Stratified Temporal Risk of Skin Cancer by Age Associated with Hydrochlorothiazide: A Retrospective Cohort Study Using the TriNetX Database

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Ilyas This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7538065/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 15 You are reading this latest preprint version Abstract Hydrochlorothiazide (HCTZ) is known to have photosensitizing properties with recent FDA labeling updates warning of its increased risk of nonmelanoma skin cancer (NMSC). There are few and at times conflicting studies in the current literature on the topic, in particular with regard to melanoma associations and significant confounders. This retrospective cohort study utilizing the TriNetX database investigates age and temporal associations between the initiation of HCTZ as monotherapy for hypertension (HTN) and the diagnosis of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma. Six adult (age >18) cohorts were created with (1) HTN (ICD10: I10) as control and (2) HTN with HCTZ; then further stratified by age from 18 to 49 and 50 to 75. Outcomes assessed were BCC, cSCC, and melanoma at 5 and 10 years. HCTZ usage in cohorts aged 50 to 75 years old was significantly (p<0.05) associated with an increased risk ratio of BCC and cSCC at 5 and 10 years and with melanoma only at 10 years. This study refines prior reports of HCTZ usage associated with development of BCC and cSCC particularly in older adults while controlling for confounders such as concurrent antihypertensives and smoking. The association with melanoma in the older aged cohorts and with longer durations of HCTZ usage suggests a role for cumulative actinic damage among other risk factors. We highlight the need for increased dermatological surveillance and counseling among this vulnerable population, especially for those over the age of 50 on sustained HCTZ therapy. hydrochlorothiazide skin cancer antihypertensives squamous cell carcinoma basal cell carcinoma melanoma Introduction Hydrochlorothiazide (HCTZ), a diuretic widely used in the chronic management of hypertension (HTN), underwent a labeling change update by the FDA to include an elevated risk of nonmelanoma skin cancer (NMSC) in 2020 [ 9 ]. Although some studies show such associations, the conflicting reports supporting evidence regarding the medication’s increased risks are limited by concerns over controlling for confounding variables, such as age, dosage, sun exposure, skin type, smoking status, and concurrent antihypertensive usage [ 4 , 7 – 8 ]. An association with melanoma and HCTZ usage alone is not well established [ 1 , 3 ]. This study investigates the age and temporal association between the initiation of HCTZ as monotherapy for HTN and the diagnosis of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma. Methods A multicenter retrospective study was conducted using the TriNetX US Collaborative Network database with six total adult (age > 18) cohorts (1) HTN (ICD10: I10) as control, (2) HTN with HCTZ all dosages, then further stratified by age with, (3) HTN control ages 18 to 49, (4) HTN with HCTZ ages 18 to 49 (5), HTN control ages 50 to 75 (6) HTN with HCTZ ages 50 to 75. All cohorts excluded patients with other antihypertensive drugs, smoking, and history of solid organ transplant to reduce confounding. The study period was from January 1, 2010 to January 1, 2015. Treatment cohorts were required to have 2 instances of HCTZ prescriptions at least 1 year apart within the study period to support treatment compliance. Demographic variables (age, gender, race, and ethnicity) were propensity score matched 1:1 between cohorts (Table 1 ). Cohorts were followed and compared across outcomes assessed of BCC, cSCC, and melanoma at 5- and 10-years following index event (defined as within one year of treatment initiation or diagnosis) with median follow up time recorded. Patients with prior skin cancer were excluded. Risk ratios (RR) with 95% confidence intervals (CI) with p-value < 0.05 as statistically significant. (Table 2 ) Table 1 Demographics of cohorts after propensity score matching with associated standardized difference (std diff). A standardized difference value of 18 (n = 20,911) HTN + HCTZ > 18 (n = 20,911) Std diff. HTN 18–49 (n = 5,656) HTN + HCTZ 18–49 (n = 5,656) Std diff. HTN 50–75 (n = 14,424) HTN + HCTZ 50-75 (n = 14,424) Std diff. Current Age 67.8 +/- 12.4 68.1 +/- 12.0 0.022 52.6 +/- 6.7 52.4 +/- 6.9 0.035 73.1 +/- 6.9 73.1 +/- 6.9 < 0.001 Age at Index 55.8 +/- 12.3 56.1 +/- 11.8 0.024 40.8 +/- 6.6 40.6 +/- 6.6 0.03 61.1 +/- 6.7 61.2 +/- 6.7 0.005 Sex Female 14,810 14,433 0.039 3,918 3,790 0.049 10,336 10,080 0.039 Male 6,100 6,476 0.039 1,738 1,866 0.049 4,085 4,343 0.039 Ethnicity Hispanic or Latino 1,138 1,212 0.015 425 464 0.026 675 735 0.019 Not Hispanic or Latino 15,200 15,217 0.002 4,177 4,114 0.025 10,507 10,503 0.001 Uknown Ethnicity 4,573 4,482 0.011 1,054 1,078 0.011 3,242 3,186 0.009 Race White 13,574 13,809 0.024 2,756 2,875 0.042 10,015 10,125 0.017 Black or African American 4,778 4,633 0.017 2,167 2,054 0.041 2,595 2,625 0.005 Asian 464 511 0.015 120 130 0.012 342 357 0.007 Native Hawaiian or Other Pacific Islander 76 80 0.003 32 33 0.002 40 49 0.011 American Indian or Alaska Native 39 50 0.011 25 25 < 0.001 18 20 0.004 Uknown Race 1,573 1,418 0.029 417 401 0.011 1,152 989 0.043 Other Race 407 410 0.001 139 138 0.001 262 259 0.002 Table 2 Time-stratified risk ratios (RR) of skin cancer associated with hydrochlorothiazide (HCTZ) use by age and cancer type compared to matched controls with untreated hypertension (HTN) in the TriNetX Database. 