Abstract
The associations of testosterone therapy (TTh) and statins use with prostate cancer (PCa) remain conflicted. However, the joint effects of TTh and statins use on the incidence of PCa, stage and grade at diagnosis, and PCa-specific mortality (PCSM) have not been studied.
We identified White (N=74181), Black (N=9157) and Hispanic (N=3313) men diagnosed with PCa in SEER-Medicare 2007–2016. Pre-diagnostic 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 PCa, 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 PCa. Similar inverse associations were observed with high-grade and advanced PCa in relation to TTh and statins use. TTh plus statins was inversely associated with incident PCa (OR = 0.53, 95% CI: 0.48 – 0.60), high-grade (OR = 0.43, 95% CI: 0.37 – 0.49) and advanced PCa (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.
Pre-diagnostic use of TTh or statins, independent or combined, was inversely associated with incident and aggressive PCa overall and in NHW and NHB men. Findings for statins and aggressive PCa 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 PCa in understudied populations.
Keywords: testosterone replacement therapy, statins and prostate cancer
Introduction
The association between use of TTh with prostate cancer (PCa) 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 through 2016 due to a FDA safety bulletin issued between 2013–2014 addressing a relationship between TTh use and myocardial infarction (3). A recent large meta-analysis of 11 RCTs based on 20 PCa cases concluded that TTh for symptomatic hypogonadism did not increase the risk of PCa (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 PCa seems to be consistent, but it merits a further observation with overall PCa risk (5, 6). Meta-analysis found an inverse association between use of statins and high grade, advanced stage PCa and prostate cancer-specific mortality (PCSM) (7, 8)]. Yet, the effect on total PCa was minimal with a <10% risk reduction. Another recent study did not find significant associations between statin use and incident PCa (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= 44126) reported a significant inverse association between current statin use and lethal PCa (10), whereas another prospective cohort study with more than 20 years of follow-up (n=6518) reported a non-statistically significant inverse association between statin use and lethal PCa (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, 13, 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 PCa, stage and grade at diagnosis and prostate cancer-specific mortality (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 US, 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 (Galveston, TX) 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=94980) 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 (Figure 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 PCa from Seer-Medicare files
Prediagnostic use of TTh and statin prescription
Prescription of TTh was identified before PCa diagnosis from Medicare Part D file using national drug codes (NDC) and from Current Procedural Terminology (CPT) Codes (Appendix Supplemental Table S1). Similarly, use of statin was identified from Part D- NDC file (Appendix Supplemental Table S2). Based on the use of TTh (Yes/No) or statin (Yes/No), PCa patients were categorized into four groups: No TTh plus No statin (reference group), statin alone, TTh alone, and TTh plus statin. The index date was 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 PCa 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 PCa outcomes of interest of this study were incident PCa, advanced-stage, high- tumor grade and PCSM among the subset of participants with previous PCa diagnosis. Advanced stage PCa was defined as AJCC stage III and IV definition (18). The SEER grading system indicates that “Well Differentiated” corresponds to Gleason scores 2–4, “Moderately Differentiated” corresponds with Gleason scores 5–7, and “Poorly Differentiated” corresponds with Gleason scores 8–10 (19). We defined high tumor grade as Gleason score 8–10. PCSM was available from SEER database through December 31, 2016. Causes of PCa 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) (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 PCa diagnosis date, all covariates were ascertained in the period of at least six months preceding first index date to avoid ascertainment bias and increased PCa 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. Non-cancer controls were sampled from the Medicare population, whereas cancer patients 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 PCa (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 PCa, 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 PCa versus non-cancer cases, high-grade PCa versus non-cancer cases, and the odds of advanced-stage PCa versus non-cancer cases. In a similar manner, the effect of TTh and statin use (No TTh plus No statin was the reference group) on incident PCa, and PCa 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 hazard ratios for PCSM adjusting for stage and grade at diagnosis (adjustment with stage and grade was only done among men diagnosed with PCa). 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 PCa 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, Cary, NC). P-values were considered significant at ≤ 0.05.
Results
We identified 74181 NHW, 9157 NHB and 3313 Hispanic men diagnosed with PCa in SEER-Medicare data 2007–2016. Mean age was 75 years old, and the median follow-up time from diagnosis of PCa to death or end of study was 5.5 years (12/31/2015). 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 to 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 non-cancer participants to extrapolate to full population were similar as in shown Table 1 (Supplemental Table 1).
