Skin Cancer Associated with Using Thiazides in Hypertensive Patients

Skin cancer associated with using thiazides in hypertensive patients

Supervisor: Elko Hak and Bob Wilffert

Student: Moustafa Naasan

Medical Pharmaceutical Sciences Master

Pharmacoepidemiology and Pharmacoeconomics department - Groningen University

Table of contents

Abstract …………………………………………. 3

Background ………………………………………4 1. Thiazide diuretics and Hypertension 2. Thiazide diuretics in Nephrolithiasis 3. Chemical structure and diuretic mechanism 4. Chlorthalidone is superior to Hydrochlorothiazide 5. Thiazide diuretics and skin cancer

Methods………………………………………….6 1. Data collection 2. Inclusion and exclusion criteria

Results……………………………………………7 1. Prisma diagram 2. Table 1 3. Table 2

Discussion……………………………………….10

Conclusion………………………………………10

References………………………………………11

Abstract

Purpose: This study investigated the association between using thiazides diuretics in hypertensive patients and the potential risk of several types of skin cancer including non-melanoma skin cancer (NMSC), basal cell carcinoma (BCC), squamous cell carcinoma (SCC), merkel cell carcinoma (MCC), Lip cancer, malignant melanoma and malignant adnexal skin tumors (MAST).

Methods: All records found regarding the correlation between thiazide diuretcis and skin cancer were collected and scanned from our data source PubMed after applying inclusion and exclusion criteria.

Results: Pedersen et al reported adjusted odd ratios for merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST) correlated with high use (≥50,000 mg) of hydrochlorothiazide were 2.3 and 3.6, respectively. These results increased to 3.3 for MCC and 5.6 for MAST when higher doses were applied (≥100,000 mg). Pottegard et al has found that thiazide diuretics was associated with an increased risk of squamous cell carcinoma (SCC), [adjusted odds ratio (aOR), 1.86; 95% confidence interval (CI), 1.23–2.80] and slightly increased risk of basal cell carcinoma (BCC) (aOR,1.19; 95% CI, 1.02–1.38). Kreutz et reported in their 6 studies [two studies suggested increased risk of malignant melanoma by (17% and 32%)], [two studies suggested increased risk of squamous cell carcinoma by (58% and 75%)] and [two studies suggested increased risk of lip cancer by (110% and 119%). Mayne and Colleagues reported that 95% of lip cancers are squamous cell carcinoma (SCC) and they found that hydrochlorothiazide (HCTZ) has a strong association with lip cancer (147 cases and RR 2.29) [1.84-2.86] p<0.001 and other types of skin cancer (95 cases RR 1.56 [1.2-2.01] p=0.001. Humbert et al reported an association between using hydrochlorothiazide (HCTZ) and risk of squamous cell carcinoma (SCC) with an odds ratio (OR) of 2.86 (95% confidence interval, 2.11-3.89). Moreover, they found an equal association between hydrochlorothiazide (HCTZ) and basal cell carcinoma (BCC) with an odds ratio (OR) of 2.85 (95% confidence interval, 2.23-3.63) in addition to other thiazide diuretics and both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC).

Conclusions: There is a strong association between using hydrochlorothiazide (HCTZ) and occurrence of various types of skin cancer, which makes thiazides less preferable drugs to mange hypertension unlike the fact that they have always been the first and cheapest available drug choices to manage hypertension. Moreover, combination between thiazides and other antihypertensive drugs to treat hypertension in addition to reducing thiazides doses might be helpful to overcome this problem.

Background Thiazide diuretics and Hypertension

Since their discovery, thiazides have been commonly used as a part of managing large-scale hypertension clinical trials and are undoubtedly effective in enhancing the outcomes of patients with hypertension [5]. Additionally, thiazides always have been recommended as a first drug choice for managing most hypertensive patients as mentioned in all major recent guidelines [9,10]. Thiazides are usually used as add-on therapy to other antihypertensive agents [5].

Although, thiazide diuretics are most prescribed in hypertensive patients as well as other diuretics or antihypertension drugs, diuretics are no longer considered to be the best drugs for hypertension, they still in use as an acceptable first-line drugs [18]. Thiazides diuretics are recommended in the current adult guidelines for the management of hypertension [19-20]. Additionally, they are considered as one of the various preferred available agents to treat hypertension.

