Background: Diabetes mellitus (DM) increases the risk for cancer at almost all sites, but data on the association with prostate cancer are inconsistent.
Methods: We assessed the risk of a prostate cancer diagnosis among men with type 2 (T2)DM in a nationwide population-based case-control study including 44,352 men with prostate cancer identified through the Prostate Cancer data Base Sweden (PCBaSe) between 2002 and 2006 and 221,495 age-matched men from the general population.
Results: Overall, the risk of prostate cancer among men with T2DM was lower than among men without T2DM [OR, 0.80; 95% confidence interval (CI), 0.76–0.85]. The risk decreased with longer disease duration and was observed across all tumor risk categories, although most clearly among men with low risk tumors (OR, 0.71; 95% CI, 0.64–0.80). The risk for prostate cancer was reduced among diabetic men on dietary treatment only (OR, 0.89; 95% CI, 0.80–0.99) but more markedly among men on oral hypoglycemic agents (OR, 0.80; 95% CI, 0.74–0.87) and insulin (OR, 0.72; 95% CI, 0.69–0.81). Obese diabetic men (BMI > 30 kg/m2) showed a reduced risk (OR, 0.72; 95% CI, 0.65–0.80) compared with men without diabetes. There was a trend of decreasing risk with increasing levels of HbA1c (P < 0.05).
Conclusions: This nationwide study confirmed a reduced risk of being diagnosed with prostate cancer among men with T2DM, especially for low-risk tumors. An altered hormonal milieu is a plausible explanation, although the possibility of decreased prostate cancer detection among diabetic men cannot be ruled out.
Impact: This is the largest study to examine the association between T2DM and prostate cancer accounting for tumor risk group and diabetes treatment. Cancer Epidemiol Biomarkers Prev; 22(6); 1102–9. ©2013 AACR.
Insulin resistance and hyperinsulinemia have been associated with an increased risk of malignancies (1, 2) including prostate cancer in some (3, 4) but not all studies (5). In line with these findings, type 2 diabetes mellitus (T2DM) increases the risk of a range of malignancies (6–8). In contrast, a growing body of evidence supports a reduced risk for a diagnosis of prostate cancer among men with T2DM; 2 meta-analyses totally including 22,000 prostate cancer cases (9, 10), as well as a number of smaller studies have reported a modest risk reduction among men with diabetes mellitus (11–15). Still, no large-scale population-based study has comprehensively evaluated the potential link between T2DM, related treatments, and prostate cancer occurrence.
This study examines the risk of prostate cancer, overall, and for prostate cancer risk categories among men with T2DM carefully characterized regarding glucose-lowering therapy, duration of disease, body mass index (BMI), and circulating levels of glycated hemoglobine (HbA1c). We have used detailed data from the Prostate Cancer data Base Sweden (PCBaSe) including more than 40,000 cases from the Swedish National Prostate Cancer Register (NPCR) in combination with prospectively collected exposure information from the Swedish National Diabetes Register (NDR).
Materials and Methods
We identified 44,352 men diagnosed with prostate cancer between 2002 and 2006 in the PCBaSe which is based on the NPCR, a population-based register that is nationwide since 1998 (16). Reporting to the NPCR exceeds the 96% coverage of the Swedish Cancer Register, to which registration is mandatory by law. Individual data on tumor characteristics and prostate-specific antigen (PSA; at diagnosis) were obtained from NPCR. For each prostate cancer case in PCBaSe, 5 population-based prostate cancer–free male controls were randomly selected from the continuously updated population register, matched on calendar time, age, and county of residence (N = 221,495). All Swedish citizens are assigned a personal identity number (PIN), a unique identifier that allows record linkage across the Swedish Health Care Registers (17). By use of the PIN, we obtained data on vital status, comorbiditiy, and socioeconomic factors for men in NPCR and their matched controls from The Inpatient Register, the Population Register, and the National Longitudinal Integrated Database from Statistics Sweden, as previously described (18).
