Abstract
Background:
Several studies have reported the association between statin use and skin cancer; however, the results have been conflicting. Furthermore, no large-scale studies have reported the relationship between statin exposure and skin cancer in Asian countries.
Aims:
The aim of this study was to investigate the association between statin exposure and skin cancer in Korea.
Methods and Material:
This nationwide population-based case-control study used data from the National Health Insurance Service database between 2007 and 2018. We enrolled 109,327 patients in the skin cancer group and extracted 109,327 controls using 1:1 propensity score matching. Data on statin exposure within 5 years were collected, and multivariable-adjusted conditional logistic regression analysis was performed.
Results:
Statin exposure was present in 29.6% of patients in the skin cancer group and 22.3% of patients in the control group, with a statistically significant difference between the two groups. The adjusted odds ratio (OR) (95% confidence interval [CI]) for the association between statin exposure and skin cancer was 1.71 (1.67-1.75). All types of statins, especially lipophilic statins (adjusted OR, 1.58; 95% CI, 1.54-1.62), were associated with skin cancer. However, the association with skin cancer was not statistically significantly different between lipophilic and hydrophilic statins. Subgroup analyses according to age, sex and comorbidity showed a significant association between statin exposure and skin cancer, regardless of subgroup.
Conclusions:
Our study revealed an association between statin exposure and skin cancer in Korea.
KEY WORDS: Basal cell carcinoma, melanoma, skin cancer, squamous cell carcinoma, statin
Introduction
As the Korean population ages, the incidence of skin cancer is also increasing. Skin cancer can be classified as malignant melanoma (MM) and keratinocyte carcinoma (KC), or nonmelanoma skin cancer, which can be subclassified into squamous cell carcinoma (SCC) and basal cell carcinoma (BCC).
Statins are hydroxymethylglutaryl coenzyme A reductase inhibitors that are commonly used in the treatment of dyslipidemia. Beyond their ability to lower blood cholesterol levels, statins are also known to be able to affect cell division.[1]
Statins show antineoplastic properties by inhibiting cell proliferation, angiogenesis, and metastasis; inducing apoptosis; and affecting cancer stem cells.[2] Conversely, statins can also induce cancer formation. This is because their immunomodulatory action can suppress tumour-specific effector T-cell responses, thereby hindering the antitumor immune response.[3]
Several previous studies have reported a positive association between statin use and skin cancer risk.[4,5,6,7] Lin et al.[8] revealed that the effect of statins on the occurrence of skin cancer varies according to sex. Conversely, other studies have shown that statins reduce the risk of skin cancer.[9,10] Meanwhile, some studies found no association between statin exposure and skin cancer.[11,12,13,14] Owing to these conflicting findings and the differences in the epidemiology, related genetic factors and molecular pathogenesis of skin cancer between Asians and other populations, the applicability of the results of foreign studies to Korea is limited.[15] Considering that the incidence of skin cancer is increasing in Asia and that statins are commonly prescribed for dyslipidemia across all ethnic groups, the relationship between statin exposure and skin cancer in Asians should be clarified.[16] Few studies have been conducted on this topic in Asia. In this study based on the Korean National Health Insurance Service (NHIS) database, we retrospectively analysed patients with skin cancer diagnosed between 2009 and 2019 to reveal the relationship between the use of statins and the incidence of skin cancer in the general population.
Subjects and Methods
Data sources
This study used data from the Korean NHIS database, encompassing extensive data on nearly the entire Korean population (approximately 51 million individuals or approximately 97% of the population).[17] The NHIS mandates health insurance coverage for this significant demographic, and its database contains data on various types of insurance claims, demographic data, and information on diagnoses classified according to the International Classification of Disease, 10th revision (ICD-10) with treatment and drug prescription.
Study design
This case-control study included patients diagnosed with skin cancer between January 1, 2007, and December 31, 2018. The case group comprised patients with registered ICD-10 codes for KC (C440-C449 for the invasive form, D040-D049 for the in situ form) and MM (C430-C439 for the invasive form, D030-D039 for the in situ form). The control group included patients who were not diagnosed with KC or MM during the study period. The control group was selected through 1:1 propensity score matching with the case group, based on the index year, age, sex, income, psoralen plus ultraviolet A (PUVA) exposure, Charlson comorbidity index (CCI), and underlying diseases such as hypertension (I10-I15), diabetes (E10-E14), dyslipidemia (E78), cerebrovascular disease (I60-I69), cancer (C code), human immunodeficiency virus or acquired immune deficiency syndrome (B20-B24), and organ transplantation (Z94, T86). The study design is illustrated in Figure 1.