The effectiveness of using thiazide diuretics to prevent all sorts of cardiovascular morbidities and mortality has been proven in RCTs and meta-analyses [27]. Thiazide diuretics are usually prescribed as a fixed-dose combination with other antihypertensive drugs (angiotensin-converting enzyme inhibitors/ angiotensin receptor blockers, calcium channel blockers) to manage hypertension or with other types of diuretics (such as amiloride and spironolactone) to treat oedema and congestive heart failure (CHF) [28]

In hypertension management with chronic kidney disease (CKD) and proteinuria, including black patients ACE inhibitor or ARB considered to be first-line drugs in added to a diuretic agent if the targeted blood pressure is not reached [19]. Thiazides diuretics are preferred in the case of primary hypertension unless there is a non-thiazide diuretic preferred in such a case.

In some cases when hypertension is associated with advanced CKD, acute glomerulonephritis, oliguric acute kidney injury (AKI), hyperaldosteronism, heart failure, ENaC mutations and drug resistance a non-thiazide diuretic might be an option [18]. When thiazides are not the first option in management of primary hypertension, they are more likely to be added on the antihypertensive regimen when blood pressure targets are not achieved with initial selected drug [18].

Thiazides diuretics represent a flat to shallow dose-response curve which means that there is a slight difference between the blood pressure reduction observed at the lowest and highest effective dose [18]. The recommended dose of hydrochlorothiazide is 25 mg/day which is the lowest dose to achieve maximal blood pressure reduction in primary hypertension [19]. Interestingly, blood pressure reduction when thiazides diuretics are used occurs slowly mainly between 4-6 weeks [21,22]. In some cases, it might take up to 12 weeks to achieve the complete blood pressure reduction [22].

Using thiazides is often correspondent to several metabolic side effect such as Hypokalemia, hyperglycemia, hyperlipidemia, hyperuricemia, and hypomagnesemia. All previously mentioned side effects are dose dependent. Therefore, keeping the dose used under safety margins is extremely important to achieve maximal blood pressure reduction and enhancing CV outcomes with minimal side effects [11] Thiazide diuretics in Nephrolithiasis

Lamberg and Kuhlback found in the fifties of last century that chlorothiazide (dosed 1 g b.i.d) and hydrochlorothiazide (dosed 100 mg b.i.d) decreased urinary calcium excretion [6]. Lichtwitz

4 proposed that this mechanism can be exploited to prevent calcium-containing renal stone recurrence [7]. In 1970 in uncontrolled studies, Yendt reported decreased renal stone recurrence rates using hydrochlorothiazide in doses between 100 mg o.d. and 100 b.i.d [8]. However, we will focus in this review on using thiazides diuretics only in hypertensive patients.

Chemical structure and diuretic mechanism

Thiazides were discovered in 1950s and the first approved drug of this class was chlorothiazide with a chemical structure illustrated in Figure 1 [3]. Those drugs considered to be the cheapest antihypertensive agents [4]. Thiazides main indications are hypertension, nephrolithiasis [5] and edema caused by water retention or certain conditions associated with unbalanced calcium metabolism [1].The diuretic effect of the Thiazide-like diuretics takes place via binding and inhibiting Na-Cl cotransporter in the distal convoluted tubule and connecting tubule [5].

For most thiazide diuretics the onset of action ranges between two to three hours, with slight natriuretic effect which takes place beyond six hours [2]. The differences in pharmacokinetics of different thiazides, and hydrochlorothiazide (HCTZ) is explained by difference of their bioavailability and half-lives. Hydrochlorothiazide owns the best drug profile and was selected as a standard thiazide to treat hypertension. It has half-life between eight and twelve hours which makes it preferable choice for once daily doses among other members from its drug class [32].

Figure 1 (Chemical structure of Chlorothiazide sodium) [1]

Chlorthalidone is characterized by a long-acting effect with a half-life of 50 to 60 hours and twice as potent as hydrochlorothiazide [32]. Reductions in extracellular fluid and plasma volumes are responsible for the initial decrease in blood pressure. The overall reduction in systemic resistance result in the continued lowering antihypertensive effects [32].

