In a large cohort of individuals at high risk for BCC, we did not observe any significant association between statin exposure and risk of subsequent BCC. The observed crude risk of subsequent BCC was noted to be higher with both any use of statin therapy and with increasing duration of treatment, although these associations were attenuated after adjustment for age, sex and health care utilization. These results were consistent in the overall cohort and in the subset of patients who met national guidelines for eligibility for lipid-lowering therapy. The results were also robust to other sensitivity analyses that assessed different methods of classifying statin exposure (lag 0 vs. 90 days), and identifying subsequent BCCs (arising within 1 day vs. >90 days of the index date). In addition, we did not observe any significant association between receipt of non-statin anti-lipemic agents and risk of subsequent BCC, although those analyses had limited power given the infrequent use of these agents in our population.
Studying the epidemiology of non-melanoma skin cancer is difficult because unlike most malignancies, they are not systematically reported to centralized cancer registries. A unique strength of our study was the leveraging of data within a large integrated health care delivery system that included electronic capture of all pathology reports, making it feasible to study the epidemiology of non-melanoma skin cancers. The automated health plan pharmacy database facilitated accurate quantification of longitudinal exposure to statin therapy over time, minimizing recall bias. Our follow-up period of up to ten years also allowed assessment of potential long-term effects of statin use on cancer risk. Importantly, our study design focused on a cohort of patients who were previously diagnosed with BCC before the widespread use of statins. This approach mitigates the lack of systematic data on risk factors that contribute to the initial development of BCC such as sun sensitivity, skin type, and history of sun exposure. Finally, we conducted multiple sensitivity analyses that varied cohort and statin exposure definitions, all of which yielded consistent results.
Our findings are consistent with clinical outcome data from several large randomized placebo-controlled trials of statin use for cardiovascular endpoints which observed a slightly increased risk of non-melanoma skin cancer with statin therapy,21-24
although the results did not reach statistical significance. In contrast, a recently published article analyzing cancer outcome data from three statin trials did not observe any increased risk of skin cancer.25
These trials were designed to assess cardiovascular endpoints rather than non-melanoma skin cancer, which were not systematically ascertained, and the trials were likely underpowered to detect a possible association with statin use.
Selected lines of evidence support the hypothesis that statins may increase the risk of BCC. Statins have been shown to enhance UV phototoxicity in human skin cell lines, an effect that was reversed with cholesterol supplementation.26
Certain statins have been associated with UVB phototoxicity.27
Also, Smith-Lemli-Opitz syndrome which is characterized by a mutation in the enzyme involved in the last step of cholesterol biosynthesis is associated with marked UVA photosensitivity.28
Alternatively, statins could exert possible carcinogenic effects by inhibiting lymphocyte function,29
thereby altering immune surveillance. In rodents, statins have also been shown to cause cancer in selected studies at exposure levels comparable with those used in humans.30
Our study had several limitations. We relied on information from filled prescriptions to characterize statin exposure and were unable to directly measure drug use, which may lead to misclassification. Cohort members may have filled their prescriptions for statins outside a health plan pharmacy, although use of non-Kaiser pharmacies by health plan members is estimated to be rare.31
We were not able to examine possible differences between individual statins given that the majority of treated patients received lovastatin. Information about sun exposure history was unavailable, although we attempted to minimize the impact of this by selecting a cohort of patients who by virtue of having one BCC in 1997, shared common risk factor profiles that would make them at similarly increased risk for subsequent BCC. We attempted to control for possible screening bias by adjusting for overall healthcare utilization. We also accounted for confounding by indication by performing a secondary analysis among the subset of patients who appeared eligible for statin therapy based on national clinical practice guidelines.
As an observational study of clinical practice, we cannot completely exclude residual confounding or other treatment selection biases as an alternative explanation of our findings. It is also possible that a small number of subsequent BCCs were treated outside of health plan facilities that were not captured by our pathology database. However, since cohort members already had at least one BCC treated at health plan facilities, it is unlikely that subsequent BCCs would be treated outside the health plan or that this would differ by statin treatment status. Finally, as our study was conducted among insured adults in Northern California, our results may not be completely generalizable to uninsured persons and other health care or geographic settings.
In conclusion, we found that statin exposure was not associated with a lower risk of subsequent BCC. Point estimates were suggestive of potential higher risk with statin therapy although not statistically significant. Our study detects no association between use of statins, the most commonly prescribed medications in the U.S., and risk of subsequent BCC, the most common cancer.1,7
Given the ubiquitous and growing use of statin therapy and the public health relevance of BCC, additional studies are needed to clarify the relationship of statins to these cancers.