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

Sara Pusceddu, Claudio Vernieri, Massimo Di Maio, Riccardo Marconcini, Francesca Spada, Sara Massironi, Toni Ibrahim, Maria Pia Brizzi, Davide Campana, Antongiulio Faggiano, Dario Giuffrida, Maria Rinzivillo, Sara Cingarlini, Francesca Aroldi, Lorenzo Antonuzzo, Rossana Berardi, Laura Catena, Chiara De Divitiis, Paola Ermacora, Vittorio Perfetti & 32 others Annalisa Fontana, Paola Razzore, Carlo Carnaghi, Maria Vittoria Davì, Carolina Cauchi, Marilina Duro, Sergio Ricci, Nicola Fazio, Federica Cavalcoli, Alberto Bongiovanni, Anna La Salvia, Nicole Brighi, Annamaria Colao, Ivana Puliafito, Francesco Panzuto, Silvia Ortolani, Alberto Zaniboni, Francesco Di Costanzo, Mariangela Torniai, Emilio Bajetta, Salvatore Tafuto, Silvio Ken Garattini, Daniela Femia, Natalie Prinzi, Laura Concas, Giuseppe Lo Russo, Massimo Milione, Luca Giacomelli, Roberto Buzzoni, Gianfranco Delle Fave, Vincenzo Mazzaferro, Filippo de Braud

Research output: Contribution to journalArticle

Abstract

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 < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results.

CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

Original languageEnglish
Pages (from-to)479-489.e7
JournalGastroenterology
Volume155
Issue number2
DOIs
Publication statusPublished - Aug 2018

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Neuroendocrine Tumors
Metformin
Somatostatin
Disease-Free Survival
Everolimus
Confidence Intervals
Therapeutics
Glucose
Octreotide
Hyperglycemia
Italy

Keywords

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents/therapeutic use
  • Child
  • Diabetes Mellitus, Type 2/drug therapy
  • Disease-Free Survival
  • Everolimus/therapeutic use
  • Female
  • Humans
  • Hypoglycemic Agents/therapeutic use
  • Italy/epidemiology
  • Kaplan-Meier Estimate
  • Male
  • Metformin/therapeutic use
  • Middle Aged
  • Neuroendocrine Tumors/drug therapy
  • Pancreatic Neoplasms/drug therapy
  • Retrospective Studies
  • Somatostatin/analogs & derivatives
  • Time Factors
  • Treatment Outcome
  • Young Adult

Cite this

Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. / Pusceddu, Sara; Vernieri, Claudio; Di Maio, Massimo; Marconcini, Riccardo; Spada, Francesca; Massironi, Sara; Ibrahim, Toni; Brizzi, Maria Pia; Campana, Davide; Faggiano, Antongiulio; Giuffrida, Dario; Rinzivillo, Maria; Cingarlini, Sara; Aroldi, Francesca; Antonuzzo, Lorenzo; Berardi, Rossana; Catena, Laura; De Divitiis, Chiara; Ermacora, Paola; Perfetti, Vittorio; Fontana, Annalisa; Razzore, Paola; Carnaghi, Carlo; Davì, Maria Vittoria; Cauchi, Carolina; Duro, Marilina; Ricci, Sergio; Fazio, Nicola; Cavalcoli, Federica; Bongiovanni, Alberto; La Salvia, Anna; Brighi, Nicole; Colao, Annamaria; Puliafito, Ivana; Panzuto, Francesco; Ortolani, Silvia; Zaniboni, Alberto; Di Costanzo, Francesco; Torniai, Mariangela; Bajetta, Emilio; Tafuto, Salvatore; Garattini, Silvio Ken; Femia, Daniela; Prinzi, Natalie; Concas, Laura; Lo Russo, Giuseppe; Milione, Massimo; Giacomelli, Luca; Buzzoni, Roberto; Delle Fave, Gianfranco; Mazzaferro, Vincenzo; de Braud, Filippo.

In: Gastroenterology, Vol. 155, No. 2, 08.2018, p. 479-489.e7.