Table 1.
Baseline characteristics of men 65+ years old with PCa by current use of testosterone therapy (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 PCa, N (%) | 17176 (36.17) | 13677 (31.06) | 529 (36.79) | 526 (26.16) | <.0001 |
| PCa Stage†, N | 33377 | 32405 | 970 | 1553 | |
| Localized, N (%) | 12395 (80.19) | 10118 (83.21) | 427 (87.50) | 415 (85.92) | <.0001 |
| Advanced, N (%) | 3063 (19.81) | 2041 (16.79) | 61 (12.50) | 68 (14.08) | |
| PCa Grade‡, (N) | 38686 | 36522 | 1147 | 1682 | |
| Low grade, N (%) | 7182 (46.17) | 6337 (50.72) | 264 (52.59) | 304 (60.68) | <.0001 |
| High grade, N (%) | 8372 (53.83) | 6158 (49.28) | 238 (47.41) | 197 (39.32) | |
| PCSM¥, N | 3981 (23.18) | 3052 (22.52) | 62 (15.86) | 121 (15.31) | |
| Age, N (%) | |||||
| 65–70 | 18351 (38.64) | 16704 (37.93) | 681 (47.36) | 966 (48.04) | <.0001 |
| 70–75 | 13355 (28.12) | 12391 (28.14) | 384 (26.70) | 580 (28.84) | |
| 75–80 | 8003 (16.85) | 7500 (17.03) | 221 (15.37) | 282 (14.02) | |
| >=80 | 7781 (16.38) | 7446 (16.91) | 152 (10.57) | 183 (9.10) | |
| Race, N (%) | |||||
| Black, | 5064 (10.66) | 3872 (8.79) | 98 (6.82) | 123 (6.12) | <.0001 |
| Hispanic | 1769 (3.72) | 1487 (3.38) | 16 (1.11) | 41 (2.04) | |
| White | 36579 (77.02) | 34581 (78.52) | 1267 (88.11) | 1754 (87.22) | |
| Other | 4078 (8.59) | 4101 (9.31) | 57 (3.96) | 93 (4.62) | |
| Hypogonadism, N (%) | 145 (0.31) | 192 (0.44) | 555 (38.6) | 393 (19.54) | <.0001 |
| Hypertension, N (%) | 11530 (24.28) | 19796 (44.95) | 530 (36.86) | 839 (41.72) | <.0001 |
| Muscular wasting and disuse atrophy, N(%) | 116 (0.24) | 125 (0.28) | <11 (<0.60) | 12 (0.6) | <.0001 |
| Malaise and fatigue, N(%) | 1717 (3.62) | 2783 (6.32) | 263 (18.29) | 218 (10.84) | <.0001 |
| Osteoporosis, N(%) | 371 (0.78) | 432 (0.98) | 56 (3.89) | 42 (2.09) | <.0001 |
| Erectile dysfunction, organic, N(%) | 316 (0.67) | 416 (0.94) | 233 (16.2) | 176 (8.75) | <.0001 |
| Depressive disorder, N(%) | 506 (1.07) | 791 (1.8) | 27 (1.88) | 38 (1.89) | <.0001 |
| Anterior pituitary disorder, N(%) | 11 (0.02) | 24 (0.05) | 25 (1.74) | 22 (1.09) | <.0001 |
| Diabetes, N(%) | 4575 (9.63) | 11990 (27.22) | 276 (19.19) | 576 (28.64) | <.0001 |
| CCI comorbidity, N(%) | |||||
| 0 | 42529 (89.55) | 33810 (76.77) | 1183 (82.27) | 1556 (77.37) | <.0001 |
| 1 | 3059 (6.44) | 6105 (13.86) | 166 (11.54) | 307 (15.27) | |
| 2 | 1018 (2.14) | 2162 (4.91) | 55 (3.82) | 96 (4.77) | |
| 3 or more | 884 (1.86) | 1964 (4.46) | 34 (2.36) | 52 (2.59) | |
| Use of insulin, N(%) | 647 (1.36) | 2112 (4.80) | 34 (2.36) | 76 (3.78) | <.0001 |
| Number of PSA tests, mean (SD) | 0.24 (0.50) | 0.39 (0.59) | 0.63 (0.67) | 0.55 (0.65) | <.0001 |
| Number of visits, mean (SD) | 5.8 (7.9) | 9.5 (9.4) | 11.2 (9.2) | 11 (9.7) | <.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) | <.0001 |
| Percent of adults below poverty, mean (SD) | 12.2 (8.9) | 11,7 (8.7) | 11.3 (7.6) | 11.2 (7.9) | <.0001 |
Advanced stage PCa cases were consistent with AJCC stage III and IV definition where localized PCA cases were defined with stages 0-II.