Figure 1.
Schematic illustration for the study design
For both the case and control groups, the index date was defined as the date of the first skin cancer diagnosis. Information about statin prescriptions including type and days was extracted from the NHIS database, and exposure to statins was determined based on the drug administration within 5 years before the index date. Statin exposure was defined according to exposure to specific drugs (rosuvastatin, atorvastatin, simvastatin, pravastatin, pitavastatin, or fluvastatin), including both single and combination drugs. Furthermore, statins were classified based on their lipophilicity, with atorvastatin, simvastatin, pitavastatin and fluvastatin considered lipophilic. In addition to the statin class, information on the duration of statin exposure was extracted, and cumulative durations were calculated by adding them. Information on the time since first statin exposure was also extracted.
Statistical analysis
We conducted 1:1 propensity score matching to minimise the impact of confounding variables. Thereafter, we used standardised mean differences to assess the balance of covariates between groups. Baseline characteristics were reported as means and standard deviations for continuous variables and as numbers and percentages for categorical variables. We used the Chi-square test to compare the difference in statin exposure between the skin cancer and control groups. To determine the association between statin exposure and skin cancer, we employed conditional logistic regression analysis to calculate the odds ratios (ORs) and 95% confidence intervals (CIs). Furthermore, a multivariable-adjusted logistic model was used to estimate the adjusted ORs after adjusting for several confounding factors, including age, sex, income, PUVA exposure, underlying diseases and CCI. Statistical analysis was performed using SAS software (version 9.4; SAS Institute, Cary, NC). Statistical significance was set at P < 0.05.
Ethics statement
This study was approved by the institutional review board of Hallym University Sacred Heart Hospital (approval no. 2019-09-014). The requirement for informed consent was waived owing to the de-identified nature of the NHIS dataset.
Results
Baseline characteristics of the study population
The baseline characteristics of the participants are shown in Table 1. The sample size was 109,327 for each group. The standardised mean difference of the variables between the groups was <0.01. The mean age in the skin cancer and control groups was 66.6 ± 17.1 and 67.2 ± 16.6 years, respectively. The proportions of men and women 44.2% and 55.8%, respectively, in both the skin cancer and control groups.
Table 1.
Baseline characteristics for study population after propensity score matching
| Baseline characteristics | Skin cancer group (n=109, 327) | Control group (n=109, 327) | Standardised mean difference |
|---|---|---|---|
| Age, mean±SD | 66.6±17.1 | 67.2±16.6 | 0.03 |
| Sex, n (%) | 0 | ||
| Male | 48,337 (44.2) | 48,337 (44.2) | |
| Female | 60,990 (55.8) | 60,990 (55.8) | |
| Income, n (%) | 0.02 | ||
| 1st quartile | 22,110 (20.2) | 21,830 (20.0) | |
| 2nd quartile | 15,500 (14.2) | 14,862 (13.6) | |
| 3rd quartile | 21,556 (19.7) | 21,263 (19.4) | |
| 4th quartile | 50,161 (45.9) | 51,372 (47.0) | |
| PUVA exposure | 475 (0.4) | 475 (0.4) | 0 |
| Underlying disease, n (%) | |||
| Hypertension | 63,142 (57.8) | 63,142 (57.8) | 0 |
| Diabetes | 45,236 (41.4) | 45,236 (41.4) | 0 |
| Dyslipidemia | 60978 (55.8) | 60978 (55.8) | 0 |
| Cerebrovascular disease | 31,398 (28.7) | 31,398 (28.7) | 0 |
| Cancer | 24,336 (22.3) | 24,336 (22.3) | 0 |
| HIV or AIDS | 20 (0.02) | 20 (0.02) | 0 |
| Organ transplantation | 412 (0.4) | 412 (0.4) | 0 |
| Charlson comorbidity index, n (%) | 0.03 | ||
| 0 | 32,337 (29.6) | 33,575 (30.7) | |
| 1 | 23,769 (21.7) | 24,107 (22.0) | |
| 2 | 22,853 (20.9) | 22,284 (20.4) | |
| ≥3 | 30,368 (27.8) | 29,361 (26.9) |
SD: Standard deviation
Statin exposure according to study population
We analysed the two groups according to statin exposure, cumulative exposure duration, time since first exposure, statin types and statin lipophilicity. The distribution of statin exposure in the study population is shown in Table 2. The rate of statin exposure, regardless of statin type, was 29.6% in the skin cancer group and 22.3% in the control group. Atorvastatin was the most commonly used statin in the skin cancer (15.4%) and control (11.4%) groups, followed by simvastatin and rosuvastatin. In both groups, the number of patients exposed to lipophilic statins was higher than that of patients exposed to hydrophilic statins.
