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. Author manuscript; available in PMC: 2019 Apr 1.
Published in final edited form as: J Am Acad Dermatol. 2017 Dec 5;78(4):682–693. doi: 10.1016/j.jaad.2017.11.050

Statin Use and Risk of Skin Cancer

Brian M Lin 1,2,3, Wen-Qing Li 4,5, Eunyoung Cho 2,4,5, Gary C Curhan 2,3,6,7, Abrar A Qureshi 2,4,5
PMCID: PMC5957516  NIHMSID: NIHMS941589  PMID: 29208416

Abstract

Background

Statins are among the most commonly used medications in the United States, and statin use is associated with increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). However, previous studies are limited by lack of adjustment for important confounders.

Objective

Examine the relation between statins and skin cancer risk in the Nurses’ Health Study and Health Professionals Follow-up Study.

Methods

Cox proportional hazards regression was used to evaluate associations.

Results

During follow-up (2000–2010), we documented 10,201 BCC, 1,393 SCC, and 333 melanoma cases. History of high cholesterol was not associated with risk of BCC (pooled multivariable-adjusted Hazard ratio (HR)=1.04 [1.00, 1.09], SCC (HR=0.95 [0.85, 1.06]), or melanoma (HR=0.87 [0.64, 1.19]). Statin use was not associated with risk of BCC (HR=1.04 [0.99, 1.09]), SCC (HR=1.08 [0.94, 1.24]), or melanoma (HR=1.04 [0.78, 1.38]). There was a trend towards higher BCC risk with longer duration of statin use in men (P-trend=0.003), but not in women (P-trend=0.86).

Limitations

Lack of treatment data.

Conclusion

History of high cholesterol was not associated with skin cancer risk. Longer duration of statin use was associated with a trend towards higher BCC risk in men.

Keywords: Statins, basal cell carcinoma, squamous cell carcinoma, melanoma

INTRODUCTION

The incidence of melanoma and keratinocyte carcinomas (KCs) – which are comprised of squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin – have been increasing in the United States and worldwide, and represent a significant economic burden.1–5

High cholesterol is also common and affects approximately 13% of adults in the United States.6 Several cellular mechanisms that promote altered cholesterol homeostasis have been associated with cancer development,7–12 and high cholesterol has been associated with increased risk of certain malignancies including prostate cancer.13, 14 However, the potential relation between high cholesterol, KCs, and melanoma has not been previously investigated.

Recent estimates from the National Health and Nutrition Examination Survey (NHANES) suggest that 17% of adults in the United States are on a statin medication.15 In contrast to the lack of studies on the potential relation between skin cancers and high cholesterol, there has been some investigation of the relation between skin cancers and statin (3-hydroxy-3 methylglutaryl coenzyme A inhibitors) use.

Although primarily prescribed as cholesterol-lowering medications, statins have been shown to have pleiotropic properties, which include inhibition of tumor cell growth.16–19 Conversely, statins have also been associated immunosuppression and inhibition of the Ras signaling pathway,20–23 which has been associated with development of KCs.24–26 A large prospective study in women demonstrated no significant association between statin use and risk of melanoma.27 Previous studies investigating the relation between statin use and KCs found an increased risk of KCs with statin use.28–31 However, data from these studies are limited by lack of adjustment for UV light exposure28 and lack of malignancy verification and diagnosis date.29

We prospectively investigated the relation between high cholesterol, statin use and risk of melanoma, SCC, and BCC in the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS) – two cohorts followed by our research group.

MATERIALS AND METHODS

Study participants

The Nurses’ Health Study (NHS) is a prospective cohort of 121,700 registered female nurses aged 30–55 years at study onset in 1976. The Health Professionals’ Follow-up Study (HPFS) was established when 51,529 male health professionals aged 40–75 years were enrolled in 1986. In both cohorts, follow-up questionnaires are administered biennially, with an average follow-up rate of greater than 90% of the eligible person-time. This study was approved by the Partners Healthcare Institutional Review Board (1999P011114).

Ascertainment of high cholesterol

On the 1976 and 1978 NHS questionnaires, participants were asked whether they had elevated cholesterol. On the 1980 NHS questionnaire and 1986 HPFS questionnaire, and every two years thereafter, participants were asked whether a clinician had diagnosed them as having elevated cholesterol. We classified participants who answered, “yes” to this question as having a history of high cholesterol from that time onwards. A previous validation study in NHS demonstrated self-reported cases of elevated cholesterol levels are highly reliable, with greater than 85% of reported cases confirmed via review of medical records.32

Ascertainment of medication use

In 2000, and every two years thereafter, NHS and HPFS participants were asked whether they regularly used statins. We considered women who answered “yes” to have taken the statins for the previous two years. Participants were also asked in 2000 the number of years they used “Statin cholesterol-lowering drugs” prior to the 2000 questionnaire cycle.

