New Research Reveals Alarming Link Between HCTZ and Skin Cancer!

This article discusses the studies that showed a link between thiazides, a common blood pressure medication and skin cancer.

Introduction

High blood pressure (hypertension) is one of the most common chronic health conditions worldwide, affecting nearly 1.3 billion people.

Hydrochlorothiazide (HCTZ), a type of thiazide diuretic. It is widely prescribed to control hypertension. This is due to its effectiveness, low cost, and long-term safety profile.

However, in recent years, concerns have emerged about its potential link to nonmelanoma skin cancer (NMSC).

Regulatory agencies, including the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), have issued warnings about an increased risk of skin cancer related to long-term HCTZ use. This risk is particularly high at high cumulative doses.

What Are Nonmelanoma Skin Cancers?

Nonmelanoma skin cancers (NMSC) are a type of skin cancer. They develop in keratinocyte cells. These cells are found in the outer layer of the skin. The two most common types of NMSC are:

1. Basal Cell Carcinoma (BCC)
   • Most common type of skin cancer worldwide.
   • Develops in basal cells in the lower epidermis.
   • Typically, appears as a pearly or waxy bump, a flat, flesh-colored lesion, or a sore that won’t heal.
   • Grows slowly and is rarely life-threatening, but can cause disfigurement if untreated.
2. Squamous Cell Carcinoma (SCC)
   • It’s more aggressive than BCC, but still treatable.
   • Forms in squamous cells in the upper layers of the epidermis.
   • Presents as a red, scaly patch, a wart-like growth, or an open sore that may bleed or crust.
   • If untreated, SCC can spread (metastasize) to lymph nodes and other organs, making it life-threatening.

How Are NMSCs Treated?

Treatment for BCC and SCC depends on size, location, and stage:

• Surgical excision: The most common treatment, where the tumor is cut out with a margin of healthy skin.
• Mohs micrographic surgery: A precise method used for high-risk tumors, especially on the face and head.
• Cryotherapy: Freezing small tumors with liquid nitrogen.
• Topical treatments (5-fluorouracil, imiquimod): Used for superficial BCC and SCC.
• Radiation therapy or chemotherapy: Used for advanced or inoperable cases.

What Happens if NMSC is Left Untreated?

• Basal cell carcinoma can invade nearby tissues, damaging nerves, muscles, and bones.
• Squamous cell carcinoma is more aggressive and can spread to internal organs, leading to serious complications or death if untreated.
• Untreated NMSC significantly increases healthcare costs due to the need for complex surgeries, radiation, or systemic treatments.

NMSC has a high incidence and potentially severe consequences. Understanding HCTZ’s role in increasing skin cancer risk is crucial for patients and healthcare providers.

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II. Mechanism: How HCTZ Increases Skin Cancer Risk

The association between hydrochlorothiazide and skin cancer is believed to be due to its photosensitizing properties. This means that HCTZ makes the skin more sensitive to ultraviolet (UV) radiation, which increases the likelihood of DNA damage and cancerous mutations.

1. Photosensitization and UV Damage

• HCTZ belongs to a class of photosensitizing drugs. This means it absorbs UV radiation, making skin cells more vulnerable to DNA damage.
• Chronic UV exposure causes mutations in key tumor suppressor genes, like p53, leading to uncontrolled cell growth.
• This increases the risk of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), particularly in sun-exposed areas.

2. Dose-Dependent Effects

• Several studies show that higher cumulative doses of HCTZ lead to a greater risk of skin cancer.
• Threshold dose for risk: Studies suggest that 50,000 mg or more of HCTZ significantly increases the risk of NMSC. This increase is noted in research findings.
• Why dose matters: The longer someone takes HCTZ, the more UV exposure compounds the DNA damage. This exposure increases cancer risk over time.

3. Impact on Skin Cells

• HCTZ may reduce the skin’s ability to repair UV-induced damage, leading to higher rates of mutation and tumor formation.
• This effect is strongest in fair-skinned individuals and those with high sun exposure (e.g., outdoor workers).

4. Added Risk Factors

• Fair skin, blue eyes, blond/red hair: Naturally lower melanin levels, reducing UV protection.
• Geographic location: Higher sun exposure (Australia, Southern US, Mediterranean regions) increases risk.
• Immunosuppression: Organ transplant recipients on immunosuppressants have an even greater risk of developing skin cancers while taking HCTZ.