Exposure information was obtained from the NDR, a register initiated in 1996 that currently covers 86% of all incident cases of diabetes mellitus. We retrieved data on type of diabetes mellitus, date of diagnosis, duration of diabetes, pharmacologic treatment, BMI, HbA1c, and microalbuminuria (19). The definition of T2DM was treatment with diet only, oral hypoglycemic agents only, or onset age of diabetes ≥40 years and insulin only or combined with oral agents. We disregarded exposure information from later than 1 year before the date of prostate cancer diagnosis to minimize potential influence of impending prostate cancer. HbA1c analyses were quality assured nationwide by regular calibration with the HPLC Mono-S method. In this study, all HbA1c values were converted to the DCCT standard values using the formula: HbA1c (DCCT) = 0.923 × HbA1c (Mono-S) + 1.345; R2 = 0.998 (20). Microalbuminuria was defined as urine albumin excretion 20 to 200 μg/min in 2 of 3 consecutive tests.
Logistic regression, conditioned on age, year, and county of residency at date of diagnosis, was used to estimate ORs and 95% confidence intervals (CI) for prostate cancer risk. Models were adjusted for socioeconomic status (SES; high, low, and not gainfully employed), civil status (married, widower, divorced, not married), comorbidity (CCI; 0, 1, 2, 3+), age at prostate cancer diagnosis (<65, 65–69, 70–74, 75–79, 80–84, 85+ years), and recorded diabetes prevalence in the county of residence (levels, <0.1%, 0.1%–1%, 1%–2%, 2%+). To explore the potential influence of factors related to T2DM, we conducted stratified analyses where the diabetic men were grouped according to type and duration of T2DM, pharmacologic treatment, BMI, HbA1c, creatinine, and microalbuminuria.
In NPCR, men with prostate cancer are categorized into 5 risk categories according to a modified version of the National Comprehensive Cancer Network (NCCN) guidelines. Risk categories are defined as: low-risk = clinical local stage T1,T2 tumor, PSA < 10 ng/mL and Gleason score < 6; intermediate-risk = T1, T2, and PSA 10–<20 ng/mL or Gleason score 7; high-risk = T3 tumor or PSA 20–<50 ng/mL or Gleason score > 8; regional metastases = T4 or N1 or PSA 50–100 ng/mL; and distant metastases = M1 or PSA > 100 ng/mL. In the present analysis, the groups of high risk, regionally metastatic, and distant metastatic disease were merged into one group.
The study protocol was approved by the Central Research Ethics Board (DNR: Ö 14-2007).
The mean age at diabetes mellitus onset among cases was 60.3 (SD = 13.2) and among controls 62.2 (SD = 12.4; Table 1). A slightly higher proportion of men with prostate cancer were married and belonged to a higher socioeconomic category than among the controls. The groups did not differ with regard to comorbidity score.
Among the total of 44,410 men with prostate cancer, 1,539 had a previous diagnosis of diabetes mellitus (3.5%; Table 2). Mean age at prostate cancer diagnosis was 72.4 years among men with T2DM and 70.2 years in men without T2DM (Table 2). Prostate cancer cases with T2DM tended to have a more adverse risk profile at the date of diagnosis than cases without T2DM; there was a higher proportion of cases with advanced local disease T3,4 tumors (27.6% vs. 25%), a higher proportion of poorly differentiated tumors, Gleason score 8–10 (25.7% vs. 19.3%), and metastatic disease (24.3% vs. 21%).
Diabetes mellitus duration and treatment
Overall, there was a 20% reduced risk of being diagnosed with prostate cancer among men with T2DM compared with men without (Table 3). We observed a continuous trend of decreasing prostate cancer risk with increasing time since diagnosis of diabetes; among men who were diagnosed 20 years or more before their prostate cancer, the risk was reduced by 35%. On average, this represents a 1% reduced risk per year with diabetes (OR, 0.989; 95% CI, 0.983–0.995). There was a lower risk of prostate cancer both among users of oral hypoglycemic agents (OHA) and insulin than among men without these drugs. However, “diet only” also conferred a modest but statistically significant risk reduction. The overall risk for prostate cancer decreased with increasing BMI among the diabetic men compared with diabetes-free controls, and we observed a trend of lower prostate cancer risks with higher HbA1c levels.
Prostate cancer risk categories
We observed a decreasing prostate cancer risk with longer duration of T2DM across all risk categories but less clearly so among men high-risk/metastatic prostate cancer (Table 4). The use of insulin and OHA therapies was associated with a lower risk of prostate cancer in all risk categories, but the associations were stronger among men with low- and intermediate-risk prostate cancer than among men with high-risk/metastatic prostate cancer. We observed an inverse association between diabetes treated with diet only and low-risk prostate cancer but not with intermediate- or high-risk/metastatic prostate cancer. There was a trend of reduced risk of prostate cancer with higher BMI among diabetic men compared with the average risk among nondiabetic men, but the trend was largely confined to low-risk prostate cancer. Younger age at diabetes onset conferred a reduced prostate cancer risk for low- and intermediate-risk cancer but not for high-risk/metastatic cancer.