Identification of skin cancer cases

Cohort participants reported new cases of skin cancer biennially. Study physicians reviewed participant medical and pathology reports to verify cases of SCC and melanoma. Although medical records were not obtained for cases of reported BCC, previous validation studies performed in these cohorts have demonstrated approximately 90% accuracy in self-reported BCC cases, when confirmed by pathology or medical records.32, 33

Ascertainment of covariates

Covariates were selected based on previously reported related factors for melanoma and KCs.34 Factors considered included age, natural hair color, number of skin moles, cumulative ultraviolet flux, skin reaction to prolonged sun exposure during childhood/adolescence, number of lifetime severe or blistering sunburns, family history of melanoma, smoking status, body mass index, citrus consumption,35, 36 and physical activity. Data on covariates were obtained from the biennial questionnaires. Dietary factors were derived from semiquantitative food frequency questionnaires mailed to participants every four years. Physical activity was derived from questionnaire information obtained every four years in NHS, and every two years in HPFS. Time-dependent covariates were updated with each questionnaire cycle, when available. In cases where covariate information was missing, information from the previous questionnaire cycle was carried forward.

Statistical analysis

All analyses were performed in a prospective manner using information on high cholesterol and medication use that was collected before the reported case of melanoma or KC. We considered participants who reported high cholesterol in or prior to 2000 (the baseline year of our study) as having a history of high cholesterol. If on a subsequent questionnaire, participants reported having high cholesterol, they were considered to have a history of high cholesterol from that point onward. Duration of statin use was derived by taking the number of years participants reported using statins prior to the 2000 questionnaire cycle, and assigning two additional years of statin use for participants who reported use of statins in any given two-year time period over the follow-up period. Duration of statin use was categorized as <1 year, 1–2 years, 3–4 years, 5–6 years, 7–8 years, and >8 years of statin use in our SCC and BCC analyses, and <1 year, 1–2 years, 3–4 years, >4 years of statin use in our melanoma analyses. A P-trend was utilized to test for an overall trend towards significance by increasing categorical duration of statin use.

Multivariable-adjusted relative risks were calculated using Cox proportional hazards regression models. We examined the relation between high cholesterol, statin use, and skin cancer by first examining the relation between history of high cholesterol and skin cancer and subsequently limiting our analysis on statin use and risk of skin cancer to participants with a history of high cholesterol. We performed a separate analysis investigating high cholesterol, statin use, and risk of melanoma that did not exclude participants with a history of SCC or BCC at baseline, and instead adjusted for a history of SCC or history of BCC in the statistical model. We also ran separate models that included adjustment for use of oral steroid medications. We also performed a secondary analysis to evaluate whether the relation between high serum cholesterol, statin use, and risk of skin cancers varied by health screening among participants. Participants were asked each questionnaire cycle whether they underwent a physical examination over the past two years, and we accounted for their responses in our multivariable models. All p-values are two-sided, with 95% confidence intervals calculated for all relative risks. SAS software, version 9.4 (SAS Institute Inc., Cary, North Carolina) was used to perform all statistical analyses.

RESULTS

Participant characteristics at baseline according to history of high cholesterol and statin use are shown in Table 1. At baseline, 34,376 women (60.0%) and 10,590 men (50.3%) reported a history of high cholesterol. Among participants who reported a history of high cholesterol, 11,743 women (34.2%) and 4,341 men (41.0%) reported statin use.

Table 1.

Baseline Characteristics of Participants According to History of High Cholesterol and Statin use in Women in the Nurses’ Health Study (NHS) and in Men in the Health Professionals Follow-up Study (HPFS)

