Metformin Use and Risk of Prostate Cancer: Results from the REDUCE Study

Abstract

The role of metformin in prostate cancer chemoprevention remains unclear. REDUCE, which followed biopsy-negative men with protocol-dictated PSA-independent biopsies at 2- and 4-years, provides an opportunity to evaluate the link between metformin use and prostate cancer diagnosis with minimal confounding from screening biases. In diabetic men from REDUCE, we tested the association between metformin use, use of other anti-diabetic medications, vs. no anti-diabetic medication use and prostate cancer diagnosis as well as prostate cancer grade (low-grade Gleason 4–6, high-grade Gleason 7–10) using logistic regression. Of the 540 diabetic men with complete data, 205 (38%) did not report use of any anti-diabetic medications, 141 (26%) reported use of at least one anti-diabetic medication other than metformin, and 194 (36%) reported use of metformin. During the 4-year study, 122 men (23%) were diagnosed with prostate cancer. After adjusting for various clinical and demographic characteristics, we found that metformin use was not significantly associated with total (OR=1.19, p=0.50), low- (OR=1.01, p=0.96), or high-grade (OR=1.83, p=0.19) prostate cancer diagnosis. Likewise, there was no significant association between the use of non-metformin anti-diabetic medications and prostate cancer risk in both crude (OR=1.02, p=0.95) and multivariable analysis (OR=0.85, p=0.56). Furthermore, the interactions between anti-diabetic medication use and BMI, geographic location, coronary artery disease, smoking, and treatment group were not significant (all p>0.05). Among diabetic men with a negative pre-study biopsy who all underwent biopsies largely independent of PSA, metformin use was not associated with reduced risk of prostate cancer diagnosis.

Prospective study of Type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer

“…In the subgroup of men with T2DM with more than 1 year disease duration, we found no decrease in risk of prostate cancer for men on metformin and a weak decrease in risk for men on insulin/sulfonylurea compared to men with T2DM not on anti‐diabetic drugs. These results are in line with previous studies on metformin in a similar setting …”

“…These results are in line with previous studies on metformin in a similar setting. 11,40 Other studies of men with T2DM have investigated the association between metformin and risk of prostate cancer with other referents than used in our study. One study investigated metformin versus sulfonylurea, 14 one study compared ever-users with never-users of metformin 41 and three metaanalyses looked at metformin versus all other therapies combined.…”

ERR1- and PGC1α-associated mitochondrial alterations correlate with pan-cancer disparity in African Americans

“…Interestingly, clinical trial data for metformin, a mitochondrial inhibitor, has shown that African American patients, in general, respond better to this drug than European American patients (20). Metformin was also more effective in reducing the incidence of PCa and the risk of colorectal cancer death in African American patients compared with European American patients (21,22). These findings provide a rationale for evaluating existing mitochondrial drugs to treat tumors from African American patients.…”

A spatiotemporal hypothesis for the regulation, role, and targeting of AMPK in prostate cancer

“…Accordingly, several reports using pharmacological modulators of AMPK as well as genetic knockout of one of the catalytic subunits of AMPK, PRKAA2 , support a tumor suppressive role for AMPK in prostate cancer 7,17,63–65 . However, more recent retrospective studies did not find any link between metformin use and decreased cancer risk 66–77 . In fact, some studies even suggested that increased metformin use correlated with more aggressive prostate cancers 66,71 .…”