Tofacitinib Improves Insulin Resistance in Patients with RA, Type 2 Diabetes

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Treatment with tofacitinib was shown to improve insulin resistance and inflammatory disease activity in a cohort of patients with rheumatoid arthritis (RA) and type 2 diabetes, leading to a bidirectional benefit, according to a study published in Arthritis Research and Therapy.¹ Despite these promising results, future research is necessary to confirm and determine the metabolic effects of the drug within this patient population.

Although RA can be improved using current treatment strategies, the condition is still associated with a high rate of comorbidities, which may lead to increased rates of disability, morbidity, and mortality. For example, previous research has indicated a consistent connection between chronic inflammatory process and glucose derangement, which is demonstrated in the higher prevalence of type 2 diabetes and insulin resistance in this patient population.²

“Considering that Janus kinase (JAK) inhibitors are successfully used in RA, it could be theoretically hypothesized that these drugs could bidirectionally improve inflammatory signs and associated glucose abnormalities in patients with type 2 diabetes,” wrote a group of Italian investigators. “In fact, according to previous findings, the administration of some RA-specific therapies could target the mechanisms of the concomitant cardiometabolic comorbidity providing a study model to be applied in this context.”

To determine if the selective JAK inhibitor tofacitinib could improve glycemic parameters and inflammatory marks in patients with RA and concomitant type 2 diabetes, investigators enrolled 40 patients into the 6-month proof-of-concept, open, prospective, clinical study. The primary endpoint was the change in the 1998-updated homeostatic model assessment of insulin resistance (HOMA2-IR) post-treatment with tofacitinib, while other endpoints evaluated RA disease activity and metabolic parameters.

Eligible patients were aged ≥18 years, met the RA classification criteria, were diagnosed with type 2 diabetes by a physician, and had moderate to severe disease activity despite being treated with conventional synthetic or biologic disease-modifying antirheumatic drugs (csDMARDs/bDMARDs).

Most (68.9%) patients were female, and the mean age was 63.4 years. Throughout the 6-month study period, a steady reduction of HOMA2-IR was reported in patients with RA and type 2 diabetes treated with tofacitinib. In particular, a significant effect of tofacitinib was demonstrated on the overall reduction of HOMA2-IR (β = −1.1, P = .019, 95% confidence interval [CI] − 1.5 to − 076). Further HOMA2-β had underscored improvement of insulin sensitivity. A trend in glycated hemoglobin reduction was observed, although a longer follow-up is required.

Treatment with tofacitinib improved disease activity in these patients, as demonstrated by a significant reduction in Simple Disease Activity Index (SDAI) and Disease Activity Score-28 C-reactive Protein (DAS28-CRP). Most (76.8%) patients were able to achieve a good clinical response.

In terms of safety, no major adverse events were reported and no new safety signals were observed. Particularly, no life-threatening adverse events, cardiovascular events, and/or thromboembolic events were recorded during the follow-up period.

Investigators noted limitations including the single-center study design, which may have hindered the generalization of data. Additionally, the lack of data regarding the titers of autoantibodies may impact future assessment of the findings. The small number of patients included in the sample was also considered a limitation.

“Taking together these findings, a more tailored management of RA could be advocated also including the evaluation of associated comorbidities,” investigators concluded. “In addition, the development of a more accurate biomarker profile of these issues, also considering adipocytokine profile, may also improve the management of these patients with both RA and T2D.”

References

1. ^{Di Muzio C, Di Cola I, Shariat Panahi A, et al. The effects of suppressing inflammation by tofacitinib may simultaneously improve glycaemic parameters and inflammatory markers in rheumatoid arthritis patients with comorbid type 2 diabetes: a proof-of-concept, open, prospective, clinical study. Arthritis Res Ther. 2024;26(1):14. Published 2024 Jan 4. doi:10.1186/s13075-023-03249-7}
2. ^{Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023–38. https://doi.org/10.1016/S0140-6736(16)30173-8. Epub 2016 May 3. Erratum in: Lancet. 2016 Oct 22;388(10055):1984. PMID: 27156434.}