Fasting serum C-peptide is a biomarker of insulin production and insulin resistance, but its association with vascular complications in type 2 diabetes mellitus (T2DM) has never been fully elucidated. This study aimed to investigate whether C-peptide is associated with cardiovascular disease (CVD) and diabetic retinopathy (DR).

A total of 4793 diabetes patients were enrolled from seven communities in Shanghai, China, in 2018. CVD was defined as a self-reported combination of previous diagnoses, including coronary heart disease, myocardial infarction and stroke. DR was examined using fundus photographs. Logistic regression analyses were performed, and multiple imputed data were used to obtain stabilized estimates.

Prevalence of CVD increased with increasing C-peptide levels (Q1, Q2, Q3 and Q4: 33%, 34%, 37% and 44%, respectively; P_{for trend} < 0.001), whereas DR prevalence decreased with increasing C-peptide quartiles (Q1, Q2, Q3 and Q4: 21%, 19%, 15% and 12%, respectively; P_{for trend} < 0.001). On logistic regression analysis, C-peptide levels were significantly associated with CVD prevalence (1.27, 95% CI: 1.13–1.42; P < 0.001) and C-peptide quartiles (Q1: reference; Q2: 1.31, 95% CI: 1.00–1.70; Q3: 1.53, 95% CI: 1.16–2.01; Q4: 1.76, 95% CI: 1.32–2.34; P_{for trend} < 0.001). Given the interaction between C-peptide and BMI and the association between C-peptide and CVD (P_{for interaction} = 0.015), study participants were divided into two subgroups based on BMI which revealed that the association persisted despite different BMI statuses. However, DR prevalence decreased with increasing C-peptide levels (0.73, 95% CI: 0.62–0.86; P < 0.001) and quartiles (Q1: reference; Q2: 1.00, 95% CI: 0.76–1.33; Q3: 0.69, 95% CI: 0.50–0.94; Q4: 0.51, 95% CI: 0.36–0.72; P_{for trend} < 0.001).

C-peptide was positively associated with CVD, but inversely associated with DR progression. The association between C-peptide and CVD could be due to associated metabolic risk factors.