Evidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes

Diabetes. 2024 Jun 1;73(6):823-833. doi: 10.2337/dbi23-0012.


Type 1 diabetes is a chronic autoimmune disease in which destruction of pancreatic β-cells causes life-threatening metabolic dysregulation. Numerous approaches are envisioned for new therapies, but limitations of current clinical outcome measures are significant disincentives to development efforts. C-peptide, a direct byproduct of proinsulin processing, is a quantitative biomarker of β-cell function that is not cleared by the liver and can be measured in the peripheral blood. Studies of quantitative measures of β-cell function have established a predictive relationship between stimulated C-peptide as a measure of β-cell function and clinical benefits. C-peptide levels at diagnosis are often high enough to afford glycemic control benefits associated with protection from end-organ complications of diabetes, and even lower levels offer protection from severe hypoglycemia in type 1 diabetes, as observed in large prospective cohort studies and interventional trials of islet transplantation. These observations support consideration of C-peptide not just as a biomarker of β-cell function but also as a specific, sensitive, feasible, and clinically meaningful outcome defining β-cell preservation or restoration for clinical trials of disease-modifying therapies. Regulatory acceptance of C-peptide as a validated surrogate for demonstration of efficacy would greatly facilitate development of disease-modifying therapies for type 1 diabetes.

Publication types

  • Review

MeSH terms

  • Biomarkers* / blood
  • Biomarkers* / metabolism
  • C-Peptide* / blood
  • C-Peptide* / metabolism
  • Clinical Trials as Topic
  • Diabetes Mellitus, Type 1* / drug therapy
  • Humans
  • Insulin-Secreting Cells* / drug effects
  • Insulin-Secreting Cells* / metabolism