Statin Use as a Moderator of Metformin Effect on Risk for Prostate Cancer Among Type 2 Diabetic Patients

Abstract

OBJECTIVEMetformin and statins have shown promise for cancer prevention. This study assessed whether the effect of metformin on prostate cancer (PCa) incidence varied by statin use among type 2 diabetic patients.RESEARCH DESIGN AND METHODSThe study cohort consisted of 5,042 type 2 diabetic male patients seen in the Veteran Administration Health Care System who were without prior cancer and were prescribed with metformin or sulfonylurea as the exclusive hypoglycemic medication between fiscal years 1999 and 2005. Cox proportional hazards analyses were conducted to assess the differential hazard ratio (HR) of PCa due to metformin by statin use versus sulfonylurea use, where propensity scores of metformin and statin use were adjusted to account for imbalances in baseline covariates across medication groups.RESULTSMean follow-up was ∼5 years, and 7.5% had a PCa diagnosis. Statin use modified the effect of metformin on PCa incidence (P < 0.0001). Metformin was associated with a significantly reduced PCa incidence among patients on statins (HR 0.69 [95% CI 0.50–0.92]; 17 cases/533 metformin users vs. 135 cases/2,404 sulfonylureas users) and an increased PCa incidence among patients not on statins (HR 2.15 [1.83–2.52]; 22 cases/175 metformin users vs. 186 cases/1,930 sulfonylureas users). The HR of PCa incidence for those taking metformin and statins versus those taking neither medication was 0.32 (0.25–0.42).CONCLUSIONSAmong men with type 2 diabetes, PCa incidence among metformin users varied by their statin use. The potential beneficial influence on PCa by combination use of metformin and statin may be due to synergistic effects.

Pharmacokinetics of atorvastatin and sustained-release metformin fixed-dose combination tablets: two randomized, open-label, 2-way crossover studies in healthy male subjects under fed conditions

“…[8,9] Furthermore, in the male type 2 diabetic population with a generally high prevalence of dyslipidemia, treatment with both metformin and statin may have a significantly more favorable effect on prostatic cancer incidence than treatment by either medication alone. [10] There was no significant interaction between atorvastatin and metformin. [11] Based on such findings, a fixed-dose combination (FDC) tablet of atorvastatin and metformin sustained-release (SR) was developed for patients with type 2 diabetes with or without dyslipidemia.…”

Investigating Metformin for Cancer Prevention and Treatment: The End of the Beginning

“…[36][37][38][39]. Some studies suggest unexpected variables that might modify the effects of metformin, including pharmacoepidemiologic evidence that exposure to both a statin drug and metformin is necessary for an important antineoplastic effect to be observed ( 40 ) and laboratory evidence that administration of proton pump inhibitors limits cellular uptake of metformin ( 41 ).…”

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

“…10,11) Finally, a recent study suggested statin use moderates the risk of prostate cancer among type II diabetic patients using metformin. 12) Epidemiological studies have shown a reduced risk of advanced prostate cancer with the use of statins. [13][14][15][16] Statin use was also found to be associated with a reduction in the risk of biochemical recurrence in patients with prostate cancer 17) and a decreased risk of cancer mortality.…”