Risk assessment for cancer development associated with the use of antihypertensives

    Authors

    Abstract

    Numerous clinical trials have evaluated the potential cancerogenic effect of antihypertensive medications. Their influence on the development of prostate, skin, breast, kidney, and lung cancer has been examined. It was demonstrated that using antihypertensives does not elevate the total risk for cancer development. For some cancer groups there was even a reduction in risk of the development of malignant diseases under antihypertensive therapy. The results were the same in long-term use of the medications (>7.5 years), and longer application of the treatment did not lead to the expected increase in risk, with some studies finding a reduction in relative risk values with longer use of antihypertensives. No group of antihypertensives was associated with increased relative risk for the development of prostate cancer, and the use of beta-blockers and long-term use of alfa-blockers even had a protective effect. HALMED and the European Medicines Agency reported increased risk for the development of non-melanoma skin cancer with the use of hydrochlorothiazide. The Croatian Society of Hypertension recommends evaluating of the risk-benefit ratio of hydrochlorothiazide therapy in clinical practice, adequately informing the patient, and then deciding on the further use of hydrochlorothiazide in therapy together with the patient. The relative risk of breast cancer development was not increased due to the use of calcium channel blockers or other hypertensives, and the values did not differ from the control groups. It is more likely that the risk of kidney cancer development is associated with the pathogenesis of arterial hypertension rather than the use of diuretic therapy. In conclusion, apart from the demonstrated association between the use of hydrochlorothiazide and the development of non-melanoma skin cancer, there is still no valid evidence for the possible cancerogenic effect of other antihypertensives; in clinical practice we therefore recommend continuing to follow current guidelines for the treatment of arterial hypertension with a reevaluation of the use of hydrochlorothiazide therapy as recommended by the Croatian Society of Hypertension.