Table 2.
The odds ratio and 95% confidence interval between statin exposure and skin cancer
| Statin exposure variable | Skin cancer group (n=109,327) | Control group (n=109,327) | Crude OR (95% CI) | P | Adjusted OR (95% CI)*** | P |
|---|---|---|---|---|---|---|
| Statin exposure | ||||||
| No | 76,966 (70.4) | 84,904 (77.7) | 1 (reference) | 1 (reference) | ||
| Yes | 32,361 (29.6) | 24,423 (22.3) | 1.46 (1.43-1.49) | <0.0001 | 1.71 (1.67-1.75) | <0.0001 |
| Cumulative duration of exposure (days) | ||||||
| Never | 76,966 (70.4) | 84,904 (77.7) | 1 (reference) | 1 (reference) | ||
| <794 days* | 17,074 (15.6) | 11,303 (10.3) | 1.67 (1.62-1.71) | <0.0001 | 1.93 (1.87-1.98) | <0.0001 |
| ≥794 days | 15,287 (14.0) | 13,120 (12.0) | 1.29 (1.25-1.32) | <0.0001 | 1.50 (1.46-1.55) | <0.0001 |
| Time since first exposure (days) | ||||||
| Never | 76,966 (70.4) | 84,904 (77.7) | 1 (reference) | 1 (reference) | ||
| <1,240 days* | 15,183 (13.9) | 13,207 (12.1) | 1.27 (1.24-1.30) | <0.0001 | 1.47 (1.43-1.51) | <0.0001 |
| ≥1,240 days | 17,178 (15.7) | 11,216 (10.2) | 1.69 (1.65-1.73) | <0.0001 | 2.00 (1.94-2.05) | <0.0001 |
| Type | ||||||
| Never | 76,966 (70.4) | 84,904 (77.7) | 1 (reference) | 1 (reference) | ||
| Rosuvastatin | 4,670 (4.3) | 3,566 (3.3) | 1.32 (1.27-1.38) | <0.0001 | 1.33 (1.27-1.39) | <0.0001 |
| Atorvastatin | 16,870 (15.4) | 12,406 (11.4) | 1.43 (1.39-1.46) | <0.0001 | 1.50 (1.46-1.54) | <0.0001 |
| Simvastatin | 7,333 (6.7) | 5,743 (5.3) | 1.30 (1.25-1.34) | <0.0001 | 1.31 (1.26-1.36) | <0.0001 |
| Pravastatin | 1,301 (1.2) | 957 (0.9) | 1.36 (1.25-1.48) | <0.0001 | 1.36 (1.25-1.48) | <0.0001 |
| Pitavastatin | 1,677 (1.5) | 1,372 (1.3) | 1.23 (1.14-1.32) | <0.0001 | 1.22 (1.14-1.31) | <0.0001 |
| Fluvastatin | 510 (0.5) | 379 (0.4) | 1.34 (1.18-1.54) | <0.0001 | 1.33 (1.17-1.53) | <0.0001 |
| Lipophilicity** | ||||||
| Never | 76,966 (70.4) | 84,904 (77.7) | 1 (reference) | 1 (reference) | ||
| Lipophilic | 26,390 (24.1) | 19,900 (18.2) | 1.43 (1.40-1.46) | <0.0001 | 1.58 (1.54-1.62) | <0.0001 |
| Hydrophilic | 5,971 (5.5) | 4,523 (4.1) | 1.34 (1.29-1.39) | <0.0001 | 1.35 (1.30-1.41) | <0.0001 |
|
| ||||||
| Outcome variable classification | Keratinocyte carcinoma (KC) group | Control group | Crude OR (95% CI) | P | Adjusted OR (95% CI)* | P |
|
| ||||||
| Statin exposure | ||||||
| No | 64,235 (69.7) | 71,166 (77.2) | 1 (reference) | 1 (reference) | ||
| Yes | 27,942 (30.3) | 21,011 (22.8) | 1.47 (1.44-1.50) | <0.0001 | 1.72 (1.69-1.77) | <0.0001 |
|
| ||||||
| Outcome variable classification | Malignant melanoma (MM) group | Control group | Crude OR (95% CI) | P | Adjusted OR (95% CI)* | P |
|
| ||||||
| Statin exposure | ||||||
| No | 16,060 (73.4) | 17,845 (81.5) | 1 (reference) | 1 (reference) | ||
| Yes | 5,832 (26.6) | 4,047 (18.5) | 1.60 (1.53-1.68) | <0.0001 | 1.94 (1.84-2.05) | <0.0001 |
OR: Odds ratio, CI: Confidence interval, CCI: Charlson comorbidity index. *median value for cumulative duration of exposure and time since first exposure. **Lipophilic statin includes atorvastatin, simvastatin, pitavastatin and fluvastatin. ***adjusted for age, sex, income, psoralen plus ultraviolet A exposure, underlying disease, Charlson comorbidity index
