The associations of testosterone therapy (TTh) and statins use with prostate cancer remain conflicted. However, the joint effects of TTh and statins use on the incidence of prostate cancer, stage and grade at diagnosis, and prostate cancer-specific mortality (PCSM) have not been studied.

We identified White (N = 74,181), Black (N = 9,157), and Hispanic (N = 3,313) men diagnosed with prostate cancer in SEER-Medicare 2007–2016. Prediagnostic prescription of TTh and statins was ascertained for this analysis. Weighted multivariable-adjusted conditional logistic and Cox proportional hazards models evaluated the association of TTh and statins with prostate cancer, including statistical interactions between TTh and statins.

We found that TTh (OR = 0.74; 95% CI, 0.68–0.81) and statins (OR = 0.77; 95% CI, 0.0.75–0.88) were inversely associated with incident prostate cancer. Similar inverse associations were observed with high-grade and advanced prostate cancer in relation to TTh and statins use. TTh plus statins was inversely associated with incident prostate cancer (OR = 0.53; 95% CI, 0.48–0.60), high-grade (OR = 0.43; 95% CI, 0.37–0.49), and advanced prostate cancer (OR = 0.44; 95% CI, 0.35–0.55). Similar associations were present in White and Black men, but among Hispanics statins were associated with PCSM.

Prediagnostic use of TTh or statins, independent or combined, was inversely associated with incident and aggressive prostate cancer overall and in NHW and NHB men. Findings for statins and aggressive prostate cancer are consistent with previous studies. Future studies need to confirm the independent inverse association of TTh and the joint inverse association of TTh plus statins on risk of prostate cancer in understudied populations.

Prevention Relevance:

The study investigates a potential interaction between TTh and statin and its effect on incident and aggressive prostate cancer in men of different racial and ethnic backgrounds. These results suggest that among NHW and non-Hispanic Black men TTh plus statins reduced the odds of incident prostate cancer, high-grade and advance stage prostate cancer.

The association between use of testosterone therapy (TTh) with prostate cancer in larger studies remains unclear (1). The use of TTh in the United States increased from 0.81% in 2001 to 2.9% in 2011 (2). However, it decreased from 2013 to 2016 due to a FDA safety bulletin issued between 2013 and 2014 addressing a relationship between TTh use and myocardial infarction (3). A recent large meta-analysis of 11 RCTs based on 20 prostate cancer cases concluded that TTh for symptomatic hypogonadism did not increase the risk of prostate cancer (4). Due to this small number, the power to make conclusions is minimal. Although RCTs represent the most rigorous study design in terms of reducing confounding and selection bias, they often have small cohort samples with limited generalizability to non-Hispanic Blacks (NHB) and Hispanics.

The association of use of statins with aggressive prostate cancer seems to be consistent, but it merits a further observation with overall prostate cancer risk (5, 6). Meta-analysis found an inverse association between use of statins and high grade, advanced stage prostate cancer and prostate cancer-specific mortality (PCSM; refs. 7, 8). Yet, the effect on total prostate cancer was minimal with a <10% risk reduction. Another recent study did not find significant associations between statin use and incident prostate cancer (9). These meta-analyses did not examined NHB and Hispanic men as separate groups. A prospective cohort study with 24 years of follow-up (n = 44,126) reported a significant inverse association between current statin use and lethal prostate cancer (10), whereas another prospective cohort study with more than 20 years of follow-up (n = 6,518) reported a nonstatistically significant inverse association between statin use and lethal prostate cancer (11). These two latter studies did not find (11) or reported (10) racial differences, and they did not analyze Hispanics as a separate group.

It is plausible that TTh and statins can work or interact together as the prevalence of testosterone deficiency and hypercholesterolemia has increased among older men, and subsequently their treatment with TTh and statins (12–14). There is also biological plausibility in the interaction between testosterone and cholesterol, and potentially with their treatments, TTh and statins, because cholesterol is a required intermediate precursor in steroidogenesis (15).

Therefore, the objectives of this study are to investigate the independent and joint effects of TTh and statins use on the incidence of prostate cancer, stage and grade at diagnosis and PCSM, and to examine whether these associations vary among non-Hispanic White (NHW), NHB, and Hispanic men.

Patients and Methods

Data source

We analyzed data from Surveillance, Epidemiology and End Results (SEER)-Medicare, a linkage of population based cancer registries from 19 SEER regions, which cover approximately 30% of the population of the United States, with Medicare administrative data (16). Approximately 95% of patients recorded in the SEER registry with incident cancer cases have been linked to their Medicare claims for covered health related services. We used the Summarized Denominator file to collect information on the 5% sample of non-cancer patients. The SEER program collects clinical, demographic, and survival information from American cancer patients 65 years or older (17). Medicare claims are linked through unique SEER identifiers covering the time of Medicare eligibility until death. This study was conducted in accordance with the U.S. Common Rule. The Institutional Review Board of UTMB approved this study. Informed consent was waived for this study of existing records without direct identifies. The data that support the findings of this study are available from Information Management Services Inc. (IMS).

Study cohort

All males (n = 94,980) with at least one year of continuous enrollment in Part D anytime between 2007 and 2015 were eligible for inclusion in the study. Eligible subjects were divided in two groups; the exposed, including those that received any testosterone or statin prescription between 07/2007 and 06/2015 and the unexposed who did not receive any of the two drugs during the same period. Exposed subjects were excluded from consideration if they were younger than 65 years old at the time of the first drug prescription (index date), if they had less than 6 months continuous part A and B enrollment prior to the index date or if the index date was less than 6 months prior to the prostate cancer diagnosis date (if any) or the participant's race and ethnicity were not specified (NHW, NHB, or Hispanic). Unexposed subjects that were at least 65 years old and had at least 6 months of part A and B enrollment at any time during the study period formed the pool of eligible matched controls. These patients were matched 1:1 on birth year with the exposed group and were assigned the same index date as their match, while ensuring they had at least 6 months A and B enrollment before and the index date was at least 6 months before any prostate cancer diagnosis (Fig. 1). If a participant of the exposed group matched to more than one participant of the unexposed group, only one was selected at random.

