OR19-06 Safety and Effectiveness of Sulfonylureas for Pancreas-Cancer Induced Metabolic Dysregulation

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Abstract Disclosure: J.H. Flory: None. H. Martirosova: None. E. Tan: None. M. Bakkar: None. M. Goncalves: None. W. Park: None. E. O'Reilly: None. Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by new-onset diabetes with rapid weight loss in a phenomenon termed ‘pancreas-cancer induced metabolic dysregulation syndrome’. For these patients, choice of antidiabetic drug may impact weight loss and thereby quality of life and survival. For example, metformin causes weight loss, while secretagogues (e.g., the sulfonylurea glipizide) cause weight gain. Evidence that hyperglycemia in PDAC is due to paraneoplastic suppression of beta-cell activity suggests that secretagogues might be particularly effective treatment. Methods: This report includes a prospective single-arm study assessing the safety and effectiveness of sulfonylureas in patients with PDAC-associated hyperglycemia, with systematic metabolic phenotyping (including quality of life and continuous glucose monitoring) before and after initiation of low-dose glipizide. An accompanying retrospective study compared patients with PDAC who initiated either metformin or sulfonylurea with change in weight as the primary outcome. Results: The prospective study has enrolled 24 patients. Median baseline HbA1c was 7.15 % (interquartile range [IQR] 6.50, 8.20), fructosamine was 307 mcmol/L (IQR 244, 401), fasting glucose was 187 mg/dL (IQR 127, 276), and insulin level was 6.6 mcU/mL (IQR 3.4, 11.3). After one month, fructosamine declined (-57 mcmol/L [95% CI -32 to -82]) with similar improvements in other glucose control measures. Body weight declined but not statistically significantly (-0.41 kg [95% CI -1.4 to 0.58]). There was no severe hypoglycemia. The retrospective study identified 31 new users of sulfonylurea and 70 new users of metformin. Sulfonylurea users were older (69 versus 64 years, p =0.04) and had lower body mass index (BMI) (23.5 versus 26.3 kg/m2, p = 0.003). Sulfonylurea initiation was associated with a slower rate of weight loss by 0.71 kg/month (95% CI 0.33-1.12). Exploratory analysis found an adjusted hazard ratio (aHR) of 1.36 (95% CI 0.76 to 2.45) for mortality for sulfonylurea versus metformin. In planned subgroup analysis, patients with baseline BMI <= 25 kg/m2, aHR was 0.63 (0.25 to 1.64). For baseline BMI > 25 kg/m2 the aHR was 4.9 (95% CI 2.10 to 11.4). Conclusions: Glipizide was associated with improved glucose control without significant hypoglycemia. In retrospective analysis, glipizide slowed the rate of weight loss relative to metformin. Exploratory analysis showed no increased mortality with sulfonylureas in patients with BMI <= 25 kg/m2. Increased mortality hazard in patients with BMI > 25 warrants further investigation, but this exploratory finding may be due to confounding. Sulfonylureas are a safe and effective choice for glycemic management in patients with PDAC and BMI <= 25 mg/kg2, and may ameliorate cachexia in this group. A randomized trial is warranted to test this hypothesis. Presentation: Sunday, July 13, 2025

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