Prospective Study Reveals Associations Between Colorectal Cancer and Type 2 Diabetes Mellitus or Insulin Use in Men

GASTROENTEROLOGY 2010;139:1138 1146 Prospective Study Reveals Associations Between Colorectal Cancer and Type 2 Diabetes Mellitus or Insulin Use in PETER T. CAMPBELL,* ANUSILA DEKA,* ERIC J. JACOBS,* CHRISTINA C. NEWTON,* JANET S. HILDEBRAND,* MARJORIE L. MCCULLOUGH,* PAUL J. LIMBURG, and SUSAN M. GAPSTUR* *Epidemiology Research Program, American Cancer Society, National Home Office, Atlanta, Georgia; Mayo Clinic Cancer Center, Rochester, Minnesota See related article, Hoffmeister M et al, on page 870 in CGH. BACKGROUND & AIMS: Type 2 diabetes mellitus (DM) is associated with an increased risk of colorectal cancer (CRC); it is not clear if this association varies by sex or other factors. Insulin use might also be associated with CRC risk. We investigated associations of type 2 DM and insulin use with CRC risk. METHODS: The Cancer Prevention Study II Nutrition Cohort is a prospective study of cancer incidence. In 1992 or 1993, adult participants (n 184,194) completed a detailed, self-administered questionnaire. Follow-up questionnaires were sent in 1997 and every 2 years thereafter. Cox proportional hazards regression analysis was used to calculate relative risks (RR) and 95% confidence intervals (CI), adjusting for covariates. RESULTS: After exclusions, 73,312 men and 81,663 women remained in the final analytic cohort; 1567 men (227 with type 2 DM) and 1242 women (108 with type 2 DM) were diagnosed with colon or rectal cancer by 2007. Among men, type 2 DM was associated with increased risk of incident CRC compared to not having type 2 DM (RR: 1.24; 95% CI: 1.08 1.44); risk was higher for participants with type 2 DM using insulin (RR: 1.36; 95% CI: 1.05 1.78), and participants with type 2 DM not using insulin (RR: 1.22, 95% CI: 1.04 1.45). Among women, type 2 DM and insulin use were not associated with risk of incident CRC (RR: 1.01; 95% CI: 0.82 1.23 and RR: 0.95; 95% CI: 0.64 1.41, respectively). CONCLUSIONS: There is a modest association between type 2 DM and CRC among men, but not women. Insulin use is not associated with a substantially increased risk of CRC. Keywords: Carcinogenesis; Family History; Cigarette Smoking; Colon Cancer. View this article s video abstract at www.gastrojournal.org Obesity, Western-style diet, and lack of physical activity are established risk factors for colorectal cancer (CRC). 1 Hyperglycemia and hyperinsulinemia, which are especially pronounced during the early stages of type 2 diabetes mellitus (DM), have been proposed as mediators for these associations. 2,3 In support of this hypothesis, a 2005 meta-analysis 4 of epidemiologic studies reported that DM was associated with a moderate increased risk of CRC overall, with almost identical associations when men and women were analyzed separately. More recent studies, however, consistently demonstrate stronger associations for men than for women. 5 9 There is some evidence of differences in association by duration of type 2 DM, 10,11 and cigarette smoking. 7 Few epidemiologic studies have evaluated whether insulin treatment is associated with risk of CRC. 12 14 Two retrospective studies, 12,14 with clinical data from the United Kingdom, reported roughly 2-fold higher odds of CRC among type 2 DM patients who used insulin. There was a null association between insulin use and CRC risk in a similar retrospective study conducted with data from US pharmacies. 13 An effect of insulin on colon carcinogenesis is biologically plausible. In studies conducted with rats, insulin administration appears to promote colon cancer growth 15 and to increase proliferation in colonic epithelial tissue. 16 Whether insulin treatment increases risk of CRC is an important question because almost all patients with type 2 DM will eventually require insulin treatment. 17,18 Worldwide prevalence of type 2 DM was approximately 171 million in 2000, and 366 million people are projected to have the disease by 2030. 19 Given the significant morbidity and mortality of CRC, studies of the associations of type 2 DM and insulin use with risk of CRC have strong public health and clinical relevance. Materials and Methods Study Cohort and women in this study were selected from the 184,194 participants of the Cancer Prevention Study Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; CPS-II, Cancer Prevention Study II; CRC, colorectal cancer; DM, diabetes mellitus; ICD-O, International Classification of Diseases for Oncology; NSAID, nonsteroidal anti-inflammatory drug; RR, relative risk. 2010 by the AGA Institute 0016-5085/$36.00 doi:10.1053/j.gastro.2010.06.072