5-, and 10-year RR estimates with 95% confidence intervals and p-values for total basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma. ICD-10 codes used: BCC (C44.X1), SCC (C44.X2), and melanoma (C43.X, D03.X), where X = 0–9. Smoking (Z87.891, Z72.0), nicotine dependence (F17), history of solid organ transplant (Z94.89) and other antihypertensives were excluded. RxNorm codes for HCTZ and exclusion of HCTZ-related drugs: hydrochlorothiazide (5487), chlorothiazide (2396), hydroflumethiazide (5495), bendroflumethiazide (1369), methyclothiazide (6860), polythiazide (8565), trichlormethiazide (10772). ATC codes used to exclude other classes of antihypertensives: C03AB, C03B, C03C, C03D, C03X, C07, C08, C09A, C09C. Age Cancer 5-Year RR (95% CI) Median follow-up 5 year (days) 10-Year RR (95% CI) Median follow-up 10 year (days) Age > 18 (adult) n = 20,911 BCC Total 2.735 (2.288,3.27) p < 0.0001 1,825 (HCTZ) 1,825 (control) 2.038 (1.814,2.29) p < 0.0001 3,650 (HCTZ) 3,646 (control) cSCC Total 2.234 (1.768,2.823) p < 0.0001 2.19 (1.871,2.562) p < 0.0001 Melanoma Total 1.786 (1.264,2.524) p = 0.0009 1.35 (1.059,1.721) p = 0.0150 Age 18–49 n = 5,656 BCC Total 1.503 (0.799,2.826) p = 0.2031 1,825 (HCTZ) 1,825 (control) 1.962 (1.201,3.203) p = 0.0060 3,650 (HCTZ) 3,593.5 (control) cSCC Total 1.5 (0.674,3.336) p = 0.3168 2.9 (1.415,5.945) p = 0.0023 Melanoma Total 1.002 (0.417,2.405) p = 0.9972 0.751 (0.356,1.586) p = 0.751 Age 50–75 n = 14,424 BCC Total 2.518 (2.089,3.036) p < 0.0001 1,825 (HCTZ) 1,825 (control) 2.332 (2.05,2.652) p < 0.0001 3,650 (HCTZ) 3,650 (control) cSCC Total 2.446 (1.874,3.191) p < 0.0001 2.423 (2.034,2.885) p < 0.0001 Melanoma Total 1.379 (0.962,1.977) p = 0.0788 1.315 (1.006,1.718) p = 0.0442 Results A total of 20,911 adult HCTZ users were identified after matching and controlling for concurrent antihypertensives, smoking, and organ transplant. Increased RR were associated with all three skin cancer types, BCC [RR = 2.735 (2.288, 3.27), p < 0.0001; RR = 2.038 (1.814, 2.29), p < 0.0001], cSCC [RR = 2.234 (1.768, 2.823), p < 0.0001; RR = 2.19 (1.871, 2.562), p < 0.0001], and melanoma [RR = 1.786 (1.264, 2.524), p = 0.0009; RR = 1.35 (1.059, 1.721), p = 0.0150] at 5 and 10 years respectively. Median follow-ups times for these cohorts remained consistent at 1,825 days at 5 years and increased to 3,650 and 3,646 at 10 years for both HCTZ users and controls respectively. Further refining cohorts by those aged 18 to 49, with 5,656 patients, increased RR were observed only for BCC [RR = 1.962 (1.201, 3.203), p = 0.0060] and cSCC [RR = 2.9 (1.415, 5.945), p = 0.0023] at 10 years. There were no statistically significant associations with HCTZ for melanoma at either time point in this cohort or for BCC or cSCC at 5 years. There were 14,424 total patients in the cohort aged 50 to 75 which displayed similar results to the adult cohort with increased RR associated with BCC [RR = 2.518 (2.089, 3.036), p < 0.0001; RR = 2.332 (2.05, 2.652), p < 0.0001] and cSCC [RR = 2.446 (1.874, 3.191), p < 0.0001; RR = 2.423 (2.034, 2.885), p < 0.0001] at 5 and 10 years respectively. Melanoma risk was only significant at 10 years [RR = 1.315 (1.006, 1,718), p = 0.0442]. Discussion The prevalence of HTN varies by demographic with estimates reaching as high as 30% of U.S. adults impacted with chronic therapy often including diuretics as mono or combination therapy [ 2 , 5 ]. Prior research has demonstrated enhanced DNA damage and impaired DNA repair associated with HCTZ photosensitivity [ 6 ]. The use of HCTZ resulted in an increased risk of NMSC, namely BCC and cSCC in a Danish population-based study [ 8 ]. Additionally, an FDA Sentinel Initiative Study reported that cSCC has been reported to increase by one case per 16,000 patients per year among patients taking HCTZ [ 9 ]. In our study, evaluating an association of HCTZ use overall with BCC, cSCC, and melanoma without controlling for dosage or age, an association was noted at 5 and 10 years for BCC and cSCC, with less of an association noted with melanoma at 10 years. This association was consistently observed after controlling for smoking, history of solid organ transplant, and use of other antihypertensive medications. Prior studies suggest that cumulative HCTZ exposure is associated with an increased risk of skin cancer, particularly at longer durations and higher total doses, especially those ≥ 100,000 mg [ 1 , 3 ]. In our study, further refining cohorts by age revealed no significant associations with HCTZ and BCC, cSCC or melanoma in those aged 18 to 49 at 5 years while a notable association was found in the cohort age 50 to 75 specifically for BCC and cSCC at 5 years and with BCC, cSCC, and melanoma at 10 years. Although cumulative dosages in these cohorts cannot be confirmed based on the data available, comparing age cohorts suggests that advanced age at longer follow-up times was more consistently associated with significant RR values. Few studies have examined the relationship between HCTZ and melanoma. One found cumulative dosage of more than 50,000 mg of HCTZ with higher risk of melanoma, specifically for lentigo maligna and possibly nodular subtypes and less so for the superficial spreading subtype of melanoma. These patterns emphasize a possible role for photosensitivity [ 3 ]. In our study, a slight association with melanoma was observed overall at 10 years with further age refinement demonstrating the association in the cohort aged 50 to 75. These findings suggest that cumulative actinic damage and other comorbidities potentially associated with age may play a stronger role in melanoma development, with longer durations of HCTZ exposure possibly