High tumor grade was defined with Gleason score 8–10 and low-grade Gleason score 2–7.
Prostate cancer-specific mortality
Table 2 shows the multivariable-adjusted independent and joint effects of TTh plus statin use on incident PCa, high-grade PCa, advanced-stage PCa and PCSM. Compared with no statin use, statin use was independently inversely associated with incident PCa (OR = 0.77, 95% CI, 0.75–0.80), high-grade PCa (OR = 0.72, 95% CI, 0.69–0.74), and advanced-stage PCa (OR = 0.71, 95% CI, 0.68–0.75). Compared with no TTh use, TTh was independently inversely associated with incident PCa (OR = 0.74, 95% CI, 0.68–0.81), high-grade PCa (OR = 0.68, 95% CI, 0.61–0.75), and advanced stage PCa (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 PCa (OR = 0.53, 95% CI, 0.48–0.60), high-grade PCa (OR = 0.43, 95% CI, 0.37–0.49), and advanced stage PCa (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 PCa (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 PCa, grade and stage at diagnosis, and prostate cancer specific mortality among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016
| Incident PCa† | High grade prostate cancer† | Advanced stage prostate cancer† | Prostate cancer mortality (adjusted for stage and grade at diagnosis)† | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | HR | 95% CI | |
| Statin (Yes vs No) | 14203/ 651183 | 0.77 | 0.75,0.80 | 6355/ 643315 | 0.72 | 0.69,0.74 | 2109/ 639089 | 0.71 | 0.68,0.75 | 867/ 14341 | 0.96 | 0.87,1.05 |
| TTh (Yes vs No) | 1055/ 48935 | 0.74 | 0.68,0.81 | 435/ 48315 | 0.68 | 0.61,0.75 | 129/ 48009 | 0.59 | 0.49,0.70 | 34/ 1181 | 0.90 | 0.61,1.31 |
| TTh & Statin Use | ||||||||||||
| No TTh/No Statin | 17176/ 623456 | 1.0 | 8372/ 614652 | 1.0 | 3063/ 609343 | 1.0 | 1358/ 17176 | 1.0 | ||||
| Statin alone | 13677/ 620957 | 0.78 | 0.76,0.81 | 6158/ 613438 | 0.73 | 0.70,0.76 | 2041/ 609321 | 0.72 | 0.68,0.75 | 842/ 13551 | 0.95 | 0.86,1.05 |
| TTh alone | 529/ 18709 | 0.87 | 0.77,0.98 | 238/ 18418 | 0.84 | 0.73,0.98 | 61/ 18241 | 0.59 | 0.46,0.76 | <11/ 391 | 0.72 | 0.36,1.45 |
| TTh+Statin | 526/ 30226 | 0.53 | 0.48,0.60 | 197/ 29897 | 0.43 | 0.37,0.49 | 68/ 29768 | 0.44 | 0.35,0.55 | 25/ 790 | 0.76 | 0.50,1.16 |
Multivariable analysis adjusted for age, race/ethnicity, Charlson Comorbidity Index (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), prostate-specific antigen (PSA), and mutual adjustment for TTh and statin.
Interaction term for TTh and statin use and its association with Incident PCa (Pinteraction = 0.002), and high- grade (Pinteraction = 0.002).
Table 3.