History of High Cholesterol Statin Use
No Yes No Yes
Women in NHS (2000)
No. of participants 22,862 34,376 45,119 12,119
Age, years a 64.1(7.1) 66.1(6.9) 64.9(7.1) 67.0(6.8)
Family history of melanoma, % 6.9 7.3 7.2 7.2
Red/blonde hair, % 14.8 14.4 14.6 14.5
Painful burn/blisters reaction as a child/adolescent, % 12.8 13.8 13.1 14.5
No. of blistering sunburns 8.2(6.9) 8.5(6.8) 8.4(6.9) 8.6(6.9)
Use of sunscreen, % 23.9 23.0 23.3 23.5
Annual UV flux (×10−4 RB count) 123.3(25.4) 123.6(26.0) 123.8(25.9) 122.5(25.4)
Body mass index (kg/m2) 26.2(5.4) 27.4(5.4) 26.6(5.4) 28.2(5.4)
Physical activity level (metabolic-equivalents hrs/wk) 18.3(23.0) 16.2(21.2) 17.5(21.8) 15.5(22.8)
Current smoking, % 10.8 9.2 9.8 9.8
Menopausal status, % 97.3 97.7 97.5 97.8
Current postmenopausal hormones use, b % 48.5 50.1 49.8 48.4
Total energy intake (kcal/d) 1741.6(534.0) 1722.1(531.9) 1738.3(533.9) 1696.5(527.3)
Alcohol intake (g/d) 5.4(9.3) 4.7(9.0) 5.1(9.2) 4.3(8.5)
Total citrus intake (serving/d) 0.8(0.6) 0.8(0.6) 0.8(0.6) 0.8(0.6)
Statin use, % 1.8 33.6 - -
History of high cholesterol, % - - 50.6 96.9
Men in HPFS (2000)
No. of participants 10,453 10,590 16,304 4,739
Age, years a 64.0(8.7) 64.6(8.3) 64.0(8.6) 65.4(8.1)
Family history of melanoma, % 4.5 4.9 4.7 4.9
Red/blonde hair, % 12.9 11.9 12.6 11.5
Painful burn/blisters reaction as a child/adolescent, % 21.7 21.8 22.1 20.8
No. of blistering sunburns 12.6(12.1) 12.6(11.9) 12.8(12.1) 12.2(11.7)
Use of sunscreen, % 58.5 60.3 58.9 60.8
Annual UV flux (×10−4 RB count) 129.4(27.3) 129.5(27.5) 129.5(27.4) 129.1(27.5)
Body mass index (kg/m2) 25.6(5.1) 26.2(4.9) 25.7(5.0) 26.5(4.9)
Physical activity level (metabolic-equivalents hrs/wk) 35.2(43.3) 30.7(36.3) 33.7(40.7) 30.3(36.8)
Current smoking, % 4.5 4.1 4.5 3.7
Total energy intake (kcal/d) 2019.7(545.1) 1970.5(532.4) 2013.4(543.3) 1930.7(518.0)
Alcohol intake (g/d) 10.4(13.8) 11.0(13.9) 10.7(14.0) 10.8(13.2)
Total citrus intake (serving/d) 1.0(0.7) 0.9(0.7) 0.9(0.7) 0.9(0.7)
Statin use, % 3.9 40.6 - -
History of high cholesterol, % - - 38.4 91.7
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Values are means (SD), or percentages and have been standardized to the age distribution of the study population.

a

Values are not age adjusted.

b

Percentages among postmenopausal women

During the ten-year follow-up period (2000–2010), 10,201 incident cases of BCC, 1,393 incident cases of SCC, and 333 incident cases of melanoma were identified. History of high cholesterol was not associated with risk of BCC (multivariable adjusted relative risk (MVRR) = 1.03; 95% confidence interval (CI) = 0.98, 1.08), SCC (MVRR = 0.94; 95% CI = 0.82, 1.08), or melanoma (MVRR = 0.77; 95% CI = 0.58, 1.01) among women (Table 2). Among men, history of high cholesterol was not associated with risk of any skin cancer; the HR [95% CI] was 1.08 [1.00, 1.16] for BCC, 0.97 [0.81, 1.16] for SCC, and 1.06 [0.71, 1.57] for melanoma.

Table 2.

Age- and Multivariable-Adjusted Relative Risks of Skin Cancer According to History of High Cholesterol, Nurses’ Health Study (NHS, 2000–2010) and Health Professionals Follow-Up Study (HPFS, 2000–2010)

No. of Cases Person-Years Age-Adjusted RR 95% CI Multivariable-Adjusted RR* 95% CI
Basal cell carcinoma
 NHS
  No history of high cholesterol 2,215 159,784 1.00 Reference 1.00 Reference
  History of high cholesterol 5,072 318,951 1.02 0.97, 1.07 1.03 0.98, 1.08
 HPFS
  No history of high cholesterol 1,212 73,058 1.00 Reference 1.00 Reference
  History of high cholesterol 1,702 93,196 1.06 0.99, 1.14 1.08 1.00, 1.16
 Pooled†
  No history of high cholesterol 3,427 232,842 1.00 Reference 1.00 Reference
  History of high cholesterol 6,774 412,147 1.03 0.99, 1.08 1.04 1.00, 1.09
Squamous cell carcinoma
 NHS
  No history of high cholesterol 298 160,676 1.00 Reference 1.00 Reference
  History of high cholesterol 586 321,044 0.90 0.78, 1.04 0.94 0.82, 1.08
 HPFS
  No history of high cholesterol 222 74,096 1.00 Reference 1.00 Reference
  History of high cholesterol 287 94,658 0.95 0.80, 1.13 0.97 0.81, 1.16
 Pooled†
  No history of high cholesterol 520 234,772 1.00 Reference 1.00 Reference
  History of high cholesterol 873 415,702 0.92 0.82, 1.03 0.95 0.85, 1.06
Melanoma
 NHS
  No history of high cholesterol 87 160,872 1.00 Reference 1.00 Reference
  History of high cholesterol 141 321,436 0.78 0.60, 1.03 0.77 0.58, 1.01
 HPFS
  No history of high cholesterol 44 74,255 1.00 Reference 1.00 Reference
  History of high cholesterol 61 94,839 1.07 0.73, 1.59 1.06 0.71, 1.57
 Pooled†
  No history of high cholesterol 131 235,127 1.00 Reference 1.00 Reference
  History of high cholesterol 202 416, 275 0.89 0.66, 1.20 0.87 0.64, 1.19
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*