    Keywords

    antihypertensives, carcinoma, hydrochlorothiazide

    DOI

    https://doi.org/10.15836/ccar2019.126

    Full Text

    ## Introduction Arterial hypertension, as one of the leading risk factors for the development of cardiovascular diseases, can now be successfully regulated by antihypertensive therapy. The risk of cardiovascular and cerebrovascular events is significantly reduced at satisfactory arterial pressure (AP) values. Multiple groups of antihypertensive medications are in use today: ACE inhibitors, beta-blockers, diuretics, and alpha-blockers. While some patients achieve AP regulation with monotherapy, most will be treated with one of the now well-known antihypertensive combination treatments, i.e. dual or triple antihypertensive therapy such as ACE inhibitor/calcium blocker, ACE inhibitor/thiazide diuretic, ARB/thiazide diuretic, ACE inhibitor/thiazide diuretic/calcium channel blocker. All these groups of medications have a chance of resulting in side-effects ranging from neurological disturbances, gastrointestinal issues, coughing, electrolyte imbalance (potassium), and so on. Over the last few years, several studies have been conducted on the risk of malignant diseases associated with the application of all groups of antihypertensives. The greatest number of studies examined ACE inhibitors and angiotensin receptor blockers, followed by calcium channel blockers, beta-blockers, diuretics, and alpha-blockers. Most patients, depending on the timing of the diagnosis, will be receiving antihypertensive therapy for several years to several decades, so many studies followed patients over a longer period of time, which makes the results more reliable and allows detection of medication side-effects that manifest later. Assessing total cancer risk associated with use of antihypertensives The total risk for the development of malignant diseases with antihypertensive use was examined in the studies described below. A meta-analysis performed on 70 randomized control studies and 148 control groups confirmed that there was no difference in cancer development with ARBs (proportion 2.04%; OR 1.01, 95% CI 0.93-1.09), ACE inhibitors (2.03%; 1.00, 0.92-1.09), beta-blockers (1.97%; 0.97, 0.88-1.07), calcium channel blockers (2.11%; 1.05, 0.96-1.13), diuretics (2.02%; 1.00, 0.90-1.11), and other controls (1.95%, 0.97, 0.74-1.24) in comparison with placebo (2.02%), RR 5-10%. ( 1 ) Using data from the Longitudinal Health Insurance Database 2000, a cohort study was performed on 24 238 participants that examined the relative risk for cancer development with propranolol use. The results of the study do not indicate an increase in risk, but rather found a reduction in total risk (HR: 0.75; 95% CI: 0.67-0.85; P < 0.001) with an additional significant reduction in risk of the development of individual types of cancer, for instance: head and neck cancer (HR: 0.58; 95% CI: 0.35-0.95), digestive track cancer and esophageal cancer (HR: 0.35; 95% CI: 0.13-0.96), stomach cancer (HR: 0.54; 95% CI: 0.30–0.98), colon cancer (HR: 0.68; 95% CI: 0.49–0.93), and prostate cancer (HR: 0.52; 95% CI: 0.33–0.83). ( 2 ) Data from the General Practice Research Database, UK, were used for a nested case-control study that demonstrated long-term use of antihypertensive (>7.5 years) was not associated with development of malignant diseases. ( 3 ) Assessment of two groups of patients, those treated with combined antihypertensive therapy with ACE inhibitors and calcium channel blockers compared with a group of patients treated with beta-blockers, found mildly elevated relative risk for the development of all types of cancer – 1.27 (95% CI 0.98–1.63) – in the group of patients treated with calcium channel blockers and ACE inhibitors in comparison with a reduced relative risk for cancer development– 0.79 (0.58–1.06) – in the group treated with beta-blockers. Mildly elevated relative risk for cancer development in the first group can be refuted by the fact that the relative risk with use of calcium blockers did not rise as expected over a longer period of time; on the contrary, the relative risk value was reduced with extended application of the therapy (RR for calcium channel blockers at 1 year (1.46), at 1-3 years (1.26), and 4 years or more (1.23). ( 4 ) A cohort study (General Practice Research Database, UK) on a large number of participants, 377 649 (using the Cox model for adjustment), who were treated with ARBs or ACE inhibitors within the last year found no increase in their relative risk for cancer development with the use of ARBs (HR 1.03, 95% Cl 0.99 do 1.06, P=0.10); in fact, a reduction of risk was