NWH men- Independent and joint effect of TTh and statin use with incident PCa, grade and stage at diagnosis, and prostate cancer specific mortality among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016
| Incident PCa† | High grade prostate cancer† | Advanced stage prostate cancer† | Prostate cancer mortality (adjusted for stage and grade at diagnosis)† | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | HR | 95% CI | |
| Statin (Yes vs No) | 11091/ 515971 | 0.76 | 0.74,0.78 | 4964/ 509844 | 0.70 | 0.68,0.73 | 1686/ 506566 | 0.70 | 0.67,0.74 | 655/ 11213 | 0.94 | 0.84,1.04 |
| TTh (Yes vs No) | 923/ 42883 | 0.76 | 0.70,0.82 | 377/ 42337 | 0.68 | 0.62,0.75 | 118/ 42078 | 0.62 | 0.53,0.73 | 27/ 1034 | 0.83 | 0.54,1.28 |
| TTh & Statin Use | ||||||||||||
| No TTh/No Statin | 13228/ 480248 | 1.0 | 6424/ 473444 | 1.0 | 2392 / 469412 | 1.0 | 998/ 13228 | 1.0 | ||||
| Statin alone | 10633/ 489593 | 0.77 | 0.74,0.79 | 4790/ 483750 | 0.71 | 0.67,0.74 | 1624/ 480584 | 0.70 | 0.67,0.74 | 635/ 10522 | 0.94 | 0.84,1.04 |
| TTh alone | 465/ 16505 | 0.87 | 0.77,0.97 | 203/ 16243 | 0.81 | 0.71,0.93 | 56/ 16096 | 0.62 | 0.46,0.78 | <11/ 343 | 0.44 | 0.21,0.94 |
| TTh+Statin | 458/ 26378 | 0.54 | 0.49,0.60 | 174/ 26094 | 0.44 | 0.38,0.50 | 62/ 25982 | 0.46 | 0.37,0.56 | 20/ 691 | 0.68 | 0.44,1.07 |
Multivariable analysis adjusted for age, Charlson Comorbidity Index (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), prostate-specific antigen (PSA), and mutual adjustment for TTh and statin.
Interaction term for TTh and statin use and its association with Incident PCa (Pinteraction = 0.005), and high-grade (Pinteraction = 0.002).
Table 4.
NHB men- Independent and joint effect of TTh and statin use with incident PCa, grade and stage at diagnosis, and prostate cancer specific mortality among men 65+ years old with a prostate cancer diagnosis in SEER-Medicare 2007–2016
| Incident PCa† | High grade prostate cancer† | Advanced stage prostate cancer† | Prostate cancer mortality (adjusted for stage and grade at diagnosis)† | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | OR | 95% CI | Event Rate | HR | 95% CI | |
| Statin (Yes vs No) | 1679/ 47999 | 0.78 | 0.76,0.80 | 720/ 47040 | 0.68 | 0.66,0.70 | 209/ 46529 | 0.72 | 0.69,0.76 | 128/ 1688 | 1.08 | 0.84,1.4 |
| TTh (Yes vs No) | 87 /2767 | 0.65 | 0.60,0.72 | 38/ 2718 | 0.63 | 0.56,0.71 | <11/ 2686 | 0.34 | 0.21,0.91 | <11/ 96 | 1.99 | 0.81,4.90 |
| TTh & Statin Use | ||||||||||||
| No TTh/No Statin | 2468/ 54388 | 1.0 | 1248/ 53168 | 1.0 | 407/ 52327 | 1.0 | 235/ 2468 | 1.0 | ||||
| Statin alone | 1636/ 46356 | 0.80 | 0.72,0.88 | 705/ 45425 | 0.69 | 0.67,0.72 | 205/ 44925 | 0.72 | 0.69,0.76 | 124/ 1627 | 1.06 | 0.83,1.36 |
| TTh alone | 44/ 1124 | 0.80 | 0.72,0.88 | 23/ 1103 | 0.94 | 0.84,1.04 | < 11 /1082 | 0.29 | 0.27,0.31 | <11/ 35 | 1.66 | 0.40,6.85 |
| TTh+Statin | 43/ 1643 | 0.45 | 0.39,0.51 | 15/ 1615 | 0.29 | 0.23,0.38 | < 11/ 1604 | 0.28 | 0.14,0.56 | <11/ 61 | 1.74 | 0.63,4.81 |
Multivariable analysis adjusted for age, Charlson Comorbidity Index (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), prostate-specific antigen (PSA), and mutual adjustment for TTh and statin.
Interaction term for TTh and statin use and its association with Incident PCa (Pinteraction = 0.001), and high-grade (Pinteraction = 0.001).
