Metabolic Syndrome and Risk of Cancer

A Systematic Review and Meta-analysis

Katherine Esposito, MD, PHD; Paolo Chiodini, PHD; Annamaria Colao, MD; Andrea Lenzi, MD; Dario Giugliano, MD, PHD

Diabetes Care. 2012;35(11):2402-2411.

Abstract and Introduction

Abstract

Objective—Available evidence supports the emerging hypothesis that metabolic syndrome may be associated with the risk of some common cancers. We did a systematic review and meta-analysis to assess the association between metabolic syndrome and risk of cancer at different sites.
Research Design and Methods—We conducted an electronic search for articles published through October 2011 without restrictions and by reviewing reference lists from retrieved articles. Every included study was to report risk estimates with 95% CIs for the association between metabolic syndrome and cancer.
Results—We analyzed 116 datasets from 43 articles, including 38,940 cases of cancer. In cohort studies in men, the presence of metabolic syndrome was associated with liver (relative risk 1.43, P < 0.0001), colorectal (1.25, P < 0.001), and bladder cancer (1.10, P = 0.013). In cohort studies in women, the presence of metabolic syndrome was associated with endometrial (1.61, P = 0.001), pancreatic (1.58, P < 0.0001), breast postmenopausal (1.56, P = 0.017), rectal (1.52, P = 0.005), and colorectal (1.34, P = 0.006) cancers. Associations with metabolic syndrome were stronger in women than in men for pancreatic (P = 0.01) and rectal (P = 0.01) cancers. Associations were different between ethnic groups: we recorded stronger associations in Asia populations for liver cancer (P = 0.002), in European populations for colorectal cancer in women (P = 0.004), and in U.S. populations (whites) for prostate cancer (P = 0.001).
Conclusions—Metabolic syndrome is associated with increased risk of common cancers; for some cancers, the risk differs betweens sexes, populations, and definitions of metabolic syndrome.

Introduction

The metabolic syndrome is a cluster of risk factors for cardiovascular disease and type 2 diabetes and constitutes a growing problem worldwide.^[1] These factors include obesity (particularly central adiposity), dysglycemia, raised blood pressure, elevated triglyceride levels, and low HDL cholesterol levels. On the basis of the most recent epidemiological analysis using the American Heart Association/National Heart, Lung, and Blood Institute 2005 guidelines, similar to those of National Cholesterol Education Program/Adult Treatment Panel III, slightly more than one-third (35%) of adults in the U.S. could be characterized as having the metabolic syndrome.^[1] This translates to nearly 80 million U.S. adults affected by the syndrome (calculated from U.S. Bureau of the Census data for 2007, with an adult resident population of 228 million). A higher percentage (40.1%) of prevalence occurred with revised International Diabetes Federation 2005 criteria, which use a lower cutoff point for waist (≥94 cm in men and ≥80 cm in women).

Available evidence from epidemiologic investigations and experimental, translational, and clinical studies supports the emerging hypothesis that metabolic syndrome may be an important etiologic factor for the development and progression of certain types of cancer and also for overall cancer mortality.^[2] Differences in the study populations, length of follow-up, sample sizes, frequency of events, study end points, and statistical adjustment for confounding may all have contributed to the conflicting patterns of association seen in earlier studies. Moreover, both obesity^[3] and diabetes^[4] have repeatedly been associated with increased incidence for some common cancers, and both conditions represent two important factors contributing to the prevalence of the metabolic syndrome. There is also some evidence that dyslipidemia (low HDL cholesterol levels and/or raised triglyceride) is associated with some cancers.^[5] It therefore remains possible that some of the associations between metabolic syndrome and cancer risk may be mediated by the coexistence of obesity and overt diabetes.

A systematic and quantitative assessment of published studies is not available. Therefore, we conducted a meta-analysis to summarize all published studies to date on the incidence of cancer associated with metabolic syndrome.

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Next Section

Table 1. Baseline characteristics of studies included in meta-analysis
Cancer sites	No. of datasets*	Population group				No. of cases in men	No. of cases in women	MS: traditional vs. non-traditional§	Type of studies
Cancer sites	No. of datasets*	U.S.	Europe	Asia	Other	No. of cases in men	No. of cases in women	MS: traditional vs. non-traditional§	Type of studies
Colorectal	38	6	23	9		6,661	4,341	14 vs. 8	9 cohorts, 2 n-c/c, 1 RCT, 2 c/c
Colon	11		7	4		1,529	1,035
Rectum	11		7	4		1,035	647
Breast cancer	12	1	7	3	1, Brazil		9,643	5 vs. 4	4 cohorts, 1 RCT, 2 n-c/c, 2 c/c
Postmenopausal	7	1	4	2		5,161
Hepatobiliary	14	3	5	6		Total 5,580 M and F		5 vs. 5	5 cohorts, 2 c/c
Liver	10	3	3	4		3,199	1,758
Gallbladder	4		2			54	10
				2		559 M and F
Prostate	14	4	8	2		4,623		6 vs. 5	10 cohorts, 1 n-c/c, 2 c/c, 1 series
Endometrium	5		4		1, Canada		2,190		2 cohorts, 1 n-c/c, 2 c/c
Pancreas	9	1	6	2		823	527	3 vs. 6	4 cohorts, 1 c/c
Gastric	7	1	2	4		506	309		4 cohorts
Lung	7	1	2	4		536	174		4 cohorts
Bladder	4		4			1641	337		4 cohorts
Thyroid	4		4			137	258		4 cohorts
Ovary	2		2				654		2 cohorts
Total	116	17	67	30	2	18,180†	20,010†