III. Summary of Key Studies on HCTZ and Skin Cancer

Over the past decade, multiple studies have investigated the link between hydrochlorothiazide (HCTZ) use and skin cancer risk. Below, we summarize six major studies that provide strong evidence for this association.

Understanding the Risk: What Do the Numbers Mean?

When researchers analyze whether a medication increases disease risk, they use statistical measures like Odds Ratio (OR) and Hazard Ratio (HR):

• Odds Ratio (OR): This tells us how much more likely a condition (e.g., skin cancer) is to occur in one group (HCTZ users) than in another group (non-users).
  • Example: If the OR for HCTZ and squamous cell carcinoma (SCC) is 2.0, this means HCTZ users are twice as likely to develop SCC compared to those who do not use it.
• Hazard Ratio (HR): This is similar to OR but measures how quickly an event happens over time. A higher HR means the event (e.g., skin cancer diagnosis) happens sooner in one group than another.
  • Example: An HR of 1.5 means HCTZ users develop skin cancer 50% faster than non-users.

OR and HR above 1.0 mean increased risk, while values below 1.0 show a protective effect.

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A. Study 1: Pedersen et al. (2018) – Danish Cancer Registry Analysis

Study Type: Large case-control study
Population: Patients from the Danish Cancer Registry (2004–2012)
Key Findings:

• HCTZ use significantly increased the risk of skin cancer:
  • Squamous cell carcinoma (SCC): OR 3.98 → Nearly 4× higher risk.
  • Basal cell carcinoma (BCC): OR 1.29 → 29% higher risk.
• Dose-response relationship:
  • Patients taking ≥200,000 mg of HCTZ had a 7.38× increased SCC risk.
• Conclusion: The study provides strong evidence that long-term HCTZ use raises skin cancer risk, especially SCC.

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B. Study 2: Shin et al. (2019) – Meta-Analysis of 9 Studies

Study Type: Meta-analysis (merged data from 7 case-control and 2 cohort studies)
Population: Studies from multiple countries
Key Findings:

• HCTZ use was linked to all three major types of skin cancer:
  • SCC: OR 1.86 → 86% higher risk.
  • BCC: OR 1.19 → 19% higher risk.
  • Melanoma: OR 1.14 → 14% higher risk.
• Hydrochlorothiazide had the strongest link to SCC (OR 2.04 in subgroup analysis).
• Conclusion: This meta-analysis reinforces earlier findings that HCTZ increases the risk of skin cancer, especially SCC.

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C. Study 3: Eworuke et al. (2021) – US FDA Sentinel System Study

Study Type: Retrospective cohort study
Population: 5.2 million matched HCTZ and ACE inhibitor users in the US
Key Findings:

• HCTZ slightly increased SCC risk but not BCC risk overall:
  • SCC: HR 1.04 → 4% higher risk.
  • BCC: HR 0.99 → No significant difference.
• In Caucasians, the risk was higher:
  • SCC: HR 1.15 → 15% higher risk.
  • BCC: HR 1.09 → 9% higher risk.
• Higher cumulative dose (≥50,000 mg HCTZ) further increased SCC risk (IRR = 1.19).
• Conclusion: While the overall increase in SCC risk was modest, it was more pronounced in fair-skinned populations.

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D. Study 4: Carney et al. (2022) – UK Health Improvement Network (THIN) Study

Study Type: Case-control study
Population: UK patients from the THIN database (1999–2016)
Key Findings:

• HCTZ use significantly increased the risk of:
  • SCC (OR highly elevated).
  • BCC.
  • Lip cancer.
• No significant increase in melanoma or oral cancer.
• Conclusion: This study confirms HCTZ’s association with skin and lip cancers, emphasizing the importance of screening patients taking this medication.

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E. Study 5: Rahaminov et al. (2024) – Kidney Transplant Recipients Study

Study Type: Single-center retrospective analysis
Population: 520 kidney transplant recipients (KTRs)
Key Findings:

• HCTZ users had a much higher risk of skin cancer:
  • NMSC overall: HR 2.54 → More than 2× higher risk.
  • BCC: HR 3.03 → 3× higher risk.
• No significant increase in SCC risk in this group.
• Conclusion: In immunosuppressed individuals (e.g., kidney transplant recipients), HCTZ significantly raises BCC risk.