Figure 1.

Study inclusion and exclusion criteria for identifying men with incident prostrate cancer from Seer-Medicare files.

Figure 1.

Study inclusion and exclusion criteria for identifying men with incident prostrate cancer from Seer-Medicare files.

Close modal

Prediagnostic use of TTh and statin prescription

Prescription of TTh was identified before prostate cancer diagnosis from Medicare Part D file using national drug codes (NDC) and from Current Procedural Terminology (CPT) Codes (Supplementary Table S1). Similarly, use of statin was identified from Part D- NDC file (Supplementary Table S2). On the basis of the use of TTh (yes/no) or statin (yes/no), prostate cancer patients were categorized into four groups: no TTh plus No statin (reference group), statin alone, TTh alone, and TTh plus statin. The index date were defined as the date of the first prescription within the study period. For patients who used both TTh and statin, at least 6 months between the later of the two dates and prostate cancer diagnosis (if any) was required. These criteria also applied to statin and TTh only groups, including PCSM analysis. For the outcome of PCSM, we evaluated TTh and statins use at any time during the study period (before or after diagnosis).

Prostate cancer endpoints

The prostate cancer outcomes of interest of this study were incident prostate cancer, advanced-stage, high-tumor grade, and PCSM among the subset of participants with previous prostate cancer diagnosis. Advanced stage prostate cancer was defined as AJCC stage III and IV definition (18). The SEER grading system indicates that “Well Differentiated” corresponds to Gleason scores 2 to 4, “moderately differentiated” corresponds with Gleason scores 5 to 7, and “poorly differentiated” corresponds with Gleason scores 8 to 10 (19). We defined high tumor grade as Gleason score 8 to 10. PCSM was available from SEER database through December 31, 2016. Causes of prostate cancer death in the SEER record were based on the underlying causes of death in the death certificate, which has a high agreement (87%–92%) with medical record review (20). PCSM was censored upon loss-to-follow-up because of discontinuation of enrollment or the administrative end of calendar year and for those who died of other causes. A subcohort analysis of Hispanics with PCSM was conducted due to a smaller sample size. Therefore, it was not feasible to conduct 1:1 match on birth year for PCSM analysis among Hispanics, and we followed a nested-case-control approach in this group. Stage information was extracted from the PEDSF file.

Covariates

Patient characteristics included in the model were age at diagnosis, race and ethnicity, marital status, number of primary care physician (PCP) visits, and number of prostate-specific antigen (PSA) tests and NCI-Charlson Comorbidity Index (CCI; ref. 21). We used the NCI–CCI from 6 months prior to the index date to determine comorbidity burden. In fact, in addition to the 6 months period required between first medication date and prostate cancer diagnosis date, all covariates were ascertained in the period of at least six months preceding first index date to avoid ascertainment bias and increased prostate cancer detection in those being worked up for a prescription compared with the referent group of no prescription. Clinical indicators identified from Medicare claims using NDC and CPT codes included hypogonadism, hypertension, diabetes, use of insulin, muscular wasting and disuse atrophy, malaise and fatigue, osteoporosis, erectile dysfunction, depressive disorder, anterior pituitary disorder, and decreased libido. We measured PCP visits and PSA tests by summarizing the number of associated claims and grouping them as categorical variables 6 months prior to the index exposure date. US Census tract socioeconomic status that measured the percentage of persons older than 25 years with less than 12 years education and the percentage of adults below the poverty line in the census tract were also included.

Statistical analysis

Patient characteristics, clinical indicators, census tract socioeconomic status variables, medical resources use were compared by drug group (TTh plus statins) using Chi-square tests for categorical variables and Student t tests for continuous variables with normal distribution. Noncancer controls were sampled from the Medicare population, whereas patients with cancer were not (SEER). To account for this difference, we developed and applied weights to extrapolate to full population of men (65+ years old) to able to estimate the incidence of prostate cancer (as well as grade and stage), and to conduct weighted multivariable-adjusted conditional logistic and Cox proportional hazards models. Independent associations of TTh and statins with incident prostate cancer, stage, and grade at diagnosis were assessed by conducting weighted multivariable conditional logistic regression models using a priori knowledge (22) to identify potential confounders as previously described in the Covariates section. These weighted multivariable adjusted models compared the odds of incident prostate cancer versus noncancer cases, high-grade prostate cancer versus noncancer cases, and the odds of advanced-stage prostate cancer versus noncancer cases. In a similar manner, the effect of TTh and statin use (no TTh + no statin was the reference group) on incident prostate cancer, and prostate cancer stage and grade at diagnosis was assessed by conducting multivariable logistic regression models after adjusting for potential confounders. The weighted multivariable adjusted Cox proportional hazards models estimated HRs for PCSM adjusting for stage and grade at diagnosis (adjustment with stage and grade was only done among men diagnosed with prostate cancer). This conditional survival analyses took into account the matching procedure. Scaled Schoenfeld residuals were used to test the proportional hazards assumption (23). We conducted stratified analysis to determine whether the association between TTh plus statin use and prostate cancer outcomes was different in NHW, NHB, and Hispanic men (24). Multiplicative interactions terms were incorporated into the models and tested using the Wald test. Statistical analyses were performed using SAS (SAS Institute v.9.4). P values were considered significant at ≤0.05.