Chlorthalidone is superior to Hydrochlorothiazide

The data from Multiple Risk Factor Intervention Trial (MRFIT) proposed that chlorthalidone might have more benefits in decreasing mortality rates over hydrochlorothiazide [32]. In the

Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), conducted between 1994 and 2002 in order to compare between the effect of three dug classes diuretics (chlorthalidone), Ca blocker (CCB-amlodipine) and ACE-inhibitor (lisinopril) on CV patients. The results demonstrated that thiazide –type diuretic was superior in preventing major forms of cardiovascular disease [33]. Thiazide diuretics and skin cancer

Drug-induced photosensitivity is explained by the ability of some drugs to modify a patient’s sensitivity to solar radiation or or artificial light [12,13]. Unfortunately, photosensitivity reactions are occurring more frequently in dermatology. Although new drugs are well tested before they enter the pharmaceutical market, new reports of photosensitivity reactions are yet increasing [12,14].

Not surprisingly, skin cancer incidence keeps increasing due to ultraviolet radiation exposure as a known cause [15,16] Studies suggest that there is a correlation between exposure to thiazides and occurrence of , basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM) while the underlying mechanism remain unclear [17].

Studies suggests that a photosensitising reaction followed by sun exposure may increase the risk of sunburns which increase the risk of skin cancers [23]. The mechanism of drug-induced photosensitivity that results in skin cancer is well-understood and it implies psoralens combined with ultraviolet light-A (PUVA) therapy, which also increase the risk of getting squamous cell carcinoma (SCC) [24,25,26]. HCTZ owns a chlorine substituent which dissociates upon its exposure to ultraviolet radiations, leading to formation of free radical that cause DNA damage [39].

Another type of skin cancer known as non-melanoma skin cancer (NMSC) is the most common cancer in humans, with an increasing incidence especially among elderly [29]. Ultraviolet (UV) exposure and UV-susceptible skin phenotype have been known to be crucial risk factors for NMSC [30]. There was a strong association between using hydrochlorothiazide (HCTZ) and the incidence of squamous cell carcinoma (SCC) of the lip [31] when 100,000 mg or more of cumulative use of HCTZ takes place [30].

Several studies suggest that hydrochlorothiazide is slightly associated with increased risk of basal cell carcinoma (BCC) [34] and potentially other melanoma subtypes [35]. Based on that data, hydrochlorothiazide is classified as ‘possibly carcinogenic to humans’ (Group 2B) by the International Agency for Research on Cancer (IARC) in 2013 [36,37].The carcinogenic effect is explained by photosensitizing properties of HCTZ which increase the patients vulnerability to ultraviolet radiation (UVR)- induced DNA damage [38].

The aim of this study is to investigate the association between exposure to thiazides as antihypertensive agents and the occurrence of different types of skin cancer.

Methods

Data collection

The main source of data was PubMed using MeSH terms for “thiazides “, “diuretics, thiazide” , “bendroflumethiazide “, “hydrochlorothiazide “, “chlorothiazide”, “indapamide”, “chlortalidone”, “skin neoplasms”, “basal cell carcinoma”, “malignant melanoma”, “squamous cell carcinoma”, “merkel cell carcinoma”, “ nonmelanoma skin cancer “or “skin cancer”.

Study domain was hypertensive adults. We searched for the association between the exposure (suing thiazides) and the outcome (any type of skin cancer). We collected data from different studies and analyzed them to estimate the association between occurrence of skin cancer and using thiazide diuretics. Inclusion and exclusion criteria

Inclusion criteria are using thiazides in adults as for hypertension. All types of skin cancer or other dermatological problems corresponded to the use of thiazides.

Exclusion criteria are:

• where multiple drugs were studied with thiazides such as other antihypertensive drugs since thiazides are commonly prescribed as add-on therapy. We want to be sure that thiazides were the only medicine in use for our study. • skin problems associated with other types of diuretics (non-thiazides diuretics) because we want to study only thiazide drug class. • case reports studies and case series studies to increase the precision of our study. • Meta-analysis and systematic reviews also to increase the precision of the results.

We applied exclusion criteria after reading abstracts and titles. Prisma diagram has been made to illustrate selection criteria of the found literature in Figure 2.

