Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's Esophagus

Amitabh Chak, Navtej Singh Buttar, Nathan R. Foster, Drew K. Seisler, Norman E. Marcon, Robert Schoen, Marcia R. Cruz-Correa, Gary W. Falk, Prateek Sharma, Chin Hur, David A Katzka, Luz M. Rodriguez, Ellen Richmond, Anamay N. Sharma, Thomas Christopher Smyrk, Sumithra J Mandrekar, Paul John Limburg

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background and Aims: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. Methods: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n= 38) or placebo (n= 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. Results: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P= .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P= .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P= .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). Conclusions: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

Original languageEnglish (US)
Pages (from-to)665-672
Number of pages8
JournalClinical Gastroenterology and Hepatology
Volume13
Issue number4
DOIs
StatePublished - Apr 1 2015

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Barrett Esophagus
Metformin
Cell Proliferation
Placebos
Insulin
Insulin Resistance
Obesity
Serum
Apoptosis
Ribosomal Protein S6 Kinases
Digestive System Endoscopy
Neoplasms
Chemoprevention
Caspase 3
Carcinogenesis
Biomarkers

Keywords

  • Cancer Development
  • Diabetes Drug
  • HOMA-IR
  • Tumorigenesis

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology

Cite this

Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's Esophagus. / Chak, Amitabh; Buttar, Navtej Singh; Foster, Nathan R.; Seisler, Drew K.; Marcon, Norman E.; Schoen, Robert; Cruz-Correa, Marcia R.; Falk, Gary W.; Sharma, Prateek; Hur, Chin; Katzka, David A; Rodriguez, Luz M.; Richmond, Ellen; Sharma, Anamay N.; Smyrk, Thomas Christopher; Mandrekar, Sumithra J; Limburg, Paul John.

In: Clinical Gastroenterology and Hepatology, Vol. 13, No. 4, 01.04.2015, p. 665-672.

Research output: Contribution to journalArticle

Chak, A, Buttar, NS, Foster, NR, Seisler, DK, Marcon, NE, Schoen, R, Cruz-Correa, MR, Falk, GW, Sharma, P, Hur, C, Katzka, DA, Rodriguez, LM, Richmond, E, Sharma, AN, Smyrk, TC, Mandrekar, SJ & Limburg, PJ 2015, 'Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's Esophagus', Clinical Gastroenterology and Hepatology, vol. 13, no. 4, pp. 665-672. https://doi.org/10.1016/j.cgh.2014.08.040
Chak, Amitabh ; Buttar, Navtej Singh ; Foster, Nathan R. ; Seisler, Drew K. ; Marcon, Norman E. ; Schoen, Robert ; Cruz-Correa, Marcia R. ; Falk, Gary W. ; Sharma, Prateek ; Hur, Chin ; Katzka, David A ; Rodriguez, Luz M. ; Richmond, Ellen ; Sharma, Anamay N. ; Smyrk, Thomas Christopher ; Mandrekar, Sumithra J ; Limburg, Paul John. / Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's Esophagus. In: Clinical Gastroenterology and Hepatology. 2015 ; Vol. 13, No. 4. pp. 665-672.
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abstract = "Background and Aims: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. Methods: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78{\%}; 52 with BE >2 cm [70{\%}]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n= 38) or placebo (n= 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. Results: The percent change in median level of pS6K1 did not differ significantly between groups (1.4{\%} among subjects given metformin vs -14.7{\%} among subjects given placebo; 1-sided P= .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7{\%} among subjects given metformin vs 23.6{\%} increase among those given placebo, P= .08) as well as in homeostatic model assessments of insulin resistance (median -7.2{\%} among subjects given metformin vs 38{\%} increase among those given placebo, P= .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). Conclusions: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.",
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T1 - Metformin does not reduce markers of cell proliferation in esophageal tissues of patients with Barrett's Esophagus

AU - Chak, Amitabh

AU - Buttar, Navtej Singh

AU - Foster, Nathan R.

AU - Seisler, Drew K.

AU - Marcon, Norman E.

AU - Schoen, Robert

AU - Cruz-Correa, Marcia R.

AU - Falk, Gary W.

AU - Sharma, Prateek

AU - Hur, Chin

AU - Katzka, David A

AU - Rodriguez, Luz M.

AU - Richmond, Ellen

AU - Sharma, Anamay N.

AU - Smyrk, Thomas Christopher

AU - Mandrekar, Sumithra J

AU - Limburg, Paul John

PY - 2015/4/1

Y1 - 2015/4/1

N2 - Background and Aims: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. Methods: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n= 38) or placebo (n= 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. Results: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P= .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P= .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P= .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). Conclusions: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

AB - Background and Aims: Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1), a biomarker of insulin pathway activation. Methods: Seventy-four subjects with BE (mean age, 58.7 years; 58 men [78%; 52 with BE >2 cm [70%]) were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4, n= 38) or placebo (n= 36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary end point. Results: The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs -14.7% among subjects given placebo; 1-sided P= .80). Metformin was associated with an almost significant reduction in serum levels of insulin (median -4.7% among subjects given metformin vs 23.6% increase among those given placebo, P= .08) as well as in homeostatic model assessments of insulin resistance (median -7.2% among subjects given metformin vs 38% increase among those given placebo, P= .06). Metformin had no effects on cell proliferation (on the basis of assays for KI67) or apoptosis (on the basis of levels of caspase 3). Conclusions: In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis. ClinicalTrials.gov number, NCT01447927.

KW - Cancer Development

KW - Diabetes Drug

KW - HOMA-IR

KW - Tumorigenesis

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