Statin use and risk of cancer: An overview of meta-analyses

Table 1 Characteristics of the included meta-analyses

First author, Yeara (Country)b	Databases searched (Period)c	Studies included (n)	Studies published between (Years)	Total subjects involved	Total cancer cases	Heterogeneity presents?	Pooled RR (95%CI) for primary outcome (n)d	Pooled RR (95%CI) for secondary outcome (n)	Pooled RR (95%CI) for Sub-group analysise	AMSTAR score
Bladder cancer
Zhang X, 2013 (China)[15]	MEDLINE, EMBASE and Ovid (January 1966 to October 2012)	RCTs (3), Cohort (5) and CC (5)	2001-2012	1266268	2511	Yes (q = 0.001, I2 = 62.6%)	1.07 (0.95-1.21) (↔)	LSU = 1.21 (0.92-1.51) (8) (↔)	RCTs = 0.83 (0.63-1.10) (↔); Cohort = 1.11 (0.91-1.35) (↔); CC = 1.12 (0.98-1.28) (↔)	7
Breast cancer
Bonovas S, 2005 (Greece)[16]	MEDLINE (1966 to March2005) and SCI (1970 to March2005)	RCTs (7), Cohort (4) and CC (5)	1993-2005	327238	24599	No (q = 0.12, I2 = 30%)	1.03 (0.93-1.14) (↔)	None	RCTs = 1.04 (0.81-1.33) (↔) ; Cohort = 1.06 (0.92-1.21) (↔); CC = 0.99 (0.83-1.18) (↔)	7
Undela K, 2012 (India)[17]	PubMed (1966 to January 2012) and ASCO, AACR conference abstracts	Cohort (13) and CC (11)	1993-2011	2440988	76759	Yes (q < 0.001, I2 = 57%)	0.99 (0.94-1.04) (↔)	LSU = 1.03 (0.96-1.11) (10) (↔); Recurrence 0.53 (0.37-0.76) (2) (↓)	Cohort = 1.01 (0.98-1.04) (↔); CC = 0.95 (0.84-1.08) (↔)	5
Colorectal cancer
Bonovas S, 2007 (Greece)[18]	MEDLINE (1966 to December 2006) and WS (1970 to December 2006)	RCTs (6), Cohort (3) and CC (9)	2000-2007	1527721	38734	No (q = 0.35, I2 = 7%)	0.92 (0.90-0.95) (↓)	None	RCTs = 0.95 (0.81-1.11) (↔); Cohort = 0.96 (0.84-1.11) (↔); CC = 0.92 (0.89-0.95) (↓)	7
Bardou M, 2010 (Canada)f[47]	EMBASE, MEDLINE, CENTRAL, and ISI WK	RCTs (11)	NA	95984	1659	No (NA)	0.94 (0.85-1.04) (↔)	None	NA	--
Bardou M, 2010 (Canada)f[48]	EMBASE, MEDLINE, CENTRAL, and ISI WK	Cohort (8) and CC (13)	NA	1606234	NA	No (NA)	0.92 (0.87-0.98) (↓)	None	Cohort = 0.89 (0.75-1.05) (↔); CC = 0.92 (0.90-0.94) (↓)	--
Ditah I, 2010 (United States)[49]f	NA	RCTs (6), Cohort (6) and CC (12)	Up to Jun 2010	> 1.7 million	NA	NA	0.89 (0.85-0.94) (↓)	None	RCTs = 0.95 (0.80-1.13) (↔); Cohort = 0.89 (0.85-0.94) (↓); CC = 0.86 (0.79-0.94) (↓)	--
Samadder NJ, 2010 (United States)[50]f	MEDLINE, EMBASE, WS and abstracts of national GI conferences (up to October 2009)	Cohort (5) and CC (17)	NA	2.5 million	NA	Yes (q < 0.01, I2 = 47%)	0.88 (0.84-0.93) (↓)	Rectal = 0.81 (0.62-1.05) (8) (↓)	Cohort = 0.88 (0.84-0.93) (↓); CC = 0.90 (0.86-0.94) (↓)	--