Results

Records defined after database screening (n=32). No duplication was found (n=0). We screened all 32 records and excluded (n=24) after applying exclusion criteria. We assessed (n=8) articles after full- text screening and included (n=7) ours study as demonstrated in Figure2. The one article excluded after full text assessment was due to lack of quantitative results. All results were summarized in Table 1 and Table 2.

The association between hydrochlorothiazide (HCTZ) and the risk of Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST) have been studied by Pedersen et al [40]. The calculated adjusted odd ratios for MCC and MAST correlated with high use (≥50,000 mg) of hydrochlorothiazide were 2.3 and 3.6, respectively [40]. These numbers increased to 3.3 for MCC and 5.6 for MAST when highest use was applied (≥100,000 mg) which leads to the conclusion that hydrochlorothiazide (HCTZ) use is associated with an increased risk of MCC and MAST [40].

Pottegard et al has found that thiazide diuretics was associated with an increased risk of squamous cell carcinoma (SCC), [adjusted odds ratio (aOR), 1.86; 95% confidence interval (CI), 1.23–2.80] and slightly increased risk of basal cell carcinoma (BCC) (aOR,1.19; 95% CI, 1.02–1.38) [41]. Authors of Pottegard et al found that patients who use hydrochlorothiazide (HCTZ) had 22% higher odds of melanoma in comparison to non-hydrochlorothiazide users [41]. Additionally, the authors carried on additional analyses to investigate potential confounding and they found no clinically significant correlation between the risk of melanoma and using other antihypertensive agents [41]. They collected their data from the Danish Cancer Registry in which patients with histologically confirmed melanoma were matched 1: 10 to cancer free populations [41]. Unfortunately, they have not collected data about sun exposure, skin pigmentation, and family history of melanoma that diminishes the interpretability of their results [41].

PubMed Records identified through database screening (n=32)

Records removed after duplication (n=0)

Records screened (n=32) Records excluded (n=24)

Full-text articles assessed Full-text articles excluded for eligibility (n=8) with reasons (n=1)

Studies included (n=7)

Figure 2 (Inclusion and exclusion criteria)

Kreutz et al investigated the association between the use of various thiazide or thiazide-like diuretics and the risk of multiple skin cancer types [41]. Data were collected from Northern Europe [Denmark (n¼7) other European countries (n¼3)] and the United States (n¼3). Two studies out of six studies demonstrated a positive correlation with malignant melanoma (17% and 32% increased risk), two studies with squamous cell carcinoma (58% and 75% increased risk), and the last two were with lip cancer (110% and 119% increased risk) [41].

Nevertheless, SCC known to be more common than other types of lip cancer, Mayne and Colleagues reported that 95% of lip cancers are squamous cell carcinoma (SCC) utilizing surveillance, epidemiology, and end results (SEER) data from 1992 to 1999 from 11 SEER sites in the United States [42]. They also found that hydrochlorothiazide (HCTZ) has a strong association with lip cancer (147 cases and RR 2.29) [1.84-2.86] p<0.001 and other types of skin cancer (95 cases RR 1.56 [1.2-2.01] p=0.001 [42].

Another study has been conducted by Humbert et al provided additional evidence of the association between hydrochlorothiazide (HCTZ) and skin cancer using data from pharmacovigilance database (VigiBase) [44]. They investigated use of thiazides and occurrence of nonmelanoma [44]. They estimated an odds ratio (OR) for all thiazides and the main two subtypes of skin cancer, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [44]. They reported an association between using hydrochlorothiazide (HCTZ) and risk of squamous cell carcinoma (SCC) with an odds ratio (OR) of 2.86 (95% confidence interval, 2.11-3.89). Moreover, they found an equal association between hydrochlorothiazide (HCTZ) and basal cell carcinoma (BCC) with an odds ratio (OR) of 2.85 (95% confidence interval, 2.23-3.63) in addition to other thiazide diuretics and both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) [44].