We identified 74,181 NHW, 9,157 NHB, and 3,313 Hispanic men diagnosed with prostate cancer in SEER-Medicare data 2007–2016. Mean age was 75 years old, and the median follow-up time from diagnosis of prostate cancer to death or end of study was 5.5 years (December 31, 2015). Table 1 shows patient characteristics by combination of TTh and statin use. Approximately 46.30% of men used statin alone, 2.00% used TTh alone, and 2.11% used both TTh plus statin. Compared with men with no TTh plus no statin, users of TTh alone, statin alone, or their combination were less likely to report <12 years of education and lower percentage below poverty line, but more likely to be younger, NHW, hypertensive, diabetic, reported muscular wasting and malaise and fatigue, reported erectile dysfunction and higher score of CCI comorbidity, hypogonadism, osteoporosis, depressive disorder, anterior pituitary disorder, higher use of insulin, and higher number of PCP visits, and PSA tests. Frequencies of the weighted characteristics for the noncancer participants to extrapolate to full population were similar as in shown Table 1 (Supplementary Table S1).

Table 1.

Baseline characteristics of men 65+ years old with prostate cancer by current use of TTh and/or statin with a median follow-up (PCMS) of 5.5 years in the SEER-Medicare 2007–2016.

No TTh/No Statin (N = 47,490) (50%)Statin alone (N = 44,041) (46.4%)TTh alone (N = 1,438) (1.5%)TTh+Statin (N = 2,011) (2.1%)P
Incident prostate cancer, N (%) 17,176 (36.17) 13,677 (31.06) 529 (36.79) 526 (26.16) <0.0001 
Prostate cancer Stagea, N 33,377 32,405 970 1,553  
Localized, N (%) 12,395 (80.19) 10,118 (83.21) 427 (87.50) 415 (85.92) <0.0001 
Advanced, N (%) 3,063 (19.81) 2,041 (16.79) 61 (12.50) 68 (14.08)  
Prostate cancer Gradeb, N 38,686 36,522 1,147 1,682  
Low grade, N (%) 7,182 (46.17) 6,337 (50.72) 264 (52.59) 304 (60.68) <0.0001 
High grade, N (%) 8,372 (53.83) 6,158 (49.28) 238 (47.41) 197 (39.32)  
PCSMc, N 3,981 (23.18) 3,052 (22.52) 62 (15.86) 121 (15.31)  
Age, N (%)      
65–70 18,351 (38.64) 16,704 (37.93) 681 (47.36) 966 (48.04) <0.0001 
70–75 13,355 (28.12) 12,391 (28.14) 384 (26.70) 580 (28.84)  
75–80 8,003 (16.85) 7,500 (17.03) 221 (15.37) 282 (14.02)  
≥80 7,781 (16.38) 7,446 (16.91) 152 (10.57) 183 (9.10)  
Race, N (%)      
Black, 5,064 (10.66) 3,872 (8.79) 98 (6.82) 123 (6.12) <0.0001 
Hispanic 1,769 (3.72) 1,487 (3.38) 16 (1.11) 41 (2.04)  
White 36,579 (77.02) 34,581 (78.52) 1267 (88.11) 1,754 (87.22)  
Other 4,078 (8.59) 4,101 (9.31) 57 (3.96) 93 (4.62)  
Hypogonadism, N (%) 145 (0.31) 192 (0.44) 555 (38.6) 393 (19.54) <0.0001 
Hypertension, N (%) 11,530 (24.28) 19,796 (44.95) 530 (36.86) 839 (41.72) <0.0001 
Muscular wasting and disuse atrophy, N (%) 116 (0.24) 125 (0.28) <11 (<0.60) 12 (0.6) <0.0001 
Malaise and fatigue, N (%) 1,717 (3.62) 2,783 (6.32) 263 (18.29) 218 (10.84) <0.0001 
Osteoporosis, N (%) 371 (0.78) 432 (0.98) 56 (3.89) 42 (2.09) <0.0001 
Erectile dysfunction, organic, N (%) 316 (0.67) 416 (0.94) 233 (16.2) 176 (8.75) <0.0001 
Depressive disorder, N (%) 506 (1.07) 791 (1.8) 27 (1.88) 38 (1.89) <0.0001 
Anterior pituitary disorder, N (%) 11 (0.02) 24 (0.05) 25 (1.74) 22 (1.09) <0.0001 
Diabetes, N (%) 4,575 (9.63) 11,990 (27.22) 276 (19.19) 576 (28.64) <0.0001 
CCI comorbidity, N (%)      
42,529 (89.55) 33,810 (76.77) 1,183 (82.27) 1,556 (77.37) <0.0001 
3,059 (6.44) 6,105 (13.86) 166 (11.54) 307 (15.27)  
1,018 (2.14) 2,162 (4.91) 55 (3.82) 96 (4.77)  
3 or more 884 (1.86) 1,964 (4.46) 34 (2.36) 52 (2.59)  
Use of insulin, N (%) 647 (1.36) 2,112 (4.80) 34 (2.36) 76 (3.78) <0.0001 
Number of PSA tests, mean (SD) 0.24 (0.50) 0.39 (0.59) 0.63 (0.67) 0.55 (0.65) <0.0001 
Number of visits, mean (SD) 5.8 (7.9) 9.5 (9.4) 11.2 (9.2) 11 (9.7) <0.0001 
Percent of adults with <12 years education, mean (SD) 19.9 (12.8) 19.9 (12.8) 17.7 (11.2) 18.4 (11.8) <0.0001 
Percent of adults below poverty, mean (SD) 12.2 (8.9) 11,7 (8.7) 11.3 (7.6) 11.2 (7.9) <0.0001 
No TTh/No Statin (N = 47,490) (50%)Statin alone (N = 44,041) (46.4%)TTh alone (N = 1,438) (1.5%)TTh+Statin (N = 2,011) (2.1%)P
Incident prostate cancer, N (%) 17,176 (36.17) 13,677 (31.06) 529 (36.79) 526 (26.16) <0.0001 
Prostate cancer Stagea, N 33,377 32,405 970 1,553  
Localized, N (%) 12,395 (80.19) 10,118 (83.21) 427 (87.50) 415 (85.92) <0.0001 
Advanced, N (%) 3,063 (19.81) 2,041 (16.79) 61 (12.50) 68 (14.08)  
Prostate cancer Gradeb, N 38,686 36,522 1,147 1,682  
Low grade, N (%) 7,182 (46.17) 6,337 (50.72) 264 (52.59) 304 (60.68) <0.0001 
High grade, N (%) 8,372 (53.83) 6,158 (49.28) 238 (47.41) 197 (39.32)  
PCSMc, N 3,981 (23.18) 3,052 (22.52) 62 (15.86) 121 (15.31)  
Age, N (%)      
65–70 18,351 (38.64) 16,704 (37.93) 681 (47.36) 966 (48.04) <0.0001 
70–75 13,355 (28.12) 12,391 (28.14) 384 (26.70) 580 (28.84)  
75–80 8,003 (16.85) 7,500 (17.03) 221 (15.37) 282 (14.02)  
≥80 7,781 (16.38) 7,446 (16.91) 152 (10.57) 183 (9.10)  
Race, N (%)      
Black, 5,064 (10.66) 3,872 (8.79) 98 (6.82) 123 (6.12) <0.0001 
Hispanic 1,769 (3.72) 1,487 (3.38) 16 (1.11) 41 (2.04)  
White 36,579 (77.02) 34,581 (78.52) 1267 (88.11) 1,754 (87.22)  
Other 4,078 (8.59) 4,101 (9.31) 57 (3.96) 93 (4.62)  
Hypogonadism, N (%) 145 (0.31) 192 (0.44) 555 (38.6) 393 (19.54) <0.0001 
Hypertension, N (%) 11,530 (24.28) 19,796 (44.95) 530 (36.86) 839 (41.72) <0.0001 
Muscular wasting and disuse atrophy, N (%) 116 (0.24) 125 (0.28) <11 (<0.60) 12 (0.6) <0.0001 
Malaise and fatigue, N (%) 1,717 (3.62) 2,783 (6.32) 263 (18.29) 218 (10.84) <0.0001 
Osteoporosis, N (%) 371 (0.78) 432 (0.98) 56 (3.89) 42 (2.09) <0.0001 
Erectile dysfunction, organic, N (%) 316 (0.67) 416 (0.94) 233 (16.2) 176 (8.75) <0.0001 
Depressive disorder, N (%) 506 (1.07) 791 (1.8) 27 (1.88) 38 (1.89) <0.0001 
Anterior pituitary disorder, N (%) 11 (0.02) 24 (0.05) 25 (1.74) 22 (1.09) <0.0001 
Diabetes, N (%) 4,575 (9.63) 11,990 (27.22) 276 (19.19) 576 (28.64) <0.0001 
CCI comorbidity, N (%)      
42,529 (89.55) 33,810 (76.77) 1,183 (82.27) 1,556 (77.37) <0.0001 
3,059 (6.44) 6,105 (13.86) 166 (11.54) 307 (15.27)  
1,018 (2.14) 2,162 (4.91) 55 (3.82) 96 (4.77)  
3 or more 884 (1.86) 1,964 (4.46) 34 (2.36) 52 (2.59)  
Use of insulin, N (%) 647 (1.36) 2,112 (4.80) 34 (2.36) 76 (3.78) <0.0001 
Number of PSA tests, mean (SD) 0.24 (0.50) 0.39 (0.59) 0.63 (0.67) 0.55 (0.65) <0.0001 
Number of visits, mean (SD) 5.8 (7.9) 9.5 (9.4) 11.2 (9.2) 11 (9.7) <0.0001 
Percent of adults with <12 years education, mean (SD) 19.9 (12.8) 19.9 (12.8) 17.7 (11.2) 18.4 (11.8) <0.0001 
Percent of adults below poverty, mean (SD) 12.2 (8.9) 11,7 (8.7) 11.3 (7.6) 11.2 (7.9) <0.0001 