observed for the development of lung cancer (0.84, 0.75 to 0.94), while there was no effect on the development of colon cancer (1.02, 0.91 to 1.16) and somewhat elevated risk for the development of prostate and breast cancer (1.11, 1.01-1.21, P=0.02; and 1.10, 1.00-1.20, P=0.04), which can be interpreted as being risk that is actually low in absolute assessment (0.5 and 1.1 per 1000 persons annually) and given that this study examined a group of high-risk patients. ( 5 ) Assessing risk for the development of prostate cancer associated with the use of antihypertensives Total relative risk for the development of prostate cancer with the use of all groups of antihypertensive medications was assessed in a Canadian study with 2 221 cases of cancer and 11 105 controls and was not found to be elevated; 0.98 (CI, 0.88-1.08). RR was reduced with the use of beta-blockers (OR= 0.86, Cl 0.77-0.96), and risk did not increase with extended use of the medication: <1 year RR 0.89 (0.75-1.05), 1-4 years RR 0.91 (0.75-1.09), >4 years RR 0.82 (0.69-0.96). Beta-blockers and long-term use of alfa-blockers can have a preventive effect on the development of malignant diseases, whereas the use of calcium channel blockers and ACE inhibitors has no effect on prostate carcinoma. ( 6 ) Assessment of each individual antihypertensive in the ACE inhibitor group did not find an association with risk of prostate cancer for any of the medications, and the use of captopril was actually demonstrated to reduce risk for the development of malignancies: 0.7 (95% CI: 0.4-1.2). ( 7 ) A meta-analysis performed on a large number of participants, 20 267 patients including 6 cohort studies and 3 nested case-control studies on three continents, demonstrated a protective effect of RAS inhibitors for prostate cancer. The relative risk for the development of prostate cancer was less than 1, i.e. there was no relative risk in any of the included studies. ( 8 ) Risk assessment for the development of skin cancer associated with the use of antihypertensives On October 17, 2018, the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) and the European Medicines Agency (EMA) published a warning on increased risk for non-melanoma skin cancer (NMSC; basal cell carcinoma, squamous cell carcinoma) associated with the use of hydrochlorothiazide at higher doses of the medication (12.5 mg). Their recommendations for patients taking hydrochlorothiazide in their treatment include: adequately informing the patient on the potential risk of NMSC, recommending regular dermatologic examinations, potentially performing histological tests for suspect skin lesions, and a warning on limiting and protecting against exposure to the sun and UV rays. A recommendation to reexamine the indication for introducing hydrochlorothiazide to the treatment was given only for the group of patients with previous skin malignancies. On December 12, 2018, the Statement of the Croatian Society of Hypertension on the observed increased risk of NMSC associated with the use of hydrochlorothiazide in treatment was that the risk of non-melanoma skin and lip cancer was higher in patients treated with this medication than in those that were not treated with it, was higher in older patients, that risk increased with duration of treatment, and that the mechanism of carcinogenesis was based on photosensitivity. In clinical practice they recommended reassessing the risk-benefit ratio, adequately informing the patient on the existing risk and alternative treatments, and making a decision in consultation with the patient on whether to terminate or continue the treatment; if the treatment is continued, use of adequate sun protection and regular checkups of skin changes should be recommended to the patient. ( 9 ) Risk assessment for the development of breast cancer associated with the use of antihypertensives Using data from the Taiwan National Health Insurance Research Database and a large sample of 330 699 patients, it was shown that the use of non-selective beta-blockers, selective and non-selective alpha-blockers, ACE inhibitors, and angiotensin II antagonists was not associated with risk of developing breast cancer, whereas the use of calcium channel blockers was associated with minimal risk (OR 1.09; 95% CI 1.03-1.16). ( 10 ) Two American cohort studies on a sample of 210 641 women, the U.S. Nurses’ Health Study (NHS 1988-2012) and Nurses’ Health Study II (NHS II 1989-2011) using the multivariate hazard model (with the Cox modification), examined the influence of diuretics, beta-blockers, calcium channel blockers, and ACE inhibitors on the risk of breast cancer development. In 10 