients in primary prevention [6]. Thus, will a major decrease of LDL-C be always advantageous in patients with high cholesterol? Is there any threshold not to overcome in primary prevention?