Research output: Contribution to journalArticle

Pusceddu, S, Vernieri, C, Di Maio, M, Marconcini, R, Spada, F, Massironi, S, Ibrahim, T, Brizzi, MP, Campana, D, Faggiano, A, Giuffrida, D, Rinzivillo, M, Cingarlini, S, Aroldi, F, Antonuzzo, L, Berardi, R, Catena, L, De Divitiis, C, Ermacora, P, Perfetti, V, Fontana, A, Razzore, P, Carnaghi, C, Davì, MV, Cauchi, C, Duro, M, Ricci, S, Fazio, N, Cavalcoli, F, Bongiovanni, A, La Salvia, A, Brighi, N, Colao, A, Puliafito, I, Panzuto, F, Ortolani, S, Zaniboni, A, Di Costanzo, F, Torniai, M, Bajetta, E, Tafuto, S, Garattini, SK, Femia, D, Prinzi, N, Concas, L, Lo Russo, G, Milione, M, Giacomelli, L, Buzzoni, R, Delle Fave, G, Mazzaferro, V & de Braud, F 2018, 'Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues', Gastroenterology, vol. 155, no. 2, pp. 479-489.e7. https://doi.org/10.1053/j.gastro.2018.04.010
Pusceddu, Sara ; Vernieri, Claudio ; Di Maio, Massimo ; Marconcini, Riccardo ; Spada, Francesca ; Massironi, Sara ; Ibrahim, Toni ; Brizzi, Maria Pia ; Campana, Davide ; Faggiano, Antongiulio ; Giuffrida, Dario ; Rinzivillo, Maria ; Cingarlini, Sara ; Aroldi, Francesca ; Antonuzzo, Lorenzo ; Berardi, Rossana ; Catena, Laura ; De Divitiis, Chiara ; Ermacora, Paola ; Perfetti, Vittorio ; Fontana, Annalisa ; Razzore, Paola ; Carnaghi, Carlo ; Davì, Maria Vittoria ; Cauchi, Carolina ; Duro, Marilina ; Ricci, Sergio ; Fazio, Nicola ; Cavalcoli, Federica ; Bongiovanni, Alberto ; La Salvia, Anna ; Brighi, Nicole ; Colao, Annamaria ; Puliafito, Ivana ; Panzuto, Francesco ; Ortolani, Silvia ; Zaniboni, Alberto ; Di Costanzo, Francesco ; Torniai, Mariangela ; Bajetta, Emilio ; Tafuto, Salvatore ; Garattini, Silvio Ken ; Femia, Daniela ; Prinzi, Natalie ; Concas, Laura ; Lo Russo, Giuseppe ; Milione, Massimo ; Giacomelli, Luca ; Buzzoni, Roberto ; Delle Fave, Gianfranco ; Mazzaferro, Vincenzo ; de Braud, Filippo. / Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues. In: Gastroenterology. 2018 ; Vol. 155, No. 2. pp. 479-489.e7.
@article{586da9d51fe24cdb86ae0636907823aa,
title = "Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues",
abstract = "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 < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95{\%} confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results.CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.",
keywords = "Adolescent, Adult, Aged, Aged, 80 and over, Antineoplastic Agents/therapeutic use, Child, Diabetes Mellitus, Type 2/drug therapy, Disease-Free Survival, Everolimus/therapeutic use, Female, Humans, Hypoglycemic Agents/therapeutic use, Italy/epidemiology, Kaplan-Meier Estimate, Male, Metformin/therapeutic use, Middle Aged, Neuroendocrine Tumors/drug therapy, Pancreatic Neoplasms/drug therapy, Retrospective Studies, Somatostatin/analogs & derivatives, Time Factors, Treatment Outcome, Young Adult",
author = "Sara Pusceddu and Claudio Vernieri and {Di Maio}, Massimo and Riccardo Marconcini and Francesca Spada and Sara Massironi and Toni Ibrahim and Brizzi, {Maria Pia} and Davide Campana and Antongiulio Faggiano and Dario Giuffrida and Maria Rinzivillo and Sara Cingarlini and Francesca Aroldi and Lorenzo Antonuzzo and Rossana Berardi and Laura Catena and {De Divitiis}, Chiara and Paola Ermacora and Vittorio Perfetti and Annalisa Fontana and Paola Razzore and Carlo Carnaghi and Dav{\`i}, {Maria Vittoria} and Carolina Cauchi and Marilina Duro and Sergio Ricci and Nicola Fazio and Federica Cavalcoli and Alberto Bongiovanni and {La Salvia}, Anna and Nicole Brighi and Annamaria Colao and Ivana Puliafito and Francesco Panzuto and Silvia Ortolani and Alberto Zaniboni and {Di Costanzo}, Francesco and Mariangela Torniai and Emilio Bajetta and Salvatore Tafuto and Garattini, {Silvio Ken} and Daniela Femia and Natalie Prinzi and Laura Concas and {Lo Russo}, Giuseppe and Massimo Milione and Luca Giacomelli and Roberto Buzzoni and {Delle Fave}, Gianfranco and Vincenzo Mazzaferro and {de Braud}, Filippo",
note = "Copyright {\circledC} 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.",
year = "2018",
month = "8",
doi = "10.1053/j.gastro.2018.04.010",
language = "English",
volume = "155",
pages = "479--489.e7",
journal = "Gastroenterology",
issn = "0016-5085",
publisher = "W.B. Saunders Ltd",
number = "2",

