Research in context
Evidence before this study
We searched MEDLINE on July 24, 2017, with the terms “cholesterol, LDL” and either “myocardial infarction” or “stroke.” The search was limited to publications from 2014 onwards since that was the date of a comprehensive meta-analysis on this topic. Abstracts were reviewed by two of the authors (RPG and MSS) to find publications describing the association of on-treatment LDL cholesterol and cardiovascular outcomes in patients with atherosclerotic cardiovascular disease. Relevant publications were supplemented with additional relevant publications known by the authors. None of the trials studying patients treated with statins provided data on a cutpoint of less than 1·3 mmol/L. We have published data on ezetimibe from IMPROVE-IT, in which the lowest cutpoint was 0·8 mmol/L, but there were fewer than 1000 patients in that subgroup. There is a published pooled analysis of smaller lipid-lowering trials of another proprotein convertase subtilisin-kexin type 9 inhibitor, alirocumab, but with approximately a tenth of the number of patients with an LDL-cholesterol concentration of less than 0·5 mmol/L.
Added value of this study
We found a strong relationship between achieved LDL cholesterol down to concentrations 0·2 mmol/L and a progressive reduction in major cardiovascular outcomes, with no increase in safety events. These observations extend previous findings with statins and ezetimibe to lower concentrations of LDL cholesterol than previously reported, in a larger sample size, and with the newest and most potent lipid-lowering therapy approved to date.
Implications of all the available evidence
All evidence to date from trials of intensive lipid lowering supports reduction of LDL cholesterol in high-risk patients to concentrations below those currently recommended in cholesterol guidelines. Studies with a longer follow-up period than in this study are needed to exclude the development of late complications of persistent very-low concentrations of LDL cholesterol.