J Clin Med Res

Journal of Clinical Medicine Research, ISSN 1918-3003 print, 1918-3011 online, Open Access

Article copyright, the authors; Journal compilation copyright, J Clin Med Res and Elmer Press Inc

Journal website http://www.jocmr.org

Original Article

Volume 11, Number 4, April 2019, pages 247-255

Association Between the Use of Thiazide Diuretics and the Risk of Skin Cancers: A Meta-Analysis of Observational Studies

Figure 2. The risk of skin cancers among those who used thiazide diuretics. OR: odds ratio; RR: relative risk. *Weights are from random-effects analysis.

Figure 3. Subgroup meta-analysis on the use of HCTZ or HCTZ combination medications and the risk of skin cancers. HCTZ: hydrochlorothiazide; OR: odds ratio; RR: relative risk. *Weights are from random-effects analysis.

Figure 4. Funnel plots of studies for the use of thiazide diuretics and the risk of skin cancers. (a) Basal cell carcinoma, (b) squamous cell carcinoma, and (c) malignant melanoma.

**Table 1.** Characteristics of Studies Included in the Final Analysis of Thiazide Diuretics and Skin Cancer
Study	Country	Study design	Medication	Outcome	Study population (case group or cohort)	Exposed/ unexposed	RR or OR (95% CI)	Adjusted RR or OR (95% CI)	Study period (year)	Adjustment
BCC: basal cell carcinoma; SCC: squamous cell carcinoma; MM: malignant melanoma; HCTZ: hydrochlorothiazide; RR: risk ratio; OR: odds ratio; CI: confidence interval; NA: not available; USA: United States of America.
Pottegard 2017	Denmark	Case-control	HCTZ	SCC	Mean age 72, men 67.3%	Cases: 139/494, controls:7,401/55,666	2.2 (1.8 - 2.6)	2.1 (1.7 - 2.6)	2004 - 2012	Adjusted for age, gender, calendar time, use of topical retinoids, oral retinoids, tetracycline, macrolides, aminoquinolines, amiodarone, aspirin, non-aspirin non-steroidal anti-inflammatory drugs, statins, history of heavy alcohol consumption, diabetes, or chronic obstructive pulmonary disease, non-melanoma skin cancer, Charlson Comorbidity Index score, and highest achieved education
Nardone 2017	USA	Cohort	Thiazides	BCC	Age 18 - 89, men 37.5%, white 34%	Cases: 262/457, controls: 15,166/45,498	1.73 (1.49 - 2.02)	2.11 (1.60 - 2.79)	2004 - 2014	Matched for age and time to follow-up, and adjusted for age, gender, race, and the Charlson Comorbidities Index
				SCC		Cases: 130/132, controls: 15,166/45,498	2.97 (2.33 - 3.79)	4.11 (2.66 - 6.35)
				MM		Cases: 99/145, controls:15,166/45,498	2.06 (1.59 - 2.66)	1.82 (1.01 - 3.82)
Schmidt 2015	Denmark	Case-control	Thiazides	BCC	Median age 67, men 50%	Cases: 2,710/10,473, controls: 26,504/107,016	NA	1.05 (1.00 - 1.11)	1991 - 2010	Matched for birth year, sex and county of residence, and adjusted for Charlson Comorbidity Index score, hospital-diagnosed obesity and use of systemic glucocorticoids, aspirin, non-aspirin non-steroidal, anti-inflammatory drugs and statins
				SCC	Median age 77, men 63%	Cases: 447/1,135, controls: 4,458/12,007	NA	1.03 (0.91 - 1.17)
				MM	Median age 58, men 46%	Cases: 403/2,648, controls: 3,786/26,686	NA	1.11 (0.97 - 1.25)
Robinson 2013	USA	Case-control	HCTZ or combination	SCC	Age 25 - 74, men 61.7%	Cases: 1,599 in total, controls: 1,906 in total	NA	1.3 (0.7 - 2.4)	1993 - 2009	Matched for age and sex, and adjusted for age, sex, and number of previous painful sunburns
de Vries 2012	Europe (multi-center)	Case-control	Thiazides	BCC	Median age 72, men 59.6%	Case: 94/508, control: 136/1,414	1.92 (NA)	1.27 (0.92 - 1.75)	NA	Matched for age and sex, and adjusted for age, sex, skin photo-type and country
				SCC	Median age 76, men 70.2%	Case: 99/310, control: 136/1,414	3.32 (NA)	1.66 (1.16 - 2.37)
				MM	Median age 62, men 54.4%	Cases: 33/327, control: 136/1,414	1.05 (NA)	1.22 (0.77 - 1.93)
Friedman 2012	USA	Case-control	HCTZ or combination	SCC	Mean age 68, men 74.4%, non-Hispanic white 100%	Cases: 103/609, controls: 1,896/21,008	2.22 (1.76 - 2.79)	2.19 (1.74 - 2.76)	1994 - 2008	Matched for age, sex, and year of entry into the cohort, and adjusted for smoking
Ruiter 2010	Netherlands	Cohort	Thiazides	BCC	Mean age 69, men 40%	137/385	NA	1.00 (0.95 - 1.05)	1991 - 2007	Adjusted for age and gender, and none of the potential covariates was a confounder
Jensen 2008	Denmark	Case-control	HCTZ	BCC	Mean age 69	Cases: 542/5,422, controls: 2,059/21,797	NA	1.05 (0.95 - 1.16)	1989 - 2003	Matched for age and sex, and adjusted for prior hospitalization for selected chronic diseases and use of glucocorticoids
				SCC	Mean age 77	Cases: 159/910, controls: 427/4,089	NA	1.58 (1.29 - 1.93)
				MM	Mean age 59	Cases: 98/912, controls: 303/3,737	NA	1.32 (1.03 - 1.70)
Westerdahl 1996	Sweden	Case-control	Thiazide	MM	Age 15 - 75, men 46.6%	Cases: 20/328, controls: 25/535	1.4 (0.7 - 2.7)	1.4 (0.7 - 2.8)	1988 - 1990	Matched for sex, age, parish, and adjusted for history of sunburns and host factors (hair color, number of raised naevi)

