Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials.
Mark C Genovese, Gerd R Burmester, Owen Hagino, Karthinathan Thangavelu, Melitza Iglesias-Rodriguez, Gregory St John, Miguel A González-Gay, Thomas Mandrup-Poulsen, Roy Fleischmann
Author Information
Mark C Genovese: Division of Immunology and Rheumatology, Stanford University Medical Center, 1000 Welch Road, Suite 203, Palo Alto, CA, 94304, USA. genovese@stanford.edu. ORCID
Gerd R Burmester: Charité University Medicine, Free University and Humboldt University of Berlin, Berlin, Germany.
Owen Hagino: Sanofi Genzyme, Bridgewater, NJ, USA.
Karthinathan Thangavelu: Sanofi Genzyme, Bridgewater, NJ, USA.
Melitza Iglesias-Rodriguez: Sanofi Genzyme, Bridgewater, NJ, USA.
Gregory St John: Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.
Miguel A González-Gay: University of Cantabria Hospital Universitario Marques de Valdecilla, Santander, Spain.
Thomas Mandrup-Poulsen: University of Copenhagen, Copenhagen, Denmark.
Roy Fleischmann: Metroplex Clinical Research Center and University of Texas Southwestern Medical Center, Dallas, TX, USA.
BACKGROUND: diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes. METHODS: Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RApatients with or without diabetes. RESULTS: patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was - 0.28 (- 0.40, - 0.16; nominal p < 0.0001) and - 0.42 (- 0.54, - 0.31; nominal p < 0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was - 0.13 (- 0.22, - 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA. CONCLUSIONS: In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings. TRIAL REGISTRATION: ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.