BMI and HbA1c
Diabetic men with high HbA1c levels (≥6.2) and high BMI (≥30 kg/m2) had a 35% decreased risk of prostate cancer (OR, 0.65; 95% CI, 0.55–0.75) compared with controls, whereas diabetic men with a combination of either high HbA1c and low BMI (BMI < 30) or low HbA1c (HbA1c level < 6.2%) and high BMI had 17% (OR, 0.83; 95% CI, 0.76–0.92) and 20% (OR, 0.85; 95% CI, 0.69–0.92) decreased risks, respectively (data not shown).
This nationwide study adds to the evidence of an inverse association between T2DM and prostate cancer. In these data, there was a trend of decreasing prostate cancer risk with longer T2DM duration and younger age at T2DM onset. The strongest inverse associations were observed for diabetic men treated with insulin, with high levels of HbA1c and high BMI. We observed a reduced risk of being diagnosed with prostate cancer across all tumor risk categories, although risk patterns were less clear for men with high-risk/metastatic cancer.
High- and low-risk tumors
Our finding of an inverse association between T2DM and a diagnosis of prostate cancer is in line with a number of smaller studies (11–14, 21, 22), of which a few have examined the influence of T2DM duration (12–14, 21) and high- versus low-risk tumors (11, 12, 22), separately. Our results largely confirm those of the Prostate Cancer Prevention Trial (PCPT) including 92 prostate cancer cases with T2DM that reported a risk reduction of 28% for high-grade cancer and a 47% reduction for low-grade cancer (11). The Health Professionals Follow-up study reported an inverse association between T2DM and prostate cancer both among cases of localized and advanced-stage prostate cancer in the pre-PSA era, but no association with advanced-stage tumors in the PSA era (12). The uptake of PSA testing has been slower and less pronounced in Sweden in comparison to the United States. It has been estimated that in 2007, 56% of Swedish men 55–69 years of age had undergone at least one PSA test (23).
Detection of prostate cancer among men with T2DM
Speculatively, differences in the mode of detection of prostate cancer could explain the inverse association between T2DM and prostate cancer. Diabetic (24–26) and obese men (27–29) have lower levels of PSA than healthy men. Therefore, men with T2DM and obesity may be less likely to be diagnosed with prostate cancer initiated by an elevated PSA level. Also, less PSA testing has been reported among men with T2DM (21, 30, 31) and overweight (21, 30, 31) than among healthy men. Accordingly, in the REDUCE trial, where all study participants underwent prostate biopsy regardless of serum PSA, no association between T2DM and prostate cancer risk was observed (32). Our findings of higher age and more advanced tumors among men with T2DM and prostate cancer could thus indicate that selection may contribute to the observed inverse association between T2DM and prostate cancer. Differences in marital status and social class may point in the same direction.
Hormonal and metabolic factors in relation to prostate cancer risk
The observed risk reduction was not, however, only observed among men with low-risk prostate cancer. Metabolic aberrations including changes in insulin, insulin-like growth factor-1 (IGF-1), and testosterone levels have previously been suggested as a link between T2DM and prostate cancer (12, 33). Elevated C-peptide levels, reflecting serum insulin concentrations, have been associated with high-risk prostate cancer (11, 34) as well as prostate cancer–specific death (35). Moreover, insulin influences prostate cancer cell growth in vivo as well as in vitro (36–38). In accordance with an earlier finding (5), we found that the risk of low- and intermediate-risk prostate cancer decreased with increasing HbA1c concentrations. In theory, this could be related to higher androgenicity among men with low glucose levels. The influence of metabolic factors may further need a relatively well-differentiated target tissue for their action. T2DM and long-term hyperglycemia frequently results in microvascular complications due to capillary dysfunction and altered shape and size of intraprostatic microvessels have been linked to the risk of lethal prostate cancer (39). Decreased microcirculation might thus alternatively explain the reduced risk among men with T2DM (40).
