Elevations in total cholesterol (TC) and low density lipoprotein (LDL) were observed in clinical trials of tocilizumab. However the interleukin 6 receptor pathway has been implicated as part of the causal pathway for CVD in a genetic analysis, suggesting that blocking this pathway (the mechanism of action for tocilizumab) may reduce CV risk. On the basis of such contradictory data, it is unknown whether elevations in TC and LDL with tocilizumab (or other DMARDs) are clinically important and related to higher CV risk in patients with rheumatoid arthritis (RA).
This post-hoc analysis of data from RCTS and extension studies of tocilizumab in RA (n=3,986) looked for associations between CV events and changes in a range of laboratory markers and RA disease activity measurements. Over a mean of 3.7 years there were 50 major adverse cardiac events (MACE). Although there was a 16% increase in TC, a 19% increase in LDL and a 7% increase in HDL after 24 weeks of tocilizumab treatment, this was not associated with an increased CV risk in analyses adjusted for age and baseline lipid values (limited statistical power). There was however a consistent relationship observed between disease activity (DAS28) and CV events.
Although the lack of any safety signal for CV events is reassuring, this study has a number of limitations and cannot provide definitive answers regarding the safety of tocilizumab. There is an ongoing phase 4 study of tocilizumab versus etanercept in RA that will examine the rates of CV events, and additional observational studies comparing CV risk in tocilizumab versus other biologic DMARD users should also provide data to address this issue.