Adjusted for family history of melanoma (yes vs. no), natural hair color (red, blonde, light brown, dark brown, black), number of arm moles (0, 1–2, 3–9, ≥10), sunburn susceptibility as a child/adolescent (none/some redness, burn, painful burn/blisters), number of lifetime blistering sunburns (0, 1–4, 5–9, ≥10), cumulative UV flux since baseline (quintiles), body mass index (<25.0, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), physical activity (quintiles), smoking status (never, past, or current), total energy intake (quintiles), alcohol (0, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0 g/d), and citrus intake (quintiles). Analyses for women were also adjusted for menopausal status and postmenopausal hormone use.

†

The multivariate-adjusted hazard ratios from each cohort were combined with meta-analytic methods using random effects model.

Among participants with a history of high cholesterol, we did not find significant associations between statin use and risk of BCC, SCC, or melanoma in either women or men (Table 3). In a pooled analysis of the cohorts, the HR [95% CI] was 1.04 [0.99, 1.09] for BCC, 1.08 [0.94, 1.24] for SCC, and 1.04 [0.78, 1.38] for melanoma.

Table 3.

Age- and Multivariable-Adjusted Relative Risks of Skin Cancer Among Women and Men with a History of High Cholesterol, According to Statin use, Nurses’ Health Study (NHS, 2000–2010) and Health Professionals Follow-Up Study (HPFS, 2000–2010)

No. of Cases Person-Years Age-Adjusted RR 95% CI Multivariable-Adjusted RR* 95% CI
Basal cell carcinoma
 NHS
  No statin use 2,646 176,403 1.00 Reference 1.00 Reference
  Statin use 2,426 142,548 1.01 0.95, 1.07 1.03 0.97, 1.09
 HPFS
  No statin use 742 43,444 1.00 Reference 1.00 Reference
  Statin use 960 49,752 1.07 0.97, 1.18 1.07 0.97, 1.18
 Pooled†
  No statin use 3,388 219,847 1.00 Reference 1.00 Reference
  Statin use 3,386 192,300 1.03 0.97, 1.08 1.04 0.99, 1.09
Squamous cell carcinoma
 NHS
  No statin use 319 177,555 1.00 Reference 1.00 Reference
  Statin use 267 143,489 0.99 0.84, 1.17 1.03 0.87, 1.22
 HPFS
  No statin use 117 44,097 1.00 Reference 1.00 Reference
  Statin use 170 50,561 1.15 0.91, 1.46 1.18 0.93, 1.50
 Pooled†
  No statin use 436 221,652 1.00 Reference 1.00 Reference
  Statin use 437 194,050 1.04 0.90, 1.20 1.08 0.94, 1.24
Melanoma
 NHS
  No statin use 73 177,778 1.00 Reference 1.00 Reference
  Statin use 68 143,657 1.11 0.79, 1.55 1.11 0.79, 1.56
 HPFS
  No statin use 30 44,173 1.00 Reference 1.00 Reference
  Statin use 31 50,666 0.94 0.56, 1.58 0.89 0.52, 1.50
 Pooled†
  No statin use 103 221,951 1.00 Reference 1.00 Reference
  Statin use 99 194,323 1.06 0.80, 1.40 1.04 0.78, 1.38
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*

Adjusted for family history of melanoma (yes vs. no), natural hair color (red, blonde, light brown, dark brown, black), number of arm moles (0, 1–2, 3–9, ≥10), sunburn susceptibility as a child/adolescent (none/some redness, burn, painful burn/blisters), number of lifetime blistering sunburns (0, 1–4, 5–9, ≥10), cumulative UV flux since baseline (quintiles), body mass index (<25.0, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), physical activity (quintiles), smoking status (never, past, or current), total energy intake (quintiles), alcohol (0, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0 g/d), and citrus intake (quintiles). Analyses for women were also adjusted for menopausal status and postmenopausal hormone use.

†

The multivariate-adjusted hazard ratios from each cohort were combined with meta-analytic methods using random effects model.

Duration of statin use was not associated with risk of BCC (P-trend = 0.86), SCC (P-trend = 0.89), or melanoma (P-trend = 0.68) among women (Table 4). Longer duration of statin use was associated with increased risk of BCC (P-trend = 0.003) among men. Men who reported statin use for 3–4 years, 5–6 years, and >8 years had an approximately 7%, 12%, and 28% higher risk of BCC, respectively, compared with men who reported <1 year of statin use. Duration of statin use was not associated with risk of SCC (P-trend = 0.09) or melanoma among men (P-trend = 0.80). In a pooled analysis of the cohorts, longer duration of statin use was not associated with risk of BCC (P-trend = 0.20), SCC (P-trend = 0.28) or melanoma (P-trend = 0.68).

