Metformin Use Associates With Longer Progression-free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

Metformin seems to have anti-cancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with NETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy, from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose ≥126 mg/dL, HbA1c ≥6.5% (48 mmol/L), or a random sample of plasma glucose ≥200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during anti-tumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses, excluding patients who developed diabetes while receiving cancer treatment, and to exclude a potential immortal time bias related to metformin intake. PFS was significantly longer in patients with diabetes (median 32.0 months) than without diabetes (15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% CI, 0.50-0.80; P=.0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% CI, 0.32-0.62; P