title: The Relationship Between Metformin and Serum Prostate-Specific Antigen Levels.
abstract: Metformin is the first-line oral antihyperglycemic of choice for individuals with type 2 diabetes. Recent evidence supports a role for metformin in prostate cancer chemoprotection. However, whether metformin indeed influences prostate biology is unknown. We aimed to study the association between metformin and serum prostate-specific antigen (PSA) levels-the primary prostate cancer biomarker.
  
  
  
  We conducted a cross-sectional study of 326 prostate cancer-free men with type 2 diabetes were recruited between 2004 and 2013 at St. Michael's Hospital. Men were excluded if they had a PSA ≥10-ng/ml, or used >2,550-mg/d metformin or supplemental androgens. Multivariate linear regressions quantified the association between metformin dose and log-PSA. Secondary analyses quantified the association between other antihyperglycemics (sulfonylureas, thiazolidinediones) and PSA; sensitivity analyses tested covariate interactions.
  
  
  
  Median PSA was 0.9-ng/ml (IQR: 0.5-1.6-ng/ml). Metformin dose associated positively with BMI, HbA1c, diabetes duration, and number of statin, acetylsalicylic acid, diuretic users, and number of antihyperglycemics used, and negatively with LDL-C. In multivariate models, PSA changed by -8% (95%CI: -13 to -2%, P = 0.011) per 500-mg/d increase in metformin. Men with diabetes for ≥6 years (n = 163) saw a greater difference in PSA per 500-mg/d metformin (-12% [95% CI: -19 to -4%, P = 0.002], P-interaction = 0.018). Serum PSA did not relate with sulfonylureas, thiazolidinediones, or total number of antihyperglycemic agents used. Our findings are limited by the cross-sectional design of this study.
  
  
  
  Metformin dose-dependently inversely associated with serum PSA, independent of other antihyperglycemic medications. Whether metformin confers a dose-dependent benefit on prostate tumorigenesis and progression warrants investigation. Prostate 76:1445-1453, 2016. © 2016 The Authors. The Prostate published by Wiley Periodicals, Inc.
authors.affiliation: Clinical Nutrition and Risk Factor Modification Center, St. Michael's Hospital, Toronto, Ontario, Canada.|Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Surgical Oncology-Urology, Princess Margaret Cancer Center, Toronto, Ontario, Canada.
authors.forename: Viranda H
authors.initials: VH
authors.lastname: Jayalath
authors.affiliation: Clinical Nutrition and Risk Factor Modification Center, St. Michael's Hospital, Toronto, Ontario, Canada.|Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher
authors.initials: C
authors.lastname: Ireland
authors.affiliation: Department of Surgical Oncology-Urology, Princess Margaret Cancer Center, Toronto, Ontario, Canada.|Department of Surgery-Urology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Fleshner
authors.affiliation: Department of Surgical Oncology-Urology, Princess Margaret Cancer Center, Toronto, Ontario, Canada.|Department of Surgery-Urology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Hamilton
authors.affiliation: Clinical Nutrition and Risk Factor Modification Center, St. Michael's Hospital, Toronto, Ontario, Canada. nutritionproject@smh.ca.|Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada. nutritionproject@smh.ca.|Department of Surgical Oncology-Urology, Princess Margaret Cancer Center, Toronto, Ontario, Canada. nutritionproject@smh.ca.|Li Ka Shing Knowledge Institute of St. Michael's Hospital, Toronto, Ontario, Canada. nutritionproject@smh.ca.
authors.forename: David J A
authors.initials: DJ
authors.lastname: Jenkins
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000097:blood; D018890:Chemoprevention; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D008875:Middle Aged; D017430:Prostate-Specific Antigen / Q000097:blood*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007004:Hypoglycemic Agents; D008687:Metformin; D017430:Prostate-Specific Antigen
keywords: PSA; antihyperglycemic; cross-sectional; dose-response; metformin; prostate cancer