The independent and joint effects of TTh and statins on incident PCa, PCa grade and stage and PCSM among NHW, NHB and Hispanics are shown in Tables 3–4 and Supplemental Table 2. Among NHW men (Table 3), the results were similar with the overall population. The independent associations of TTh and statin use with incident PCa, high-grade PCa, 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 odds ratio of incident PCa (OR = 0.54, 95% CI, 0.49–0.60), high-grade PCa (OR = 0.44, 95% CI, 0.38–0.50), and advanced-stage PCa (OR = 0.46, 95% CI, 0.37–0.56). Statistical interaction was only between TTh and statins and its association with incident PCa (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 PCa, high-grade PCa and advanced-stage PCa, 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 odds ratio of incident PCa (OR = 0.45, 95% CI, 0.39–0.51), high-grade PCa (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 PCa (Pinteraction = 0.001), and high-grade (Pinteraction = 0.001).
Among Hispanic men (Supplemental Table 2), statin use was inversely associated with advanced-stage PCa (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 PCa (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 PCa. We also found evidence of statistical interaction only between TTh and statins and its association with incident PCa (Pinteraction = 0.001).
Discussion
Overall, we found independent and inverse associations between pre-diagnostic statin use and pre-diagnostic TTh use with incident PCa and aggressive disease in older men.
The combination of TTh plus statin was associated with incident PCa 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 PCa 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 PCa was positive among Hispanic men, and there were other inverse associations between TTh and PCa stage and grade in small sample size groups. Due to 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 PCa, stage and grade at diagnosis, and PCSM among NHW, NHB and Hispanics in Seer-Medicare 2007–2016.
TTh use and PCa outcomes
A number of studies and reviews have previously addressed the independent association of TTh with risk of developing PCa and have reported conflicting results (4, 14, 25, 26). Our significant inverse associations with incident PCa, high-grade and advanced stage PCa seem to concur with the direction of the inverse associations found in two meta-analysis of randomized clinical trials that investigated risk of developing PCa 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 PCa (14, 26). Findings related to aggressive disease, three recent retrospective population-based studies found no increased risk of high grade PCa in men with TTh use (27–29). Two of these studies, Kaplan et al. 2013 and Yassin et al. 2017, further investigated the relationship between TTh use and likelihood to be diagnosed with advanced stage PCa (clinical stage T4) reporting protective effects (28, 29).
The direction of our measures of association seem to be agreement with these previous studies investigating PCa 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 PCa (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 to our study, this latter study (30) did not adjust for PCa stage and grade at diagnosis. We further adjusted for use of statins in the independent association of TTh with PCa stage and grade, which to our knowledge no other study has conducted similar analysis due to the widely used of statins.
Statin use and PCa outcomes
A number of prospective cohort studies and reviews have addressed the association between taking statins and risk of developing PCa, lethal disease, fatal disease, and in men with a PCa 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 PCa, as shown in a meta-analysis of 6 randomized trials and 36 observational studies (7).
The direction of our measures of association with incident PCa and aggressive disease is consistent with previous studies. Evidence is also mounting that pre-diagnostic 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 PCa, stage and grade at diagnosis, and PCSM
To our knowledge no study has investigated the combination of TTh plus statin use in relation to PCa 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 PCa 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 aged 40–69 years that 21% of TTh users have also reported statin use (14). Furthermore, a review article by Mokarram et al. 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 PCa 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 epidemiological 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 PCa, 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 PCa 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 non-advanced disease, which both scenarios lead to an OR < 1 (35). The odds ratios provided in these analyses were obtained from weighted conditional logistic regression models that consider incident cases of PCa and an exposure that preceded the PCa diagnosis, therefore, they are only approximations to hazard ratios. 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 Charlson Comorbidity Index, which include cardiovascular diseases (CVDs), 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 ‘non-user’ 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 PCa with Gleason scores 2–7, 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 PCa 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 PCa events among men who took both TTh and statin, and cases of advanced PCa 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 pre-diagnostic and post-diagnostic users. Typically, inclusion of post-diagnostic users may include immortal time bias; therefore, the findings and interpretations of our study should be made with caution.
