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. ORCID: https://orcid.org/0000-0002-3436-422X, 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. ORCID: https://orcid.org/0000-0002-6557-3462, 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 and Dutz, Jan 2023. C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes: an individual participant meta-analysis. The Lancet Diabetes & Endocrinology 11 (12) , pp. 915-925. 10.1016/S2213-8587(23)00267-X

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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.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Publisher:	Elsevier
ISSN:	2213-8587
Date of First Compliant Deposit:	23 November 2023
Date of Acceptance:	12 September 2023
Last Modified:	24 Nov 2023 09:45
URI:	https://orca.cardiff.ac.uk/id/eprint/164272

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