aAdvanced stage prostate cancer cases were consistent with AJCC stage III and IV definition where localized prostate cancer cases were defined with stages 0-II.

bHigh tumor grade was defined with Gleason score 8–10 and low-grade Gleason score 2–7.

cPCSM.

Table 2 shows the multivariable-adjusted independent and joint effects of TTh plus statin use on incident prostate cancer, high-grade prostate cancer, advanced-stage prostate cancer, and PCSM. Compared with no statin use, statin use was independently inversely associated with incident prostate cancer (OR = 0.77; 95% CI, 0.75–0.80), high-grade prostate cancer (OR = 0.72; 95% CI, 0.69–0.74), and advanced-stage prostate cancer (OR = 0.71; 95% CI, 0.68–0.75). Compared with no TTh use, TTh was independently inversely associated with incident prostate cancer (OR = 0.74, 95% CI, 0.68–0.81), high-grade prostate cancer (OR = 0.68, 95% CI, 0.61–0.75), and advanced stage prostate cancer (OR = 0.59; 95% CI, 0.49–0.70). Similar associations were observed when compared with no TTh plus no statins use, TTh plus statins use was inversely associated with incident prostate cancer (OR = 0.53; 95% CI, 0.48–0.60), high-grade prostate cancer (OR = 0.43; 95% CI, 0.37–0.49), and advanced stage prostate cancer (OR = 0.44; 95% CI, 0.35–0.55). We also found evidence of statistical interaction only between TTh and statins and its association with incident prostate cancer (Pinteraction = 0.002), and high-grade (Pinteraction = 0.0009). Adjusting for stage and grade there were no clear independent or joint effects on PCSM in the overall sample (Table 2), NHW (Table 3), and NHB men (Table 4).

Table 2.

Independent and joint effect of TTh and statin use with incident prostate cancer, grade and stage at diagnosis, and PCSM among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016.

Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 14,203/651,183 0.77 (0.75–0.80) 6,355/643,315 0.72 (0.69–0.74) 2,109/639,089 0.71 (0.68–0.75) 867/14,341 0.96 (0.87–1.05) 
TTh (yes vs. no) 1,055/48,935 0.74 (0.68–0.81) 435/48,315 0.68 (0.61–0.75) 129/48,009 0.59 (0.49–0.70) 34/1,181 0.90 (0.61–1.31) 
TTh and statin use         
No TTh/no statin 17,176/623,456 1.0 8,372/614,652 1.0 3,063/609,343 1.0 1,358/17,176 1.0 
Statin alone 13,677/620,957 0.78 (0.76–0.81) 6,158/613,438 0.73 (0.70–0.76) 2,041/609,321 0.72 (0.68–0.75) 842/13,551 0.95 (0.86–1.05) 
TTh alone 529/18,709 0.87 (0.77–0.98) 238/18,418 0.84 (0.73–0.98) 61/18,241 0.59 (0.46–0.76) <11/391 0.72 (0.36–1.45) 
TTh+Statin 526/30,226 0.53 (0.48–0.60) 197/29,897 0.43 (0.37–0.49) 68/29,768 0.44 (0.35–0.55) 25/790 0.76 (0.50–1.16) 
Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 14,203/651,183 0.77 (0.75–0.80) 6,355/643,315 0.72 (0.69–0.74) 2,109/639,089 0.71 (0.68–0.75) 867/14,341 0.96 (0.87–1.05) 
TTh (yes vs. no) 1,055/48,935 0.74 (0.68–0.81) 435/48,315 0.68 (0.61–0.75) 129/48,009 0.59 (0.49–0.70) 34/1,181 0.90 (0.61–1.31) 
TTh and statin use         
No TTh/no statin 17,176/623,456 1.0 8,372/614,652 1.0 3,063/609,343 1.0 1,358/17,176 1.0 
Statin alone 13,677/620,957 0.78 (0.76–0.81) 6,158/613,438 0.73 (0.70–0.76) 2,041/609,321 0.72 (0.68–0.75) 842/13,551 0.95 (0.86–1.05) 
TTh alone 529/18,709 0.87 (0.77–0.98) 238/18,418 0.84 (0.73–0.98) 61/18,241 0.59 (0.46–0.76) <11/391 0.72 (0.36–1.45) 
TTh+Statin 526/30,226 0.53 (0.48–0.60) 197/29,897 0.43 (0.37–0.49) 68/29,768 0.44 (0.35–0.55) 25/790 0.76 (0.50–1.16) 

aMultivariable analysis adjusted for age, race/ethnicity, CCI, hypogonadism, hypertension, diabetes, use of insulin, muscular wasting and disuse atrophy, malaise and fatigue, osteoporosis, erectile dysfunction, depressive disorder, anterior pituitary disorder, education (percentage of persons older than 25 years with less than 12 years education), percentage of adults below poverty line at census tract level, patients' primary care (PCP), PSA, and mutual adjustment for TTh and statin.

bInteraction term for TTh and statin use and its association with incident prostate cancer (Pinteraction = 0.002), and high-grade (Pinteraction = 0.002).

Table 3.

NWH men-independent and joint effect of TTh and statin use with incident prostate cancer, grade and stage at diagnosis, and PCSM among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016.

Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 11,091/515,971 0.76 (0.74–0.78) 4,964/509,844 0.70 (0.68–0.73) 1686/506,566 0.70 (0.67–0.74) 655/11,213 0.94 (0.84–1.04) 
TTh (yes vs. no) 923/42,883 0.76 (0.70–0.82) 377/42,337 0.68 (0.62–0.75) 118/42,078 0.62 (0.53–0.73) 27/1,034 0.83 (0.54–1.28) 
TTh and statin use         
No TTh/no statin 13,228/480,248 1.0 6,424/473,444 1.0 2392/469,412 1.0 998/13,228 1.0 
Statin alone 10,633/489,593 0.77 (0.74–0.79) 4,790/483,750 0.71 (0.67–0.74) 1624/480,584 0.70 (0.67–0.74) 635/10,522 0.94 (0.84–1.04) 
TTh alone 465/16,505 0.87 (0.77–0.97) 203/16,243 0.81 (0.71–0.93) 56/16,096 0.62 (0.46–0.78) <11/343 0.44 (0.21–0.94) 
TTh+Statin 458/26,378 0.54 (0.49–0.60) 174/26,094 0.44 (0.38–0.50) 62/25,982 0.46 (0.37–0.56) 20/691 0.68 (0.44–1.07) 
Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 11,091/515,971 0.76 (0.74–0.78) 4,964/509,844 0.70 (0.68–0.73) 1686/506,566 0.70 (0.67–0.74) 655/11,213 0.94 (0.84–1.04) 
TTh (yes vs. no) 923/42,883 0.76 (0.70–0.82) 377/42,337 0.68 (0.62–0.75) 118/42,078 0.62 (0.53–0.73) 27/1,034 0.83 (0.54–1.28) 
TTh and statin use         
No TTh/no statin 13,228/480,248 1.0 6,424/473,444 1.0 2392/469,412 1.0 998/13,228 1.0 
Statin alone 10,633/489,593 0.77 (0.74–0.79) 4,790/483,750 0.71 (0.67–0.74) 1624/480,584 0.70 (0.67–0.74) 635/10,522 0.94 (0.84–1.04) 
TTh alone 465/16,505 0.87 (0.77–0.97) 203/16,243 0.81 (0.71–0.93) 56/16,096 0.62 (0.46–0.78) <11/343 0.44 (0.21–0.94) 
TTh+Statin 458/26,378 0.54 (0.49–0.60) 174/26,094 0.44 (0.38–0.50) 62/25,982 0.46 (0.37–0.56) 20/691 0.68 (0.44–1.07) 

aMultivariable analysis adjusted for age, CCI, hypogonadism, hypertension, diabetes, use of insulin, muscular wasting and disuse atrophy, malaise and fatigue, osteoporosis, erectile dysfunction, depressive disorder, anterior pituitary disorder, education (percentage of persons older than 25 years with less than 12 years education), percentage of adults below poverty line at census tract level, patients' primary care (PCP), PSA, and mutual adjustment for TTh and statin.

bInteraction term for TTh and statin use and its association with incident prostate cancer (Pinteraction = 0.005), and high-grade (Pinteraction = 0.002).

