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; Kimberly S Collins; Anna Lam; Stephen R Karpen; Brianna Greeno; Frank Walker; Alejandro Lozano; Elnaz Atabakhsh; Simi T Ahmed; Marjana Marinac; Esther Latres; Peter A Senior; Mark Rigby; Peter A Gottlieb; Colin M Dayan; Trial Outcome Markers Initiative collaboration

doi:10.1016/S2213-8587(23)00267-X

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^*
, Kimberly S Collins^*
, Anna Lam^*
, Stephen R Karpen
, Brianna Greeno
, Frank Walker
, Alejandro Lozano
, Elnaz Atabakhsh
, Simi T Ahmed
, Marjana Marinac
, Esther Latres
, Peter A Senior
, Mark Rigby
, Peter A Gottlieb
, Colin M Dayan^*
, Trial Outcome Markers Initiative collaboration

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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, HbA_1c, insulin use, hypoglycaemic events, and composite scores (such as insulin dose adjusted A_1c, 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 HbA_1c (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 HbA_1c (p<0·0001). Higher initial C-peptide levels and greater preservation were associated with greater improvement in HbA_1c. For HbA_1c, 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 HbA_1c 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.

Original language	English
Pages (from-to)	915-925
Number of pages	11
Journal	The Lancet Diabetes and Endocrinology
Volume	11
Issue number	12
Early online date	3 Nov 2023
DOIs	https://doi.org/10.1016/S2213-8587(23)00267-X
Publication status	Published - Dec 2023

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Adult
Child
Humans
Diabetes Mellitus, Type 1/drug therapy
C-Peptide/therapeutic use
Cross-Sectional Studies
Glycated Hemoglobin
Hypoglycemic Agents/therapeutic use
Insulin/therapeutic use

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Cite this

Taylor, P. N., Collins, K. S., Lam, A., Karpen, S. R., Greeno, B., Walker, F., Lozano, A., Atabakhsh, E., Ahmed, S. T., Marinac, M., Latres, E., Senior, P. A., Rigby, M., Gottlieb, P. A., Dayan, C. M., & Trial Outcome Markers Initiative collaboration (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 and Endocrinology, 11(12), 915-925. https://doi.org/10.1016/S2213-8587(23)00267-X

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

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.",

keywords = "Adult, Child, Humans, Diabetes Mellitus, Type 1/drug therapy, C-Peptide/therapeutic use, Cross-Sectional Studies, Glycated Hemoglobin, Hypoglycemic Agents/therapeutic use, Insulin/therapeutic use",

author = "Taylor, \{Peter N\} and Collins, \{Kimberly S\} and Anna Lam and Karpen, \{Stephen R\} and Brianna Greeno and Frank Walker and Alejandro Lozano and Elnaz Atabakhsh and Ahmed, \{Simi T\} and Marjana Marinac and Esther Latres and Senior, \{Peter A\} and Mark Rigby and Gottlieb, \{Peter A\} and Dayan, \{Colin M\} and \{Trial Outcome Markers Initiative collaboration\} and Parth Narendran",

year = "2023",

month = dec,

doi = "10.1016/S2213-8587(23)00267-X",

language = "English",

volume = "11",

pages = "915--925",

journal = "The Lancet Diabetes and Endocrinology",

issn = "2213-8587",

publisher = "Elsevier",

number = "12",

}

Taylor, PN, Collins, KS, Lam, A, Karpen, SR, Greeno, B, Walker, F, Lozano, A, Atabakhsh, E, Ahmed, ST, Marinac, M, Latres, E, Senior, PA, Rigby, M, Gottlieb, PA, Dayan, CM & Trial Outcome Markers Initiative collaboration 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 and Endocrinology, vol. 11, no. 12, pp. 915-925. https://doi.org/10.1016/S2213-8587(23)00267-X

TY - JOUR

T1 - C-peptide and metabolic outcomes in trials of disease modifying therapy in new-onset type 1 diabetes

T2 - an individual participant meta-analysis

AU - Taylor, Peter N

AU - Collins, Kimberly S

AU - Lam, Anna

AU - Karpen, Stephen R

AU - Greeno, Brianna

AU - Walker, Frank

AU - Lozano, Alejandro

AU - Atabakhsh, Elnaz

AU - Ahmed, Simi T

AU - Marinac, Marjana

AU - Latres, Esther

AU - Senior, Peter A

AU - Rigby, Mark

AU - Gottlieb, Peter A

AU - Dayan, Colin M

AU - Trial Outcome Markers Initiative collaboration

AU - Narendran, Parth

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - Adult

KW - Child

KW - Humans

KW - Diabetes Mellitus, Type 1/drug therapy

KW - C-Peptide/therapeutic use

KW - Cross-Sectional Studies

KW - Glycated Hemoglobin

KW - Hypoglycemic Agents/therapeutic use

KW - Insulin/therapeutic use

U2 - 10.1016/S2213-8587(23)00267-X

DO - 10.1016/S2213-8587(23)00267-X

M3 - Article

C2 - 37931637

SN - 2213-8587

VL - 11

SP - 915

EP - 925

JO - The Lancet Diabetes and Endocrinology

JF - The Lancet Diabetes and Endocrinology

IS - 12

ER -

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

Abstract

Bibliographical note

UN SDGs

Keywords

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