Table 1. Characteristics of Studies Included in the Final Analysis of Thiazide Diuretics and Skin Cancer

Study

Country

Study design

Medication

Outcome

Study population (case group or cohort)

Exposed/ unexposed

RR or OR (95% CI)

Adjusted RR or OR (95% CI)

Study period (year)

Adjustment

BCC: basal cell carcinoma; SCC: squamous cell carcinoma; MM: malignant melanoma; HCTZ: hydrochlorothiazide; RR: risk ratio; OR: odds ratio; CI: confidence interval; NA: not available; USA: United States of America.

Pottegard 2017

Denmark

Case-control

HCTZ

SCC

Mean age 72, men 67.3%

Cases: 139/494, controls:7,401/55,666

2.2 (1.8 - 2.6)

2.1 (1.7 - 2.6)

2004 - 2012

Adjusted for age, gender, calendar time, use of topical retinoids, oral retinoids, tetracycline, macrolides, aminoquinolines, amiodarone, aspirin, non-aspirin non-steroidal anti-inflammatory drugs, statins, history of heavy alcohol consumption, diabetes, or chronic obstructive pulmonary disease, non-melanoma skin cancer, Charlson Comorbidity Index score, and highest achieved education

Nardone 2017

USA

Cohort

Thiazides

BCC

Age 18 - 89, men 37.5%, white 34%

Cases: 262/457, controls: 15,166/45,498

1.73 (1.49 - 2.02)

2.11 (1.60 - 2.79)

2004 - 2014

Matched for age and time to follow-up, and adjusted for age, gender, race, and the Charlson Comorbidities Index

SCC

Cases: 130/132, controls: 15,166/45,498

2.97 (2.33 - 3.79)

4.11 (2.66 - 6.35)

Cases: 99/145, controls:15,166/45,498

2.06 (1.59 - 2.66)

1.82 (1.01 - 3.82)

Schmidt 2015

Denmark

Case-control

Thiazides

BCC

Median age 67, men 50%

Cases: 2,710/10,473, controls: 26,504/107,016

1.05 (1.00 - 1.11)

1991 - 2010

Matched for birth year, sex and county of residence, and adjusted for Charlson Comorbidity Index score, hospital-diagnosed obesity and use of systemic glucocorticoids, aspirin, non-aspirin non-steroidal, anti-inflammatory drugs and statins

SCC

Median age 77, men 63%

Cases: 447/1,135, controls: 4,458/12,007

1.03 (0.91 - 1.17)

Median age 58, men 46%

Cases: 403/2,648, controls: 3,786/26,686

1.11 (0.97 - 1.25)

