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Meta-Analysis
. 2023 Dec;11(12):915-925.
doi: 10.1016/S2213-8587(23)00267-X. Epub 2023 Nov 3.

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

Peter N Taylor  1 , Kimberly S Collins  2 , Anna Lam  3 , Stephen R Karpen  2 , Brianna Greeno  2 , Frank Walker  2 , Alejandro Lozano  2 , Elnaz Atabakhsh  2 , Simi T Ahmed  4 , Marjana Marinac  5 , Esther Latres  5 , Peter A Senior  3 , Mark Rigby  2 , Peter A Gottlieb  6 , Colin M Dayan  7 ; Trial Outcome Markers Initiative collaboration
Collaborators, Affiliations
Free article
Meta-Analysis

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

Peter N Taylor et al. Lancet Diabetes Endocrinol. 2023 Dec.
Free article

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Abstract

Background: Metabolic outcomes in type 1 diabetes remain suboptimal. Disease modifying therapy to prevent β-cell loss presents an alternative treatment framework but the effect on metabolic outcomes is unclear. We, therefore, aimed to define the relationship between insulin C-peptide as a marker of β-cell function and metabolic outcomes in new-onset type 1 diabetes.

Methods: 21 trials of disease-modifying interventions within 100 days of type 1 diabetes diagnosis comprising 1315 adults (ie, those 18 years and older) and 1396 children (ie, those younger than 18 years) were combined. Endpoints assessed were stimulated area under the curve C-peptide, HbA1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A1c, total daily insulin, U/kg per day, and BETA-2 score). Positive studies were defined as those meeting their primary endpoint. Differences in outcomes between active and control groups were assessed using the Wilcoxon rank test.

Findings: 6 months after treatment, a 24·8% greater C-peptide preservation in positive studies was associated with a 0·55% lower HbA1c (p<0·0001), with differences being detectable as early as 3 months. Cross-sectional analysis, combining positive and negative studies, was consistent with this proportionality: a 55% improvement in C-peptide preservation was associated with 0·64% lower HbA1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA1c. For HbA1c, IDAAC, and BETA-2 score, sample size predictions indicated that 2-3 times as many participants per group would be required to show a difference at 6 months as compared with C-peptide. Detecting a reduction in hypoglycaemia was affected by reporting methods.

Interpretation: Interventions that preserve β-cell function are effective at improving metabolic outcomes in new-onset type 1 diabetes, confirming their potential as adjuncts to insulin. We have shown that improvements in HbA1c are directly proportional to the degree of C-peptide preservation, quantifying this relationship, and supporting the use of C-peptides as a surrogate endpoint in clinical trials.

Funding: JDRF and Diabetes UK.

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Conflict of interest statement

Declaration of interests PNT declares personal consulting fees from Immunovant and leadership roles in the Society for Endocrinology and British Thyroid Association. CMD declares lecturing or has been involved as an advisor for: Novo Nordisk, Sanofi-Genzyme, Janssen, Servier, Lilly, AstraZeneca, Provention Bio, UCB, MSD, Vielo Bio, Avotres, Worg, and Novartis. He holds patents jointly with Midatech, and Provention Bio and Sanofi. PAG declares consulting fees from Provention Bio and Viacyte and co-founded ImmunoMolecular Therapeutics for which he holds shares and serves as Chief Medical Officer and is a board member. He has received research support from the National Institutes of Health, Helmsley Charitable Trust, the Juvenile Diabetes Research Foundation, Nova Pharmaceuticals, Intrexon T1D Partners, Novartis, Imcyse, and Provention Bio. ALa received salary funding from JDRF in partnership with Diabetes UK. EL is a former Regeneron Pharmaceuticals employee and owns stock in the company. PAS holds the Charles A Allard Chair in Diabetes Research. He is a co-investigator in Diabetes Action Canada, and the board chair of Diabetes Canada. He has received consulting fees or honoraria from Abbott, Bayer, Eli Lilly, Insulet, Novo Nordisk, and Vertex. ALo, BG, EA, FW, and KSC are employees of the Critical Path Institute, a non-profit organisation supported by the US Food and Drug Administration of the Department of Health and Human Services. The Critical Path Institute is 55% funded by the Food and Drug Administration of the Department of Health and Human Services, totalling US $17 612 250, and 45% funded by non-government sources, totalling $14 203 111. The contents are those of the authors and do not necessarily represent the official views of, nor are an endorsement by, the Food and Drug Administration of the Department of Health and Human Services or the US Government. The Type 1 Diabetes Consortium at the Critical Path Institute receives funding from the following organisations: JDRF, Helmsley Charitable Trust, Novo Nordisk, Provention Bio, Sanofi, and Diamyd Medical. EA is a former employee of Abcam and owns stock in the company. All other authors declare no competing interests.

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