#248 Hydrochlorothiazide and Squamous Cell Skin Cancer: Remember when hypertension was easy?
CLINICAL QUESTION
Does hydrochlorothiazide increase the risk of squamous cell carcinoma (SCC) of the skin?
BOTTOM LINE
Observational data suggest an association between hydrochlorothiazide and the risk of SCC. Causation has not been proven. Risk appears to consistently increase with dose and duration (example: 5 years of use increases risk 3-4 times). Baseline incidence of SCC is <0.1% annually. The same risk has not been established with thiazide-like diuretics (like indapamide or chlorthalidone). The benefit of switching from hydrochlorothiazide to another agent should be weighed against the risk of changing medications.
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EVIDENCE
Statistically significant unless indicated.
- Systematic review:1 2 cohort and 7 case-control studies (395,789 patients).
- Association of SCC with thiazide diuretics: Odds Ratio (OR)=1.9
- Subgroup analysis:
- Hydrochlorothiazide and hydrochlorothiazide combinations consistently increased SCC risk: OR=2.
- Long-term HCTZ use (≥4.5 years) associated with higher SCC risk OR=3.3
- Limitations: potential unmeasured confounders; recall and detection bias; multiple comparisons.
- Subgroup analysis:
- Association of SCC with thiazide diuretics: Odds Ratio (OR)=1.9
- Largest case-control study2, not in above systematic review: 80,162 SCC cases in Denmark matched with 1,603,345 controls.
- Hydrochlorothiazide ≥50,000mg cumulative dose (~6 years use) associated with SCC risk: OR=4.
- Consistent dose-response relationship observed for SCC: OR=7.4 with hydrochlorothiazide ≥200,000mg cumulative dose (~20 years use).
- Hydrochlorothiazide associated with risk of SCC lip cancer3:
- Dose-response effect observed: OR=7.7 with ≥100,000mg cumulative dose.
- Another systematic review4 reported no effect with thiazides but did not include studies reporting on hydrochlorothiazide alone.
- Basal cell carcinoma risk very small (OR=1.2-1.3), if real.1,2
- Baseline SCC risk varies with ethnicity, age, sex, and geographic location. A recent UK cohort reported an incidence of 77 cases per 100,000 people (<0.1%) per year.5 Metastatic SCC developed in 1.1-2.4% of patients with SCC.6
- Non-randomized studies may overestimate beneficial and harmful effects and cannot prove causation.
- Thiazide and thiazide-like agents reduce morbidity and mortality in randomized controlled trials and are first line therapy in hypertension.7
- One hypertension society recommends thiazide-like diuretics as preferred initial option for hypertension (like chlorthalidone or indapamide), although suggest continuing hydrochlorothiazide in stable patients.8
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