Table 4.

NHB men-Independent and joint effect of TTh and statin use with incident prostate cancer, grade and stage at diagnosis, and PCSM among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016.

Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 1,679/47,999 0.78 (0.76–0.80) 720/47,040 0.68 (0.66–0.70) 209/46,529 0.72 (0.69–0.76) 128/1,688 1.08 (0.84–1.4) 
TTh (yes vs. no) 87/2,767 0.65 (0.60–0.72) 38/2,718 0.63 (0.56–0.71) <11/2,686 0.34 (0.21–0.91) <11/96 1.99 (0.81–4.90) 
TTh and statin use         
No TTh/no statin 2,468/54,388 1.0 1,248/53,168 1.0 407/52,327 1.0 235/2,468 1.0 
Statin alone 1,636/46,356 0.80 (0.72–0.88) 705/45,425 0.69 (0.67–0.72) 205/44,925 0.72 (0.69–0.76) 124/1,627 1.06 (0.83–1.36) 
TTh alone 44/1,124 0.80 (0.72–0.88) 23/1,103 0.94 (0.84–1.04) <11/1,082 0.29 (0.27–0.31) <11/35 1.66 (0.40–6.85) 
TTh+Statin 43/1,643 0.45 (0.39–0.51) 15/1,615 0.29 (0.23–0.38) <11/1,604 0.28 (0.14–0.56) <11/61 1.74 (0.63–4.81) 
Incident prostate cancera,bHigh-grade prostate cancera,bAdvanced stage prostate canceraProstate cancer mortality (adjusted for stage and grade at diagnosis)a
Event rateOR (95% CI)Event rateOR (95% CI)Event rateOR (95% CI)Event rateHR (95% CI)
Statin (yes vs. no) 1,679/47,999 0.78 (0.76–0.80) 720/47,040 0.68 (0.66–0.70) 209/46,529 0.72 (0.69–0.76) 128/1,688 1.08 (0.84–1.4) 
TTh (yes vs. no) 87/2,767 0.65 (0.60–0.72) 38/2,718 0.63 (0.56–0.71) <11/2,686 0.34 (0.21–0.91) <11/96 1.99 (0.81–4.90) 
TTh and statin use         
No TTh/no statin 2,468/54,388 1.0 1,248/53,168 1.0 407/52,327 1.0 235/2,468 1.0 
Statin alone 1,636/46,356 0.80 (0.72–0.88) 705/45,425 0.69 (0.67–0.72) 205/44,925 0.72 (0.69–0.76) 124/1,627 1.06 (0.83–1.36) 
TTh alone 44/1,124 0.80 (0.72–0.88) 23/1,103 0.94 (0.84–1.04) <11/1,082 0.29 (0.27–0.31) <11/35 1.66 (0.40–6.85) 
TTh+Statin 43/1,643 0.45 (0.39–0.51) 15/1,615 0.29 (0.23–0.38) <11/1,604 0.28 (0.14–0.56) <11/61 1.74 (0.63–4.81) 

aMultivariable analysis adjusted for age, CCI, hypogonadism, hypertension, diabetes, use of insulin, muscular wasting and disuse atrophy, malaise and fatigue, osteoporosis, erectile dysfunction, depressive disorder, anterior pituitary disorder, education (percentage of persons older than 25 years with less than 12 years education), percentage of adults below poverty line at census tract level, patients' primary care (PCP), PSA, and mutual adjustment for TTh and statin.

bInteraction term for TTh and statin use and its association with incident prostate cancer (Pinteraction = 0.001), and high-grade (Pinteraction = 0.001).

The independent and joint effects of TTh and statins on incident prostate cancer, prostate cancer grade and stage, and PCSM among NHW, NHB, and Hispanics are shown in Tables 3 to 4 and Supplementary Table S2. Among NHW men (Table 3), the results were similar with the overall population. The independent associations of TTh and statin use with incident prostate cancer, high-grade prostate cancer, and advanced-stage were significantly, inversely associated. Compared with no TTh plus no statins use among NHW men, TTh plus statins use showed a greater reduced OR of incident prostate cancer (OR = 0.54; 95% CI, 0.49–0.60), high-grade prostate cancer (OR = 0.44; 95% CI, 0.38–0.50), and advanced-stage prostate cancer (OR = 0.46; 95% CI, 0.37–0.56). Statistical interaction was only between TTh and statins and its association with incident prostate cancer (Pinteraction = 0.005), and high-grade (Pinteraction = 0.003).

Among NHB men (Table 4), we found similar significant inverse associations, independently and joint effects of TTh and statin use with incident prostate cancer, high-grade prostate cancer and advanced-stage prostate cancer, as shown in the overall population (Table 2) and NHW men (Table 3). Compared with no TTh plus no statins use among NHB men, TTh plus statins use showed a greater reduced OR of incident prostate cancer (OR = 0.45; 95% CI, 0.39–0.51), high-grade prostate cancer (OR = 0.29; 95% CI, 0.23–0.38), and advanced-stage (OR = 0.28; 95% CI, 0.14–0.56). Statistical interaction was only between TTh and statins and its association with incident prostate cancer (Pinteraction = 0.001), and high-grade (Pinteraction = 0.001).

