Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial

Abstract

BackgroundThe inflammatory contribution to type 2 diabetes (T2D) has suggested new therapeutic targets using biologic drugs designed for rheumatoid arthritis (RA). On this basis, we aimed at investigating whether interleukin-1 (IL-1) inhibition with anakinra, a recombinant human IL-1 receptor antagonist, could improve both glycaemic and inflammatory parameters in participants with RA and T2D compared with tumour necrosis factor (TNF) inhibitors (TNFis).Methods and findingsThis study, designed as a multicentre, open-label, randomised controlled trial, enrolled participants, followed up for 6 months, with RA and T2D in 12 Italian rheumatologic units between 2013 and 2016. Participants were randomised to anakinra or to a TNFi (i.e., adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab), and the primary end point was the change in percentage of glycated haemoglobin (HbA1c%) (EudraCT: 2012-005370-62 ClinicalTrial.gov: NCT02236481).In total, 41 participants with RA and T2D were randomised, and 39 eligible participants were treated (age 62.72 ± 9.97 years, 74.4% female sex). The majority of participants had seropositive RA disease (rheumatoid factor and/or anticyclic citrullinated peptide antibody [ACPA] 70.2%) with active disease (Disease Activity Score-28 [DAS28]: 5.54 ± 1.03; C-reactive protein 11.84 ± 9.67 mg/L, respectively). All participants had T2D (HbA1c%: 7.77 ± 0.70, fasting plasma glucose: 139.13 ± 42.17 mg). When all the enrolled participants reached 6 months of follow-up, the important crude difference in the main end point, confirmed by an unplanned ad interim analysis showing the significant effects of anakinra, which were not observed in the other group, led to the study being stopped for early benefit. Participants in the anakinra group had a significant reduction of HbA1c%, in an unadjusted linear mixed model, after 3 months (β: −0.85, p < 0.001, 95% CI −1.28 to −0.42) and 6 months (β: −1.05, p < 0.001, 95% CI −1.50 to −0.59). Similar results were observed adjusting the model for relevant RA and T2D clinical confounders (male sex, age, ACPA positivity, use of corticosteroids, RA duration, T2D duration, use of oral antidiabetic drug, body mass index [BMI]) after 3 months (β: −1.04, p < 0.001, 95% CI −1.52 to −0.55) and 6 months (β: −1.24, p < 0.001, 95% CI −1.75 to −0.72). Participants in the TNFi group had a nonsignificant slight decrease of HbA1c%. Assuming the success threshold to be HbA1c% ≤ 7, we considered an absolute risk reduction (ARR) = 0.42 (experimental event rate = 0.54, control event rate = 0.12); thus, we estimated, rounding up, a number needed to treat (NNT) = 3. Concerning RA, a progressive reduction of disease activity was observed in both groups. No severe adverse events, hypoglycaemic episodes, or deaths were observed. Urticarial lesions at the injection site led to discontinuation in 4 (18%) anakinra-treated participants. Additionally, we observed nonsevere infections, including influenza, nasopharyngitis, upper respiratory tract infection, urinary tract infection, an...

Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes

“…Recently, a multicenter randomized controlled trial, specifically designed to evaluate the glycemic outcome, enrolled participants, with RA and T2D (followed up for 6 months). Thirty-nine participants were randomized to IL-1R antagonist (anakinra) or TNF inhibitors (TNFi) to assess the efficacy of these drugs in controlling glucose alterations of T2D (Ruscitti et al, 2019). After 3 and 6 months of treatment, anakinra showed a significant improvement in metabolic alteration (reduction of HbA1c by more than 1%), whereas TNFi showed no enhancement.…”

Cardio-Metabolic Effects of High-Fat Diets and Their Underlying Mechanisms—A Narrative Review

“…In addition, despite the link between systemic low-grade inflammation and type 2 diabetes, there are currently no approved drugs for managing diabetes that work via modulating immune mediators [86]. Preliminary trials involving IL-1ß antagonism (anakinra and canakinumab), TNFα inhibitors (e.g., etanercept), NF-kB pathway inhibition (salsalate) have either shown limited long-term success in improving clinical outcomes or have been associated with safety issues or both [86][87][88][89][90][91]. However, a safe and effective drug for managing diabetes via immune modulation will have the likely added advantage of beneficial effects on cardiovascular complications and rheumatological disorders [86].…”

Metabolic Checkpoints in Rheumatoid Arthritis

“…Notably patients treated with TNF inhibitors did not achieve the same results (HbA1c reduction) in this trial suggesting a different pathogenic mechanism linking inflammation, T2D and RA. Further studies are needed to dissect the implication of NLRP3 and the risk of developing T2D in patients with RA (Ruscitti et al, 2019) and to highlight the potential application of NLRP3targeted therapies for these diseases. Driven by surrounding environmental conditions, glycolytic enzymes can translocate to the nucleus ("moonlighting"), where they regulate the expression of their target mRNAs and modulate immune responses (De Rosa et al, 2015;Boukouris et al, 2016).…”