The Relationship Between Metformin and Serum Prostate‐Specific Antigen Levels

Abstract

BACKGROUNDMetformin 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.METHODSWe 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.RESULTSMedian 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.CONCLUSIONSMetformin 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.

Impact of metformin on serum prostate-specific antigen levels

“…Moreover, patients on drugs that may affect PSA levels, namely 5α-reductase inhibitors or nonsteroidal or anti-inflammatory drugs were not excluded from analysis. Jayalath et al [ 9 ] reported a relationship between metformin use and serum PSA levels in which mean PSA levels were 30% lower in metformin users, similar to our observation. In addition, an inverse dose–response relationship was observed.…”

“…Several studies have reported a negative association between PCa and serum PSA, the most widely used biomarker for PCa risk and progression. [ 9 ] However, it is still not clear whether diabetes exerts a protective role against PCa or whether long-term use of metformin itself is related to decreased PSA levels.…”

Prediction of Complications in Radical Prostatectomy Prostate Cancer Patients: Simulated Annealing versus Co-Morbidity Indexes

“…Our findings validate the importance of several wellknown co-morbid conditions such as coronary artery atherosclerosis [19,20], chronic obstructive pulmonary disease [19,[21][22][23], congestive heart failure [19,[23][24][25], anaemia [19,26] and diabetes mellitus [23,25,[27][28][29][30] in terms of their ability to predict perioperative complications. These conditions, which are directly or indirectly related to cardiovascular co-morbidities, are generally common in PCa patients [31].…”

Application of Anti-Inflammatory Agents in Prostate Cancer

“…A recent meta-analysis, which included 30 cohort studies ( n = 1,660,795), demonstrated that metformin improved both overall survival (HR 0.72, 95% CI 0.59–0.88) and cancer-specific survival (HR 0.78, 95% CI 0.64–0.94) in patients with prostate cancer compared with those not treated with metformin, although the incidence of prostate cancer was not associated with metformin [ 182 ]. Importantly, a dose-dependent inverse association between metformin and serum PSA levels was observed, which potentially affects the indication of prostate biopsy as well as detection of prostate cancer [ 216 ]. Metformin exerts its anti-cancer effect directly by acting on the tumor via inhibition of the mitochondrial electron transport chain and consequent activation of adenosine monophosphate-activated protein kinase, as well as indirectly by lowering systemic insulin levels [ 217 ].…”