Tocilizumab Increases HDL, LDL Cholesterol, Triglycerides Compared With Etanercept in RA
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Patients with rheumatoid arthritis who received tocilizumab demonstrated 11.1% higher serum LDL cholesterol, 5.7% higher HDL cholesterol and 13.6% higher triglyceride levels than those treated with etanercept, according to data published in Arthritis & Rheumatology.
“In the MEASURE trial, designed to evaluate the effects of tocilizumab therapy on [cardiovascular disease (CVD)] biomarkers, concentrations of the more atherogenic circulating small LDL particles and oxidized LDL did not increase with tocilizumab treatment and were similar to those observed with placebo, despite an increase in overall LDL [cholesterol],” Jon T. Giles, MD, MPH, of the Columbia University College of Physicians and Surgeons, and colleagues wrote.
“At the same time, tocilizumab was associated with greater reductions, relative to placebo, in potentially proatherogenic factors, such as HDL-associated serum amyloid A, secretory phospholipase A2 and lipoprotein(a),” the researchers added. “However, whether such changes affect CVD event risk has not been evaluated in a clinical trial.”
To compare the risk for major adverse cardiovascular events in patients with RA treated with tocilizumab (Actemra, Genentech) compared with etanercept (Enbrel, Amgen), Giles and colleagues conducted the ENTRACTE trial, a randomized, open-label parallel-group study. Participants included 3,080 patients with seropositive RA with an inadequate response to conventional synthetic DMARDs, as well as at least one cardiovascular risk factor.
Participants were randomly assigned to receive either a monthly 8 mg/kg dose of tocilizumab or a weekly 50 mg dose of etanercept. Patients were followed for an average of 3.2 years. The primary endpoint was the time to first major adverse cardiovascular event, with the trial powered to exclude a HR of 1.8 or higher for tocilizumab compared with etanercept.
According to the researchers, serum LDL cholesterol, HDL cholesterol, and triglyceride levels were 11.1%, 5.7%, and 13.6% higher, respectively, among patients who received tocilizumab compared with etanercept (P < .001) at 4 weeks. Throughout the follow-up period, 83 major adverse cardiovascular events occurred in the tocilizumab group compared with 78 in the etanercept group. The estimated HR of major adverse cardiovascular events for tocilizumab relative to etanercept was 1.05 (95% CI, 0.77-1.43), with similar results found in sensitivity analyses and the ontreatment analysis. Serious infection and gastrointestinal perforation were also more frequent in the tocilizumab group compared with those who received etanercept.
“The trial, which provides screening insights into the CVD safety of tocilizumab compared with etanercept, excluded a relative risk for [major adverse coronary event] of 1.43 or higher in the [intent-to-treat] population,” Giles and colleagues wrote. “Similar estimates regarding CVD safety were obtained when the analysis was restricted to events that occurred while patients were still receiving randomized treatment and regarding multiple secondary and exploratory outcomes, with the exception of stroke and [hospitalized heart failure].” – by Jason Laday
Disclosure: Giles reports no relevant disclosures. Please see the full study to a full list of author disclosures.
Perspective
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David A. McLain, MD, FACP, FACR
Tocilizumab, a fully humanized monoclonal antibody targeting interleukin-6 receptor alpha (IL-6-alpha), causes a reduction in the signs and symptoms of rheumatoid arthritis and a marked lowering of inflammatory markers. Increases in lipids in the circulation have been observed, with average increases of 12% to 20% in low-density lipoprotein cholesterol (LDL-C) concentrations noted across the pivotal clinical trials.
The chance of having elevated LDL-C levels — defined as >130 mg/dL — was 4.8-fold higher among tocilizumab-treated patients with RA than among patients treated with placebo in a meta-analysis. Triglycerides also increased in the tocilizumab treated patients. On the other hand, both IL-6 and TNF-alpha have been linked to atherogenesis in various animal and human studies.
This large, open label, post-marketing study of over 3000 patients was conducted to observe the differences in major adverse cardiovascular events (MACE) in patients over a maximum of 4.9 years of follow-up, randomized to receive IV tocilizumab or SC etanercept. Patients had to be 50 or older and have ≥1 CV risk factor; the researchers used the “classical 3-point MACE” of nonfatal MI, nonfatal stroke and cardiovascular death. Non-CVD AEs were recorded.
From prior studies, the researchers figured the noninferiority hazard ratio (HR) would be in the 1.30-1.33 range. They, therefore, set a true HR of 1.30 or less as the “noninferiority of tocilizumab to etanercept” and a true HR of 1.80 or less to rule out positive screening for MACE for tocilizumab vs. etanercept. Lipid studies showed that LDL-C increased by 11% more and triglycerides increased by 13.6% more in the tocilizumab group vs. the etanercept group.
There were numerically more fatal and nonfatal strokes in the tocilizumab group (n=26) vs. etanercept group (n=16). There were 8 gastrointestinal perforations in the tocilizumab group vs. 1 in the etanercept group; patients treated with tocilizumab also had a higher rate of infections compared with etanercept.
Although this study explored the cardiovascular effects of two popular biologic DMARDs, statistically, there was no difference. Research continues on the biologic effects of biologic DMARDs used in rheumatology and their effects in other areas than their indications.
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