Association between statin exposure and skin cancer
Table 2 shows the OR of skin cancer according to statin exposure. In patients with statin exposure, the crude OR (95% CI) of skin cancer was 1.46 (1.43-1.49) and the adjusted OR (95% CI) was 1.71 (1.67-1.75). When the non-exposure group and the two exposure groups (<794 or ≥794 days) based on cumulative exposure duration were compared, the adjusted ORs (95% CIs) were 1.93 (1.87-1.98) and 1.50 (1.46-1.55), respectively. When the non-exposure group and the two exposure groups (<1240 or ≥1240 days) based on the time since first exposure were compared, the adjusted ORs (95% CIs) were 1.47 (1.43-1.51) and 2.00 (1.94-2.05), respectively. Moreover, all statin types were associated with skin cancer. Among them, atorvastatin (adjusted OR, 1.50; 95% CI, 1.46-1.54) showed the highest correlation with skin cancer. When the exposure groups were divided according to statin lipophilicity, the lipophilic statin group (adjusted OR, 1.58; 95% CI, 1.54-1.62) showed a higher correlation with skin cancer than the hydrophilic statin group (adjusted OR, 1.35; 95% CI, 1.30-1.41). However, the association with skin cancer was not statistically significantly different between the lipophilic and hydrophilic groups (adjusted OR, 1.01; 95% CI, 0.97-1.06). We also analysed the differences in outcome variables between patients with KC and those with MM. Both patients with KC (adjusted OR, 1.72; 95% CI, 1.69-1.77) and MM (adjusted OR 1.94; 95% CI 1.84-2.05) showed a significant relationship to statin exposure.
Subgroup analyses for association between statin exposure and skin cancer
Subgroup analyses were performed according to age, sex and comorbidity. The results of the subgroup analyses are shown in Figure 2. Based on age, the adjusted ORs (95% CIs) were 1.38 (1.30-1.46) and 1.80 (1.76-1.85) in the <60 and ≥60 years groups, respectively. When subgroup analysis was performed according to sex, the adjusted OR (95% CI) was 1.67 (1.61-1.73) in men and 1.73 (1.68-1.79) in women. Among the four groups divided according to comorbidity based on CCI scores, the CCI ≥3 group had the highest adjusted OR (95% CI): 1.98 (1.90-2.06).
Figure 2.
Subgroup analysis for association between statin exposure and skin cancer
Discussion
We examined the association between statin exposure and skin cancer in a representative sample in Korea. We found that statin exposure was associated with skin cancer, including KC and MM, with lipophilic statins showing a greater association; however, no statistically significant difference was observed between lipophilic and hydrophilic statins. Additionally, we observed a trend of increasing association with increasing time since first exposure. The subgroup analyses according to age, sex and comorbidity showed a significant association between statin exposure and skin cancer regardless of subgroup.
