Lower Prostate Cancer Risk in Men with Diabetes May Be Due to Detection Bias

A JAMA Network Open study indicated that a potential detection bias due to fewer biopsies among men receiving antidiabetic medications may explain the lower prostate cancer risk in men with diabetes.¹

Findings however did not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering prostate-specific antigen (PSA) levels to mask prostate cancer. These results are inconsistent with previous reports of increased prostate cancer detection among men with diabetes or poor glycemic control.

In this cohort of 564,666 men, with respect to frequency of prostate biopsy procedures, men prescribed metformin had reduced biopsy rates (relative rate ratio [RR], 0.76; 95% CI, 0.70-0.83), as did those prescribed insulin (RR, 0.67; 95% CI, 0.60-0.75). Biopsy rates did not differ for sulfonylurea. Overall, men who received any antidiabetic medication during follow-up had a significantly lower rate of prostate biopsy (RR, 0.59; 95% CI, 0.55-0.62).

Rates of PSA testing were slightly higher among men prescribed metformin (RR, 1.07; 95% CI, 1.06-1.09) and sulfonylurea (RR, 1.06; 95% CI, 1.03-1.08), but lower for insulin (RR, 0.79; 95% CI, 0.77-0.81). Overall, men who received antidiabetic medications at any time during follow-up had slightly lower rates of PSA testing (RR, 0.93; 95% CI, 0.92-0.94) than those never exposed.

“In contrast to previous studies, our study specifically measured differences in PSA levels with adjustment for PSA before the first prescription. This is advantageous, as associations between the medications and outcome can be more easily distinguished from associations between disease and outcome,” the researchers wrote.

Median PSA levels prior to first prescriptions were lower for exposed men compared with unexposed men, for any antidiabetic use (1.2[0.7-2.5]ng/mL vs 1.6[0.8-3.2]ng/mL respectively) and across all age groups for each antidiabetic medication. No differences in post medication PSA levels were observed for any class of medication compared with nonexposed men.

Results indicated that previous exposure to metformin, sulfonylurea, or insulin was not associated with biopsy findings. Results were also similar when considering all biopsy events and first biopsy only. There was no indication of a dose-response association for any class of medication. Results of analyses also showed no association at any PSA ranges.

“An important strength of this report is the availability of baseline PSA values prior to exposure to diabetes medications and inclusion of length of exposure to diabetes medications in the analysis,” John T. Leppert, MD, MS, department of medicine and department of urology, Stanford University Medical School, and Kyla N. Velaer, MD, department of urology, Stanford University Medical School, wrote in an accompanying editorial.²

Previous studies have not specifically examined biopsy findings in relation to specific antidiabetic medications, which may ameliorate the effects of diabetes itself.

“While the volume and grade of prostate cancer was not included in this report, future studies will help determine whether diabetes medications may be associated with the diagnosis of clinically significant (high-grade or high-volume) prostate cancer,” Leppert and Velaer wrote.

Prospective clinical trials are currently enrolling patients to test whether metformin is associated with improved outcomes when combined with approved systemic treatments for patients with metastatic prostate cancer.

References:
1. Beckmann K, Crawley D, Nordström T, et al. Association Between Antidiabetic Medications and Prostate-Specific Antigen Levels and Biopsy Results. JAMA Netw Open.
doi:10.1001/jamanetworkopen.2019.14689
2. Leppert JT, Velaer KN. Diabetes Medications, Prostate-Specific Antigen Values, and the Chemoprevention of Prostate Cancer. JAMA Netw Open.
doi:10.1001/jamanetworkopen.2019.14644