Table 4.

Age- and Multivariable-Adjusted Relative Risks of Skin Cancer Among Women and Men with a History of High Cholesterol, According to Duration of Statin use, Nurses’ Health Study (NHS, 2000–2010) and Health Professionals Follow-Up Study (HPFS, 2000–2010)

No. of Cases Person-Years Age-Adjusted RR 95% CI Multivariable-Adjusted RR* 95% CI
Basal cell carcinoma
 NHS
  <1 year statin use 2,322 158,556 1.00 Reference 1.00 Reference
  1–2 years statin use 788 50,908 1.02 0.94, 1.11 1.05 0.96, 1.14
  3–4 years statin use 658 41,587 0.99 0.91, 1.08 1.01 0.93, 1.11
  5–6 years statin use 491 26,515 1.04 0.94, 1.15 1.07 0.96, 1.18
  7–8 years statin use 393 20,693 1.02 0.92, 1.14 1.05 0.94, 1.17
  >8 years statin use 420 20,692 0.93 0.83, 1.03 0.95 0.85, 1.06
P-trend = 0.86
 HPFS
  <1 year statin use 660 39,363 1.00 Reference 1.00 Reference
  1–2 years statin use 235 13,890 0.98 0.84, 1.14 0.98 0.85, 1.14
  3–4 years statin use 265 14,140 1.06 0.92, 1.23 1.07 0.93, 1.24
  5–6 years statin use 191 9,473 1.12 0.95, 1.32 1.12 0.95, 1.32
  7–8 years statin use 138 7,067 1.07 0.89, 1.30 1.07 0.89, 1.30
  >8 years statin use 213 9,263 1.28 1.08, 1.50 1.28 1.08, 1.50
P-trend = 0.003
 Pooled†
  <1 year statin use 2,982 197,918 1.00 Reference 1.00 Reference
  1–2 years statin use 1,023 64,798 1.02 0.95, 1.10 1.03 0.96, 1.11
  3–4 years statin use 923 55,727 1.04 0.96, 1.12 1.05 0.97, 1.13
  5–6 years statin use 682 35,989 1.09 1.00, 1.18 1.09 1.00, 1.19
  7–8 years statin use 531 27,761 1.05 0.96, 1.15 1.05 0.95, 1.15
  >8 years statin use 633 29,955 1.04 0.95, 1.14 1.03 0.94, 1.13
P-trend = 0.20
Squamous cell carcinoma
 NHS
  <1 year statin use 294 159,586 1.00 Reference 1.00 Reference
  1–2 years statin use 77 51,278 0.80 0.62, 1.02 0.85 0.66, 1.09
  3–4 years statin use 85 41,849 1.04 0.82, 1.33 1.10 0.86, 1.40
  5–6 years statin use 55 26,686 1.04 0.77, 1.40 1.09 0.81, 1.47
  7–8 years statin use 40 20,828 0.94 0.67, 1.32 0.96 0.69, 1.35
  >8 years statin use 35 20,817 0.84 0.59, 1.21 0.86 0.60, 1.24
P-trend = 0.89
 HPFS
  <1 year statin use 102 39,943 1.00 Reference 1.00 Reference
  1–2 years statin use 39 14,082 1.02 0.71, 1.48 1.04 0.72, 1.51
  3–4 years statin use 40 14,374 1.02 0.71, 1.48 1.07 0.74, 1.55
  5–6 years statin use 50 9,636 1.83 1.28, 2.61 1.89 1.32, 2.70
  7–8 years statin use 20 7,187 0.91 0.56, 1.50 0.95 0.58, 1.56
  >8 years statin use 36 9,435 1.28 0.86, 1.92 1.31 0.87, 1.96
P-trend = 0.09
 Pooled†
  <1 year statin use 396 199,529 1.00 Reference 1.00 Reference
  1–2 years statin use 116 65,360 0.87 0.71, 1.07 0.90 0.73, 1.11
  3–4 years statin use 125 56,224 1.07 0.87, 1.30 1.08 0.88, 1.32
  5–6 years statin use 105 36,322 1.36 1.09, 1.70 1.35 1.08, 1.68
  7–8 years statin use 60 28,015 1.00 0.76, 1.31 0.97 0.73, 1.28
  >8 years statin use 71 30,252 1.10 0.84, 1.43 1.04 0.79, 1.35
P-trend = 0.28
Melanoma
 NHS
  <1 year statin use 68 159,792 1.00 Reference 1.00 Reference
  1–2 years statin use 25 51,315 1.13 0.71, 1.78 1.13 0.71, 1.80
  3–4 years statin use 18 41,907 0.95 0.56, 1.60 0.96 0.57, 1.62
  >4 years statin use 30 68,422 0.92 0.59, 1.45 0.93 0.59, 1.47
P-trend = 0.68
 HPFS
  <1 year statin use 26 40, 008 1.00 Reference 1.00 Reference
  1–2 years statin use 11 14,109 1.24 0.61, 2.53 1.22 0.60, 2.49
  3–4 years statin use 6 14,397 0.67 0.27, 1.64 0.67 0.27, 1.66
  >4 years statin use 18 26,326 1.11 0.58, 2.12 1.02 0.52, 1.97
P-trend = 0.80
 Pooled†
  <1 year statin use 94 199,800 1.00 Reference 1.00 Reference
  1–2 years statin use 36 65,424 1.18 0.80, 1.73 1.18 0.80, 1.74
  3–4 years statin use 24 56,304 0.89 0.56, 1.40 0.89 0.56, 1.39
  >4 years statin use 48 94,747 1.00 0.70, 1.44 0.97 0.67, 1.41
P-trend = 0.68
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*

