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Background <p>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.</p> Methods <p>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.</p> Results <p>Nineteen studies (<i>n</i> = 1,852) were analyzed. Immunotherapy significantlypreserved C-peptide (SMD = 0.221, 95%CI: 0.069–0.373, <i>p</i> = 0.007) without improvingHbA1c (SMD = 0.033, 95%CI: −0.070–0.136, <i>p</i> = 0.488), demonstratingbiomarker-clinical outcome disconnect. Paradoxically, low-dose IL-2 producedmassive regulatory T-cell expansion (SMD = 2.23, <i>p</i> = 0.003) and improved HbA1c(SMD = −0.514, <i>p</i> = 0.025) without preserving C-peptide (SMD = 0.020, <i>p</i> = 0.967),suggesting non-immunological metabolic pathways. Insulin requirements showedmodest reduction in sensitivity analysis (SMD = −0.453, <i>p</i> = 0.021) with significanttime-dependent attenuation (R² = 49.06%, <i>p</i> = 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.</p> Conclusion <p>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.</p> Clinical trial number <p>Not applicable.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月20日

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  • Shankar Biswas,
  • Bhavya Dhir,
  • Susmitha Talasila,
  • Spurthy Namala,
  • Ankush Kimmatkar,
  • Neeharika Bhamidi,
  • Sudharshan Raajkumar Ezhil,
  • Ummul Barka Safa,
  • I. M. Khalid Reza,
  • Vamsi Priya Sribhashyam,
  • Yashasvi Srivastava,
  • Urvashi Bharia,
  • Shaan Mohammad,
  • Ashish Jaswal,
  • Zain Ul Abedin,
  • Vikash Kumar,
  • Shivalika Singh,
  • Raymond Haward

摘要

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.