Anti-IL-1 Drug May Be Better in RA With Type 2 Diabetes

Janis C. Kelly

October 10, 2019

For patients with both rheumatoid arthritis (RA) and type 2 diabetes (T2D), interleukin-1 (IL-1) inhibition with anakinra (Kineret, Biovitrium AB), a human IL-1 receptor antagonist, was more effective than tumor necrosis factor inhibition (TNFi) at improving both glycemic and inflammatory parameters, a study found.

Findings from the study by Piero Ruscitti, MD, Division of Rheumatology, Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, Italy, and colleagues were reported online September 12 in PLOS Medicine.

The results of the TRACK study ― a small, open-label, multicenter, randomized trial involving patients who had both RA and T2D ― raise the possibility that the IL-1 pathway might be more important for patients with RA and T2D than for those with RA alone.

Marc Y. Donath, MD, chief of endocrinology, diabetes, and metabolism, and research; and dean, Faculty of Medicine, University Hospital, Basel, Switzerland (who was not involved in the study), told Medscape Medical News, "This is one of the very exciting aspects of this study. Typically, IL-1 antagonism is not very efficient in patients with RA, and anti-TNF is preferred. In the present study with patients suffering from both RA and T2D, a progressive reduction of RA disease activity was observed in both groups, numerically even more under anakinra. RA and T2D are strongly associated, and it is conceivable that this is due to a common pathological activation of the IL-1 system leading to a progression of both diseases."

The researchers suggest that their data support considering IL-1 inhibition as a targeted treatment for RA and T2D that might improve compliance and cardiovascular (CV) risk for patients with RA. Other experts are more skeptical because of problems regarding compliance that are related to the daily injections required for anakinra and to the fact that some other biologicals have demonstrated greater efficacy against RA.

The authors did not respond to multiple requests for comments.

Donath said, "From a clinical point of view, I believe that there is sufficient evidence for treatment of T2D and RA with anakinra. However, anakinra is not an attractive drug (daily injections with local side effects). Therefore, it would be worthwhile to conduct similar studies with long-acting (anti-IL-1β antibodies) or oral (NRLP3 inhibitors) drugs tackling the IL-1 pathway."

Gerd R. Burmester, MD, professor of medicine and director, Department of Rheumatology and Clinical Immunology, Charité – University Medicine, Berlin, Germany, was even more cautious. Burmester, who was not involved in the study, told Medscape Medical News, "Surprisingly, the efficacy of anakinra here was better than previously reported in larger trials." He also said that recent studies of IL-6 receptor inhibitors reported at the American College of Rheumatology found them to be more effective than IL-1 inhibition for treating RA.

The investigators' study enrolled participants between 2013 and 2016 who had RA and T2D. Participants maintained their baseline diabetes therapy, RA therapy, diet, and lifestyle habits.

Participants were randomly assigned to receive either anakinra or a TNFi (adalimumab, certolizumab pegol, etanercept, infliximab, or golimumab). The primary endpoint was the change in percentage of glycated hemoglobin (A1c%).

The study was designed for a sample size of 200 to provide a 90% power to detect a 0.25% difference in A1C% with a significance level (α) of 5%; however, at the time of the planned interim analysis 12 months after beginning recruitment, the researchers had enrolled only 10 patients who had been randomly assigned to receive anakinra and nine patients who had been assigned to receive TNFi. This reduced the study power to 45% and raised doubts about achieving the planned sample size. Despite this problem, the researchers found a 0.71 crude clinical difference in A1C% between anakinra and TNFi after 3 months and decided to continue the analysis.

Burmester commented, "This is, unfortunately, what happens frequently in investigator-initiated studies with a discrepancy between recruitment expectations/hopes and real life, with low fees for enrollment and many regulatory hurdles. The conclusions can be followed, but larger trials are needed."

Donath added, "This was an investigator-initiated study, not sponsored by an industrial partner. In this kind of study, with limited means, recruitment problems are almost a rule, often requiring some adaptation in the design. However, the statistics remained solid, and the effects were very strong (decrease of HbA1c at 6 months of −1.05, P < .001) and consistent over time. Therefore, the conclusion remains reliable."

The final study population included 39 eligible participants, 70% of whom had seropositive RA disease and active RA (Disease Activity Score–28 [DAS28], 5.54; C-reactive protein, 11.84 mg/L). Of these, 22 patients were randomly assigned to receive open-label anakinra, and 17 were randomly assigned to receive TNF1. All patients continued using their usual RA and diabetes drugs.

An unplanned interim analysis was conducted after all participants had at least 6 months of follow-up. This confirmed the results seen in the 3-month analysis. For patients in the anakinra group, there was a significant reduction in A1C% in a linear model that was adjusted for relevant RA and T2D clinical confounders: 0.85 at 3 months (P < .001), and 1.05 at 6 months (P < .01). For patients in the TNFi group, there was a nonsignificant decrease of A1C% at both points. This difference triggered early-stopping rules for the study, owing to the early benefit seen with anakinra. Progressive reductions of RA disease activity were observed in both groups and were not significantly different between groups.

The authors write, "The study hypothesis was unexpectedly proven earlier than the predesignated timetable schedule, and with a larger percentage of anakinra-treated participants meeting the primary end point than TNFi-treated participants. 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."

They add, "[C]comparing our results to the previous study on T2D, we observed a more evident reduction of HbA1c%, suggesting that the inflammatory pathogenic mechanisms of T2D could be exaggerated in the context of RA." They also suggest that therapy targeting IL-1 in RA patients with T2D might also decrease CV risk in those patients.

The authors acknowledge study limitations, including the open-label design, unplanned interim analysis, small size, lack of some laboratory evaluations, and ongoing use of other drugs by most participants. Burmester said that because of these limitations, this is mainly a hypothesis-generating study. He said that long-term studies would be useful, "but anakinra is mostly no longer used in RA because of a (at least perceived) lower clinical efficacy on the joints."

Burmester concluded, "Since the coincidence of RA and T2D is not rare, IL-1 and IL-6 inhibition are certainly very interesting options, especially in T2D/RA patients requiring glucocorticoid therapy because of high disease activity. Because of the lower RA efficacy of anakinra in the pivotal trials, it will, however, be doubtful if anakinra will have a 'revival' here, especially if more data are published on the effects of IL-6 inhibition. But trials corroborating the anakinra effects are highly welcome."

The study received no funding. The authors have disclosed no relevant financial relationships. Editorial assistance was supported by Swedish Orphan Biovitrum AB, an international specialty biopharmaceutical company dedicated to rare diseases that is based in Stockholm, Sweden. Burmester has consulted and lectured for Roche, Sanofi-Genzyme, and Novartis unrelated to anakinra. Donath is the inventor on a patent filed in 2003 for the use of an IL-1 receptor antagonist for the treatment of or prophylaxis for type 2 diabetes.

PLoS Med. Published online September 12, 2019. Full text

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