escalating this risk. The limitations of this study include the inherent challenges of using coding data from the TriNetX US Collaborative Network database and its retrospective design. This database allows for accessing data related to prescriptions written but cannot confirm medication compliance or specific dosing. To address this challenge, cohorts were refined to require HCTZ prescriptions to have been written within 1 year of each other and occurring at least twice within the 5 years of the study period. Confounding variables were reduced by excluding concurrent anti-hypertensive medication use, smoking, and through a 1:1 propensity score match for cohorts based on age, gender, race, and ethnicity. Additionally, although a detection bias may be present as those that carry a diagnosis of hypertension without taking antihypertensive medications may have less access or interaction with the healthcare system which could in turn affect the reported incidence of skin cancer in the control cohort [ 1 ]. To control this confounder, mean follow-up times were assessed which were consistent between control and medication cohorts to ensure some level of healthcare access consistency. Future studies are needed to investigate the potential effects of other photosensitizing drugs in combination with HCTZ usage as well as sun exposure, sunscreen use, family history, and medication adherence or dosing to gauge cumulative dose. Conclusion This study adds clarity to the association of HCTZ use and non-melanoma skin cancer, noting a stronger relationship in individuals aged 50 to 75. Longer follow-up times further reveal an association with melanoma in this age group. These findings can help clinicians identify higher risk patients to guide skin cancer screening recommendations, especially for those over the age of 50. Statements and Declarations Author Contribution T.M. wrote the main manuscript text and prepared table 2. E.I. provided edits and data interpretation. C.O. assisted in editing and writing of the introduction and discussion as well as prepared table 1. All authors reviewed the manuscript. Funding Sources: None Conflict of Interest: The authors declare that they have no conflict of interest. References Azoulay L, St-Jean A, Dahl M, Quail J, Aibibula W, Brophy JM, Chan AW, Bresee L, Carney G, Eltonsy S, Tamim H, Paterson JM, Platt RW; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators (2023) Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study. J Am Acad Dermatol 89(2):243–253. https://doi.org/10.1016/j.jaad.2023.04.035 Derington CG, King JB, Herrick JS, Shimbo D, Kronish IM, Saseen JJ, Muntner P, Moran AE, Bress AP (2020) Trends in antihypertensive medication monotherapy and combination use among US adults, National Health and Nutrition Examination Survey 2005–2016. Hypertension 75(4):973–981. https://doi.org/10.1161/HYPERTENSIONAHA.119.14360 Habel LA, Achacoso N, Fireman B, Pedersen SA, Pottegård A (2021) Hydrochlorothiazide and risk of melanoma subtypes. Pharmacoepidemiol Drug Saf 30(10):1396–1401. https://doi.org/10.1002/pds.5266 Heisel AGU, Vuurboom MD, Daams JG, de Rie MA, Vogt L, van den Born BH, Olde Engberink RHG (2023) The use of specific antihypertensive medication and skin cancer risk: A systematic review of the literature and meta-analysis. Vascul Pharmacol 150:107173. https://doi.org/10.1016/j.vph.2023.107173 Khalid N, Haider S, Hasnat M, Abdullah M, Asghar S, Shamoon Y, Elkattawy S, Vasudev R, Fayez SE (2024) Trends and disparities in prevalence of diagnosed hypertension among U.S. adults from 2019 to 2022. Curr Probl Cardiol 49(10):102750. https://doi.org/10.1016/j.cpcardiol.2024.102750 Kunisada M, Masaki T, Ono R, Morinaga H, Nakano E, Yogianti F, Okunishi K, Sugiyama H, Nishigori C (2013) Hydrochlorothiazide enhances UVA-induced DNA damage. Photochem Photobiol 89(3):649–654. https://doi.org/10.1111/php.12048 Nochaiwong S, Chuamanochan M, Ruengorn C, Noppakun K, Awiphan R, Phosuya C, Tovanabutra N, Chiewchanvit S, Sood MM, Hutton B, Thavorn K, Knoll GA (2022) Use of thiazide diuretics and risk of all types of skin cancers: An updated systematic review and meta-analysis. Cancers (Basel) 14(10):2566. https://doi.org/10.3390/cancers14102566 Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S, Pottegård A (2018) Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol 78(4):673–681.e9. https://doi.org/10.1016/j.jaad.2017.11.042 U.S. Food and Drug Administration (2020) FDA approves label changes to hydrochlorothiazide to describe small risk of non-melanoma skin cancer. U.S. Food and Drug Administration. Available via FDA website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-label-changes-hydrochlorothiazide-describe-small-risk-non-melanoma-skin-cancer. Accessed 7 Aug 2025 Additional Declarations No competing interests reported. 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Although some studies show such associations, the conflicting reports supporting evidence regarding the medication\u0026rsquo;s increased risks are limited by concerns over controlling for confounding variables, such as age, dosage, sun exposure, skin type, smoking status, and concurrent antihypertensive usage [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. An association with melanoma and HCTZ usage alone is not well established [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. This study investigates the age and temporal association between the initiation of HCTZ as monotherapy for HTN and the diagnosis of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA multicenter retrospective study was conducted using the TriNetX US Collaborative Network database with six total adult (age\u0026thinsp;\u0026gt;\u0026thinsp;18) cohorts (1) HTN (ICD10: I10) as control, (2) HTN with HCTZ all dosages, then further stratified by age with, (3) HTN control ages 18 to 49, (4) HTN with HCTZ ages 18 to 49 (5), HTN control ages 50 to 75 (6) HTN with HCTZ ages 50 to 75.