Diabetic men who did develop prostate cancer showed a higher proportion of high-risk tumors than patients with prostate cancer without diabetes in our study. Low androgen levels among men with diabetes could be involved in driving that difference, as suggested by findings of an increased risk of high-risk tumors among men using 5-α reductase inhibitors (41). In line with results from 2 earlier studies (12, 21), a stronger inverse relation between T2DM and prostate cancer was suggested among diabetic men with a high BMI in our data. Additional influence of an altered hormonal milieu in obese men with low testosterone levels may speculatively explain this observation (42).
Earlier studies have provided evidence in support of a reduced prostate cancer risk among men on glucose-lowering agents (43–45). Our study provides new knowledge with regard to tumor characteristics; we observed that insulin therapy was associated with a clear risk reduction among men with low- and intermediate-risk prostate cancer but less so among men with high-risk tumors. Our data further showed a reduced risk of prostate cancer across all diabetic treatment groups, although most clearly among men on insulin and oral treatment and for low-risk disease. Although clearly difficult to disentangle, this may suggest that diabetes and the severity of the disease affects the risk of prostate cancer rather than the treatment.
Strengths of this study include its size that to our knowledge represents the largest study on this topic, the nested case–control design that preserves the validity of the underlying population-based cohort, the prospective data collection that minimized differential misclassification of the exposure data, as well as the detailed exposure and endpoint information. As prostate cancer incidence is closely linked to diagnostic intensity as shown, for example, by large differences in incidence between regions in Sweden (46), a similar pattern for diabetes diagnosis could have influenced the relation between T2DM and prostate cancer. Controlling for a constructed diagnostic likelihood index in the models left the estimates unchanged, however. Adjustment for other potential confounders did not alter the results materially. However, given the observational design of the study, influence of unknown or unmeasured confounders (such as family history) cannot be entirely ruled out.
In summary, this nationwide register study confirmed earlier findings of an inverse association between T2DM and the diagnosis of prostate cancer. The strongest risk reduction was observed for men with low-risk cancer, long duration of T2DM, and for men who received insulin or oral hypoglycemic agents. We speculate that the association is related to an altered hormonal milieu, most strongly affecting well-differentiated tumors. However, influence of less PSA testing and reduced efficacy of such testing among men with diabetes cannot be excluded. Future studies examining the influence of diabetes on survival among patients with prostate cancer may bring further insights into the underlying mechanism. If confirmed, a link between diabetes—with its associated hormonal milieu—and prostate carcinogenesis could potentially lead to identification of targets for therapeutic intervention.
Disclosure of Potential Conflicts of Interest
B.O.M. Zethelius is employed by the Medical Products Agency (MPA), Uppsala, Sweden. No potential conflicts of interest were disclosed by the other authors.
Results and views of the present study represent the authors and are not necessarily any official views of the MPA.
Conception and design: K. Fall, H. Garmo, P. Stattin, B.O.M. Zethelius
Development of methodology: S. Gudbjornsdottir
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): P. Stattin, B.O.M. Zethelius
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): K. Fall, H. Garmo, S. Gudbjornsdottir
Writing, review, and/or revision of the manuscript: K. Fall, H. Garmo, P. Stattin, B.O.M. Zethelius
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): S. Gudbjornsdottir, P. Stattin, B.O.M. Zethelius
Study supervision: B.O.M. Zethelius
This work was supported by grants from The Swedish Research Council (grant no 5950) and the Swedish Cancer Society (grant no 0750 and 0471; Principal investigator: P. Stattin). The Swedish Association of Local Authorities and Regions funds the NDR.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
The authors thank all regional NDR coordinators, contributing nurses, physicians, and patients. The patient organization Swedish Diabetes Association, and the Swedish Society of Diabetology support the NDR.
This project was also made possible by the continuous work of the NPCR of Sweden steering group P. Stattin, chair Anders Widmark, Stefan Carlsson, Magnus Törnblom, Jan Adolfsson, Anna Bill-Axelson, Ove Andrén, David Robinson, Bill Pettersson, Jonas Hugosson, Jan-Erik Damber, Ola Bratt, Göran Ahlgren, Lars Egevad, Mats Lambe, Karin Hellström, and Maria Nyberg.
- Received September 12, 2012.
- Revision received March 11, 2013.
- Accepted March 25, 2013.
- ©2013 American Association for Cancer Research.