Robinson 2013

USA

Case-control

HCTZ or combination

SCC

Age 25 - 74, men 61.7%

Cases: 1,599 in total, controls: 1,906 in total

1.3 (0.7 - 2.4)

1993 - 2009

Matched for age and sex, and adjusted for age, sex, and number of previous painful sunburns

de Vries 2012

Europe (multi-center)

Case-control

Thiazides

BCC

Median age 72, men 59.6%

Case: 94/508, control: 136/1,414

1.92 (NA)

1.27 (0.92 - 1.75)

Matched for age and sex, and adjusted for age, sex, skin photo-type and country

SCC

Median age 76, men 70.2%

Case: 99/310, control: 136/1,414

3.32 (NA)

1.66 (1.16 - 2.37)

Median age 62, men 54.4%

Cases: 33/327, control: 136/1,414

1.05 (NA)

1.22 (0.77 - 1.93)

Friedman 2012

USA

Case-control

HCTZ or
combination

SCC

Mean age 68, men 74.4%, non-Hispanic white 100%

Cases: 103/609, controls: 1,896/21,008

2.22 (1.76 - 2.79)

2.19 (1.74 - 2.76)

1994 - 2008

Matched for age, sex, and year of entry into the cohort, and adjusted for smoking

Ruiter 2010

Netherlands

Cohort

Thiazides

BCC

Mean age 69, men 40%

137/385

1.00 (0.95 - 1.05)

1991 - 2007

Adjusted for age and gender, and none of the potential covariates was a confounder

Jensen 2008

Denmark

Case-control

HCTZ

BCC

Mean age 69

Cases: 542/5,422, controls: 2,059/21,797

1.05 (0.95 - 1.16)

1989 - 2003

Matched for age and sex, and adjusted for prior hospitalization for selected chronic diseases and use of glucocorticoids

SCC

Mean age 77

Cases: 159/910, controls: 427/4,089

1.58 (1.29 - 1.93)

Mean age 59

Cases: 98/912, controls: 303/3,737

1.32 (1.03 - 1.70)

Westerdahl 1996

Sweden

Case-control

Thiazide

Age 15 - 75, men 46.6%

Cases: 20/328, controls: 25/535

1.4 (0.7 - 2.7)

1.4 (0.7 - 2.8)

1988 - 1990

Matched for sex, age, parish, and adjusted for history of sunburns and host factors (hair color, number of raised naevi)

**Table 2.** Subgroup Analyses for Use of Thiazides and Risk of Skin Cancers Using Random-Effects Model
	No. of studies	OR (95% CI)	I² (%)	Q-statistics	P value
I²: Higgins score; NA: not available. *More than 4.5 years.
Basal cell carcinoma
Duration of use, long-term use*	2	1.10 (0.96 - 1.25)	0.0	0.0	1.000
Study design
Case-control	2	1.08 (0.95 - 1.23)	89.6	1.3	0.252
Cohort	2	1.43 (0.69 - 2.98)	96.3	26.8	< 0.001
Squamous cell carcinoma
Duration of use, long-term use*	3	3.30 (1.85 - 5.89)	90.7	21.4	< 0.001
Study design
Case-control	5	1.61 (1.08 - 2.38)	92.3	52.3	< 0.001
Cohort	1	NA	NA	NA	NA
Malignant melanoma
Duration of use, long-term use*	1	NA	NA	NA	NA
Study design
Case-control	3	1.13 (1.00 - 1.27)	0.0	0.6	0.761
Cohort	1	NA	NA	NA	NA

Table 2. Subgroup Analyses for Use of Thiazides and Risk of Skin Cancers Using Random-Effects Model

No. of studies

OR (95% CI)

I² (%)

Q-statistics

P value

I²: Higgins score; NA: not available. *More than 4.5 years.

Basal cell carcinoma

Duration of use, long-term use*

1.10 (0.96 - 1.25)

0.0

1.000

Study design

Case-control

1.08 (0.95 - 1.23)

89.6

1.3

0.252

Cohort

1.43 (0.69 - 2.98)

96.3

26.8

< 0.001

Squamous cell carcinoma

Duration of use, long-term use*

3.30 (1.85 - 5.89)

90.7

21.4

< 0.001

Study design

Case-control

1.61 (1.08 - 2.38)

92.3

52.3

< 0.001

Cohort

Malignant melanoma

Duration of use, long-term use*

Study design

Case-control

1.13 (1.00 - 1.27)

0.0

0.6

0.761

Cohort