\u003c/p\u003e\u003cp\u003eAll cohorts excluded patients with other antihypertensive drugs, smoking, and history of solid organ transplant to reduce confounding. The study period was from January 1, 2010 to January 1, 2015. Treatment cohorts were required to have 2 instances of HCTZ prescriptions at least 1 year apart within the study period to support treatment compliance.\u003c/p\u003e\u003cp\u003eDemographic variables (age, gender, race, and ethnicity) were propensity score matched 1:1 between cohorts (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cohorts were followed and compared across outcomes assessed of BCC, cSCC, and melanoma at 5- and 10-years following index event (defined as within one year of treatment initiation or diagnosis) with median follow up time recorded. Patients with prior skin cancer were excluded. Risk ratios (RR) with 95% confidence intervals (CI) with p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 as statistically significant. (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e)\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographics of cohorts after propensity score matching with associated standardized difference (std diff). A standardized difference value of \u0026lt;\u0026thinsp;0.1 indicates good balance between the cohorts.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eHTN\u0026thinsp;\u0026gt;\u0026thinsp;18\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20,911)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHTN\u0026thinsp;+\u0026thinsp;HCTZ\u0026thinsp;\u0026gt;\u0026thinsp;18\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20,911)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStd\u003c/p\u003e\u003cp\u003ediff.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eHTN 18\u0026ndash;49\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;5,656)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eHTN\u0026thinsp;+\u0026thinsp;HCTZ 18\u0026ndash;49\u003c/p\u003e\u003cp\u003e (n\u0026thinsp;=\u0026thinsp;5,656)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eStd\u003c/p\u003e\u003cp\u003ediff.\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eHTN 50\u0026ndash;75\u003c/p\u003e\u003cp\u003e(n\u0026thinsp;=\u0026thinsp;14,424)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eHTN\u0026thinsp;+\u0026thinsp;HCTZ\u003c/p\u003e\u003cp\u003e50-75\u003c/p\u003e\u003cp\u003e (n\u0026thinsp;=\u0026thinsp;14,424)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eStd\u003c/p\u003e\u003cp\u003ediff.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCurrent Age\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e67.8 +/- 12.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e68.1 +/- 12.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e52.6 +/- 6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e52.4 +/- 6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.035\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e73.1 +/- 6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e73.1 +/- 6.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at Index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e55.8 +/- 12.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.1 +/- 11.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e40.8 +/- 6.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e40.6 +/- 6.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e61.1 +/- 6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e61.2 +/- 6.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFemale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14,810\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14,433\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e3,918\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e3,790\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10,336\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10,080\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6,100\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6,476\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,738\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,866\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.049\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e4,085\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e4,343\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEthnicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHispanic or Latino\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,138\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,212\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e425\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e464\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e675\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e735\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNot Hispanic or Latino\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15,200\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15,217\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e4,177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e4,114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10,507\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10,503\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUknown Ethnicity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,573\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,482\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1,054\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1,078\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e3,242\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3,186\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.009\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRace\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13,574\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e13,809\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.024\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2,756\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2,875\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e10,015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e10,125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBlack or African American\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4,778\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4,633\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2,167\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2,054\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.041\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2,595\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2,625\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAsian\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e464\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e511\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e342\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e357\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.007\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNative Hawaiian or Other Pacific Islander\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAmerican Indian or Alaska Native\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eUknown Race\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1,573\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1,418\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.029\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e417\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e401\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1,152\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e989\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOther Race\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e407\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e410\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e139\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e138\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e262\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e259\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.002\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eTime-stratified risk ratios (RR) of skin cancer associated with hydrochlorothiazide (HCTZ) use by age and cancer type compared to matched controls with untreated hypertension (HTN) in the TriNetX Database. 5-, and 10-year RR estimates with 95% confidence intervals and p-values for total basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma. ICD-10 codes used: BCC (C44.X1), SCC (C44.X2), and melanoma (C43.X, D03.X), where X\u0026thinsp;=\u0026thinsp;0\u0026ndash;9. Smoking (Z87.891, Z72.0), nicotine dependence (F17), history of solid organ transplant (Z94.89) and other antihypertensives were excluded. RxNorm codes for HCTZ and exclusion of HCTZ-related drugs: hydrochlorothiazide (5487), chlorothiazide (2396), hydroflumethiazide (5495), bendroflumethiazide (1369), methyclothiazide (6860), polythiazide (8565), trichlormethiazide (10772). ATC codes used to exclude other classes of antihypertensives: C03AB, C03B, C03C, C03D, C03X, C07, C08, C09A, C09C.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"6\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCancer\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5-Year RR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMedian follow-up 5 year (days)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10-Year RR (95% CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMedian follow-up 10 year (days)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eAge\u0026thinsp;\u0026gt;\u0026thinsp;18 (adult)\u003c/p\u003e\u003cp\u003e n\u0026thinsp;=\u0026thinsp;20,911\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.735 (2.288,3.27)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1,825 (HCTZ)\u003c/p\u003e\u003cp\u003e1,825 (control)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.038 (1.814,2.29)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e3,650 (HCTZ)\u003c/p\u003e\u003cp\u003e3,646 (control)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ecSCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.234 (1.768,2.823)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.19 (1.871,2.562)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMelanoma\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.786 (1.264,2.524)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0009\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.35 (1.059,1.721)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0150\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eAge 18\u0026ndash;49\u003c/p\u003e\u003cp\u003e n\u0026thinsp;=\u0026thinsp;5,656\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.503 (0.799,2.826)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.2031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1,825 (HCTZ)\u003c/p\u003e\u003cp\u003e1,825 (control)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.962 (1.201,3.203)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0060\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e3,650 (HCTZ) \u003c/p\u003e\u003cp\u003e3,593.5 (control)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ecSCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.5 (0.674,3.336)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.3168\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.9 (1.415,5.945)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0023\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMelanoma\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.002 (0.417,2.405)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.9972\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.751 (0.356,1.586) p\u0026thinsp;=\u0026thinsp;0.751\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eAge 50\u0026ndash;75\u003c/p\u003e\u003cp\u003e n\u0026thinsp;=\u0026thinsp;14,424\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eBCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.518 (2.089,3.036)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1,825 (HCTZ)\u003c/p\u003e\u003cp\u003e1,825 (control)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.332 (2.05,2.652)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e3,650 (HCTZ)\u003c/p\u003e\u003cp\u003e3,650 (control)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ecSCC\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.446 (1.874,3.191)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e2.423 (2.034,2.885)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eMelanoma\u003c/p\u003e\u003cp\u003e Total\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.379 (0.962,1.977)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0788\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.315 (1.006,1.718)\u003c/p\u003e\u003cp\u003e p\u0026thinsp;=\u0026thinsp;0.0442\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 20,911 adult HCTZ users were identified after matching and controlling for concurrent antihypertensives, smoking, and organ transplant. Increased RR were associated with all three skin cancer types, BCC [RR\u0026thinsp;=\u0026thinsp;2.735 (2.288, 3.27), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; RR\u0026thinsp;=\u0026thinsp;2.038 (1.814, 2.29), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001], cSCC [RR\u0026thinsp;=\u0026thinsp;2.234 (1.768, 2.823), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; RR\u0026thinsp;=\u0026thinsp;2.19 (1.871, 2.562), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001], and melanoma [RR\u0026thinsp;=\u0026thinsp;1.786 (1.264, 2.524), p\u0026thinsp;=\u0026thinsp;0.0009; RR\u0026thinsp;=\u0026thinsp;1.35 (1.059, 1.721), p\u0026thinsp;=\u0026thinsp;0.0150] at 5 and 10 years respectively. Median follow-ups times for these cohorts remained consistent at 1,825 days at 5 years and increased to 3,650 and 3,646 at 10 years for both HCTZ users and controls respectively.\u003c/p\u003e\u003cp\u003eFurther refining cohorts by those aged 18 to 49, with 5,656 patients, increased RR were observed only for BCC [RR\u0026thinsp;=\u0026thinsp;1.962 (1.201, 3.203), p\u0026thinsp;=\u0026thinsp;0.0060] and cSCC [RR\u0026thinsp;=\u0026thinsp;2.9 (1.415, 5.945), p\u0026thinsp;=\u0026thinsp;0.0023] at 10 years. There were no statistically significant associations with HCTZ for melanoma at either time point in this cohort or for BCC or cSCC at 5 years.\u003c/p\u003e\u003cp\u003eThere were 14,424 total patients in the cohort aged 50 to 75 which displayed similar results to the adult cohort with increased RR associated with BCC [RR\u0026thinsp;=\u0026thinsp;2.518 (2.089, 3.036), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; RR\u0026thinsp;=\u0026thinsp;2.332 (2.05, 2.652), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] and cSCC [RR\u0026thinsp;=\u0026thinsp;2.446 (1.874, 3.191), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; RR\u0026thinsp;=\u0026thinsp;2.423 (2.034, 2.885), p\u0026thinsp;\u0026lt;\u0026thinsp;0.0001] at 5 and 10 years respectively. Melanoma risk was only significant at 10 years [RR\u0026thinsp;=\u0026thinsp;1.315 (1.006, 1,718), p\u0026thinsp;=\u0026thinsp;0.0442].\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe prevalence of HTN varies by demographic with estimates reaching as high as 30% of U.S. adults impacted with chronic therapy often including diuretics as mono or combination therapy [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Prior research has demonstrated enhanced DNA damage and impaired DNA repair associated with HCTZ photosensitivity [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. The use of HCTZ resulted in an increased risk of NMSC, namely BCC and cSCC in a Danish population-based study [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, an FDA Sentinel Initiative Study reported that cSCC has been reported to increase by one case per 16,000 patients per year among patients taking HCTZ [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In our study, evaluating an association of HCTZ use overall with BCC, cSCC, and melanoma without controlling for dosage or age, an association was noted at 5 and 10 years for BCC and cSCC, with less of an association noted with melanoma at 10 years. This association was consistently observed after controlling for smoking, history of solid organ transplant, and use of other antihypertensive medications.