Liu Y, 2014 (China)[19]	PubMed, EMBASE, WS, Cochrane Library (up to 30th July 2013)	RCTs (11), Cohort (13) and CC (18)	1995-2013	7908674	519317	Yes (q < 0.001, I2 = 66.5%)	0.90 (0.86-0.95) (↓)	LSU = 0.96 (0.88-1.04) (20) (↔)	RCTs = 0.96, (0.85-1.08) (↔); Cohort = 0.93 (0.87-0.99) (↓); CC = 0.84 (0.76-0.93) (↓)	7
Lytras T, 2014 (Greece)[20]	MEDLINE (1966 to July 2013)	RCTs (8), Cohort (13) and CC (19)	1996-2013	8224019	130992	Yes (q < 0.001, I2 = 71%)	0.91 (0.87-0.96) (↓)	None	RCTs = 0.90 (0.78-1.04) (↔); Cohort = 0.91 (0.83-1.00) (↓); CC = 0.92 (0.87-0.98) (↓)	0034
Gastric cancer
Shimoyama S, 2011 (Japan)[21]	PubMed Central (1993 to 2008)	RCTs (6)	1994-2007	37851	284	No (q = 0.42, I2 = 0.0%)	1.37 (0.57-3.25) (3) (↔)	UGIC = 1.20 (0.94-1.53) (3) (↔)	None	0
Singh PP, 2013 (United States)[22]	PubMed (1966 to 1st December 2012), EMBASE (1988 to	RCTs (post-hoc analyses) (3),	2004-2012	5459975	5581	Yes (q < 0.01, I2 = 89%)	0.68 (0.51-0.91) (↓)	None	RCTs = 0.83 (0.66-1.05) (↔); OSs = 0.65 (0.45-0.93) (↓)	8
	1st December 2012) and WS (1993 to 1st December 2012)	Cohort (1) and CC (7)
Wu X, 2013 (China)[23]	PubMed and EMBASE (up to March 2013)	RCTs (3), Cohort (3) and CC (5)	2004-2013	1136918	7611	Yes (q < 0.001, I2 = 88.9%)	0.73 (0.58-0.93) (↓)	None	RCTs = 0.84 (0.61-1.14) (↔); Cohort = 0.87 (0.77-0.99) (↓); CC = 0.56 (0.31-1.01) (↔)	6
Ma Z, 2014 (China)[24]	Cochrane CRCT (Issue 12, 2012), PubMed, EMBASE, ISI WK, CNKI, CBML, CSJFD and Wanfang Database	CC (6)	2004-2013	60793	5993	Yes (q < 0.001, I2 = 97%)	0.56 (0.35-0.90) (↓)	None	None	6
Gynaecologic cancer
Liu Y, 2014 (China)[25]	PubMed, EMBASE and Cochrane Library (up to 10th February 2014)	RCTs (4), Cohort (5) and CC (5)	2000-2013	928721	12904	Yes (q = 0.016, I2 = 42.3%)	0.89 (0.78-1.01) (↔)	Endometrial = 0.90 (0.75-1.07) (10) (↔); Ovarian = 0.79 (0.64-0.98) (5) (↓)	RCTs = 0.97 (0.62-1.50) (↔); Cohort = 0.97 (0.87-1.09) (↔); CC = 0.61 (0.40-0.91) (↓)	7
Haematological cancer
Bonovas S, 2007 (Greece)[26]	MEDLINE (1966 to December 2006) and WS (1970 to December 2006)	RCTs (6), Cohort (1) and CC (7)	1996-2006	412053	5619	Yes (q < 0.001, I2 = 71%)	0.85 (0.64-1.12) (↔)	None	RCTs = 0.92 (0.72-1.16) (↔); OSs = 0.83 (0.53-1.29) (↔)	5
Yi X, 2014 (China)[27]	PubMed, EMBASE and Cochrane CRCT (January 1966 to July 2013)	RCTs (6), Cohort (4), CC (10)	1996-2012	1139584	15297	Yes (q < 0.001, I2 = 59%)	0.81 (0.70-0.92) (↓)	None	RCTs = 0.92 (0.77-1.09) (↔); OSs = 0.79 (0.67-0.93) (↓)	4