012 cases of invasive breast cancer (6 718 cases in NHS and 3 294 cases in NHS II), none of the hypertensives were associated with the risk of breast cancer in comparison with the control groups: NHS (RR = 1.00, 95% CI = 0.95–1.06) and NHS II (RR = 0.94, 95% CI = 0.86–1.03). The results were the same for long-term antihypertensive use. ( 11 ) A British cohort study compared three groups of patients: the first group used calcium channel blockers (150 750 patients), the second group received a different hypertensive (557 931 patients), while the third group received combined antihypertensive treatment that include a calcium channel blocker (156 966 patients). The resulting relative risk values for cancer development were not significantly increased: RR 0.88 (0.86 to 0.89) and 1.01 (0.98 to 1.04); HR for the development of prostate, breast, and colon carcinoma with the application of calcium channel blockers was not significantly increased for any of the cancer groups: HR 0.95 (0.87 to 1.04), 1.07 (0.98 to 1.16) and 0.89 (0.81 do 0.98). ( 12 ) Risk assessment for the development of kidney cancer associated with the use of antihypertensives Using antihypertensives, especially diuretics, was examined as a risk factor for kidney cancer development in recent literature data. However, taking into account the mechanism of arterial hypertension, which causes a permanent proinflammatory state in the blood vessels and the release of free radicals as well as many other effects favorable to the cell mutation, it is possible that there is an association between arterial hypertension itself as a risk factor for the development of kidney carcinoma that is not associated with the use of diuretics in therapy. Studies have indicated higher risk in women (OR 2.01, 95% CI 1.56-2.67) than in men (OR 1.69, 95% CI 1.34-2.13), however the relative risk for kidney cancer development in women was 1.8, and with adequate antihypertensive therapy and well-regulated AP values this risk dropped to 1.1. In conclusion, it is important to compare the strengths and weaknesses of every treatment including diuretics, comparing the relatively low total risk of cancerogenic effect with the undoubtedly large benefits of diuretics. As an example, for every 1 case of kidney cancer the use of diuretics prevents 17-30 ischemic cerebrovascular incidents, 3-20 cardiovascular deaths, and 4-18 prevented deaths in the general population. ( 13 - 17 ) ## Conclusion The above results of current studies did not establish a definitive association between the use of any group of antihypertensives and cancer development, except the risk of non-melanoma skin cancer with the use of hydrochlorothiazide. Increased duration of antihypertensive therapy did not lead to the expected increase in relative risk for cancer development; in fact, some studies found a paradoxical linear reduction in relative risk. Furthermore, current studies did not include other risk factors for the development of malignancies, e.g. smoking, exposure to UV rays and the sun, and other hazardous effects, and the results of future studies that include risk factors with the use of antihypertensives are yet to be seen. It is important to remember that proper regulation of arterial hypertension leads to a significant reduction in mortality from cardiovascular events, cerebrovascular events, and a reduction in total mortality in the general population; we therefore recommend adhering to the current guidelines for the treatment of arterial hypertension of the European Society of Hypertension, with additional caution when applying hydrochlorothiazide. According to the recommendations of the Croatian Society of Hypertension, it is important to inform the patient in a timely manner on the potential hazardous effects of hydrochlorothiazide and reach a joint decision with the patient on the further application or termination of the therapy in those patients who do not have a higher total risk of skin cancer than the standard population, whereas in the group of high-risk patients, those who have already had skin cancer, hydrochlorothiazide should be replace by one of the other antihypertensives available in Croatia such as a non-thiazide diuretic, indapamide, or an antihypertensive from a different group, based on an individualized assessment of every patient. If hydrochlorothiazide treatment is continued, patients should be advised to avoid sunlight and UV radiation and instructed to visit a dermatologist in case suspect skin lesions appear. For all other antihypertensives, we recommend continuing their application according to guidelines for the treatment of arterial hypertension.

