Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials

Abstract

Background Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. Methods Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes. Results Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was − 0.28 (− 0.40, − 0.16; nominal p < 0.0001) and − 0.42 (− 0.54, − 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was − 0.13 (− 0.22, − 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. Conclusions In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. Trial registration ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

Evaluation of Some Inflammatory Cytokines Levels as A Marker for Diabetes

“…The current study's findings revealed that serum cytokine IL-6 level were significantly higher in diabetic group 82.24% p < 0.001 in compared to control group. These findings are consistent with Genovese, et al [17] who stated that high levels of IL-6 are a risk factor for T2D and that IL-6 alone or in combination with IL-1β, impairs β cell activity. Furthermore, IL-15 and IL-6 could be employed as biomarkers for the development risk of autoimmune diabetes Siewko, et al [18].…”

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

“… 140 Consistent results were observed with SAR in a posthoc analysis, where SAR was associated with a greater reduction in glycosylated haemoglobin (HbA1c) than placebo or ADA in patients with diabetes. 141 …”

“…results were observed with SAR in a posthoc analysis, where was associated with a greater reduction in glycosylated haemoglobin (HbA1c) than placebo or ADA in patients with diabetes. 141 Safety analyses of TCZ on haematological variables found significant increases in haemoglobin and haematocrit levels in anaemic and non-anaemic patients with RA compared with other biological and non-biological DMARDs. By contrast, TCZ-treated patients had higher rates of grade 1/2 or 3/4 neutropenia than placebo; however, neutropenia was not associated with serious infections and improved after dose reduction or discontinuation of TCZ.…”

Therapeutic Potential of Combining IL-6 and TNF Blockade in a Mouse Model of Allergic Asthma

“…In particular, simultaneous blockade of IL-4Ra, a common part of the receptor complex of IL-4 and IL-13, with Dupilumab showed significant therapeutic effect and is approved for patients with severe eosinophilic asthma [ 8 , 9 ], despite poor efficacy of single anti-IL-4 and anti-IL-13 therapeutics [ 58 , 59 , 60 , 61 ]. Under inflammatory conditions TNF and IL-6 demonstrate some functional redundancy: for example, they both mediate inflammatory response during sepsis [ 62 ], and may act as immunometabolic transmitters [ 63 , 64 , 65 ]. On the other hand, due to distinct intracellular signaling of their cognate receptors, these cytokines may exhibit distinct functions or work synergistically to promote inflammation [ 66 , 67 , 68 , 69 ].…”