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

S. Pusceddu, C. Vernieri, M. Di Maio, R. Marconcini, F. Spada, S. Massironi, T. Ibrahim, M.P. Brizzi, D. Campana, A. Faggiano, D. Giuffrida, M. Rinzivillo, S. Cingarlini, F. Aroldi, L. Antonuzzo, R. Berardi, L. Catena, C. De Divitiis, P. Ermacora, V. PerfettiA. Fontana, P. Razzore, C. Carnaghi, M.V. Davì, C. Cauchi, M. Duro, S. Ricci, N. Fazio, F. Cavalcoli, A. Bongiovanni, A. La Salvia, N. Brighi, A. Colao, I. Puliafito, F. Panzuto, S. Ortolani, A. Zaniboni, F. Di Costanzo, M. Torniai, E. Bajetta, S. Tafuto, S.K. Garattini, D. Femia, N. Prinzi, L. Concas, G. Lo Russo, M. Milione, L. Giacomelli, R. Buzzoni, G. Delle Fave, V. Mazzaferro, F. de Braud

Research output: Contribution to journalArticlepeer-review


Background & Aims: Metformin seems to have anticancer 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 pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. Methods: 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 level ≥ 126 mg/dL, hemoglobin A1c ≥ 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 antitumor 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 to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. Results: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 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% confidence interval, 0.32–0.62; P
Original languageEnglish
Pages (from-to)479
Issue number2
Publication statusPublished - 2018


  • Chemoprevention
  • Drug
  • Insulin Resistance
  • Pancreas
  • angiopeptin
  • everolimus
  • glucose
  • hemoglobin A1c
  • insulin
  • metformin
  • octreotide
  • somatostatin derivative
  • antidiabetic agent
  • antineoplastic agent
  • somatostatin
  • adolescent
  • adult
  • aged
  • Article
  • cancer prognosis
  • child
  • clinical outcome
  • confidence interval
  • controlled study
  • correlation analysis
  • diabetic patient
  • dose response
  • drug effect
  • drug megadose
  • female
  • glucose blood level
  • glycemic control
  • hazard ratio
  • human
  • hyperglycemia
  • lifestyle
  • low drug dose
  • major clinical study
  • male
  • multicenter study
  • multivariate analysis
  • non insulin dependent diabetes mellitus
  • outcome assessment
  • overall survival
  • pancreas islet cell tumor
  • priority journal
  • progression free survival
  • retrospective study
  • sensitivity analysis
  • statistical analysis
  • analogs and derivatives
  • clinical trial
  • comparative study
  • disease free survival
  • epidemiology
  • Italy
  • Kaplan Meier method
  • middle aged
  • mortality
  • neuroendocrine tumor
  • pancreas tumor
  • pathology
  • time factor
  • treatment outcome
  • very elderly
  • young adult
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents
  • Child
  • Diabetes Mellitus, Type 2
  • Disease-Free Survival
  • Everolimus
  • Female
  • Humans
  • Hypoglycemic Agents
  • Kaplan-Meier Estimate
  • Male
  • Metformin
  • Middle Aged
  • Neuroendocrine Tumors
  • Pancreatic Neoplasms
  • Retrospective Studies
  • Somatostatin
  • Time Factors
  • Treatment Outcome
  • Young Adult


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