Anti-TNF, methotrexate impart ‘off-target benefits’ in inflammatory arthritis, diabetes

TNF inhibitors and methotrexate produced similar reductions in HbA1c among patients with psoriatic arthritis, rheumatoid arthritis or ankylosing spondylitis who also have diabetes, according to data published in BMC Rheumatology.

“[TNF-alpha] has been found to promote insulin resistance and disrupt insulin signaling,” Santhi Mantravadi, MD, of Thomas Jefferson University and the University of Pennsylvania Perelman School of Medicine, and colleagues wrote. “Thus, it may be presumed that modulating this pathway in [inflammatory arthritis (IA)] patients with diabetes may improve insulin sensitivity.”

“Little is known about the role of MTX in insulin resistance and existing studies have conflicting messages,” they added. “… Overall, little is known about how TNFi and [methotrexate (MTX)] impact HbA1c in patients with IA and diabetes.”

To analyze whether TNF inhibitors or methotrexate would improve HbA1c in patients with PsA, RA or AS who also have diabetes, Mantravadi and colleagues conducted a retrospective cohort study of Optum’s Clinformatics Data Mart database. According to the researchers, Clinformatics provides de-identified administrative claims data, including demographics, prescription drug use, diagnostic codes, medical claims history and laboratory values, for approximately 13 million beneficiaries in the United States.

Focusing on data from 2000 to 2014, the researchers included patients with PsA, RA or AS who also had diabetes, or an HbA1c level of 7% or greater, who started treatment with either TNF inhibitors, methotrexate or metformin. Patients who received metformin served as a positive control. The researchers studied changes in HbA1c following drug initiation, and used the Wilcoxon rank sum test and linear regression models to assess statistical differences, adjusting for potential confounders.

Among the available 10,389 drug initiations across 9,541 patients with PsA, RA or AS and available HbA1c values, a baseline of 7% or greater was present in 254 TNF-inhibitor initiations, 361 methotrexate initiations and 2,144 metformin initiations.

According to the researchers, the median change in HbA1c change –0.35 (IQR = –1.1 to 0.3) following initiation with TNF inhibitors, –0.4 (IQR = –1.2 to 0.3) following methotrexate, and –0.8 (IQR = –1.6 to –0.1) after metformin. In the adjusted analyses, TNF inhibitors produced less of a reduction in HbA1c compared with methotrexate (Beta = 0.22; 95% CI, 0.004-0.43). Further, metformin demonstrated a significantly greater decrease in HbA1c than methotrexate (Beta = –0.38; 95% CI, –0.52 to –0.23).

“Initiation of a TNFi or MTX among patients with an elevated HbA1c is associated with a modest decrease in HbA1c that is approximately half as much (about 0.4units) as the decrease observed after initiation of metformin (about0.8units),” Mantravadi and colleagues wrote. “This study found no compelling evidence for a difference in the effect between TNFi and MTX, suggesting similar treatment effects.”

“This study suggests that, in addition to limiting glucocorticoid exposure in patients with diabetes, controlling inflammatory disease may have off-target benefits, regardless of the drug choice,” they added. “Future research is needed to understand the complex relationship between inflammatory arthritis, insulin resistance, glucocorticoids and metabolic pathways.”