Work

Immunomodulatory interventions in type 1 diabetes: a systematic review and meta-analysis revealing paradoxical dissociation between beta-cell preservation and glycemic control

Year: 2025

Type: review

Study designs: Systematic Review, Meta-Analysis

Abstract: BACKGROUND: Immunomodulatory therapies aim to preserve beta-cell function in type 1diabetes (T1D), yet their clinical translation remains inconsistent. Weconducted a systematic review and meta-analysis to quantify treatment effectson beta-cell preservation, glycemic control, and insulin requirements whileexamining time-dependent efficacy and safety profiles. METHODS: We searched PubMed, Embase, and Cochrane CENTRAL for randomizedcontrolled trials evaluating immunomodulatory interventions (teplizumab,otelixizumab, low-dose IL-2) in T1D patients. Primary outcomes includedC-peptide area under curve, HbA1c, and insulin requirements analyzed asstandardized mean differences (SMD) using random-effects models.Meta-regression examined time-dependent treatment attenuation. RESULTS: Nineteen studies (n = 1,852) were analyzed. Immunotherapy significantlypreserved C-peptide (SMD = 0.221, 95%CI: 0.069-0.373, p = 0.007) without improvingHbA1c (SMD = 0.033, 95%CI: -0.070-0.136, p = 0.488), demonstratingbiomarker-clinical outcome disconnect. Paradoxically, low-dose IL-2 producedmassive regulatory T-cell expansion (SMD = 2.23, p = 0.003) and improved HbA1c(SMD = -0.514, p = 0.025) without preserving C-peptide (SMD = 0.020, p = 0.967),suggesting non-immunological metabolic pathways. Insulin requirements showedmodest reduction in sensitivity analysis (SMD = -0.453, p = 0.021) with significanttime-dependent attenuation (R² = 49.06%, p = 0.009), indicating benefits fadeprogressively. WBCs Clearance agents demonstrated 3.2-fold higher seriousadverse event rates than Treg Enhancement agents (34.5% vs 10.8%), with all five reported deaths occurring with WBCs Clearance. CONCLUSION: Immunomodulation provides modest, temporary beta-cell preservationwithout consistent glycemic improvement. The C-peptide-HbA1c disconnect likelyreflects intensive insulin management masking treatment benefits. IL-2'sparadoxical HbA1c improvement without beta-cell preservation warrants mechanistic investigation. Time-dependent benefit attenuation suggests maintenance therapy may be necessary. Safety profiles favor Treg Enhancementover WBCs Clearance approaches. Future trials should employ continuous glucosemonitoring endpoints, longer follow-up, and combination strategies to optimizedisease-modifying therapy development. CLINICAL TRIAL NUMBER: Not applicable.

Source: BMC Endocrine Disorders

DOI: 10.1186/s12902-025-02088-8