C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001.
The underlying cause of type 1 diabetes, loss of beta-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 beta-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. HbA(1c) is a highly valuable clinical measure of glycemic control, but it is an insensitive measure of beta-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 beta-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 beta-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 beta-cell function as determined by C-peptide measurement as the primary efficacy outcome.
Palmer
Jerry P
JP
Department of Medicine, University of Washington,and DVA Puget Sound Health Care System, Seattle, Washington 98108, USA. jpp@u.washington.edu
Fleming
G Alexander
GA
Greenbaum
Carla J
CJ
Herold
Kevan C
KC
Jansa
Lisa D
LD
Kolb
Hubert
H
Lachin
John M
JM
Polonsky
Kenneth S
KS
Pozzilli
Paolo
P
Skyler
Jay S
JS
Steffes
Michael W
MW
D002096:C-Peptide / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000628:therapy; D006801:Humans; D007515:Islets of Langerhans / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D016896:Treatment Outcome
D002096:C-Peptide