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Diabetes 53:250-264, 2004
© 2004 by the American Diabetes Association, Inc.

C-Peptide Is the Appropriate Outcome Measure for Type 1 Diabetes Clinical Trials to Preserve ß-Cell Function

Report of an ADA Workshop, 21–22 October 2001

Jerry P. Palmer1,2, G. Alexander Fleming3, Carla J. Greenbaum4, Kevan C. Herold5, Lisa D. Jansa3, Hubert Kolb6, John M. Lachin7, Kenneth S. Polonsky8, Paolo Pozzilli9, Jay S. Skyler10, and Michael W. Steffes11

1Department of Medicine, University of Washington, Seattle, Washington
2Department of Medicine, DVA Puget Sound Health Care System, Seattle, Washington
3Kinexum, LLC, Harpers Ferry, West Virginia
4Diabetes Clinical Research Unit, Benaroya Research Institute, Seattle, Washington
5Department of Medicine, Columbia University, New York, New York
6University of Düsseldorf, Düsseldorf, Germany
7The Biostatistics Center, George Washington University, Washington, DC
8Department of Medicine, Washington University, St. Louis, Missouri
9University Campus Bio-Medico, Rome, Italy
10Department of Medicine, Diabetes Research Institute, University of Miami, Miami, Florida
11Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota

The underlying cause of type 1 diabetes, loss of ß-cell function, has become the therapeutic target for a number of interventions in patients with type 1 diabetes. Even though insulin therapies continue to improve, it remains difficult to achieve normal glycemic control in type 1 diabetes, especially long term. The associated risks of hypoglycemia and end-organ diabetic complications remain. Retention of ß-cell function in patients with type 1 diabetes is known to result in improved glycemic control and reduced hypoglycemia, retinopathy, and nephropathy. To facilitate the development of therapies aimed at altering the type 1 diabetes disease process, an American Diabetes Association workshop was convened to identify appropriate efficacy outcome measures in type 1 diabetes clinical trials. The following consensus emerged: While measurements of immune responses to islet cells are important in elucidating pathogenesis, none of these measures have directly correlated with the decline in endogenous insulin secretion. HbA1c is a highly valuable clinical measure of glycemic control, but it is an insensitive measure of ß-cell function, particularly with the currently accepted standard of near-normal glycemic control. Rates of severe hypoglycemia and diabetic complications ultimately will be improved by therapies that are effective at preserving ß-cell function but as primary outcomes require inordinately large and protracted trials. Endogenous insulin secretion is assessed best by measurement of C-peptide, which is cosecreted with insulin in a one-to-one molar ratio but unlike insulin experiences little first pass clearance by the liver. Measurement of C-peptide under standardized conditions provides a sensitive, well accepted, and clinically validated assessment of ß-cell function. C-peptide measurement is the most suitable primary outcome for clinical trials of therapies aimed at preserving or improving endogenous insulin secretion in type 1 diabetes patients. Available data demonstrate that even relatively modest treatment effects on C-peptide will result in clinically meaningful benefits. The development of therapies for addressing this important unmet clinical need will be facilitated by trials that are carefully designed with ß-cell function as determined by C-peptide measurement as the primary efficacy outcome.

Address correspondence and reprint requests to Jerry P. Palmer, MD, Director, Endocrinology, DVA Puget Sound Health Care System (111), 1660 South Columbian Way, Seattle, WA 98108. E-mail: jpp{at}u.washington.edu


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