Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and this is attributed to it being diagnosed at an advanced stage. Understanding the pathways involved in initial development may improve early detection strategies. This systematic review assessed the association between circulating protein and metabolite biomarkers and PDAC development. Methods: A literature search until August 2020 in MEDLINE, EMBASE and Web of Science was performed. Studies were included if they assessed circulating blood, urine or salivary biomarkers and their association with PDAC risk. Quality was assessed using the Newcastle-Ottawa scale for cohort studies. Random-effects meta-analyses were used to calculate pooled relative risk. Results: A total of 65 studies were included. Higher levels of glucose were found to be positively associated with risk of developing PDAC (n=4 studies; pooled relative risk (RR): 1.61; 95% CI: 1.16-2.22). Additionally, an inverse association was seen with pyridoxal 5′-phosphate (PLP) levels (n=4 studies; RR: 0.62; 95% CI: 0.44-0.87). Meta-analyses showed no association between levels of C-peptide, members of the insulin growth factor signaling pathway, C-reactive protein, adiponectin, 25-hydroxyvitamin D and folate/homocysteine and PDAC risk. Four individual studies also reported a suggestive positive association of branched chain amino acids with PDAC risk but due to differences in measures reported, a meta-analysis could not be performed. Conclusions: Our pooled analysis demonstrates that higher serum glucose levels and lower levels of PLP are associated with risk of PDAC. Impact: Glucose and PLP levels are associated with PDAC risk. More prospective studies are required to identify biomarkers for early detection.