Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes

Danzig, Matthew R.; Kotamarti, Srinath; Ghandour, Rashed; Rothberg, Michael B.; Dubow, Byron; Benson, Mitchell C.; Badani, Ketan K.; McKiernan, James M.

doi:10.1038/pcan.2014.47

Cited by 28 publications

(21 citation statements)

References 32 publications

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“…Given data that other commonly used medicines may be associated with lower PC risk 15, 16 and the high frequency of PDE-5i use in older men (i.e. those at greatest risk for PC), several studies examined the relationship between PDE-5i use and PC with conflicting results.…”

Section: Discussionmentioning

confidence: 99%

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study

et al. 2016

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Purpose Despite the routine use of phosphodiesterase type-5 inhibitors (PDE-5i) for treatment of erectile dysfunction, their role in prostate cancer (PC) chemoprevention remains unclear with only a few studies exploring the link between PDE-5i use and PC. We tested the association between PDE-5i use and PC risk in the REDUCE study. Materials & Methods REDUCE was a four-year multi-center study testing the effect of daily dutasteride on PC risk in men with a PSA of 2.5 to 10.0 ng/mL and a negative biopsy, with men undergoing study-mandated biopsies at 2- and 4-years. The association between PDE-5i use and overall PC risk and disease grade (Gleason 2–6 and 7–10) was examined using adjusted logistic and multinomial regression analysis. Secondary analysis was performed exploring the association between PDE-5i use and PC risk in North American men given the significantly higher use of PDE-5i among these subjects. Results PDE-5i inhibitor use was not associated with PC diagnosis (OR=0.90, 95%CI 0.68–1.20, p=0.476) or low- (OR=0.93, 95%CI 0.67–1.27, p=0.632) or high-grade disease (OR=0.85, 95%CI 0.51–1.39, p=0.508). An inverse trend was seen between PDE-5i use and PC diagnosis in North American men, but was not statistically significant (OR=0.67, 95%CI 0.42–1.07, p=0.091). Conclusions PDE-5i use was not associated with decreased PC diagnosis in post-hoc analysis of the REDUCE study. In North American men, who had a much higher baseline use of PDE-5i, use was associated with an inverse trend of PC diagnosis that approached, but did not reach, statistical significance.

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Section: Discussionmentioning

confidence: 99%

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study

et al. 2016

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“…Clinical trials to investigate treatment with statins in combination with other agents are warranted, particularly combinations with compounds that show synergy with statins in animal models and whose mechanism of synergistic activity is known. Indeed, a study published in 2015 in 767 diabetic men with prostate cancer undergoing radical prostatectomy found that combined treatment with statins and metformin, but neither statin nor metformin use alone, resulted in a significantly reduced risk of biochemical recurrence during a follow-up period of 27 months ( P = 0.037 for combined statin and metformin use, P = 0.676 for statin use alone and P = 0.117 for metformin use alone) 113 . Liver X receptor agonists are a group of other potential candidates for combination treatments with statins.…”

Section: Future Perspectivementioning

confidence: 99%

The current evidence on statin use and prostate cancer prevention: are we there yet?

et al. 2016

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An increasing amount of data supports an inverse association between statin use and cancer risk. The findings for prostate cancer, particularly advanced disease, are the most promising of all cancers studied. Use of these agents seems to also be associated with improved prostate-cancer-specific survival, particularly in men undergoing radiotherapy, suggesting usefulness of statins in secondary and tertiary prevention. Some study results might be influenced by increased PSA screening and health-conscious behaviour in statin users but these factors are unlikely to completely account for observed beneficial effects. The epidemiological evidence is supported by preclinical studies that show that statins directly inhibit prostate cancer development and progression in cell-based and animal-based models. The antineoplastic effect of statins might arise from a number of cholesterol-mediated and non-cholesterol-mediated mechanisms that affect pathways essential for cancer formation and progression. Understanding these mechanisms is instrumental in drug discovery research for the development of future prostate cancer therapeutics, as well as in designing clinical trials to test a role for statins in prostate cancer prevention. Currently, sufficient data are lacking to support the use of statins for the primary prevention of prostate cancer and further research is clearly warranted. Secondary and tertiary prevention trials in men who have been diagnosed with prostate cancer might soon be performed.

