Characteristics and Clinical Course of Diabetes of the Exocrine Pancreas: A Nationwide Population-Based Cohort Studybrief Title: Diabetes of the Exocrine Pancreas

Background: The natural course of diabetes of the exocrine pancreas (DEP) is not well established. We aimed to compare the risk of insulin initiation, diabetic complications, and mortality between DEP and type 2 diabetes. Methods: Using the Korean National Health Insurance Service–Health Screening Cohort between 2012-2017, we divided diabetic patients into those with diabetes without prior pancreatic disease (indicated type 2 diabetes, n=153 894) and diabetes following pancreatic disease (indicated DEP, n=3661). ICD-10 codes and pharmacy prescription information were used to define type 2 diabetes, DEP, and acute and chronic diabetes complications. Reverse Kaplan-Meier curves were produced to compare insulin use over time between groups. We created logistic regression models for odds of progression to diabetic complications and mortality. Findings: DEP was associated with a higher risk of insulin use than type 2 diabetes (adjusted hazard ratio 1·25 at 1 year [95% confidence interval 1·16–1·35], p<0·0001; at 5 years 1·28 [1·20–1·35], p<0·0001). Individuals with DEP showed higher risks of hypoglycaemia (odds ratio 1·82 [1·52–2·18], p<0·0001), diabetic neuropathy (1·37 [1·27–1·48], p<0·0001), nephropathy (1·34 [1·24–1·45], p<0·0001), retinopathy (1·12 [1·03–1·22], p=0·0110), cardiovascular disease (1·50 [1·39–1·61], p<0·0001), cerebrovascular disease (1·24 [1·14–1·34], p<0·0001), and peripheral artery disease (1·24 [1·15–1·33], p<0·0001). All-cause mortality was higher in those with DEP (1·52 [1·37–1·70], p<0·0001) than in those with type 2 diabetes. Interpretation: DEP is more likely to require insulin therapy than type 2 diabetes. Hypoglycaemia, micro- and macrovascular complications, and all-cause mortality events are higher in DEP compared to type 2 diabetes. Awareness of these differences in the natural history of DEP may better enable clinicians to address the challenges posed by this diabetes sub-type and better achieve glycaemic control targets, avoid hypoglycaemia, and monitor and prevent complications. Funding: This study was funded by the National Research Foundation of Korea Ministry of Science and ICT (No. NRF-2018R1C1B5044056) and Korea Medical Institute. Declaration of Interest: None to declare. Ethical Approval: This study was approved by the Institutional Review Board of Ajou University Hospital (AJIRB-MED-EXP-19-106]