    Cardiologia Croatica
    Back to search

    Risk assessment for cancer development associated with the use of antihypertensives

    Review Article
    Issue5-6
    Published
    Pages126-131
    PDF via DOIhttps://doi.org/10.15836/ccar2019.126
    antihypertensives
    carcinoma
    hydrochlorothiazide

    Authors

    Rea LevickiORCIDCroatia
    Martina Lovrić Benčić*ORCIDCroatia
    Bojan JelakovićORCIDCroatia

    Abstract

    Numerous clinical trials have evaluated the potential cancerogenic effect of antihypertensive medications. Their influence on the development of prostate, skin, breast, kidney, and lung cancer has been examined. It was demonstrated that using antihypertensives does not elevate the total risk for cancer development. For some cancer groups there was even a reduction in risk of the development of malignant diseases under antihypertensive therapy. The results were the same in long-term use of the medications (>7.5 years), and longer application of the treatment did not lead to the expected increase in risk, with some studies finding a reduction in relative risk values with longer use of antihypertensives. No group of antihypertensives was associated with increased relative risk for the development of prostate cancer, and the use of beta-blockers and long-term use of alfa-blockers even had a protective effect. HALMED and the European Medicines Agency reported increased risk for the development of non-melanoma skin cancer with the use of hydrochlorothiazide. The Croatian Society of Hypertension recommends evaluating of the risk-benefit ratio of hydrochlorothiazide therapy in clinical practice, adequately informing the patient, and then deciding on the further use of hydrochlorothiazide in therapy together with the patient. The relative risk of breast cancer development was not increased due to the use of calcium channel blockers or other hypertensives, and the values did not differ from the control groups. It is more likely that the risk of kidney cancer development is associated with the pathogenesis of arterial hypertension rather than the use of diuretic therapy. In conclusion, apart from the demonstrated association between the use of hydrochlorothiazide and the development of non-melanoma skin cancer, there is still no valid evidence for the possible cancerogenic effect of other antihypertensives; in clinical practice we therefore recommend continuing to follow current guidelines for the treatment of arterial hypertension with a reevaluation of the use of hydrochlorothiazide therapy as recommended by the Croatian Society of Hypertension.

