Back to Search
Start Over
Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial
- Source :
- PLoS Medicine, Vol 16, Iss 9, p e1002901 (2019), PLoS Medicine
- Publication Year :
- 2019
- Publisher :
- Public Library of Science (PLoS), 2019.
-
Abstract
- Background The 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 findings This 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, and diarrhoea in both groups. Our study has some limitations, including open-label design and previously unplanned ad interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs. Conclusions In this study, we observed an apparent benefit of IL-1 inhibition in participants with RA and T2D, reaching the therapeutic targets of both diseases. Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Trial registration The trial is registered with EU Clinical Trials Register, EudraCT Number: 2012-005370-62 and with ClinicalTrial.gov, number NCT02236481.<br />Roberto Giacomelli and co-authors study treatment of comorbid rheumatoid arthritis and type 2 diabetes via interleukin-1 blockade.<br />Author summary Why was this study done? A growing body of evidence suggests the inflammatory contribution to type 2 diabetes (T2D) as observed in rheumatoid arthritis (RA). Interleukin-1 (IL-1) would be a common pathogenic mediator in T2D and RA, suggesting a possible common therapeutic target. We investigated whether IL-1 inhibition with anakinra, a 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). What did the researchers do and find? In a multicentre, open-label, randomised controlled trial, 39 participants with RA and T2D (age 62.72 ± 9.97 years, 74.4% female sex) were randomised to anakinra or to TNFi in order to evaluate the efficacy of these drugs in controlling the metabolic alterations of T2D. Anakinra showed a significant improvement of metabolic alteration (reduction of percentage of glycated haemoglobin [HbA1c%]) after both 3 months and 6 months of therapy (crude difference of 0.93 HbA1c% between groups), whereas TNFi did not show any significant improvement on these features. No severe adverse events, hypoglycaemic episodes, or deaths were observed. What do these findings mean? Our results suggest the concept that IL-1 inhibition may be considered a targeted treatment for RA and T2D. Managing the inflammatory disease and the metabolic comorbidity by an agent inhibiting IL-1 may lead to a consequent beneficial impact on participants’ compliance, their overall cardiovascular (CV) risk, and the burden of healthcare costs. Our study has some limitations, mainly due to open-label design, and future studies are necessary to fully clarify this topic.
- Subjects :
- Blood Glucose
Male
Glycated Hemoglobin A
Time Factors
Physiology
030204 cardiovascular system & hematology
Pathology and Laboratory Medicine
Biochemistry
Etanercept
Arthritis, Rheumatoid
Endocrinology
0302 clinical medicine
Drug Metabolism
Rheumatoid
Immune Physiology
Receptors
Medicine and Health Sciences
Diabetes diagnosis and management
Insulin
Medicine
030212 general & internal medicine
Certolizumab pegol
Immune Response
Innate Immune System
Pharmaceutics
General Medicine
Middle Aged
Type 2 Diabetes
Treatment Outcome
Italy
Antirheumatic Agents
Rheumatoid arthritis
Number needed to treat
Cytokines
Female
Type 2
Research Article
medicine.drug
medicine.medical_specialty
HbA1c
Endocrine Disorders
Immunology
Rheumatoid Arthritis
Autoimmune Diseases
03 medical and health sciences
Signs and Symptoms
Rheumatology
Drug Therapy
Internal medicine
Diabetes Mellitus
Adalimumab
Humans
Pharmacokinetics
Hemoglobin
Aged
Inflammation
Diabetic Endocrinology
Pharmacology
Glycated Hemoglobin
Anakinra
business.industry
Arthritis
Biology and Life Sciences
Proteins
Receptors, Interleukin-1
Molecular Development
medicine.disease
Diagnostic medicine
Hormones
Infliximab
Golimumab
Interleukin 1 Receptor Antagonist Protein
Diabetes Mellitus, Type 2
Metabolic Disorders
Immune System
Clinical Immunology
Tumor Necrosis Factor Inhibitors
Clinical Medicine
business
Biomarkers
Interleukin-1
Developmental Biology
Subjects
Details
- ISSN :
- 15491676
- Volume :
- 16
- Database :
- OpenAIRE
- Journal :
- PLOS Medicine
- Accession number :
- edsair.doi.dedup.....794cbe20fd76cffd946c7db69fed7655