C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis

Taylor, Peter N; Collins, Kimberly S; Lam, Anna; Karpen, Stephen R; Greeno, Brianna; Walker, Frank; Lozano, Alejandro; Atabakhsh, Elnaz; Ahmed, Simi T; Marinac, Marjana; Latres, Esther; Senior, Peter A; Rigby, Mark; Gottlieb, Peter A; Dayan, Colin M; Greenbaum, Carla; Krisher, Jeffrey; Skyler, Jay; Wherrett, Diane; Hannelius, Ulf; Lindqvist, Anton; Nowak, Christoph; Bebu, Ionut; Braffett, Barbara; Napolitano, Antonella; Jan Mohamed, Salim; Weir, Gordon; Nepom, Gerald; Beck, Roy; Richard, Claudia; Hedrick, Joseph; Ludvigsson, Johnny; Von Herrath, Matthias; Leon, Francisco; Ramos, Eleanor; Narendran, Parth; Gitelman, Stephen; Dabelea, Dana; Andrews, Rob; Haller, Michael; Jensen, Elizabeth; Harold, Kevan; Dutz, Jan

doi:10.1016/s2213-8587(23)00267-x

Cited by 18 publications

(3 citation statements)

References 38 publications

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“…Differences in response are noted between new‐onset cases and those with a longer disease duration 23 . Our findings align with the results of previous trials 7,8,19,24 and meta‐analyses, 9,31,32 emphasizing a robust effect of teplizumab on this critical endpoint. Notably, the subgroups aged 8–11 and 12–17 years exhibited a nonsignificant difference in AUC of C‐peptide levels, demonstrating that teplizumab is equally effective in the two age groups.…”

Section: Discussionsupporting

confidence: 89%

Safety and efficacy of teplizumab in the treatment of type 1 diabetes mellitus: An updated systematic review and meta‐analysis of randomized controlled trials

Grando Alves,

Cunha,

Henkes Machado

et al. 2024

Diabetes Obesity Metabolism

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AimTo provide updated efficacy and safety information for teplizumab in the treatment of Stage 3 type 1 diabetes mellitus (T1DM).Materials and MethodsThe PubMed, Embase and Cochrane databases were searched for randomized controlled trials (RCTs) comparing teplizumab to placebo for T1DM that reported any of the following outcomes: (1) C‐peptide area under the curve (AUC); (2) glycated haemoglobin (HbA1c) levels; (3) insulin requirements; and (4) adverse events. Heterogeneity was examined with I2 statistics. p values <0.05 were taken to indicate statistical significance. The continuous endpoints were compared through the pooled mean difference (MD) and binary endpoints were assessed using risk ratios, both with 95% confidence intervals (CIs). Statistical analyses were performed using Review Manager Web software.ResultsEight RCTs with 1052 patients (754 receiving teplizumab) were included. Teplizumab significantly increased the AUC of C‐peptide levels at 6 (MD 0.10 nmol/L, 95% CI 0.05, 0.16), 12 (MD 0.13 nmol/L, 95% CI 0.06, 0.20), 18 (MD 0.18 nmol/L, 95% CI 0.09, 0.27) and 24 months (MD 0.16 nmol/L, 95% CI 0.02, 0.31), significantly reduced HbA1c levels at 6 (MD −0.57%, 95% CI −1.07, −0.08) and 12 months (MD −0.31%, 95% CI −0.59, −0.02), and significantly reduced insulin requirements at 6 (MD −0.12 U/kg, 95% CI −0.16, −0.08), 12 (MD −0.11 U/kg, 95% CI −0.15, −0.07), 18 (MD −0.17 U/kg, 95% CI −0.26, −0.09) and 24 months (MD −0.11 U/kg, 95% CI −0.22, −0.01).ConclusionTeplizumab increases AUC of C‐peptide levels and decreases HbA1c levels and insulin use, without raising serious adverse event risk.

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Section: Discussionsupporting

confidence: 89%

Safety and efficacy of teplizumab in the treatment of type 1 diabetes mellitus: An updated systematic review and meta‐analysis of randomized controlled trials

Grando Alves,

Cunha,

Henkes Machado

et al. 2024

Diabetes Obesity Metabolism

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“…With immunotherapies as adjuncts to insulin showing promise in preserving C‐peptide, 162 the stratification of patients into these endotypes allows for tailoring of these therapies based on the pathological processes behind disease development. Additionally, further studies which can compare the effects of these drugs between endotypes may also allow us to better understand the disease processes behind the different endotypes.…”

Section: Final Remarksmentioning

confidence: 99%

“…deepen our understanding of the complexity and diversity of diabetic endotypes. These endotypes are not necessarily mutually exclusive and further subclassifications may arise with future studies.With immunotherapies as adjuncts to insulin showing promise in preserving C-peptide,162 the stratification of patients into these endotypes allows for tailoring of these therapies based on the T A B L E 6…”

mentioning

confidence: 99%

Type 1 diabetes: A new vision of the disease based on endotypes

Weston,

Boehm,

Pozzilli

2024

Diabetes Metabolism Res

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Diagnosis and management of type 1 diabetes (T1D) have remained largely unchanged for the last several years. The management of the disease remains primarily focused on its phenotypical presentation and less on endotypes, namely the specific biological mechanisms behind the development of the disease. Furthermore, the treatment of T1D is essentially universal and indiscriminate—with patients administering insulin at varying dosages and frequencies to maintain adequate glycaemic control. However, it is now well understood that T1D is a heterogeneous disease with many different biological mechanisms (i.e. endotypes) behind its complex pathophysiology. A range of factors, including age of onset, immune system regulation, rate of β‐cell destruction, autoantibodies, body weight, genetics and the exposome are recognised to play a role in the development of the condition. Patients can be classified into distinct diabetic subtypes based on these factors, which can be used to categorise patients into specific endotypes. The classification of patients into endotypes allows for a greater understanding of the natural progression of the disease, giving rise to more accurate and patient‐centred therapies and follow‐up monitoring, specifically for other autoimmune diseases. This review proposes 6 unique endotypes of T1D based on the current literature. The recognition of these endotypes could then be used to direct therapeutic modalities based on patients' individual pathophysiology.

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