Among Hispanic men (Supplementary Table S2), statin use was inversely associated with advanced-stage prostate cancer (OR = 0.89; 95% CI, 0.86–0.93) and PCSM (HR = 0.70; 95% CI, 0.55–0.90). Similar inverse associations were observed with statin alone related to advanced-stage (OR = 0.89; 95% CI, 0.86–0.92) and PCSM (OR = 0.70; 95% CI, 0.54–0.89). Compared with no TTh use, TTh was independently positively associated with incident prostate cancer (OR = 1.18; 95% CI, 1.18–1.24), but in small sample size <11 events TTh was inversely associated with high-grade (OR = 0.93; 95% CI, 0.88–0.98) and advanced-stage prostate cancer. We also found evidence of statistical interaction only between TTh and statins and its association with incident prostate cancer (Pinteraction = 0.001).

Overall, we found independent and inverse associations between prediagnostic statin use and prediagnostic TTh use with incident prostate cancer and aggressive disease in older men.

The combination of TTh plus statin was associated with incident prostate cancer and aggressive disease. In NHW and NHB men, the significance and direction of these associations remained similar. Among Hispanic men, use of statin was independently inversely associated with advanced-stage prostate cancer and PCSM, and similarly the use of statin alone compared with not taking either medication was inversely associated with advanced-stage and PCSM. However, the independent association of TTh with incident prostate cancer was positive among Hispanic men, and there were other inverse associations between TTh and prostate cancer stage and grade in small sample size groups. Because of these small sample size numbers among Hispanics, the findings of this study are presented in supplemental tables as exploratory and not conclusive for the power to make conclusions is minimal; therefore, they should be interpreted with caution. To our knowledge, this is the first epidemiological study to quantify joint effects of TTh and statin on the incidence of prostate cancer, stage and grade at diagnosis, and PCSM among NHW, NHB, and Hispanics in Seer-Medicare 2007–2016.

TTh use and prostate cancer outcomes

A number of studies and reviews have previously addressed the independent association of TTh with risk of developing prostate cancer and have reported conflicting results (4, 14, 25, 26). Our significant inverse associations with incident prostate cancer, high-grade, and advanced stage prostate cancer seem to concur with the direction of the inverse associations found in two meta-analysis of randomized clinical trials that investigated risk of developing prostate cancer in relation to TTh use, albeit findings from these meta-analyses did not reach statistical significance (4, 25). Yet, it is important to note that in those meta-analyses transdermal was the most common delivery method, but in our analysis we combined injections and use of gels of testosterone therapy. Furthermore, two recent retrospective cohort studies capitalized on U.S. commercial insurance claims data and reported an inverse association between TTh and incident prostate cancer (14, 26). Findings related to aggressive disease, three recent retrospective population-based studies found no increased risk of high-grade prostate cancer in men with TTh use (27–29). Two of these studies, Kaplan and colleagues 2013 and Yassin and colleagues 2017, further investigated the relationship between TTh use and likelihood to be diagnosed with advanced stage prostate cancer (clinical stage T4) reporting protective effects (28, 29).

The direction of our measures of association seem to be agreement with these previous studies investigating prostate cancer high-grade and advanced-stage. We did not find any significant association with PCSM among NHW and NHB men, but a suggestive association among NHW men that may be due to a small sample size (<11 events). Among Hispanic men, there were some associations between TTh and prostate cancer (independently and jointly), but these association may be driven by small sample sizes (<11 events). Due to the small sample size in these groups, the power to make conclusions is minimal. Compared with our study, a recent population-based cancer registry study showed a risk reduction of PCSM in relation to TTh use in an overall population (30). However, compared with our study, this latter study (30) did not adjust for prostate cancer stage and grade at diagnosis. We further adjusted for use of statins in the independent association of TTh with prostate cancer stage and grade, which to our knowledge no other study has conducted similar analysis due to the widely used of statins.

Statin use and prostate cancer outcomes

A number of prospective cohort studies and reviews have addressed the association between taking statins and risk of developing prostate cancer, lethal disease, fatal disease, and in men with a prostate cancer diagnosis, risk of PCSM (7–9). There is growing evidence that the use of statin is significantly inversely associated with the risk of aggressive disease, including a lower risk of high-grade and advanced stage prostate cancer, as shown in a meta-analysis of 6 randomized trials and 36 observational studies (7).

The direction of our measures of association with incident prostate cancer and aggressive disease is consistent with previous studies. Evidence is also mounting that prediagnostic use of statins is inversely associated with PCSM; a meta-analysis of 12 cohort studies reported a significant reduced risk of PCSM (8). The null association in our prospective analysis of pre-diagnostic use of statins and PCSM is not consistent with that meta-analysis, although it is consistent with another study that reported hazard ratios lower than 1, but without statistical significance (31). Differences in results may be attributed to different study designs, different definitions of survivorship/mortality, the sample size in our study compare with other studies, or the role that the biological/environmental composition of racial/ethnic diverse population plays in the etiology of a disease. Although we found a significant association between use of statins and PCSM among Hispanics, it is important to note it was not feasible to conduct 1:1 match birth year, but we adjusted with age in the weighted multivariable analysis.

Joint association of TTh plus statin use with incident prostate cancer, stage and grade at diagnosis, and PCSM

To our knowledge no study has investigated the combination of TTh plus statin use in relation to prostate cancer stage and grade and PCSM. Therefore, our findings may not seem comparable with other studies. However, it is important to note there are a number of studies that have explored the interplay between statins, endogenous and exogenous testosterone, and prostate cancer in different settings that may provide insight to our findings (32, 33). For instance, a previous study noted that co-use of both medications had the possibility of confounding each other's effect (33). A meta-analysis of randomized controlled trials and an individual cohort study in humans showed that statins may lower testosterone levels (32).

