Background Insulin resistance is increased in rheumatoid arthritis (RA). Reductions in inflammation, glucocorticoid therapy and disease-modifying anti-rheumatic drugs (DMARDs) have been associated with improvement in insulin resistance in patients with RA.
Objectives To study whether tocilizumab (TCZ) therapy, an IL-6 receptor-inhibiting monoclonal antibody, improves insulin resistance in patients with RA.
Methods TOWARD was a phase 3 study in patients with moderate to severe active RA on stable oral DMARDs that compared TCZ 8 mg/kg to placebo with 2:1 randomisation. Insulin resistance was calculated using the homeostatic model (HOMA-IR). Insulin resistance was classified as a HOMA-IR ≥2.2. Associations of baseline HOMA-IR against variables were analysed using linear regression. We examined associations between baseline HOMA-IR and baseline demographics, cardiovascular disease risk factors and disease-related factors using linear regression. Associations between change in HOMA-IR and change in RA disease parameters were also analysed using regression.
Results Of the 1123 patients in the study, HOMA-IR could be calculated in 893 (79.5%). Median (IQR) age, glucose, insulin and HOMA-IR were 54 (46-62) years, 5.1 (4.6-5.6) mmol/l, 7.6 (4.6-12.6) µU/ml and 1.7 (1.0-2.9), respectively. 328 patients (37%) had insulin resistance. In an age- and gender-adjusted analysis, baseline HOMA-IR was associated with older age, higher BMI, SBP and DBP as well as IL-6 level (β-coefficient [95% CI]; 0.01 [0.01, 0.02] per pg/dl), RF positivity (0.25 [0.12, 0.38]) and lower IL-6 receptor levels (–0.02 [–0.02,–0.01] per ng/dl). HOMA-IR was reduced over 24 weeks in patients with insulin resistance who received TCZ but not in those who received placebo (Table).
Conclusions Insulin resistance is common in RA patients with inadequate response to DMARDs and is associated with RF positivity and IL-6 levels. In patients with pre-existing insulin resistance, HOMA-IR was significantly improved by TCZ therapy while unchanged by placebo. Understanding the mechanistic links between IL-6 and insulin regulation may provide an additional rationale for a stratified approach to using biologics to reduce cardiovascular disease risk in patients with RA.
Disclosure of Interest H. Mirjafari Employee of: Roche Products Ltd, J. Wang Employee of: Roche Products Ltd, M. Klearman Employee of: Genentech, a member of the Roche group, O. Harari Employee of: Roche, I. Bruce Grant/research support from: UCB, Roche, GSK, Genzyme/Sanofi, Consultant for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Paid instructor for: Pfizer, UCB, GSK, Human Genome Sciences, Roche, Speakers bureau: Pfizer, UCB, GSK, Human Genome Sciences, Roche
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