Lower Risk of Diabetes with Abatacept Save

 Patients with rheumatoid arthritis (RA) treated with abatacept (Orencia) had a lower risk of developing diabetes mellitus compared with those receiving certain tumor necrosis factor (TNF) inhibitors, a large cohort study suggested.

Among almost 70,000 RA patients enrolled in two large U.S. claims databases, the risk of incident diabetes was doubled for patients initiating adalimumab (Humira), with a hazard ratio of 2.0 (95% CI 1.11-3.03), and for infliximab (Remicade), with a hazard ratio of 2.34 (95% CI 1.38-3.98), compared with those starting therapy with abatacept, according to Rishi J. Desai, PhD, and colleagues from Brigham and Women's Hospital and Harvard Medical School in Boston.

In addition, the hazard ratio for etanercept (Enbrel) versus abatacept was numerically higher, though not statistically significant (HR 1.65, 95% CI 0.91-2.98), the researchers reported online in ACR Open Rheumatology.

"In this large cohort study that includes data from two nationwide data sources in the United States, we noted use of abatacept to be associated with a lower risk of incident diabetes mellitus compared with use of two inhibitors (infliximab and adalimumab) in patients with RA," Desai and colleagues wrote.

However, they cautioned, the "limited number of diabetes mellitus events and incomplete capture of important risk factors for diabetes mellitus development, including obesity and RA disease activity, in administrative claims used to conduct this study precludes a causal conclusion."

That inflammation contributes to the pathogenesis of diabetes and insulin resistance is now acknowledged, and the systemic inflammatory activity characteristic of RA has been linked with a 50% increased risk of diabetes among patients with RA compared with non-rheumatic controls.

Observational data have suggested that targeted and biologic anti-inflammatory therapies in RA can help lower risks of diabetes to a greater degree than conventional nonbiologic drugs, which have more generalized immunosuppressive capabilities.

Interest has focused particularly on abatacept, a T-cell co-stimulation factor, because of its ability to modulate β-cell functioning in patients with type 1 diabetes and lower cardiovascular risks in patients with RA and type 2 diabetes.

To explore these risks in a large population, the researchers analyzed data from the Truven MarketScan (2005-2016) and Medicare (2010-2014) claims databases. The two groups included 50,505 and 17,251 patients with RA, respectively.

Additional targeted therapies used included certolizumab (Cimzia), golimumab (Simponi), tocilizumab (Actemra), and tofacitinib (Xeljanz).

The analysis adjusted for demographics, comorbidities, and other medications used, and the researchers performed inverse probability weighting.

In the Truven cohort, the most commonly used agents were etanercept (38.4%), adalimumab (36.1%), infliximab (13.4%), and abatacept (5.1%). In the Medicare cohort, the most commonly used were infliximab (32.9%), etanercept (17.8%), adalimumab (15%), and abatacept (14.9%).

Baseline differences before statistical weighting included older age and more cardiovascular comorbidities among patients initiating abatacept.

During follow-up of 368 days in the Truven group, there were 313 incident diagnoses of diabetes mellitus, and in 332 days of follow-up in the Medicare group there were 114 cases. These corresponded to incidence rates of 6.8 (95% CI 6.1-7.6) per 1,000 person-years for the Truven cohort and 6.6 (95% CI 5.4-7.9) per 1,000 in the Medicare cohort.

Compared with abatacept, the risk effect estimates for certolizumab, golimumab, tocilizumab, and tofacitinib were imprecise because of small numbers. Also, a bias analysis suggested that the prevalence of obesity was higher among the initiators in the adalimumab and infliximab groups compared with abatacept initiators, which could have influenced the risk calculations, the researchers noted.

"Results from this study provide a novel contribution to the literature by quantifying the relative risks for development of incident diabetes mellitus in patients with RA exposed to different biologics," the team stated.

The findings suggest that the effects of abatacept on diabetes risk may not be limited to anti-inflammatory actions alone, because all of the TNF inhibitors and other targeted agents "are expected to be equivalent" in control of inflammation, the researchers wrote. Rather, "we posit that direct effects of abatacept on glucose metabolism due to inhibition of T-cell co-stimulation may play a key role in explaining our results."

Another recent study from Italy identified benefits on the insulin sensitivity index and glycated hemoglobin levels among RA patients treated with abatacept for 6 months.

Because of the limitations associated with use of administrative databases, including potential confounding by RA duration and other factors, future randomized trials will be needed to more fully clarify the associations seen here between abatacept and diabetes risks, Desai and co-authors cautioned.

They concluded that if further studies confirm a lower risk of diabetes among patients given abatacept rather than TNF inhibitors, that would hold "important clinical implications because it may allow physicians to select a treatment that alters the risk of diabetes mellitus in patients with RA with a higher risk of developing diabetes mellitus, such as those with a family history of diabetes mellitus or other metabolic disturbances."

Desai reported research grants to Brigham and Women's Hospital from Bayer, Novartis, and Vertex for unrelated studies; co-authors reported research grants to Brigham and Women's Hospital from Roche, Pfizer, and AbbVie for unrelated studies.

Primary Source: ACR Open Rheumatology  Desai RJ, et al "Comparative risk of diabetes mellitus in patients with rheumatoid arthritis treated with biologic or targeted synthetic disease-modifying drugs: a cohort study" ACR Open Rheum 2020; DOI: 10.1002/acr2.11124.