Adjusted for family history of melanoma (yes vs. no), natural hair color (red, blonde, light brown, dark brown, black), number of arm moles (0, 1–2, 3–9, ≥10), sunburn susceptibility as a child/adolescent (none/some redness, burn, painful burn/blisters), number of lifetime blistering sunburns (0, 1–4, 5–9, ≥10), cumulative UV flux since baseline (quintiles), body mass index (<25.0, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), physical activity (quintiles), smoking status (never, past, or current), total energy intake (quintiles), alcohol (0, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0 g/d), and citrus intake (quintiles). Analyses for women were also adjusted for menopausal status and postmenopausal hormone use.

†

The multivariate-adjusted hazard ratios from each cohort were combined with meta-analytic methods using random effects model

An analysis of type of statin use and risk of BCC, SCC, and melanoma (Table 5) demonstrated lower risk of BCC with pravastatin use compared with no statin use in men (MVRR = 0.62; 95% CI = 0.41, 0.93) and a lower risk of BCC with pravastatin use compared with no statin use in men and women combined (MVRR = 0.88; 95% CI = 0.79, 0.99). There was a higher risk of SCC with lovastatin use compared with no statin use in women (MVRR = 1.82; 95% CI = 1.15, 2.88), and a higher risk of SCC with lovastatin use compared with no statin use in men and women combined (MVRR = 1.77; 95% CI = 1.20, 2.63).

Table 5.

Age- and Multivariable-Adjusted Relative Risks of Skin Cancer Among Women and Men with a History of High Cholesterol, According to Type of Statin use, Nurses’ Health Study (NHS, 2004–2010) and Health Professionals Follow-Up Study (HPFS, 2004–2010)

