Interleukin-1 (IL-1) inhibition with anakinra (Kineret, Sobi), a human IL-1 receptor antagonist, was more effective than tumor necrosis factor (TNF) inhibition at improving both glycemic and inflammatory parameters in patients with both rheumatoid arthritis and type 2 diabetes, say researchers writing in PLOS Medicine last month.
A growing body of evidence suggests the inflammatory contribution to type 2 diabetes as observed in rheumatoid arthritis. IL-1 is a common pathogenic mediator in type 2 diabetes and rheumatoid arthritis, suggesting a possible common therapeutic target. The recent knowledge of the contribution of inflammatory processes to the pathogenesis of type 2 diabetes has suggested new therapeutic approaches for diabetes in which biologic disease-modifying antirheumatic drugs (DMARDs) may be effective in improving glucose abnormalities. However, despite the growing body of evidence from trials confirming the role of targeting inflammatory cytokines in improving clinical and laboratory outcomes in patients with type 2 diabetes, there has been no clinical study specifically designed to evaluate the glycemic outcome in patients with rheumatoid arthritis and type 2 diabetes.
In the TRACK study, a multicenter, open-label, randomized controlled trial, 39 participants with rheumatoid arthritis and type 2 diabetes (age 62.72 ± 9.97 years, 74.4 percent female sex) were randomized to anakinra or to TNF inhibition in order to evaluate the efficacy of these drugs in improving both glycemic and inflammatory parameters. The primary end point was the change in percentage of glycated hemoglobin (HbA1c%).
When participants reached six months of follow-up, the study was stopped due to early benefit with anakinra. Participants in the anakinra group had a significant reduction in metabolic alteration after both three months (p < 0.001, 95% CI −1.28 to −0.42) and six months (p < 0.001, 95% CI −1.50 to −0.59) of therapy (crude difference of 0.93 HbA1c% between groups). Similar results were observed after adjusting for relevant rheumatoid arthritis and type 2 diabetes clinical confounders, male sex, age, ACPA positivity, use of corticosteroids, rheumatoid arthritis duration, type 2 diabetes duration, use of oral antidiabetic drug and body mass index. TNF inhibition did not show any significant improvement on these features. No severe adverse events, hypoglycemic episodes, or deaths were observed.
“Our results suggest that inhibition of IL-1 by anakinra may enable therapeutic targeting of both disorders, and use of a single agent may help in the management of both inflammatory and metabolic disease,” wrote the authors, led by Roberto Giacomelli, M.D., Ph.D., of the University of L'Aquila in Italy.
A significant correlation was seen between the decreasing levels of hemoglobin A1C and the reduction in the disease activity. However, anakinra therapy did not show any effect in participants with type 1 diabetes, which the authors said was likely because the pancreatic insulitis in type 1 diabetes is mainly driven by an autoimmune-mediated process, rather than by an autoinflammatory process.
The study also showed that a significant improvement of glycemic abnormalities as well as rheumatoid arthritis disease activity in anakinra-treated participants could counteract the synergy between traditional cardiovascular disease risk factors and inflammation in accelerating the atherosclerotic process. For every 1 percent decrease in the level of hemoglobin A1C, the risk of cardiovascular disease, the leading cause of mortality in, rheumatoid arthritis, decreased by approximately 15 percent.
“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 risk, and the burden of healthcare costs,” the authors wrote.
Piero Ruscitti, Francesco Masedu, Saverio Alvaro, et al. “Anti-interleukin-1 treatment in patients with rheumatoid arthritis and type 2 diabetes (TRACK): A multicentre, open-label, randomised controlled trial.” PLoS Med. September 12, 2019. doi: 10.1371/journal.pmed.100290