    Full Text

    ## Introduction Arterial hypertension, as one of the leading risk factors for the development of cardiovascular diseases, can now be successfully regulated by antihypertensive therapy. The risk of cardiovascular and cerebrovascular events is significantly reduced at satisfactory arterial pressure (AP) values. Multiple groups of antihypertensive medications are in use today: ACE inhibitors, beta-blockers, diuretics, and alpha-blockers. While some patients achieve AP regulation with monotherapy, most will be treated with one of the now well-known antihypertensive combination treatments, i.e. dual or triple antihypertensive therapy such as ACE inhibitor/calcium blocker, ACE inhibitor/thiazide diuretic, ARB/thiazide diuretic, ACE inhibitor/thiazide diuretic/calcium channel blocker. All these groups of medications have a chance of resulting in side-effects ranging from neurological disturbances, gastrointestinal issues, coughing, electrolyte imbalance (potassium), and so on. Over the last few years, several studies have been conducted on the risk of malignant diseases associated with the application of all groups of antihypertensives. The greatest number of studies examined ACE inhibitors and angiotensin receptor blockers, followed by calcium channel blockers, beta-blockers, diuretics, and alpha-blockers. Most patients, depending on the timing of the diagnosis, will be receiving antihypertensive therapy for several years to several decades, so many studies followed patients over a longer period of time, which makes the results more reliable and allows detection of medication side-effects that manifest later. Assessing total cancer risk associated with use of antihypertensives The total risk for the development of malignant diseases with antihypertensive use was examined in the studies described below. A meta-analysis performed on 70 randomized control studies and 148 control groups confirmed that there was no difference in cancer development with ARBs (proportion 2.04%; OR 1.01, 95% CI 0.93-1.09), ACE inhibitors (2.03%; 1.00, 0.92-1.09), beta-blockers (1.97%; 0.97, 0.88-1.07), calcium channel blockers (2.11%; 1.05, 0.96-1.13), diuretics (2.02%; 1.00, 0.90-1.11), and other controls (1.95%, 0.97, 0.74-1.24) in comparison with placebo (2.02%), RR 5-10%. ( 1 ) Using data from the Longitudinal Health Insurance Database 2000, a cohort study was performed on 24 238 participants that examined the relative risk for cancer development with propranolol use. The results of the study do not indicate an increase in risk, but rather found a reduction in total risk (HR: 0.75; 95% CI: 0.67-0.85; P < 0.001) with an additional significant reduction in risk of the development of individual types of cancer, for instance: head and neck cancer (HR: 0.58; 95% CI: 0.35-0.95), digestive track cancer and esophageal cancer (HR: 0.35; 95% CI: 0.13-0.96), stomach cancer (HR: 0.54; 95% CI: 0.30–0.98), colon cancer (HR: 0.68; 95% CI: 0.49–0.93), and prostate cancer (HR: 0.52; 95% CI: 0.33–0.83). ( 2 ) Data from the General Practice Research Database, UK, were used for a nested case-control study that demonstrated long-term use of antihypertensive (>7.5 years) was not associated with development of malignant diseases. ( 3 ) Assessment of two groups of patients, those treated with combined antihypertensive therapy with ACE inhibitors and calcium channel blockers compared with a group of patients treated with beta-blockers, found mildly elevated relative risk for the development of all types of cancer – 1.27 (95% CI 0.98–1.63) – in the group of patients treated with calcium channel blockers and ACE inhibitors in comparison with a reduced relative risk for cancer development– 0.79 (0.58–1.06) – in the group treated with beta-blockers. Mildly elevated relative risk for cancer development in the first group can be refuted by the fact that the relative risk with use of calcium blockers did not rise as expected over a longer period of time; on the contrary, the relative risk value was reduced with extended application of the therapy (RR for calcium channel blockers at 1 year (1.46), at 1-3 years (1.26), and 4 years or more (1.23). ( 4 ) A cohort study (General Practice Research Database, UK) on a large number of participants, 377 649 (using the Cox model for adjustment), who were treated with ARBs or ACE inhibitors within the last year found no increase in their relative risk for cancer development with the use of ARBs (HR 1.03, 95% Cl 0.99 do 1.06, P=0.10); in fact, a reduction of risk was observed for the development of lung cancer (0.84, 0.75 to 0.94), while there was no effect on the development of colon cancer (1.02, 0.91 to 1.16) and somewhat elevated risk for the development of prostate and breast cancer (1.11, 1.01-1.21, P=0.02; and 1.10, 1.00-1.20, P=0.04), which can be interpreted as being risk that is actually low in absolute assessment (0.5 and 1.1 per 1000 persons annually) and given that this study examined a group of high-risk patients. ( 5 ) Assessing risk for the development of prostate cancer associated with the use of antihypertensives Total relative risk for the development of prostate cancer with the use of all groups of antihypertensive medications was assessed in a Canadian study with 2 221 cases of cancer and 11 105 controls and was not found to be elevated; 0.98 (CI, 0.88-1.08). RR was reduced with the use of beta-blockers (OR= 0.86, Cl 0.77-0.96), and risk did not increase with extended use of the medication: <1 year RR 0.89 (0.75-1.05), 1-4 years RR 0.91 (0.75-1.09), >4 years RR 0.82 (0.69-0.96). Beta-blockers and long-term use of alfa-blockers can have a preventive effect on the development of malignant diseases, whereas the use of calcium channel blockers and ACE inhibitors has no effect on prostate carcinoma. ( 6 ) Assessment of each individual antihypertensive in the ACE inhibitor group did not find an association with risk of prostate cancer for any of the medications, and the use of captopril was actually demonstrated to reduce risk for the development of malignancies: 0.7 (95% CI: 0.4-1.2). ( 7 ) A meta-analysis performed on a large number of participants, 20 267 patients including 6 cohort studies and 3 nested case-control studies on three continents, demonstrated a protective effect of RAS inhibitors for prostate cancer. The relative risk for the development of prostate cancer was less than 1, i.e. there was no relative risk in any of the included studies. ( 8 ) Risk assessment for the development of skin cancer associated with the use of antihypertensives On October 17, 2018, the Agency for Medicinal Products and Medical Devices of Croatia (HALMED) and the European Medicines Agency (EMA) published a warning on increased risk for non-melanoma skin cancer (NMSC; basal cell carcinoma, squamous cell carcinoma) associated with the use of hydrochlorothiazide at higher doses of the medication (12.5 mg). Their