No. of Cases Person-Years Age-Adjusted RR 95% CI Multivariable-Adjusted RR* 95% CI
Basal cell carcinoma
 NHS
  No statin use 1583 87,512 1.00 Reference 1.00 Reference
  Lovastatin use 117 5,797 1.06 0.88, 1.28 1.04 0.86, 1.26
  Simvastatin use 394 17,803 1.02 0.91, 1.14 1.03 0.92, 1.16
  Rosuvastatin use 198 10,288 1.07 0.92, 1.24 1.08 0.93, 1.25
  Pravastatin use 337 22,202 0.92 0.82, 1.04 0.94 0.83, 1.06
  Atorvastatin use 576 28,877 1.02 0.92, 1.12 1.03 0.94, 1.14
 HPFS
  No statin use 360 19,484 1.00 Reference 1.00 Reference
  Lovastatin use 29 1,406 1.06 0.72, 1.55 1.01 0.69, 1.47
  Simvastatin use 197 8,637 1.15 0.97, 1.37 1.15 0.96, 1.37
  Rosuvastatin use 19 1,439 0.75 0.47, 1.20 0.75 0.47, 1.20
  Pravastatin use 25 2,124 0.62 0.41, 0.93 0.62 0.41, 0.93
  Atorvastatin use 291 14,261 1.11 0.95, 1.30 1.11 0.95, 1.30
 Pooled†
  No statin use 1,943 106,996 1.00 Reference 1.00 Reference
  Lovastatin use 146 7,203 1.06 0.89, 1.25 1.03 0.87, 1.22
  Simvastatin use 591 26,440 1.10 1.00, 1.20 1.09 1.00, 1.20
  Rosuvastatin use 217 11,727 1.00 0.87, 1.15 1.01 0.88, 1.16
  Pravastatin use 362 24,325 0.86 0.77, 0.96 0.88 0.79, 0.99
  Atorvastatin use 867 43,138 1.07 0.99, 1.16 1.07 0.99, 1.16
Squamous cell carcinoma
 NHS
  No statin use 162 88,126 1.00 Reference 1.00 Reference
  Lovastatin use 21 5,825 1.87 1.18, 2.95 1.82 1.15, 2.88
  Simvastatin use 27 17,919 0.88 0.58, 1.33 0.91 0.60, 1.37
  Rosuvastatin use 23 10,362 1.13 0.73, 1.77 1.17 0.75, 1.83
  Pravastatin use 45 22,343 0.99 0.70, 1.40 1.03 0.73, 1.45
  Atorvastatin use 44 29,080 0.86 0.61, 1.21 0.89 0.63, 1.26
 HPFS
  No statin use 56 19,795 1.00 Reference 1.00 Reference
  Lovastatin use 7 1,432 1.52 0.68, 3.39 1.55 0.70, 3.44
  Simvastatin use 27 8,789 1.01 0.63, 1.60 1.02 0.64, 1.62
  Rosuvastatin use 4 1,452 0.86 0.31, 2.39 0.91 0.33, 2.52
  Pravastatin use 11 2,141 1.85 0.97, 3.53 1.78 0.92, 3.42
  Atorvastatin use 52 14,512 1.29 0.88, 1.89 1.31 0.89, 1.92
 Pooled†
  No statin use 218 107,920 1.00 Reference 1.00 Reference
  Lovastatin use 28 7,257 1.83 1.23, 2.71 1.77 1.20, 2.63
  Simvastatin use 54 26,708 0.95 0.75, 1.37 0.94 0.69, 1.27
  Rosuvastatin use 27 11,814 1.05 0.71, 1.60 1.15 0.77, 1.73
  Pravastatin use 56 24,484 1.07 0.78, 1.42 1.16 0.85, 1.56
  Atorvastatin use 96 43,592 1.11 0.88, 1.43 1.04 0.81, 1.33
Melanoma
 NHS
  No statin use 40 88,241 1.00 Reference 1.00 Reference
  Lovastatin use 3 5,839 1.11 0.34, 3.61 1.10 0.34, 3.59
  Simvastatin use 6 17,939 0.70 0.29, 1.68 0.73 0.30, 1.74
  Rosuvastatin use 7 10,376 1.41 0.62, 3.20 1.46 0.64, 3.33
  Pravastatin use 15 22,364 1.41 0.76, 2.62 1.39 0.74, 2.60
  Atorvastatin use 12 29,105 0.96 0.50, 1.87 0.96 0.49, 1.88
 HPFS
  No statin use 13 19,835 1.00 Reference 1.00 Reference
  Lovastatin use 2 1,437 2.01 0.44, 9.15 1.88 0.38, 9.37
  Simvastatin use 6 8,805 1.05 0.40, 2.80 1.05 0.38, 2.89
  Rosuvastatin use 0 1,458 0.00 0.00, 0.00 0.00 0.00, 0.00
  Pravastatin use 2 2,145 1.50 0.33, 6.73 1.53 0.32, 7.24
  Atorvastatin use 7 14,545 0.88 0.35, 2.22 0.76 0.29, 1.99
 Pooled†
  No statin use 53 108,077 1.00 Reference 1.00 Reference
  Lovastatin use 5 7,276 1.32 0.53, 3.32 1.30 0.51, 3.30
  Simvastatin use 12 26,744 0.87 0.46, 1.64 0.87 0.46, 1.64
  Rosuvastatin use 7 11,834 1.20 0.54, 2.66 1.22 0.54, 2.71
  Pravastatin use 17 24,510 1.37 0.78, 2.41 1.39 0.79, 2.45
  Atorvastatin use 19 43,650 0.93 0.55, 1.58 0.90 0.52, 1.54
Open in a new tab
*

Adjusted for family history of melanoma (yes vs. no), natural hair color (red, blonde, light brown, dark brown, black), number of arm moles (0, 1–2, 3–9, ≥10), sunburn susceptibility as a child/adolescent (none/some redness, burn, painful burn/blisters), number of lifetime blistering sunburns (0, 1–4, 5–9, ≥10), cumulative UV flux since baseline (quintiles), body mass index (<25.0, 25.0–29.9, 30.0–34.9, ≥35.0 kg/m2), physical activity (quintiles), smoking status (never, past, or current), total energy intake (quintiles), alcohol (0, 0.1–4.9, 5.0–9.9, 10.0–19.9, ≥20.0 g/d), and citrus intake (quintiles). Analyses for women were also adjusted for menopausal status and postmenopausal hormone use.

†

The multivariate-adjusted hazard ratios from each cohort were combined with meta-analytic methods using random effects model.

A secondary analysis for melanoma was conducted without excluding participants having a history of BCC or SCC at baseline, but instead adjusting for history of BCC and SCC, and did not materially change the results. Accounting for oral steroid use did not materially change our results. Accounting for health screening among participants did not change our results either (data not shown).

DISCUSSION

History of high cholesterol was not associated with risk of BCC or SCC in women and men. Statin use among participants with a history of high cholesterol was not associated with risk of SCC, BCC, or melanoma, but there was a significant trend towards higher risk of BCC with longer duration of statin use in men.