Kidney cancer
Zhang X, 2014 (China)[28]	MEDLINE, EMBASE and Cochrane Library (January 1966 to October 2012)	RCTs (2), Cohort (5) and CC (5)	2001- 2012	3143236	2829	Yes (q < 0.001, I2 = 87.8%)	0.92 (0.71- 1.19) (↔)	LSU = 1.01 (0.83-1.22) (6) (↔)	RCTs = 1.01 (0.57-1.79) (↔); Cohort = 1.07 (0.96-1.20) (↔); CC = 0.74 (0.45-1.23) (↔)	5
Liver cancer
Pradelli D, 2013 (Italy)[29]	MEDLINE (up to March 2012)	Cohort (3) and CC (2)	NA	NA	2574	Yes (q < 0.001, I2 = 65%)	0.58 (0.46-0.74) (↓)	LSU = 0.66 (0.55-0.80) (↓)	None	6
Singh S, 2013 (United States)[30]	MEDLINE (1966 to 25th May 2012), EMBASE (1988 to 25th May 2012) and WS (1993 to 25th May 2012)	RCTs (3), Cohort (4) and CC (3)	2005-2012	1459417	4298	Yes (q = 0.08, I2 = 58%)	0.63 (0.52-0.76) (↓)	None	RCTs = 0.95 (0.62-1.45) (↔); OSs = 0.60 (0.49-0.73) (↓)	8
Zhang H, 2013 (China)[52]	MEDLINE, EMBASE and Cochrane Library (January 1966 to March2013)	Cohort (4) and CC (3)	2005-2013	4725593	9785	Yes (q = 0.004, I2 = 68.6%)	0.61 (0.49-0.76) (↓)	None	Cohort = 0.62 (0.3-0.89) (↓); CC = 0.63 (0.49-0.82) (↓)	5
Shi M, 2014 (China)[31]	PubMed, BIOSIS Previews, WS, EMBASE, EBSCO and Cochrane Library	RCT (IPD analysis) (1), Cohort (5) and CC (6)	2005-2013	5640313	35756	Yes (q < 0.001, I2 = 65%)	0.58 (0.51-0.67) (↓)	HCDS = 0.53 (0.36-0.79) (6) (↓)	RCT = 1.06 (0.66-1.71) (↔); Cohort = 0.51 (0.44-0.58) (↓); CC = 0.63 (0.54-0.73) (↓)	6
	(from inception to 5th March 2014)
Lung cancer
Deng Z, 2013 (China)[32]g	MEDLINE, EMBASE and WS (from inception to September 2013)	RCTs (8) Cohort (7) and CC (8)	1998-2012	2795302	38024	OSs = Yes (q < 0.001, I2 = 94.9%) RCTs = No (q = 0.483, I2 = 0.0%)	1.03 (0.96-1.11) (↔)	None	RCTs = 0.95 (0.85-1.06) (↔); Cohort = 0.94 (0.82-1.07) (↔); CC = 0.85 (0.62-1.16) (↔)	6
Tan M, 2013 (China)[33]	PubMed (up to March 2012)	RCTs (5), Cohort (7) and CC (7)	1998-2011	5009404	38013	Yes (q < 0.001, I2 = 93.3%)	0.89 (0.77-1.03) (↔)	LSU = 0.81 (0.42-1.56) (↔)	RCTs = 0.91 (0.76-1.09) (↔); Cohort = 0.94 (0.82-1.07) (↔); CC = 0.82 (0.57-1.16) (↔)	6
Wang J, 2013 (China)[34]	MEDLINE, EMBASE and Cochrane Library (January 1966 to November 2012)	RCTs (5), Cohort (8) and CC (7)	1998-2012	4980009	37560	Yes (q < 0.001, I2 = 93.6%)	0.89 (0.78-1.02) (↔)	LSU = 0.80 (0.39-1.64) (6) (↔)	RCTs = 0.92 (0.79-1.06) (↔); Cohort = 0.93 (0.82-1.06) (↔); CC = 0.81 (0.57-1.16) (↔)	8
Oesophageal cancer
Alexandre L, 2012 (United Kingdom)[35]	PubMed, EMBASE and Cochrane CRCT (up to December 2011)	Cohort (3)	2004-2011	35214	9310	No (q = 0.88, I2 = 0.0%)	0.86 (0.78-0.94) (↓)	In patients with BE = 0.53 (0.36-0.78) (↓)	None	7
