Abstract
Diabetic men appear to have a lower risk of prostate cancer. Whether antidiabetic medications are protective or potentially mask prostate cancer by lowering prostate-specific antigen (PSA) levels is unclear. To examine the associations of antidiabetic medication use with (1) PSA levels, (2) frequency of PSA testing, (3) receipt of biopsy following elevated PSA results, and (4) prostate cancer detection at biopsy. Population-based cohort study using data from the Stockholm PSA and Biopsy Register. Participants were all prostate cancer-free men aged 40 to 79 years residing in Stockholm County, Sweden, between January 1, 2006, and December 31, 2015. Data were analyzed from November 2018 to March 2019. One or more prescription for metformin, sulfonylurea, or insulin, as recorded in Sweden's National Prescribed Drug Register. Levels of PSA following first exposure to antidiabetic medications were assessed using multivariable linear regression. Frequency of PSA testing was assessed via multivariable Poisson regression. Biopsy following elevated PSA (≥3.0 ng/mL) and prostate cancer detection at biopsy were assessed via multivariable logistic regression. The cohort of 564 666 men (median [range] age, 65 [40-79] years) consisted of 4583 men initially exposed to metformin, 1104 exposed to sulfonylurea, and 978 exposed to insulin who were age matched with unexposed men (1:5). Exposed men had lower median (interquartile range) PSA levels before starting antidiabetic medications compared with unexposed men (1.2 [0.7-2.5] vs 1.6 [0.8-3.2] ng/mL). After accounting for baseline differences, PSA levels did not vary from those of unexposed men following exposure to antidiabetic medications. Frequency of PSA testing was higher for those receiving metformin (rate ratio, 1.07; 95% CI, 1.06-1.09) and sulfonylurea (rate ratio, 1.06; 95% CI, 1.03-1.08) but was lower for those receiving insulin (rate ratio, 0.79; 95% CI, 0.77- 0.81). Likelihood of biopsy after elevated PSA was lower among men receiving metformin (odds ratio, 0.87; 95% CI, 0.80-0.96) and insulin (odds ratio, 0.83; 95% CI, 0.74-0.93). There were no differences in prostate cancer detection at biopsy, regardless of PSA levels that triggered the biopsy. This study's findings do not support the hypothesis that the inverse association between diabetes and prostate cancer is mediated through antidiabetic medications lowering PSA levels to mask prostate cancer. They do suggest potential detection bias due to fewer biopsies among men receiving antidiabetic medications, which may explain the lower prostate cancer risk in men with diabetes.
Highlights
Diabetes and prostate cancer are 2 very common conditions affecting older men
The cohort of 564 666 men consisted of 4583 men initially exposed to metformin, 1104 exposed to sulfonylurea, and 978 exposed to insulin who were age matched with unexposed men (1:5)
Frequency of prostate-specific antigen (PSA) testing was higher for those receiving metformin and sulfonylurea but was lower for those receiving insulin
Summary
Numerous studies have reported lower incidence of prostate cancer among men with diabetes,[1,2,3,4] higher risk of aggressive prostate cancer[5,6] and poorer prognosis[7,8] have been noted. Some studies have proposed that the lower risk of prostate cancer may be due to use of common antidiabetic medications, acting either directly or through delayed detection.[10] Metformin, a glucose-lowering drug with antineoplastic properties commonly used as a first-line treatment for diabetes, has been suggested to be protective in the early stages of prostate cancer tumorigenesis.[11] It is possible that downregulation of prostate epithelial cell growth by metformin may result in lower prostate-specific antigen (PSA) levels, which mask the presence of prostate cancer or delay its detection, leading to an apparent reduced risk. Sulfonylureas and insulin analogues, which are commonly used as second- and third-line therapies for diabetes, may lead to increased insulinlike growth factor levels and promote prostate cancer growth and simultaneously increase PSA levels.[12,13]
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