Synergism between metformin and statins in modifying the risk of biochemical recurrence following radical prostatectomy in men with diabetes.
BACKGROUND
To determine the effect of statins and metformin in combination on biochemical recurrence (BCR) among diabetic men undergoing radical prostatectomy (RP).


METHODS
Diabetic men undergoing RP at our institution from January 1995 to March 2012 were retrospectively reviewed. Recipients of adjuvant radiation or hormonal therapy were excluded. Statin and/or metformin use was determined through review of electronic records. BCR-free survival was plotted using Kaplan-Meier analysis, and the effect of statins and metformin on BCR was assessed via a multivariate Cox proportional hazards model.


RESULTS
Seven hundred and sixty-seven men met the inclusion criteria. Seventy-six (9.9%) were users of statins only, 56 (7.3%) were users of metformin only and 42 (5.5%) were dual users. Median follow-up time was 27 months. Dual users were less likely than nonusers or users of either medication alone to have a biopsy Gleason sum of 8-10 (P=0.033), and tended towards a lower rate of pathological T stage of pT3 or higher (P=0.064). Dual users had the highest 2-year and 5-year BCR-free survival, although this was not statistically significant (P=0.205). On multivariate regression, neither statin nor metformin use alone was significantly associated with BCR-free survival. However, their interaction led to a significantly lower BCR risk than would be expected from each medication's independent effects (hazard ratio=0.2; P=0.037).


CONCLUSIONS
The combination of statins and metformin in men undergoing RP for prostate cancer (PCa) may be associated with a lower BCR risk than would be predicted based on the independent effects of both medications. A synergism between these two agents is biologically plausible based on our current understanding of their diverse molecular pathways of action. The results of future clinical trials involving the use of either medication in men with PCa should be carefully assessed for confirmatory evidence of such a relationship.
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
M R
MR
Danzig
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
S
S
Kotamarti
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
R A
RA
Ghandour
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
M B
MB
Rothberg
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
B P
BP
Dubow
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
M C
MC
Benson
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
K K
KK
Badani
Department of Urology, Herbert Irving Cancer Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.
J M
JM
McKiernan
D000368:Aged; D002986:Clinical Trials as Topic; D048909:Diabetes Complications / Q000188:drug therapy / Q000473:pathology; D018572:Disease-Free Survival; D004357:Drug Synergism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D053208:Kaplan-Meier Estimate; D008297:Male; D008687:Metformin / Q000008:administration & dosage*; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D011468:Prostatectomy / Q000009:adverse effects; D011471:Prostatic Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy / Q000601:surgery; D018714:Radiotherapy, Adjuvant
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008687:Metformin