Andrici J, 2013 (Australia)f[51]	MEDLINE, PubMed, EMBASE and Current Contents Connect (up to 29th October 2012)	7 studies	NA	NA	NA	No (q = 0.31, I2 = 15%)	0.75 (0.67-0.84) (↓)	In patients with BE = 0.56 (0.41-0.76) (↓); LSU = 0.45 (0.31-0.67) (↓)	Prospective = 0.75 (0.67-0.86) (↓); Retrospective = 0.68 (0.54-0.86) (↓)	--
Beales ILP, 2013 (United Kingdom)[36]	The PubMed, EMBASE, Cochrane Library, WS, Wiley Interscience and Google Scholar (up to 1st February 2013)	Cohort (5) and CC (6)	2004-2012	6454353	371203	No (q = 0.42, I2 = 0.0%)	0.81 (0.75-0.88) (6) (↓)	In patients with BE = 0.56 (0.41-0.76) (4) (↓)	None	6
Singh S, 2013 (United States)[37]	MEDLINE (1980 to 31st Aug 2012), EMBASE (1988 to 31st Aug 2012) and WS (1993 to 31st August 2012)	RCT (Post hoc analyses) (1), Cohort (5) and CC (7)	2004-2012	1132969	9285	Yes (q < 0.01, I2 = 74%)	0.72 (0.60-0.86) (↓)	In patients with BE = 0.59 (0.45-0.78) (5) (↓); LSU = 0.44 (0.24-0.78) (2) (↓)	RCT = 0.98 (0.69-1.40) (↔); Cohort = 0.79 (0.62-1.02) (↔); CC = 0.66 (0.51-0.85) (↓)	8
Pancreatic cancer
Bonovas S, 2008 (Greece)[38]	MEDLINE, Scopus, Google Scholar, and SCI (up to December 2007) and AACO and AACR conference abstracts	RCTs (3), Cohort (4) and CC (5)	1993-2007	914601	3521	Yes (q < 0.001, I2 = 86%)	0.88 (0.63-1.23) (↔)	None	RCTs = 0.99 (0.44-2.21) (↔); Cohort = 1.11 (0.95-1.29) (↔); CC = 0.70 (0.37-1.33) (↔)	7
Cui X, 2012 (China)[39]	MEDLINE, BIOSIS Previews and Cochrane Library (from inception to 30th August 2011)	RCTs (3), Cohort (5) and CC (8)	2001-2011	1692863	7807	Yes (q < 0.001, I2 = 81%)	0.89 (0.74-1.07) (↔)	LSU = 0.97 (0.76-1.23) (5) (↔)	RCTs = 0.99 (0.44-2.21) (↔); Cohort = 1.05 (0.93-1.19) (↔); CC = 0.74 (0.51-1.07) (↔)	8
Prostate cancer
Bonovas S, 2008 (Greece)[40]	MEDLINE (1966 to November 2007) and WK-SCI Expanded	RCTs (6), Cohort (6) and CC (7)	1993-2007	> 884871	62372	Yes (q < 0.001, I2 = 98%)	0.95 (0.73-1.23) (↔)	LSU = 0.93 (0.77-1.13) (6) (↔); APC = 0.77 (0.64-0.93) (5) (↓)	RCTs = 1.06 (0.93-1.20) (↔); Cohort = 0.98 (0.89-1.09) (↔); CC = 0.74 (0.46-1.20) (↔)	5
	(1970 to November 2007)
Bansal D, 2012 (India)[41]	PubMed (up to February 2012)	Cohort (15) and Case-control (12)	1993-2011	1893571	56847	Yes (q < 0.001, I2 = 82%)	0.93 (0.87-0.99) (↓)	LSU = 0.94 (0.84-1.05) (11) (↔); APC = 0.80 (0.70-0.90) (7) (↓)	Cohort = 0.93 (0.87-1.01) (↔); CC = 0.87 (0.72-1.05) (↔)	7