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F. Study 6: Rasmussen et al. (2024) – Global Variability in HCTZ and NMSC Risk

Study Type: Systematic review and global burden of disease analysis
Key Findings:

• HCTZ-associated NMSC risk varies widely by country:
  • No increased risk: Taiwan, India, Brazil.
  • Small increased risk (HR/OR ≤1.5): Canada, US, Korea.
  • Moderate risk (1.5 < HR/OR ≤2.5): Iceland, Spain, Japan.
  • High risk (HR/OR >2.5): UK, Denmark, Netherlands, Australia.
• Hypertensive heart disease (HHD) has a much greater global health burden than NMSC.
• Conclusion: The risk of HCTZ-associated skin cancer is not uniform worldwide, and patients in high-risk regions should be more cautious.

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Key Takeaways from the Studies

• All six studies confirm an increased risk of skin cancer with HCTZ use, particularly SCC and BCC.
• The risk is dose-dependent, with higher cumulative HCTZ exposure leading to greater cancer risk.
• Caucasians and those in high-UV regions face the highest risk.
• Kidney transplant recipients and immunosuppressed individuals have an even greater risk.
• Some regions (e.g., the UK, Denmark, Australia) show a much higher HCTZ-associated cancer risk than others (e.g., Taiwan, India, Brazil).

IV. Clinical Implications & Risk Mitigation Strategies

The association between hydrochlorothiazide (HCTZ) and increased skin cancer risk presents a challenge for both healthcare providers and patients.

While HCTZ is an effective and affordable antihypertensive medication, it poses some risks. Its photosensitizing effects and dose-dependent risk of nonmelanoma skin cancer (NMSC) require a careful risk-benefit assessment.

This section outlines who is most at risk, substitute treatment options, and protective strategies for those who need to continue HCTZ therapy.

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A. Who is at Highest Risk?

Not everyone taking HCTZ has the same level of risk for basal cell carcinoma (BCC) or squamous cell carcinoma (SCC). Studies suggest that the following groups face the greatest risk:

Patients with high cumulative HCTZ exposure:

• ≥50,000 mg lifetime dose significantly increases SCC risk.
• Higher doses (>200,000 mg) are linked to a 7× higher SCC risk.

Fair-skinned individuals (Caucasians, light skin types):

• Lower melanin levels = higher UV sensitivity and greater risk of skin damage.
• SCC risk was 15% higher in Caucasian HCTZ users (Eworuke et al., 2021).

Individuals with high sun exposure:

• Outdoor workers (farmers, construction workers, lifeguards, etc.).
• People living in high-UV regions (Australia, Southern US, Mediterranean).

Immunosuppressed patients (e.g., kidney transplant recipients):

• Higher baseline risk of skin cancer due to immunosuppressants.
• HCTZ further increases BCC risk by 3× in transplant patients (Rahaminov et al., 2024).

Patients with a history of skin cancer or precancerous lesions:

• Previous NMSC increases the likelihood of recurrence.
• HCTZ may accelerate the development of new lesions.

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B. Alternative Blood Pressure Medications

For patients at high risk of skin cancer, alternative antihypertensive options should be considered.

Safer alternatives to HCTZ:

• Angiotensin receptor blockers (ARBs) (e.g., Losartan, Valsartan):
  • No known skin cancer risk.
  • May reduce oxidative stress, offering protective effects.
• Calcium channel blockers (CCBs) (e.g., Amlodipine, Diltiazem):
  • Not linked to increased skin cancer risk.
  • Effective for hypertension and angina.
• Potassium-sparing diuretics (e.g., Spironolactone, Eplerenone):
  • May be an option for patients needing diuretics.
  • Spironolactone has been studied for potential anti-cancer properties.

Caution with ACE Inhibitors (e.g., Lisinopril, Enalapril):

• Some evidence suggests a link between ACE inhibitors and lung cancer.
• Not a first-line replacement if skin cancer risk is a major concern.

Key Takeaway: If a patient has a high risk of skin cancer, switching from HCTZ to an ARB or CCB may be a safer option.

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C. Preventative Measures for Patients Continuing HCTZ

For patients who need to stay on HCTZ, proactive skin cancer prevention is crucial.

1. Regular Dermatologic Screenings

• Annual skin exams for all HCTZ users, especially those at high risk.
• More frequent exams (every 6 months) for those with:
  • History of NMSC.
  • Fair skin or high UV exposure.
  • Immunosuppression (e.g., transplant recipients).