Conclusion
In summary, in this large racially and ethnically diverse SEER-Medicare claims based analysis, we found that pre-diagnostic use of TTh or statins, independent or in combination, was inversely associated with incidence PCa 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 PCa 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 PCa among men of different racial and ethnic backgrounds.
Supplementary Material
Funding information:
David S. Lopez was supported by the National Institutes of Health (NIH) and National Institute on Aging, Grant #: P30 AG059301.
Footnotes
Prevention Relevance Statement: The study investigates a potential interaction between TTh and statin and its effect on incident and aggressive PCa in men of different racial and ethnic backgrounds. These results suggest that among NHW and NHB men TTh plus statins reduced the odds of incident PCa, high-grade and advance stage PCa.
Conflict of interest: “The authors declare no potential conflicts of interest.”
“This study used the linked SEER-Medicare database. The interpretation and reporting of these data are the sole responsibility of the authors. The authors acknowledge the efforts of the National Cancer Institute; the Office of Research, Development and Information, CMS; Information Management Services (IMS), Inc.; and the Surveillance, Epidemiology, and End Results (SEER) Program tumor registries in the creation of the SEER-Medicare database.”
Ethics Approval and Consent to Participate: The secondary data analysis was approved by Institutional Review Board at the UTMB, Galveston, TX.
References
- 1.Claps M, Petrelli F, Caffo O et al. Testosterone Levels and Prostate Cancer Prognosis: Systematic Review and Meta-analysis. Clin Genitourin Cancer 2018;16:165–175. [DOI] [PubMed] [Google Scholar]
- 2.Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS and Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Intern Med 2013;173:1465–1466. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Baillargeon J, Kuo YF, Westra JR, Urban RJ and Goodwin JS. Testosterone Prescribing in the United States, 2002–2016. JAMA 2018;320:200–202. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Boyle P, Koechlin A, Bota M et al. Endogenous and exogenous testosterone and the risk of prostate cancer and increased prostate-specific antigen (PSA) level: a meta-analysis. BJU Int. 2016;118:731–741. [DOI] [PubMed] [Google Scholar]
- 5.Allott EH, Farnan L, Steck SE et al. Statin Use and Prostate Cancer Aggressiveness: Results from the Population-Based North Carolina-Louisiana Prostate Cancer Project. Cancer Epidemiol Biomarkers Prev 2016;25:670–677. [DOI] [PubMed] [Google Scholar]
- 6.Allott EH, Farnan L, Steck SE et al. Statin use, high cholesterol and prostate cancer progression; results from HCaP-NC. Prostate 2018;78:857–864. [DOI] [PubMed] [Google Scholar]
- 7.Tan P, Wei S, Tang Z et al. LDL-lowering therapy and the risk of prostate cancer: a meta-analysis of 6 randomized controlled trials and 36 observational studies. Sci Rep 2016;6:24521. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Mei Z, Liang M, Li L, Zhang Y, Wang Q, Yang W. Effects of statins on cancer mortality and progression: A systematic review and meta-analysis of 95 cohorts including 1,111,407 individuals. Int J Cancer 2017;140:1068–1081. [DOI] [PubMed] [Google Scholar]
- 9.Tan P, Zhang C, Wei SY et al. Effect of statins type on incident prostate cancer risk: a meta-analysis and systematic review. Asian J Androl 2017;19:666–671. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Allott EH, Ebot EM, Stopsack KH et al. Statin Use Is Associated with Lower Risk of PTEN-Null and Lethal Prostate Cancer. Clin Cancer Res 2020;26:1086–1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Mondul AM, Joshu CE, Barber JR, et al. Longer-term Lipid-lowering Drug Use and Risk of Incident and Fatal Prostate Cancer in Black and White Men in the ARIC Study. Cancer Prev Res (Phila) 2018;11:779–788. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Zhou CK, Advani S, Chaloux M et al. Trends and Patterns of Testosterone Therapy Among US Male Medicare Beneficiaries, 1999–2014. J Urol 2020;101. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Mefford MT, Rosenson RS, Deng L et al. Trends in Statin Use Among US Adults With Chronic Kidney Disease, 1999–2014. J Am Heart Assoc 2019;8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Lopez DS, Huang D, Tsilidis KK et al. Association of the extent of therapy with prostate cancer in those receiving testosterone therapy in a US commercial insurance claims database. Clin Endocrinol (Oxf) 2019;91:885–891. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Oluleye OW, Kronmal RA, Folsom AR et al. Association between statin use and sex hormone in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. J Clin Endocrinol Metab 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Warren JL, Klabunde CN, Schrag D, Bach PB, Riley GF. Overview of the SEER-Medicare data: content, research applications, and generalizability to the United States elderly population. Med Care 2002;40:IV-3–18. [DOI] [PubMed] [Google Scholar]
- 17.Zippin C, Lum D, Hankey BF. Completeness of hospital cancer case reporting from the SEER Program of the National Cancer Institute. Cancer 1995;76:2343–2350. [DOI] [PubMed] [Google Scholar]
- 18.Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 2010;17:1471–1474. [DOI] [PubMed] [Google Scholar]
- 19.Wright JL, Dalkin BL, True LD et al. Positive surgical margins at radical prostatectomy predict prostate cancer specific mortality. J Urol 2010;183:2213–2218. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Albertsen PC, Walters S, Hanley JA. A comparison of cause of death determination in men previously diagnosed with prostate cancer who died in 1985 or 1995. J Urol 2000;163:519–523. [PubMed] [Google Scholar]
- 21.Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40:373–383. [DOI] [PubMed] [Google Scholar]
- 22.Hernan MA, Hernandez-Diaz S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 2002;155:176–184. [DOI] [PubMed] [Google Scholar]
- 23.Therneau TMGP. Modeling Survival Data: Extending the Cox model. 2000. New York: Springer-Verlag. [Google Scholar]
- 24.VanderWeele TJ. On the distinction between interaction and effect modification. Epidemiology 2009;20:863–871. [DOI] [PubMed] [Google Scholar]
- 25.Cui Y, Zong H, Yan H, Zhang Y. The effect of testosterone replacement therapy on prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 2014;17:132–143. [DOI] [PubMed] [Google Scholar]
- 26.Cook MB, Beachler DC, Parlett LE et al. Testosterone Therapy in Relation to Prostate Cancer in a U.S. Commercial Insurance Claims Database. Cancer Epidemiol Biomarkers Prev 2020;29:236–245. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Baillargeon J, Kuo YF, Fang X, Shahinian VB. Long-term Exposure to Testosterone Therapy and the Risk of High Grade Prostate Cancer. J Urol 2015;194:1612–1616. [DOI] [PubMed] [Google Scholar]
- 28.Kaplan AL, Hu JC. Use of testosterone replacement therapy in the United States and its effect on subsequent prostate cancer outcomes. Urology 2013;82:321–326. [DOI] [PubMed] [Google Scholar]
- 29.Yassin A, Salman M, Talib RA, Yassin DJ. Is there a protective role of testosterone against high-grade prostate cancer? Incidence and severity of prostate cancer in 553 patients who underwent prostate biopsy: a prospective data register. Aging Male 2017;20:125–133. [DOI] [PubMed] [Google Scholar]
- 30.Kaplan AL, Lenis AT, Shah A et al. Testosterone replacement therapy in men with prostate cancer: a time-varying analysis. J Sex Med 2015;12:374–380. [DOI] [PubMed] [Google Scholar]
- 31.Caon J, Paquette M, Hamm J, Pickles T. Does Statin or ASA Affect Survival When Prostate Cancer Is Treated with External Beam Radiation Therapy? Prostate Cancer. 2014;2014:184297. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Schooling CM, Au Yeung SL, Freeman G, Cowling BJ. The effect of statins on testosterone in men and women, a systematic review and meta-analysis of randomized controlled trials. BMC Med. 2013;11:57–7015–11–57. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Jones TH, Kelly DM. Randomized controlled trials - mechanistic studies of testosterone and the cardiovascular system. Asian J Androl 2018;20:120–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Mokarram P, Alizadeh J, Razban V, Barazeh M, Solomon C, Kavousipour S. Interconnection of Estrogen/Testosterone Metabolism and Mevalonate Pathway in Breast and Prostate Cancers. Curr Mol Pharmacol 2017;10:86–114. [DOI] [PubMed] [Google Scholar]
- 35.Platz EA. Is prostate cancer prevention with selenium all in the genes? Cancer Prev Res (Phila) 2010;3:576–578. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.