Zhang Y, 2013 (China)[42]	NA	7 studies	2005-2010	NA	NA	NA	1.19 (1.01-1.40) (↑)	NA	NA	6
Skin cancer (Melanoma)
Dellavalle R, 2005 (United States)[43]	Cochrane Skin Group Specialised Register (up to February 2003) and CENTRAL (Issue 1, 2005), MEDLINE (up to March 2003), EMBASE (up to September 2003), CANCERLIT (up to October 2002), WS (up to May 2003)	RCTs (7)	1993-1998	31198	126	No (q = 0.23, I2 = 29%)	0.90 (0.56-1.44) (↔)	Lovastatin = 0.52 (0.27-0.99) (1) (↓)	None	10
Freeman SR, 2006 (United States)[44]	MEDLINE (from January 1966 to March 2003), EMBASE (from January 1980 to September 2003), The Cochrane CRCT (up to March2003), CANCERLIT (from January 1975 to October 2002), and WS - SCI (from January 1970 to May 2003)	RCTs (12)	1993-2003	39426	127	No (q = 0.31, I2 = 16.6%)	0.87 (0.61-1.23) (↔)	Lovastatin = 0.52 (0.27-0.99) (1) (↓)	None	6
Bonovas S, 2010 (Greece)[45]	MEDLINE, Scopus, Google Scholar and SCI Expanded (up to June 2009)	RCTs (16)	1994-2006	62568	165	No (q = 0.25, I2 = 22%)	0.92 (0.67-1.26) (↔)	None	None	6
Li X, 2014 (China)[46]	PubMed ( up to 2013) anwd WS (1985-2013)	RCTs (17), Cohort (4) and CC (7)	1995-2013	517887	11787	Yes (q < 0.07, I2 = 33.8%)	0.94 (0.85-1.04) (24) (↔); NMSC = 1.03 (0.90-1.19) (14) (↔)	None	None	4

^aPublication year;

^bCountry of study conducted;

^cPeriod of literature search;

^dn mentioned only where the number of studies differ from studies included;

^eThough many subgroup analyses conducted in individual studies, here we focused mainly on subgroup analysis based on study design due to space constraint;

^fConference abstracts;

^gConducted among elderly people. APC: Advanced prostate cancer; BE: Barrett’s oesophagus; CBML: China BioMedical Literature; CC: Case-control; CNKI: Chinese National Knowledge Infrastructure; CRCT: Central Register of Controlled Trials; CSJFD: Chinese Scientific Journal Full-text Database; GI: Gastro-intestinal; HCDS: Higher cumulative dosage of statin; I²: I² test value; IPD: Individual patient data; ISI WK: Institute for Scientific Information Web of knowledge (Former term for Web of science); LSU: Long-term statin use; n: Number of studies; NA: Not available; NMSC: Non-melanoma skin cancer; Oss: Observational studies; q: Cochran Q test P value; RCTs: Randomized controlled trials; RR: Relative risk; SCI: Science citation index; UGIC: Upper gastrointestinal cancer; WS: Web of science; ↔: Non-significant association; ↓: Statistically significantly decreased risk; ↑: Statistically significantly increased risk.