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Diabetes and Prostate Cancer Risk in the REDUCE Trial

A multivariate analysis showed that men with diabetes are less likely to be diagnosed with prostate cancer.

As diabetic men have lower serum PSA, it is unclear if this is due to lower prostate cancer (PCa) incidence or reflects detection bias from fewer PSA-triggered biopsies. To account for differential biopsy rates, the study used multivariate regression to examine the link between diabetes and PCa risk in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial, which required all subjects to undergo biopsy regardless of PSA.

We further tested for interaction between diabetes and obesity. Diabetes status and body mass index (BMI) measurements were obtained at baseline. On multivariate analysis, diabetes was not associated with PCa risk (odds ratio (OR) 1.01, 95% confidence interval 0.79–1.30, P=0.92) or risk of low- or high-grade disease (all P≥0.65).

When stratified by obesity, diabetes was also not associated with PCa risk in any BMI category (all P≥0.15). However, there was suggestion of effect modification by obesity for high-grade disease (P-interaction=0.053). Specifically, diabetes was associated with decreased risk of high-grade PCa in normal-weight men but increased risk in obese men (OR 0.35 vs 1.38). In the REDUCE trial, when all men underwent biopsy, diabetes was not associated with lower PCa risk, but rather equal risk of PCa, low-grade PCa and high-grade PCa.

As both type 1 and type 2 diabetes involve loss of insulin production from pancreatic β-islet cells, and as insulin is a potent mitogen, it has been postulated that the hypoinsulinemic state characterizing diabetes impairs cellular proliferation and confers protection against PCa. Indeed, many studies have reported an inverse association between diabetes and PCa risk.

However, diabetes is also linked to lower serum PSA. Thus, in clinical practice where PSA screening drives recommendations for biopsy and, hence, PCa detection, an alternative explanation for the attenuated PCa risk reported by many but not all studies is that lower PSA in diabetics leads to fewer biopsies and, consequently, to less frequent diagnosis of extant cancer. In fact, the majority of studies linking diabetes to lower PCa risk have been published in the PSA era, with a recent meta-analysis reporting significantly lower PCa risk among diabetic men in studies published after but not before 1990. Furthermore, as obesity also lowers serum PSA due to hemodilution, its frequent co-existence with diabetes may further impair PCa detection in diabetics.

To address this, the study investigated the relationship between diabetes and PCa risk in the REDUCE trial. The unique design of REDUCE required that all participants undergo prostate biopsy regardless of serum PSA. Thus, PSA testing did not serve as a gatekeeper to more definitive biopsy in REDUCE, allowing better examination of the true relationship between diabetes and PCa risk.

In summary, in the REDUCE trial, when all men undergo biopsy regardless of serum PSA, diabetes was not associated with lower PCa risk, but rather equal risk of PCa overall and equal risk of low- and high-grade disease. Our findings suggest that lower rates of PCa previously observed in diabetics may stem, at least in part, from lower serum PSA leading to fewer biopsies and less frequent detection of disease. However, other explanations for these findings exist. Thus, additional studies are needed to confirm our results and clarify the degree, if any, to which lower serum PSA obscures PCa incidence in diabetic men. Our results also add to the limited body of literature examining the interplay between obesity, diabetes and PCa by suggesting that BMI may modify the effect of diabetes on risk of high-grade PCa. Given that many diabetic men are also obese, this is an important relationship that warrants further investigation.

Prostate Cancer Prostatic Dis. 2011;14(4):326-331.