Fasting serum C-peptide levels predict cardiovascular and overall death in nondiabetic adults

Abstract

Background: Insulin resistance, characterized by hyperinsulinemia and normal or elevated serum glucose, is an established precursor to diabetes and cardiovascular disease. Despite fasting serum C-peptide levels being an accurate and stable marker of endogenous insulin production used in patients with diabetes, it is unknown whether C-peptide could serve as a marker of insulin resistance and predict outcomes in patients without diabetes.

Method and results: This is a retrospective cohort study using data from the NHANES-3 (1988-1994) survey with mortality follow-up through December 31, 2006. Participants included 5153 subjects, 40 to 74 years of age with fasting glucose ≥ 70 mg/dL, without diabetes by history or laboratory testing. Receiver-operating-curve analysis compared fasting C-peptide against known insulin resistance measures such as fasting plasma glucose, serum insulin, HOMA-IR, quantitative-insulin-sensitivity-check-index, and metabolic syndrome for the prediction of cardiovascular and overall death. Subjects were then stratified by quartiles of C-peptide levels. Cox proportional-hazards modeling compared hazards of cardiovascular and overall death amongst C-peptide quartiles and adjusted for potential confounders of cardiovascular and diabetes risk. Fasting serum C-peptide levels predicted cardiovascular and overall death better than other studied measures (AUC=0.62 and 0.60 respectively vs the rest, with AUC ≤ 0.58 and ≤ 0.57 respectively, P<0.001). When compared with the lowest C-peptide quartile, subjects in the highest quartile had significantly higher adjusted hazard ratios (HR) of cardiovascular death (HR=1.60, 95%CI 1.07 to 2.39) and overall mortality (HR=1.72, 95%CI 1.34 to 2.21) after controlling for confounders.

Conclusions: C-peptide levels significantly related to hazards of cardiovascular and overall death in nondiabetic adults and was a better predictor of these outcomes than serum insulin and/or glucose derived measures.

Keywords: cardiovascular risk; glucose intolerance; insulin resistance.

Figure 1.

Kaplan–Meier Curve and percent survival estimates for cardiovascular disease death according to quartiles of C‐peptide levels. Quartile 1=0.418 nmol/L or less, Quartile 2=0.419 to 0.652 nmol/L, Quartile 3=0.653 to 0.983 nmol/L, Quartile 4=0.984 nmol/L or greater.