recommendations for patients taking hydrochlorothiazide in their treatment include: adequately informing the patient on the potential risk of NMSC, recommending regular dermatologic examinations, potentially performing histological tests for suspect skin lesions, and a warning on limiting and protecting against exposure to the sun and UV rays. A recommendation to reexamine the indication for introducing hydrochlorothiazide to the treatment was given only for the group of patients with previous skin malignancies. On December 12, 2018, the Statement of the Croatian Society of Hypertension on the observed increased risk of NMSC associated with the use of hydrochlorothiazide in treatment was that the risk of non-melanoma skin and lip cancer was higher in patients treated with this medication than in those that were not treated with it, was higher in older patients, that risk increased with duration of treatment, and that the mechanism of carcinogenesis was based on photosensitivity. In clinical practice they recommended reassessing the risk-benefit ratio, adequately informing the patient on the existing risk and alternative treatments, and making a decision in consultation with the patient on whether to terminate or continue the treatment; if the treatment is continued, use of adequate sun protection and regular checkups of skin changes should be recommended to the patient. ( 9 ) Risk assessment for the development of breast cancer associated with the use of antihypertensives Using data from the Taiwan National Health Insurance Research Database and a large sample of 330 699 patients, it was shown that the use of non-selective beta-blockers, selective and non-selective alpha-blockers, ACE inhibitors, and angiotensin II antagonists was not associated with risk of developing breast cancer, whereas the use of calcium channel blockers was associated with minimal risk (OR 1.09; 95% CI 1.03-1.16). ( 10 ) Two American cohort studies on a sample of 210 641 women, the U.S. Nurses’ Health Study (NHS 1988-2012) and Nurses’ Health Study II (NHS II 1989-2011) using the multivariate hazard model (with the Cox modification), examined the influence of diuretics, beta-blockers, calcium channel blockers, and ACE inhibitors on the risk of breast cancer development. In 10 012 cases of invasive breast cancer (6 718 cases in NHS and 3 294 cases in NHS II), none of the hypertensives were associated with the risk of breast cancer in comparison with the control groups: NHS (RR = 1.00, 95% CI = 0.95–1.06) and NHS II (RR = 0.94, 95% CI = 0.86–1.03). The results were the same for long-term antihypertensive use. ( 11 ) A British cohort study compared three groups of patients: the first group used calcium channel blockers (150 750 patients), the second group received a different hypertensive (557 931 patients), while the third group received combined antihypertensive treatment that include a calcium channel blocker (156 966 patients). The resulting relative risk values for cancer development were not significantly increased: RR 0.88 (0.86 to 0.89) and 1.01 (0.98 to 1.04); HR for the development of prostate, breast, and colon carcinoma with the application of calcium channel blockers was not significantly increased for any of the cancer groups: HR 0.95 (0.87 to 1.04), 1.07 (0.98 to 1.16) and 0.89 (0.81 do 0.98). ( 12 ) Risk assessment for the development of kidney cancer associated with the use of antihypertensives Using antihypertensives, especially diuretics, was examined as a risk factor for kidney cancer development in recent literature data. However, taking into account the mechanism of arterial hypertension, which causes a permanent proinflammatory state in the blood vessels and the release of free radicals as well as many other effects favorable to the cell mutation, it is possible that there is an association between arterial hypertension itself as a risk factor for the development of kidney carcinoma that is not associated with the use of diuretics in therapy. Studies have indicated higher risk in women (OR 2.01, 95% CI 1.56-2.67) than in men (OR 1.69, 95% CI 1.34-2.13), however the relative risk for kidney cancer development in women was 1.8, and with adequate antihypertensive therapy and well-regulated AP values this risk dropped to 1.1. In conclusion, it is important to compare the strengths and weaknesses of every treatment including diuretics, comparing the relatively low total risk of cancerogenic effect with the undoubtedly large benefits of diuretics. As an example, for every 1 case of kidney cancer the use of diuretics prevents 17-30 ischemic cerebrovascular incidents, 3-20 cardiovascular deaths, and 4-18 prevented deaths in the general population. ( 13 - 17 ) ## Conclusion The above results of current studies did not establish a definitive association between the use of any group of antihypertensives and cancer development, except the risk of non-melanoma skin cancer with the use of hydrochlorothiazide. Increased duration of antihypertensive therapy did not lead to the expected increase in relative risk for cancer development; in fact, some studies found a paradoxical linear reduction in relative risk. Furthermore, current studies did not include other risk factors for the development of malignancies, e.g. smoking, exposure to UV rays and the sun, and other hazardous effects, and the results of future studies that include risk factors with the use of antihypertensives are yet to be seen. It is important to remember that proper regulation of arterial hypertension leads to a significant reduction in mortality from cardiovascular events, cerebrovascular events, and a reduction in total mortality in the general population; we therefore recommend adhering to the current guidelines for the treatment of arterial hypertension of the European Society of Hypertension, with additional caution when applying hydrochlorothiazide. According to the recommendations of the Croatian Society of Hypertension, it is important to inform the patient in a timely manner on the potential hazardous effects of hydrochlorothiazide and reach a joint decision with the patient on the further application or termination of the therapy in those patients who do not have a higher total risk of skin cancer than the standard population, whereas in the group of high-risk patients, those who have already had skin cancer, hydrochlorothiazide should be replace by one of the other antihypertensives available in Croatia such as a non-thiazide diuretic, indapamide, or an antihypertensive from a different group, based on an individualized assessment of every patient. If hydrochlorothiazide treatment is continued, patients should be advised to avoid sunlight and UV radiation and instructed to visit a dermatologist in case suspect skin lesions appear. For all other antihypertensives, we recommend continuing their application according to guidelines for the treatment of arterial hypertension.