Low levels of low-density lipoprotein cholesterol, intracerebral haemorrhage, and other safety issues: is there still a matter of debate?

Although some observational studies suggest a potential association of low levels of low-density lipoprotein cholesterol (LDL-C) with intracerebral haemorrhage (ICH), these analyses have issues of confounding where other factors (e.g. older age, frailty) that likely explain the findings, and the number of events was very low. More recent results from randomized clinical trials have not found an increased risk in ICH, most notably trials using PCSK9 inhibitors that achieve very low levels of LDL-C, but also in the long-term follow-up of the IMPROVE-IT trial. Also, other statin-associated safety issues, including new onset diabetes and the cancer risk should not be the reason of statin discontinuation, especially for the former, the benefits highly outweigh the risk (even 5×), and for the latter, there is no confirmed link suggesting any increased risk, in opposite, data exist suggesting benefits of statin therapy in cancer prevention. Furthermore, use of intensive lipid-lowering strategies with statins and non-statin drugs leads to decrease of ischaemic major adverse cardiac events, without safety concern, in a large population of patients with atherosclerotic cardiovascular disease (ASCVD). These data should promote the concept 'the earlier, the lower, the longer, the better' for the lipid management of patients with ASCVD. While few uncertainties remain in several populations that have been underrepresented in clinical trials (African American and Asian patients, low weight individuals), the most recent data with intensive LDL-C lowering with PCSK9 inhibitors are reassuring that the benefit outweighs any possible risk.