\u003c/p\u003e\u003cp\u003ePrior studies suggest that cumulative HCTZ exposure is associated with an increased risk of skin cancer, particularly at longer durations and higher total doses, especially those\u0026thinsp;\u0026ge;\u0026thinsp;100,000 mg [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our study, further refining cohorts by age revealed no significant associations with HCTZ and BCC, cSCC or melanoma in those aged 18 to 49 at 5 years while a notable association was found in the cohort age 50 to 75 specifically for BCC and cSCC at 5 years and with BCC, cSCC, and melanoma at 10 years. Although cumulative dosages in these cohorts cannot be confirmed based on the data available, comparing age cohorts suggests that advanced age at longer follow-up times was more consistently associated with significant RR values.\u003c/p\u003e\u003cp\u003eFew studies have examined the relationship between HCTZ and melanoma. One found cumulative dosage of more than 50,000 mg of HCTZ with higher risk of melanoma, specifically for lentigo maligna and possibly nodular subtypes and less so for the superficial spreading subtype of melanoma. These patterns emphasize a possible role for photosensitivity [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In our study, a slight association with melanoma was observed overall at 10 years with further age refinement demonstrating the association in the cohort aged 50 to 75. These findings suggest that cumulative actinic damage and other comorbidities potentially associated with age may play a stronger role in melanoma development, with longer durations of HCTZ exposure possibly escalating this risk.\u003c/p\u003e\u003cp\u003eThe limitations of this study include the inherent challenges of using coding data from the TriNetX US Collaborative Network database and its retrospective design. This database allows for accessing data related to prescriptions written but cannot confirm medication compliance or specific dosing. To address this challenge, cohorts were refined to require HCTZ prescriptions to have been written within 1 year of each other and occurring at least twice within the 5 years of the study period. Confounding variables were reduced by excluding concurrent anti-hypertensive medication use, smoking, and through a 1:1 propensity score match for cohorts based on age, gender, race, and ethnicity. Additionally, although a detection bias may be present as those that carry a diagnosis of hypertension without taking antihypertensive medications may have less access or interaction with the healthcare system which could in turn affect the reported incidence of skin cancer in the control cohort [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. To control this confounder, mean follow-up times were assessed which were consistent between control and medication cohorts to ensure some level of healthcare access consistency. Future studies are needed to investigate the potential effects of other photosensitizing drugs in combination with HCTZ usage as well as sun exposure, sunscreen use, family history, and medication adherence or dosing to gauge cumulative dose.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis study adds clarity to the association of HCTZ use and non-melanoma skin cancer, noting a stronger relationship in individuals aged 50 to 75. Longer follow-up times further reveal an association with melanoma in this age group. These findings can help clinicians identify higher risk patients to guide skin cancer screening recommendations, especially for those over the age of 50.\u003c/p\u003e"},{"header":"Statements and Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eT.M. wrote the main manuscript text and prepared table 2. E.I. provided edits and data interpretation. C.O. assisted in editing and writing of the introduction and discussion as well as prepared table 1. All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003eFunding Sources: None\u003c/p\u003e\n\u003cp\u003eConflict of Interest: The authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAzoulay L, St-Jean A, Dahl M, Quail J, Aibibula W, Brophy JM, Chan AW, Bresee L, Carney G, Eltonsy S, Tamim H, Paterson JM, Platt RW; Canadian Network for Observational Drug Effect Studies (CNODES) Investigators (2023) Hydrochlorothiazide use and risk of keratinocyte carcinoma and melanoma: A multisite population-based cohort study. \u003cem\u003eJ Am Acad Dermatol\u003c/em\u003e 89(2):243\u0026ndash;253. https://doi.org/10.1016/j.jaad.2023.04.035\u003c/li\u003e\n\u003cli\u003eDerington CG, King JB, Herrick JS, Shimbo D, Kronish IM, Saseen JJ, Muntner P, Moran AE, Bress AP (2020) Trends in antihypertensive medication monotherapy and combination use among US adults, National Health and Nutrition Examination Survey 2005\u0026ndash;2016. \u003cem\u003eHypertension\u003c/em\u003e 75(4):973\u0026ndash;981. https://doi.org/10.1161/HYPERTENSIONAHA.119.14360\u003c/li\u003e\n\u003cli\u003eHabel LA, Achacoso N, Fireman B, Pedersen SA, Potteg\u0026aring;rd A (2021) Hydrochlorothiazide and risk of melanoma subtypes. \u003cem\u003ePharmacoepidemiol Drug Saf\u003c/em\u003e 30(10):1396\u0026ndash;1401. https://doi.org/10.1002/pds.5266\u003c/li\u003e\n\u003cli\u003eHeisel AGU, Vuurboom MD, Daams JG, de Rie MA, Vogt L, van den Born BH, Olde Engberink RHG (2023) The use of specific antihypertensive medication and skin cancer risk: A systematic review of the literature and meta-analysis. \u003cem\u003eVascul Pharmacol\u003c/em\u003e 150:107173. https://doi.org/10.1016/j.vph.2023.107173\u003c/li\u003e\n\u003cli\u003eKhalid N, Haider S, Hasnat M, Abdullah M, Asghar S, Shamoon Y, Elkattawy S, Vasudev R, Fayez SE (2024) Trends and disparities in prevalence of diagnosed hypertension among U.S. adults from 2019 to 2022. \u003cem\u003eCurr Probl Cardiol\u003c/em\u003e 49(10):102750. https://doi.org/10.1016/j.cpcardiol.2024.102750\u003c/li\u003e\n\u003cli\u003eKunisada