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“…We required criterion (ii) to eliminate potential effects associated with TZD or insulin use on cancer incidence as reported in the literature. (23,24) In addition, to account for the potential interactions between metformin with statin and finasteride,(6–9) we limited the cohort to 76,733 men who (i) have had prescription(s) of statins for ≥180 days or none; and (ii) have had prescription(s) of finasteride for ≥180 days or none. All study procedures were approved by the Institutional Review Board of the University of Texas Health Science Center at San Antonio and the Research and Development Committee of the South Texas Veterans Health Care System at San Antonio.…”

Section: Methodsmentioning

confidence: 99%

“…Predictors in this Cox model included indicators of race/ethnicity groups (AA and Hispanics) with NHW being the referent, indicators of statin use (6,7,9) and finasteride use,(28) age, change in LDL, HbA1c, and BMI, and the maximum PSA level during the study period. Under this Cox regression model, the impact of race/ethnicity was assessed by the hazard ratio (HR) associated with AA or Hispanic group relative to the NHW group.…”

Section: Methodsmentioning

confidence: 99%

“…The beneficial impact of metformin on PCa reduction was found to vary by dose or concomitant use of statin or finasteride. (6–9) It is also likely that the variation of metformin’s PCa prevention effect could be attributed to individual pharmacokinetic differences. Among the polymorphisms in genes that are associated with metformin transport or glucose-lowering effects,(10–14) the allele frequency of one ethnic-specific MATE1 (multidrug and toxin compound extrusion-1) that is associated with reduced renal excretion of metformin,(11–13, 15) is strikingly high at 5% in Hispanics.…”

Section: Introductionmentioning

confidence: 99%

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Metformin for Reducing Racial/Ethnic Difference in Prostate Cancer Incidence for Men with Type II Diabetes

Wang

Lehman

Lam

et al. 2016

Cancer Prevention Research

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Racial/ethnic disparity in prostate cancer (PCa) is under studied in men with diabetes who are at higher risk for aggressive PCa. This study assessed the race/ethnic disparity in PCa incidence for men with type 2 diabetes (T2D), and whether the impact of metformin on PCa incidence varied by race/ethnicity. We conducted a retrospective study in 76,733 male veterans with T2D during 2003–2012. Cox proportional hazard model adjusting for covariates and propensity scores of metformin use and race/ethnic group membership were utilized to compute the hazard ratio (HR) of PCa incidence associated with race/ethnicity, and compare HR associated with metformin use between race/ethnic groups. Mean follow-up was 6.4±2.8 years; 7% were Hispanics; 17% were African American (AA); mean age was 67.8±9.8 years; 5.2% developed PCa; 38.9% used metformin. Among these diabetic men without metformin use, PCa incidence was higher in Hispanics and AA than in non-Hispanic White (NHW). Use of metformin alone or metformin+statins was associated with a greater PCa incidence reduction in Hispanics compared to NHW, but not between AA and NHW. Use of metformin+finasteride was associated with a greater PCa incidence reduction in Hispanics and AA compared to NHW. Our results suggested that metformin treatment could be a potential strategy to reduce PCa incidence in the minority populations who are at high risk for fatal PCa. It will be important to further examine the pleiotropic effects of metformin in multi-race/ethnic prospective studies to better inform clinical management, and potentially reduce racial/ethnic disparity in PCa incidence among diabetic men.

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Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes

Cited by 28 publications

References 32 publications

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study

The Association between Phosphodiesterase Type 5 Inhibitors and Prostate Cancer: Results from the REDUCE Study

The current evidence on statin use and prostate cancer prevention: are we there yet?

Metformin for Reducing Racial/Ethnic Difference in Prostate Cancer Incidence for Men with Type II Diabetes

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