}

TY - JOUR

T1 - Metformin Use Is Associated With Longer Progression-Free Survival of Patients With Diabetes and Pancreatic Neuroendocrine Tumors Receiving Everolimus and/or Somatostatin Analogues

AU - Pusceddu, Sara

AU - Vernieri, Claudio

AU - Di Maio, Massimo

AU - Marconcini, Riccardo

AU - Spada, Francesca

AU - Massironi, Sara

AU - Ibrahim, Toni

AU - Brizzi, Maria Pia

AU - Campana, Davide

AU - Faggiano, Antongiulio

AU - Giuffrida, Dario

AU - Rinzivillo, Maria

AU - Cingarlini, Sara

AU - Aroldi, Francesca

AU - Antonuzzo, Lorenzo

AU - Berardi, Rossana

AU - Catena, Laura

AU - De Divitiis, Chiara

AU - Ermacora, Paola

AU - Perfetti, Vittorio

AU - Fontana, Annalisa

AU - Razzore, Paola

AU - Carnaghi, Carlo

AU - Davì, Maria Vittoria

AU - Cauchi, Carolina

AU - Duro, Marilina

AU - Ricci, Sergio

AU - Fazio, Nicola

AU - Cavalcoli, Federica

AU - Bongiovanni, Alberto

AU - La Salvia, Anna

AU - Brighi, Nicole

AU - Colao, Annamaria

AU - Puliafito, Ivana

AU - Panzuto, Francesco

AU - Ortolani, Silvia

AU - Zaniboni, Alberto

AU - Di Costanzo, Francesco

AU - Torniai, Mariangela

AU - Bajetta, Emilio

AU - Tafuto, Salvatore

AU - Garattini, Silvio Ken

AU - Femia, Daniela

AU - Prinzi, Natalie

AU - Concas, Laura

AU - Lo Russo, Giuseppe

AU - Milione, Massimo

AU - Giacomelli, Luca

AU - Buzzoni, Roberto

AU - Delle Fave, Gianfranco

AU - Mazzaferro, Vincenzo

AU - de Braud, Filippo

N1 - Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

PY - 2018/8

Y1 - 2018/8

N2 - 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 < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results.CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

AB - 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 < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results.CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

KW - Adolescent

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antineoplastic Agents/therapeutic use

KW - Child

KW - Diabetes Mellitus, Type 2/drug therapy

KW - Disease-Free Survival

KW - Everolimus/therapeutic use

KW - Female

KW - Humans

KW - Hypoglycemic Agents/therapeutic use

KW - Italy/epidemiology

KW - Kaplan-Meier Estimate

KW - Male

KW - Metformin/therapeutic use

KW - Middle Aged

KW - Neuroendocrine Tumors/drug therapy

KW - Pancreatic Neoplasms/drug therapy

KW - Retrospective Studies

KW - Somatostatin/analogs & derivatives

KW - Time Factors

KW - Treatment Outcome

KW - Young Adult

U2 - 10.1053/j.gastro.2018.04.010

DO - 10.1053/j.gastro.2018.04.010

M3 - Article

VL - 155

SP - 479-489.e7

JO - Gastroenterology

JF - Gastroenterology

SN - 0016-5085

IS - 2

ER -