Study name Study population Exposure Outcome Pedersen et al Cancer-free population Hydrochlorothiazide MCC and MAST (HCTZ) Pottegard et al Cancer free population Hydrochlorothiazide SCC and BCC (HCTZ) Kreutz et al Cancer free population Thiazide or thiazide- Malignant melanoma, like diuretics SCC, and lip cancer Mayne and Colleagues Not reported Hydrochlorothiazide SCC and (HCTZ) Lip cancer Humbert et al Not reported Hydrochlorothiazide BCC and SCC (HCTZ) Table 1

Study MCC MAST SCC BCC Lip cancer Malignant name melanoma Pedersen Odds ratio Odds ratio NR NR NR NR et al (OR): 2.3 (OR): 3.6 dose dose ≥50,000 mg ≥50,000 mg Odds ratio Odds ratio (OR): 3.3 (OR): 5.6 dose dose ≥100,000 mg ≥100,000 mg Pottegard NR NR Adjusted Adjusted NR NR et al odds ratio odds ratio (aOR), 1.86; (aOR),1.19; 95% 95% confidence confidence interval (CI), interval 1.23–2.80 (CI), 1.02– 1.38 Kreutz et NR NR Two studies NR Two studies Two al (58% and (110% and studies 75% 119% (17% and increased increased 32% risk) risk) increased risk) Mayne NR NR NR Relative Relative and Risk RR Risk RR Colleagues 2.29) [1.84- 1.56 [1.2- 2.86] 2.01] p<0.001 p=0.001 Humbert NR NR Odds ratio Odds ratio NR NR et al (OR), 2.86 (OR), 2.85 (95% (95% confidence confidence interval, interval, 2.11-3.89) 2.23-3.63) Table 2

Discussion

The strength points of Pottegard and colleagues’ study is that they used of high-quality nationwide Registry data [35]. As a limitation, in their study Pottegard and colleagues corrected for potential confounders, but they did not adjust for hypertension [43]. As commonly known, hypertensive patients are more likely to visit their general practitioners which may decrease the threshold of reporting skin problems [43]. This finding is supported by the truth that using other antihypertensive agents was also correlated with (albeit not significantly) with an increase in the risk of melanoma with odds ratio 1.06 (in calcium channel blockers) and 1.18 (in angiotensin II receptor blockers). When bendroflumethiazide (another drug from thiazide class) was investigated, no association was found, besides dose effect relation was missing, which means besides the strength of association, none of Hill’s criteria for causality assessment were met [43].

Additionally, potential confounders such as sun exposure, skin pigmentation, and family history of melanoma were not collected and assessed for possible confounding, but they assessed the confounding by indication, such as using other antihypertensive drugs and the found no association between using lowering blood pressure drugs and increased risk of melanoma [41]. The findings for melanoma subtype are slightly unexpected, as lentigo and superficial occurrence of melanoma is commonly known to be correlated with high sun exposure, whereas the etiology of nodular melanoma is less elaborated [35]. Age of the participants were not studied extensively, and as it is commonly known age can increase susceptibility for different types of cancer. Sex, and other factors were not mentioned clearly in the studies, which might introduce more bias in the studies and decrease their precision. The dose -response relationship was lacking in all studies except in Pedersen et al.

Interestingly, available pharmacological evidence demonstrates that photosensitivity is not a unique feature of thiazides diuretics, but it can also be associated with thiazide-like diuretics or other diuretics and antihypertensive agents [41]. Therefore, it is essential that more well conducted observational studies should be done to provide a strong evidence on the correlation between using thiazides, thiazide-like diuretics or other antihypertensive agents and the risk of skin cancer [41]. Conclusion

According to Pedersen et al study we can conclude that there is a strong association between using hydrochlorothiazide (HCTZ) and both Merkel cell carcinoma (MCC) and malignant adnexal skin tumors (MAST). Moreover, the association get stronger when using higher doses of hydrochlorothiazide (HCTZ) ≥100,000 mg. A strong association is also established between using hydrochlorothiazide (HCTZ) and squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) according to Pottegard et al, no further details about the dose were reported. Kreutz et al found a solid correlation between using thiazides or thiazide-like diuretics and occurrence of squamous cell carcinoma (SCC), lip cancer and malignant melanoma. Mayne and Colleagues also support Kreutz et al findings, while Humbert et al found that there is a strong correlation between both of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).

Subsequently, we can conclude that using thiazide or thiazide-like diuretics is highly associated with increased risk of various types of skin cancer, which makes thiazides less preferable drugs to manage hypertension unlike the fact that they have always been the first and cheapest available drug choices to manage hypertension. Additionally, combining thiazides with other antihypertensive agents and reducing their doses might be a solution for this problem, but to support that hypothesis more studies should be conducted.

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