M, Masaki T, Ono R, Morinaga H, Nakano E, Yogianti F, Okunishi K, Sugiyama H, Nishigori C (2013) Hydrochlorothiazide enhances UVA-induced DNA damage. \u003cem\u003ePhotochem Photobiol\u003c/em\u003e 89(3):649\u0026ndash;654. https://doi.org/10.1111/php.12048\u003c/li\u003e\n\u003cli\u003eNochaiwong S, Chuamanochan M, Ruengorn C, Noppakun K, Awiphan R, Phosuya C, Tovanabutra N, Chiewchanvit S, Sood MM, Hutton B, Thavorn K, Knoll GA (2022) Use of thiazide diuretics and risk of all types of skin cancers: An updated systematic review and meta-analysis. \u003cem\u003eCancers (Basel)\u003c/em\u003e 14(10):2566. https://doi.org/10.3390/cancers14102566\u003c/li\u003e\n\u003cli\u003ePedersen SA, Gaist D, Schmidt SAJ, H\u0026ouml;lmich LR, Friis S, Potteg\u0026aring;rd A (2018) Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. \u003cem\u003eJ Am Acad Dermatol\u003c/em\u003e 78(4):673\u0026ndash;681.e9. https://doi.org/10.1016/j.jaad.2017.11.042\u003c/li\u003e\n\u003cli\u003eU.S. Food and Drug Administration (2020) FDA approves label changes to hydrochlorothiazide to describe small risk of non-melanoma skin cancer. U.S. Food and Drug Administration. Available via FDA website: https://www.fda.gov/drugs/drug-safety-and-availability/fda-approves-label-changes-hydrochlorothiazide-describe-small-risk-non-melanoma-skin-cancer. Accessed 7 Aug 2025\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"hydrochlorothiazide, skin cancer, antihypertensives, squamous cell carcinoma, basal cell carcinoma, melanoma","lastPublishedDoi":"10.21203/rs.3.rs-7538065/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7538065/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Hydrochlorothiazide (HCTZ) is known to have photosensitizing properties with recent FDA labeling updates warning of its increased risk of nonmelanoma skin cancer (NMSC). There are few and at times conflicting studies in the current literature on the topic, in particular with regard to melanoma associations and significant confounders. This retrospective cohort study utilizing the TriNetX database investigates age and temporal associations between the initiation of HCTZ as monotherapy for hypertension (HTN) and the diagnosis of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma. Six adult (age \u003e18) cohorts were created with (1) HTN (ICD10: I10) as control and (2) HTN with HCTZ; then further stratified by age from 18 to 49 and 50 to 75. Outcomes assessed were BCC, cSCC, and melanoma at 5 and 10 years. HCTZ usage in cohorts aged 50 to 75 years old was significantly (p\u003c0.05) associated with an increased risk ratio of BCC and cSCC at 5 and 10 years and with melanoma only at 10 years. This study refines prior reports of HCTZ usage associated with development of BCC and cSCC particularly in older adults while controlling for confounders such as concurrent antihypertensives and smoking. The association with melanoma in the older aged cohorts and with longer durations of HCTZ usage suggests a role for cumulative actinic damage among other risk factors. We highlight the need for increased dermatological surveillance and counseling among this vulnerable population, especially for those over the age of 50 on sustained HCTZ therapy. ","manuscriptTitle":"Stratified Temporal Risk of Skin Cancer by Age Associated with Hydrochlorothiazide: A Retrospective Cohort Study Using the TriNetX Database","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-20 01:48:42","doi":"10.21203/rs.3.rs-7538065/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-05T22:00:46+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-03T22:17:37+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"138247632589665450821297481725320853478","date":"2026-02-01T15:52:05+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"87367261809492228759020040496894860957","date":"2026-01-29T21:40:31+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-28T20:53:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"129467287563575605743957833540364575300","date":"2026-01-28T20:45:08+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"8822296386785639784127188827666308330","date":"2026-01-08T00:10:30+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-14T03:55:34+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-04T21:16:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"38424892214405975698343085268408819028","date":"2025-12-04T20:19:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"218767142785090866184836592177061956373","date":"2025-12-03T04:04:10+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-10T16:52:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-05T09:05:50+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-05T09:05:47+00:00","index":"","fulltext":""},{"type":"submitted","content":"Archives of Dermatological Research","date":"2025-09-04T16:25:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"archives-of-dermatological-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Archives of Dermatological Research](https://www.springer.com/journal/403)","snPcode":"403","submissionUrl":"https://submission.nature.com/new-submission/403/3","title":"Archives of Dermatological Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"efa37f7b-cdb0-48c7-b4fd-d60bb80a0275","owner":[],"postedDate":"November 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T22:23:17+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-20 01:48:42","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7538065","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7538065","identity":"rs-7538065","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}