High cholesterol has been associated with increased risk of developing some cancers including prostate cancer.13, 14 Cellular mechanisms associated with impaired cholesterol homeostasis have been associated with higher risk of cancer. Inhibition of the ABCA1 gene – which in normal cells mediates transfer of cholesterol across the plasma membrane – has been associated with increased mitochondrial cholesterol, which inhibits the release of mitochondrial apoptosis-promoting molecules, thus facilitating cancer cell survival.7 Our data shows no association between high cholesterol and risk of BCC, SCC, or melanoma in HPFS and NHS.

Previous studies present conflicting evidence with regards to the association between statin use and KC, reporting positive,28–31 negative,37–39 or no associations.40–43 A recent large epidemiological study in the Women’s Health Initiative demonstrated an increased risk of KC with statin use.44 However, their data were limited by the self-reported nature of KCs, and lack of malignancy diagnosis date. Some studies suggest statin use may increase risk of KC due to increased regulatory T cells secondary to immunomodulation,45–47 and statins have been associated with inhibition of the ras signaling pathway,20–22 which has been associated with development of KCs.24–26 There is increasing evidence that suggests a higher incidence of KCs among immunosuppressed individuals,48 and thus, the potential immunosuppressive behavior of statins may serve to increase risk of KCs among statin users.23 Conversely, statin-induced changes in other cellular pathways have been associated with decreased risk of KC.16, 49–54 Our data showed no association between any statin use and risk of BCC, SCC, or melanoma. However, there was a significant trend towards higher risk of BCC with longer duration of statin use in men, but no association between risk of BCC with duration of statin use in women. This finding suggests that there may be differences between the physiological consequences of long-term statin exposure between men and women. Further, it suggests that the potential effects of statin use may be the result of cumulative, long-term exposure to statins.

Statins have been shown to have inhibitory effects on human melanoma cells secondary to inhibition of angiogenesis, cell growth,18, 19, 55 and promoting apoptosis.17, 56 A recent meta-analysis that included data from a number of randomized controlled trials and cohort studies demonstrated no association between statin use and risk of melanoma.42 Further, a prospective study in postmenopausal women demonstrated no association between statin use and risk of melanoma.27 In our study, there was no association between statin use or risk of melanoma in men or in women.

Different statins have been shown to have varying degrees of solubility in octanol (lipophilicity) and lipid-lowering potency.57–60 A previous study examining the association between statin type and risk of keratinocyte carcinomas demonstrated higher odds of KC with lovastatin use and simvastatin use compared with no statin use in women, which the authors suggested may be related to varying lipophilicity and potency of these drugs.29 In our study, we found a higher risk of SCC with lovastatin use compared with no statin use in men and women, which is consistent with the findings from the previous study. However, we found no association between risk of SCC or BCC with simvastatin use in our study, and a lower risk of BCC with pravastatin use compared with no statin use in men. These findings suggest the association between statin use and risk of BCC may differ by statin type.

Our study has limitations. History of high cholesterol and statin use was self-reported, and we lacked information on duration of statin use prior to the baseline year. Although we were able to determine duration of statin use, our study lacked information on statin dose in participants. However, data were prospectively collected over 10 years in this study, and information provided by these cohorts has been shown to be highly reliable in previous studies.32, 61–63 We adjusted for many potential confounders in our multivariable models, but given the relatively few cases of melanoma in our cohort, the interpretability of our melanoma analyses may be limited. However, it is worth nothing that our findings are consistent with results from a previous large prospective study on the relation between statin use and risk of melanoma.27 We limited our analyses to white participants, given the small sample size and lack of skin cancer cases in other ethnicities.

In conclusion, history of high cholesterol was not associated with risk of keratinocyte carcinomas or melanoma, and longer duration of statin use may be associated with higher risk of basal cell carcinoma in men. Our data suggest there may be differences in the physiological consequences of long-term statin exposure and risk of skin cancers between men and women. Individuals using statins long-term may benefit from counseling on the importance of routine self-surveillance and health screening.

Acknowledgments

We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, WY.

Funding: This work was supported by the National Institutes of Health grants for the Nurses’ Health Study (UM1 CA186107 and P01 CA87969) and the Health Professionals Follow-up Study (UM1 CA167552), and the Research Career Development Award of Dermatology Foundation (WL). The sponsors of this study had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

ABBREVIATIONS

KCs

Keratinocyte carcinomas

SCC

Squamous cell carcinoma

BCC

Basal cell carcinoma

NHS

Nurses’ Health Study

HPFS

Health Professionals Follow-up Study

MVRR

Multivariable adjusted relative risk

Footnotes

Conflict of Interest Disclosure: Dr. Qureshi has received honoraria from AbbVie, Amgen, the Centers for Disease Control and Prevention, Janssen, Merck, Pfizer, and Novartis (consultant). Dr. Qureshi is an investigator (without financial compensation) for Sanofi and Regeneron.

Reprint requests: Brian Lin

Statement of prior presentation: This data has not been presented or published elsewhere.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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