Interleukin-6 Inhibition Linked to Better Glycemic Control in Rheumatoid Arthritis
Clinical Study Title:
The effect of sarilumab in combination with DMARDs on fasting glucose and glycosylated hemoglobin in patients with rheumatoid arthritis with and without diabetes
Clinical Study Abstract:
- Background/Purpose: IL-6 involvement has been reported in glucose metabolism. Sarilumab, a human mAb blocking the IL-6Rɑ, was evaluated for treatment of RA in 3 clinical trials: MOBILITY, TARGET, and MONARCH. This analysis examined effects of sarilumab or placebo (Pbo), plus DMARDs, on fasting glucose and glycosylated hemoglobin (HbA1C) in patients with RA, with and without diabetes.
- Methods: Fasting glucose and HbA1C data were collected during 2 Pbo-controlled studies of sarilumab + DMARDs: MOBILITY and TARGET. Studies excluded patients with HbA1C≥9.0%. Patients with baseline (BL) and ≥1 post-BL sample were included in post hoc pooled analyses and categorized as diabetic (DIAB) or non-DIAB based on medical history of diabetes or prior use of antidiabetic medication. Changes from BL in fasting glucose, HbA1C, and weight were analyzed with a linear regression model. Spearman rank correlation coefficient was calculated for changes in glucose, HbA1C, and high-sensitivity (hs)-CRP. Changes in these parameters were stratified by clinical response. Clinical meaningfulness was based on comparison with results of clinical trials with antidiabetic medications.
- Results: The DIAB group (n=179) compared with the non-DIAB group (n=1803) had higher BL body weight (mean ± SD, kg: 84.8 ± 21.4 vs 74.6 ± 18.8) and a larger proportion of patients with BMI ≥30 kg/m2 (56.7% vs 31.9%). Mean fasting glucose and HbA1C at BL were similar across treatment groups (Pbo, and sarilumab 150 and 200 mg every 2 weeks [q2w]) but higher in the DIAB group than in the non-DIAB group (Table). Patients in the DIAB group had a greater reduction in fasting glucose at wk 24 compared with those in the non-DIAB group. Decreases in HbA1C occurred in non-DIAB and DIAB sarilumab-treated groups but not with Pbo. The treatment effect was largest in the DIAB group. At wk 24, the change in HbA1C was -0.43% in the DIAB (sarilumab 200 mg q2w) group and +0.17% in the DIAB (Pbo) group (-0.69% mean difference; P<0.001). Reductions in fasting glucose and HbA1C were observed in sarilumab-treated DIAB subgroups independently of changes in hs-CRP, ACR50, or DAS28-CRP remission status, and despite increases in mean body weight. The overall safety of sarilumab did not differ between DIAB and non-DIAB patients with RA.
- Conclusion: Sarilumab + DMARDs reduced fasting glucose and HbA1C in DIAB and HbA1Cin non-DIAB patients with RA, independent of changes in body weight, hs-CRP, ACR50, or DAS28-CRP remission status at wk 24. In DIAB patients, the difference in HbA1C reduction between sarilumab 200 mg q2w and Pbo was clinically meaningful.
Genovese MC, Fleischmann R, Hagino O, et al. The effect of sarilumab in combination with DMARDs on fasting glucose and glycosylated hemoglobin in patients with rheumatoid arthritis with and without diabetes [abstract]. Arthritis Rheumatol. 2017;69 (suppl 10).
Professor of Medicine
“This could be viewed as proof of concept that IL-6 inhibition is working in the right direction, in terms of a physiologic metabolism.”
Abstract 1822 at the 2017 ACR/ARHP Annual Meeting was really interesting. I thought that it was one of the more provocative translational abstracts. Interleukin-6 (IL-6) is a pleomorphic cytokine, with effects on both hemopoietic and nonhemopoietic cells, and it is very active metabolically.
It’s produced by white fat, and it’s correlated with CRP, which is a biomarker of cardiovascular disease, so, they are intertwined. You know, we have been worried for many years because IL-6 inhibition drives a lipid signal of rising low-density lipoprotein and modest rises of high-density lipoprotein that, at least at first glance, could constitute an enhancement of cardiovascular risk. Studies to date, however, have shown the following: (a) there is no clinical evidence of enhancement of cardiovascular risk and (b) the effects of IL-6 inhibition on physiologic aspects of lipid biochemistry and immunochemistry tend to be favorable.
So, with that in mind, this post-hoc analysis by Genovese and colleagues examined sarilumab, an IL-6 inhibitor. It involved patients with RA, with and without diabetes, and it basically asked simple questions. Does it affect fasting glucose? Does it affect A1C? Does it affect weight? And the data were very provocative. Both in patients with diabetes and in those without, there was a tendency to lower hemoglobin A1C in both groups with reductions that were statistically significant. In patients with diabetes, it actually lowered fasting blood glucose. There was a modest statistical amount of weight gain, about 1 lb or so, in patients with diabetes. Overall, these effects appeared to be independent of effects on disease activity or weight. And so, this could be viewed as suggestive that IL-6 inhibition may have positive effects, in terms of a physiologic metabolism. If true, I would expect to see this in both of the approved IL-6 inhibitors.
Burmester GR, Lin Y, Patel R, et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):840-847.
Fleischmann R, van Adelsberg J, Lin Y, et al. Sarilumab and nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis and inadequate response or intolerance to tumor necrosis factor inhibitors. Arthritis Rheumatol. 2017;69(2):277-290.
Strand V, Kosinski M, Chen CI, et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198.