2. Sun Protection & UV Exposure Reduction

• Use broad-spectrum sunscreen (SPF 50+).
  • Apply every 2 hours if outdoors.
  • Choose zinc oxide or titanium dioxide for better UVA/UVB protection.
• Wear protective clothing:
  • Wide-brimmed hats and UV-blocking sunglasses.
  • Long sleeves and pants for extended outdoor exposure.
• Avoid peak UV hours (10 AM – 4 PM).

3. Lifestyle & Nutritional Strategies to Support Skin Health

• Increase antioxidant intake:
  • Vitamin C, Vitamin E, and polyphenols (found in berries, green tea, dark chocolate) may help counteract UV-induced DNA damage.
• Omega-3 fatty acids (from fish and flaxseeds) may reduce inflammation and skin cancer risk.
• Avoid tanning beds – UV radiation is classified as a carcinogen.

4. Discuss Dose Reduction with a Healthcare Provider

• If HCTZ must be continued, discuss:
  • Lowering the dose to minimize cumulative exposure.
  • Combination therapy with another medication to reduce the HCTZ dose.

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V. Conclusion: Balancing Blood Pressure Control & Skin Cancer Risk

• Hydrochlorothiazide is a highly effective antihypertensive medication, but long-term use is linked to increased nonmelanoma skin cancer risk, particularly SCC.
• Cumulative dose matters—higher exposure leads to greater risk.
• Patients with fair skin, high UV exposure, or a history of skin cancer should discuss alternative medications with their healthcare provider.
• For those continuing HCTZ, strict sun protection, regular skin checks, and lifestyle modifications can help reduce their risk of skin cancer.

HCTZ’s benefits in controlling hypertension should always be weighed against potential long-term risks.

Patients and doctors should work together to make personalized, informed decisions about treatment.

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References:

1. Pedersen SA, Gaist D, Schmidt SAJ, Hölmich LR, Friis S, Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J Am Acad Dermatol. 2018 Apr;78(4):673-681.e9. doi: 10.1016/j.jaad.2017.11.042. Epub 2017 Dec 4. PMID: 29217346.
2. Shin D, Lee ES, Kim J, Guerra L, Naik D, Prida X. Association Between the Use of Thiazide Diuretics and the Risk of Skin Cancers: A Meta-Analysis of Observational Studies. J Clin Med Res. 2019 Apr;11(4):247-255. doi: 10.14740/jocmr3744. Epub 2019 Mar 18. PMID: 30937114; PMCID: PMC6436572.
3. Eworuke E, Haug N, Bradley M, Cosgrove A, Zhang T, Dee EC, Adimadhyam S, Petrone A, Lee H, Woodworth T, Toh S. Risk of Nonmelanoma Skin Cancer in Association With Use of Hydrochlorothiazide-Containing Products in the United States. JNCI Cancer Spectr. 2021 Feb 4;5(2):pkab009. doi: 10.1093/jncics/pkab009. PMID: 33733052; PMCID: PMC7947823.
4. Carney K, Cousins M. Does hydrochlorothiazide increase the incidence of skin, lip and oral cancer in a UK population? Evid Based Dent. 2022 Mar;23(1):38-39. doi: 10.1038/s41432-022-0255-x. Epub 2022 Mar 25. PMID: 35338330.
5. Rahamimov R, Telem S, Davidovichi B, Bielopolski D, Steinmetz T, Nesher E, Lichtenberg S, Rozen-Zvi B. The association between hydrochlorothiazide use and non-melanoma skin cancer in kidney transplant recipients. Clin Kidney J. 2024 Apr 25;17(5):sfae126. doi: 10.1093/ckj/sfae126. PMID: 38812910; PMCID: PMC11134297.
6. Almskou Rasmussen A, Buus NH, Comerma Steffensen SG. Geographical Differences in Hydrochlorothiazide Associated Risk of Skin Cancer Balanced Against Disability Related to Hypertensive Heart Disease. Am J Hypertens. 2024 Oct 14;37(11):924-932. doi: 10.1093/ajh/hpae101. PMID: 39115345.

Image credits:

• Basal cell cancer – Public Domain, https://commons.wikimedia.org/w/index.php?curid=1216868
• Squamous cell skin cancer – By BruceBlaus – Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=44924607

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