Although our study may not comparable with other studies due to different methodological settings, what remains to be determined is whether there is an epidemiologic and biological plausibility in the interplay between low levels of testosterone/testosterone deficiency and hypercholesterolemia and their treatment with TTh and statins. Recently, it was reported that the prevalence of both, testosterone deficiency and hypercholesterolemia, has increased and subsequently their treatment medications, especially TTh and statins (12, 13). We previously identified in a US commercial claims database of 189 491 men ages 40 to 69 years that 21% of TTh users have also reported statin use (14). Furthermore, a review article by Mokarram and colleagues 2017 suggested the biological mechanistic interconnection between testosterone metabolism and the mevalonate pathway, which is required for the generation of several fundamental end-products including cholesterol that is a required precursor in steroidogenesis (34). Our multiplicative interactions between TTh and statins and their associations with incident and high-grade prostate cancer were statistically significant in the total sample population sample, NHW and NHB men. Therefore, the joint effects of TTh and statins are feasible. However, more epidemiologic studies with larger sample sizes are warranted, including in NHB and Hispanic men, to confirm findings from this study.

Strengths and limitations

Our study has strengths. This study included a large racially and ethnically (mainly statin use among Hispanics) diverse cohort, large number of men with incident prostate cancer, stage and grade at diagnosis, and a large enough sample to be able to investigate men who have used both TTh and a statin. This study also included a long follow‐up data, detailed information on patient's exposures to TTh and statin use on the basis of filled prescriptions and inclusion of clinically relevant comorbidities. These strengths increased our statistical power for the categorical comparison groups and generalizability for studies with similar prostate cancer populations. In addition, they also reduced residual confounding because of our well‐characterized modifiable factors.

Yet, the present study has limitations as well. First, our retrospective cohort design does not allow us to conclude whether these medications decrease the occurrence of advanced diseases or increase the occurrence of nonadvanced disease, which both scenarios lead to an OR < 1 (35). The ORs provided in these analyses were obtained from weighted conditional logistic regression models that consider incident cases of prostate cancer and an exposure that preceded the prostate cancer diagnosis, therefore, they are only approximations to HRs. Second, there are general limitations of retrospective analysis based on Medicare claims data, such as possible coding errors or omissions of claims. For instance, comorbidities were identified using ICD‐9 and ICD-10 codes, possibly resulting in incorrect capture of medical conditions due to undercoding, upcoding, or miscoding, leading to classification bias in those comorbidities at baseline (16). It is also possible that some of the non-users might have used TTh or statins prior to 2007, the earliest year of available Part D data. However, this potential inaccurate capture of information will be considered nondifferential misclassification because they were collected before the disease developed, which in general influences associations to the null (1.0). Third, limiting the pre‐index period to six months did not allow to capture full medical history; for instance, patients may have had the comorbidity of interest before the start of the pre index period.

Fourth, although we adjusted in the multivariable analysis for hypogonadism, age, and the CCI, which include cardiovascular diseases (CVD), we cannot rule out potential residual confounding by these factors. In most cases, statins is the primary prevention for CVDs, and this may have a positive impact on the health of the subjects in the joint use of TTh and statins. Another potential confounding in our analysis is that our statin “nonuser” group is possibly mixed with men with different cholesterol levels and treatment status (with and without high cholesterol and with and without treatment with high cholesterol medications other than statins). However, Seer-Medicare does not include laboratory results (serologic or diagnostic indications) to define hypercholesterolemia, testosterone deficiency with serum testosterone or other occupational, environmental, nutritional, and/or several lifestyle factors. Moreover, in our analysis we defined low-grade prostate cancer with Gleason scores 2 to 7, these findings should be interpreted with caution because Gleason 6 and 7 have been lumped together. Finally, our study population only included patients with Medicare claims (≥65 years old); therefore, our results may not be generalizable to patients with prostate cancer using other types of insurance, no insurance at all, or a younger population. Although our study has a large sample size, there was a still a small number of prostate cancer events among men who took both TTh and statin, and cases of advanced prostate cancer and PCSM in our population. Analysis related to duration or dose of the drug was not conducted due to small sample sizes in these categories. In our study we did not investigate the differential effects among prediagnostic and postdiagnostic users. Typically, inclusion of postdiagnostic users may include immortal time bias; therefore, the findings and interpretations of our study should be made with caution.

In summary, in this large racially and ethnically diverse SEER-Medicare claims based analysis, we found that prediagnostic use of TTh or statins, independent or in combination, was inversely associated with incidence prostate cancer and aggressive disease in total population and among NHW and NHB men. The greatest reduced association was among NHW men with combined TTh and statin use. Among Hispanic men, use of statins was only associated with advanced-stage prostate cancer and PCSM. Future prospective studies with larger sample sizes are needed to confirm the independent effects of TTh and the joint effects of TTh plus statins on fatal prostate cancer among men of different racial and ethnic backgrounds.

M. Khera reports personal fees from AbbVie, Acerus, and Clarus outside the submitted work. No disclosures were reported by the other authors.

The secondary data analysis was approved by Institutional Review Board at the UTMB, Galveston, TX.

D.S. Lopez: Conceptualization, resources, data curation, supervision, methodology. E. Polychronopoulou: Data curation, formal analysis, methodology, writing–review and editing. K.K. Tsilidis: Data curation, investigation, methodology. M. Khera: Supervision, investigation, writing–review and editing. L.J. Su: Supervision, investigation, writing–review and editing. J.H. Fowke: Supervision, investigation, writing–review and editing. M.K. Peek: Supervision, investigation, writing–review and editing. Y.-F. Kuo: Data curation, supervision, investigation, methodology, writing–review and editing. K. Markides: Supervision, investigation, writing–review and editing. S. Canfield: Conceptualization, supervision, investigation, writing–review and editing.

D.S. Lopez was supported by the NIH and National Institute on Aging, Grant No. P30 AG059301.

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.

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