c/c, case-control; MS, metabolic syndrome; n-c/c, nested case-control; RCT, randomized controlled trial; traditional, diagnosis of MS made according to national and international scientific associations. M, male. F, female. *Datasets refers to a site-specific group per article. Several articles reported multiple sites: each site counted as one dataset; if an article reported separated analysis for sex or age at the same site, these were counted as two datasets. §Analysis was performed for cohorts only when numbers of datasets were nine or more. †Total n (both sexes) = 38,381 cases, to which must be added 559 cases for gallbladder cancer in both sexes (n = 38,940 cases).

Table 2. Main analyses and prespecified subgroup analyses for cancer sites
Groups	Datasets	Identification of datasets (Supplementary Table 1)	Cases	RR (95% CI)	P	I ² (%)	P of I ²	Model
Colorectal	1–38
Cohorts, men	12	5, 7, 10, 11, 17, 19, 21, 24, 26, 28, 30, 32	4,814	1.25 (1.19–1.32)	0.000	34.9	0.111	F
U.S.	2	5, 10	601	1.33 (1.11–1.59)	0.002	0.0	0.356	F
Europe	6	7, 11, 17, 24, 30, 32	3,960	1.26 (1.09–1.46)	0.002	47.7	0.089	R
Asia	4	19, 21, 26, 28	253	1.10 (0.80–1.51)	0.568	43	0.153	F
Cohorts, women	10	6, 12, 18, 20, 22, 25, 27, 29, 31, 33	3,045	1.34 (1.09–1.64)	0.006	59.6	0.008	R
U.S	1	6	87	1.16 (0.60–2.20)
Europe	5	12, 18, 25, 31, 33	2,665	1.64 (1.17–2.28)	0.004	81	0.000	R
Asia	4	20, 22, 27, 29	293	1.02 (0.76–1.36)	0.911	0.0	0.979	F
Mortality, men and women	6	1, 2, 3, 4, 23, 34	887	1.61 (1.28–2.01)	0.000	0.0	0.776	F
Colon men	6	8, 13, 19, 26, 30, 35	1,529	1.33 (1.02–1.73)	0.033	59.3	0.031	R
Colon women	5	14, 20, 27, 31, 36	1,035	1.29 (0.93–1.78)	0.128	62.3	0.031	R
Rectum men	6	9, 15, 21, 28, 32, 37	1,035	1.23 (1.00–1.52)	0.050	41.8	0.126	F
Rectum women	5	16, 22, 29, 33, 38	647	1.49 (1.13–1.97)	0.004	16.3	0.311	F
Traditional men and women	14	5, 6, 19, 20, 21, 22, 26, 27, 28, 29, 30, 31, 32, 33	1,833	1.33 (1.10–1.62)	0.004	40.7	0.057	R
Nontraditional men and women	8	7, 10, 11, 12, 17, 18, 24, 25	6,026	1.22 (1.18–1.34)	0.000	56.2	0.025	R
Breast	39–49
All datasets	11	39–49	9,643	1.23 (1.05–1.45)	0.009	88	0.000	R
Cohorts	9	39–47	5,693	1.14 (0.98–1.32)	0.088	86	0.000	R
U.S.	1	40	162	1.12 (0.78–1.62)
Europe	6	39, 42, 43, 44, 46, 47	5,334	1.09 (0.94–1.26)	0.258	88	0.000	R
Asia	2	41, 45	197	1.53 (0.45–5.21)	0.499	91	0.001	R
Cohorts, postmenopausal	5	40, 44, 45^a, 46, 47	1,290	1.56 (1.08–2.24)	0.017	88	0.000	R
U.S.	1	40	162	1.12 (0.78–1.62)
Europe	3	44, 46, 47	1,086	1.35 (0.95–1.91)	0.094	86	0.001	R
Asia	1	45^a	42	6.73 (2.93–15.4)
Case/control	2	48, 49	3,950	1.80 (1.43–2.27)	0.000	0.0	0.383	F
Traditional	5	40, 41, 45, 46, 47	732	1.45 (1.04–2.00)	0.025	71	0.008	R
Nontraditional	4	39, 42, 43, 44	2,961	0.97 (0.86–1.10)	0.633	84	0.000	R
