Managing metabolic disruption in pancreatic cancer to prevent weight loss and improve quality of life

Pancreatic ductal adenocarcinoma (PDAC) is the fourth-leading cause of cancer death in the United States, with 60 000 cases diagnosed annually and five-year survival rate of only 10%. It is projected to become the secondleading cause of cancer-related mortality by 2030. PDAC is also associated with poor quality of life (QOL), including cachexia, in approximately 80% of patients. Cachexia is a contributing cause to 30% of deaths in PDAC and has no approved pharmacologic treatment. PDAC is also strongly associated with hyperglycemia. Half of patients have diabetes at the time of diagnosis and 80% experience hyperglycemia during treatment; the association is likely bi-directional, meaning that there is both evidence that diabetes causes PDAC and that PDAC causes diabetes. As a result, many patients with PDAC must use antidiabetic drugs such as metformin, sulfonylureas, or insulin. Hyperglycemia management during PDAC is an important aspect of supportive care with direct implications for QOL. Comparative effectiveness research on hyperglycemia management in PDAC is almost certain to improve supportive care by identifying which drugs best balance glucose control, side effects, and maintenance of healthy weight. This need for evidence in this specific population is especially pressing because the usual hierarchy of diabetes drugs may be inverted in PDAC patients. For example, prescribers deprecate sulfonylureas in routine diabetes practice in part because they promote weight gain, but that property could make them especially useful in patients with PDAC. Very little research has been done comparing sulfonylureas to metformin (the most widely used antidiabetic drug) or other alternatives as a supportive care intervention in PDAC. This proposal aims to close this evidence gap by, in Aim 1, conducting a retrospective cohort study testing the hypothesis that, compared to metformin, sulfonylureas are associated with better weight maintenance in patients with PDAC, and in Aim 2, enrolling 40 patients with hyperglycemia undergoing systemic treatment for PDAC in a trial assessing the safety of glipizide, a sulfonylurea, with respect to the key safety outcome of rate of hypoglycemia and the key effectiveness outcome of reducing blood glucose levels. This project will lay the groundwork for phase 3 clinical trials to determine whether choice of antidiabetic drug can improve QOL and even overall survival in patients with PDAC.