Numerous studies have investigated the association between statin use and skin cancer, with conflicting results. Recently, a large-scale prospective cohort study involving French women revealed that skin cancer is not related to statin exposure, cumulative exposure duration, time since first exposure and age at first exposure.[18] In a large-scale study of two cohorts, Lin et al.[8] reported that, in male patients, the longer the statin exposure duration, the higher the BCC risk. In a cohort study of postmenopausal white women, all types of statins, especially lovastatin, simvastatin and other lipophilic statins, were associated with the KC risk.[4] However, these previous studies were generally limited to Western countries, and no similar large-scale studies have been conducted in Asian countries to date. To our knowledge, this is the first study to investigate the association between statin exposure and skin cancer in Asia.
The underlying mechanism for the association between statin exposure and skin cancer is not fully understood; however, several possible mechanisms have been proposed. Statins can induce the transcription factor forkhead box P3, which induces the proliferation of CD4 + CD25 + regulatory T cells.[19] These cells can suppress tumour-specific effector T-cell responses, thereby disturbing the antitumor immune response.[3] Additionally, statin exposure can induce photosensitivity, which may increase the risk of skin cancer.[20,21,22,23] Conversely, other studies have suggested that statins can suppress cancer development by blocking the mevalonate pathway, which is upregulated in tumour cells.[24] Moreover, statins can inhibit the Ras signalling pathway related to skin cancer development.[25,26,27] As the related genetic factors and molecular pathogenesis of skin cancer differ between Asians and Caucasians, further studies are required to elucidate how statin use affects the occurrence of skin cancer in Asians.[16]
Regarding melanoma, our study found a positive association between statin exposure and MM risk. This finding is consistent with the result of a systematic review and meta-analysis of 17 randomised controlled trials and 25 observational studies, which revealed that statin use increases the incidence of melanoma (median RR 1.5, range 1.3 to 1.7).[5] Conversely, several previous laboratory studies reported that statins inhibit the proliferation of melanoma cells.[28,29] Another prospective cohort study reported no statistically significant association between statin exposure and melanoma after effect modification according to ultraviolet radiation (P = 0.052).[18] Additionally, another meta-analysis reported no association (relative risk, 0.94; 95% CI, 0.85-1.04) between statin use and melanoma.[12] As ultraviolet-associated melanomas occur less frequently in Asians, the proportion of melanoma subtypes enrolled in these previous clinical studies may be different from that in our study.[30] However, our study lacks information on melanoma subtypes, such as acral lentiginous melanoma, or low and high cumulative sun damage melanomas; therefore, further studies are needed to identify the main factor in the positive association.
Our study has several strengths. First, our study used data of Korean NHIS, which covers almost the entire population of the Korea. This is the first large-scale study to reveal an association between statin exposure and skin cancer in an Asian population; thus, our results can be applicable to the general Asian population. Second, our study was based not on self-reported data but on objective claims data, which are highly reliable. Finally, we classified our data according to relevant subgroups described in previous studies (cumulative exposure duration, time since first exposure, statin types and statin lipophilicity).
However, this study also has limitations. First, as our data were collected from a large national database, we could not consider some detailed risk factors (number of nevi and freckles, sunburn history, and ultraviolet exposure) that can only be determined from the electronic medical records of each patient. Additionally, the lack of data on the cumulative dose of statins could introduce bias in the analysis due to misclassification of exposure. Second, we could not separately analyse BCC and SCC because these diseases share the same ICD-10 diagnostic codes. Third, statin users tend to more frequently visit hospitals for monitoring, which could lead to an increased detection of skin cancer. Forth, although this study is large in scale, it can still exhibit inherent limitations of case-control study design, including selection bias, confounding, difficulty establishing causality and generalizability. Finally, while our study has identified an association between statin exposure and skin cancer, it does not provide sufficient evidence to establish a definitive causal relationship.
In conclusion, we found that statin exposure is associated with KC and MM in Korea. Physicians should be aware of this association when prescribing statins, particularly for individuals at high risk of skin cancer.
Key messages
There is an association between statin exposure and skin cancer in Korea.
Conflicts of interest
There are no conflicts of interest.
Funding Statement
Nil.
References
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