Hepatobiliary	50–63
Liver, all datasets, men and women	14	50–63	5,580	1.60 (1.32–1.94)	0.000	78.7	0.000	R
Liver, all datasets, men	7	50, 54, 56, 57, 59, 60, 61	3,199	1.65 (1.34–2.03)	0.000	79.5	0.000	R
Liver, all datasets, women	6	51, 55, 58, 59, 60, 61	1,758	1.62(1.23–2.15)	0.000	86.5	0.000	R
Liver cohorts, men	5	50, 54, 56, 57, 59	402	1.43 (1.23–1.65)	0.000	0.0	0.732	F
U.S.	1	56	18	1.62 (0.59–4.41)
Europe	2	50, 59	228	1.36 (1.16–1.60)	0.000	0.0	0.831	F
Asia	2	54, 57	156	1.81 (1.25–2.62)	0.002	0.0	0.816	F
Liver cohorts, women	4	51, 55, 58, 59	163	1.42 (0.80–2.52)	0.224	70.8	0.016	R
Europe	2	51, 59	76	1.01 (0.46–2.24)	0.973	64	0.095	R
Asia	2	55, 58	87	2.09 (0.69–6.37)	0.193	78	0.034	R
Traditional, men and women	5	54, 55, 56, 57, 58	261	1.88 (1.41–2.52)	0.000	18.5	0.297	F
Nontraditional, men and women	5	50, 51, 59, 60, 61	4,696	1.51 (1.16–1.98)	0.002	88.4	0.000	R
Gallbladder and biliary, men and women	4	52, 53, 62, 63	623	1.53 (0.90–2.59)	0.113	81.3	0.000	R
Prostate	64–77
All datasets	14	64–77	4,623	1.13 (0.94–1.37)	0.178	74.3	0.000	R
Cohorts	11	64–74	2,609	1.09 (0.88–1.34)	0.438	76	0.000	R
U.S.	3	66, 69, 72	625	0.79 (0.69–0.91)	0.001	9	0.333	F
Europe	6	64, 65, 67, 68, 71, 73	1,713	1.28 (0.89–1.87)	0.083	76.6	0.001	R
Asia	2	70, 74	271	0.98 (0.71–1.36)	0.932	52	0.149	F
Traditional	7	64, 66, 69, 70, 71, 73, 74	1,670	1.03 (0.82–1.29)	0.780	66.5	0.006	R
Nontraditional	4	65, 67, 68, 72	939	1.18 (0.75–1.87)	0.472	83	0.000	R
Endometrium	78–82
All datasets	5	78–82	2,190	1.40 (1.32–1.49)	0.000	46.3	0.114	F
Cohorts	3	78–80	1,221	1.61 (1.20–2.15)	0.001	68.7	0.04	R
Pancreas	83–91
All datasets, men	5	83, 85, 87, 89, 90	823	1.29 (0.88–1.89)	0.188	64.5	0.024	R
All datasets, women	4	84, 86, 88, 91	527	1.58 (1.35–1.84)	0.000	0.0	0.96	F
Cohorts, men	4	83, 85, 87, 89	649	1.20 (0.80–1.80)	0.378	67.2	0.027	R
Cohorts, women	3	84, 86, 88	375	1.58 (1.35–1.84)	0.000	0.0	0.870	F
Traditional, men and women	3	85, 86, 89	121	1.13 (0.53–2.43)	0.745	63	0.067	R
Nontraditional, men and women	6	83, 84, 87, 88, 90, 91	1,229	1.45 (1.12–1.87)	0.004	71	0.004	R
Gastric	92–98
Cohorts, men	4	92, 94, 96, 97	506	0.87 (0.70–1.08)	0.201	24.8	0.232	F
Cohorts, women	3	93, 95, 98	309	0.82 (0.61–1.10)	0.178	50	0.135	F
Lung	99–105
Cohorts, men	4	99, 101, 103, 104	53	0.97 (0.69–1.36)	0.861	72	0.013	R
Cohorts, women	3	100, 102, 105	174	0.76 (0.55–1.05)	0.095	0.0	0.436	F
Bladder	106–109
Cohorts, men	2	106, 108	1,641	1.10 (1.02–1.18)	0.013	0.0	0.951	F
Cohorts, women	2	107, 109	337	0.95 (0.79–1.13)	0.547	0.0	0.903	F
Thyroid	110–113
Cohorts, men	2	110, 112	137	1.15 (0.96–1.37)	0.130	7.8	0.298	F
Cohorts, women	2	111, 113	258	1.00 (0.87–1.15)	0.987	0.0	0.878	F
Ovary	114, 115
Cohorts	2	114, 115	654	1.26 (1.0–1.59)	0.054	8.8	0.295	F