Immunotherapeutic agents in type 1 diabetes: a systematic review and meta-analysis of randomized trials.

Author(s): Gandhi GY, Murad MH, Flynn DN, Elamin MB, Erwin PJ, Montori VM, Kudva YC

Affiliation(s): Division of Endocrinology, Diabetes, Metabolism and Nutrition, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.

Publication date & source: 2008-01-10, Clin Endocrinol (Oxf)., [Epub ahead of print]

Publication type:

Objective: Although recent trial results of anti-CD3 therapy are promising, there have been conflicting results of various immunotherapeutic agents used in patients with type 1 diabetes. We conducted a systematic review and meta-analysis to determine the efficacy of non-antigen based immunotherapeutic approaches for preservation of beta-cell function in patients with type 1 diabetes. Methods: We searched MEDLINE, EMBASE, Cochrane CENTRAL, reference lists, and content expert files up to September 2006. Eligible studies were randomized controlled trials (RCTs) of anti-proliferative agents (methotrexate, azathioprine), monoclonal antibodies (CD3, CD4), T-cell inhibitor (cyclosporine) and other immunotherapeutic agents (photopheresis, linomide, fusidin, buffy coat, intravenous immunoglobulin, BCG, nicotinamide) in patients with newly-diagnosed type 1 diabetes followed for >/= 6 months. Pairs of reviewers working independently and with adequate reliability assessed the trials' methodological quality, collected data, and conducted random-effects meta-analyses on measures of preservation of beta-cell function (e.g., c-peptide secretion, insulin independence). Results: Of the 299 potentially relevant articles identified after an initial search, 20 trials met selection criteria. Meta-analysis of 20 trials (n=1187 patients) found a small-to-moderate improvement in beta-cell function with immunotherapy (vs. placebo, effect size 0.37, 95% CI 0.14 to 0.6), but there was moderate inconsistency in results across trials (IA(2) 65%, 95% CI 39 to 77%). Subgroup analysis suggested a greater effect of cyclosporine and antiproliferative agents on beta cell function when used for >/= 6 months (pooled effect size 0.77 vs. -0.11, respectively; P(interaction)= 0.002). Conclusions: Long-term immunotherapy may preserve beta-cell function in newly diagnosed patients with type 1 diabetes. Patients and clinicians must await the conduct of rigorous trials reporting on diabetes resolution, adverse events, and other patient-important outcomes.