October 2010 TYPE 2 DIABETES AND COLORECTAL CANCER RISK 1139 II (CPS-II) Nutrition Cohort. Initiated in 1992, the Nutrition Cohort is a prospective study of cancer incidence. 20 Nutrition Cohort participants were selected from among the 1.2 million participants of CPS-II, a prospective mortality study, initiated in 1982. The CPS-II Nutrition Cohort has been approved by the Emory University Institutional Review Board. At enrollment in 1992 or 1993, participants were aged 50 to 74 years and completed a 10-page self-administered questionnaire concerning demographics, medical history, body height and weight, lifestyle, cancer screening and early detection, and diet. Follow-up questionnaires were sent to cohort members in 1997, 1999, 2001, 2003, 2005, and 2007 to update exposure information and to learn of newly diagnosed cancers. The response rate for each of the follow-up questionnaire cycles has been 89%. We excluded from this analysis participants who met the following criteria: history of cancer, other than nonmelanoma skin cancer, at baseline (n 21,103); selfreported CRC that could not be verified through medical record abstraction or cancer registry linkage (n 162); nonadenocarcinoma CRC (n 58); lost to follow-up (n 6,261); inconsistent diabetes data (ie, reported diabetes in 1982, but not in 1992, n 861); and missing diabetes information at baseline (n 567). To reduce potential bias from including patients with type 1 diabetes, participants who reported insulin use before age 30 years (n 196) were excluded. The final analytic cohort included 73,312 men and 81,663 women. Colorectal Cancer Case Ascertainment Most incident CRC cases were identified by selfreports on follow-up questionnaires (n 1283 men and 1026 women) that were subsequently verified by medical record abstraction (n 975 men and 763 women) or by state cancer registry linkage (n 308 men and 263 women). Nutrition Cohort participants have been shown to report cancer diagnoses with high sensitivity (0.93). 21 Fifty-five CRC cases (n 35 men and 20 women) were verified through medical record abstraction or cancer registry linkage after the verified CRC case self-reported a cancer or died of a cancer other than that of the colon or rectum. The remaining cases were verified by linking to the National Death Index, where CRC was listed as the underlying cause of death (n 249 men and 196 women). 22 Death certificates or codes for cause of death have been obtained for 99.3% of all known deaths in the Nutrition Cohort. In the analytic cohort, 1567 men and 1242 women were diagnosed with an incident colon or rectal cancer between enrollment in 1992 or 1993 and the end of follow-up in 2007. Colon or rectal cancer subsite information was obtained for all case participants in the study, including 1129 men and 967 women with colon cancer (International Classification of Diseases for Oncology [ICD-O] 23 : C18.0, C18.2-9) and 438 men and 275 women with rectal cancer (ICD-O 23 : C19.9 20.9). Proximal (ICD-O 23 : C18.0, C18.2-5), and distal (ICD-O 23 : C18.6-7) colon cancer subsite information was obtained for 92% of case participants. Surveillance Epidemiology and End Results summary stage was extracted from medical records or state cancer registries for 1445 men and 1145 women with CRC (92% of all cases). Surveillance Epidemiology and End Results summary stage includes localized tumors (668 men and 450 women), tumors confined to the colorectum; regional tumors (593 men and 530 women), tumors that extend through the bowel wall to adjacent tissue or to regional lymph nodes; and distant tumors (184 men and 165 women), tumors that metastasize to distant sites. For these analyses, regional and distant tumors were combined. Assessment of DM and Insulin Self-reported DM was recorded on the baseline questionnaire (1992 or 1993) and updated in 1997, 1999, 2001, 2003, and 2005. Participants were asked if they had ever been diagnosed with DM by a physician; beginning with the 1997 questionnaire, and for all subsequent surveys, the question was modified to exclude gestational diabetes and participants were additionally asked in what year their DM had been diagnosed. Participants were asked if they had used insulin beginning with the baseline questionnaire. Participants were not asked to specify the type or dose of insulin they used or about other drugs used to lower or maintain glucose levels (eg, metformin). To examine the validity of self-reported DM in this cohort, we reviewed medical records (primarily clinical notes) from a sample of CRC cases. Although medical records are not available from most study participants, medical records that were collected during the course of case verification were available for most cases of CRC. Medical records of 98 CRC cases (49 with and 49 without self-reported type 2 DM) were reviewed by an investigator (PTC) who was blinded to self-reported diabetes status. Of the 98 records selected, 80 were usable (12 were excluded because of illegible handwriting on the medical record; 6 were excluded because the medical record contained only a pathology report). Self-reported DM was in good agreement with data extracted from medical records; of the 46 self-reports of diabetes from the questionnaires, 38 were confirmed by review of medical records (83%). The remaining 8 self-reports of type 2 DM could have been either errors in self-reports, or accurate self-reports that were not documented in the limited medical records available. Of the 34 participants who self-reported not having diabetes from the questionnaires, none of the medical records indicated a history of DM. Thus, the overall agreement between self-reports and medical records was 90%.

1140 CAMPBELL ET AL GASTROENTEROLOGY Vol. 139, No. 4 Statistical Analyses Age-adjusted and multivariate-adjusted relative risks (RR) and 95% confidence intervals (CI) were calculated using Cox proportional hazards models to estimate the associations of type 2 DM and insulin use with risk of CRC. Follow-up time beginning in 1992 was used as the time axis. Participants without type 2 DM were the main referent group. Participants with type 2 DM were categorized altogether and also divided into 2 mutually exclusive groups, type 2 DM, using insulin or type 2 DM, not using insulin. Duration of type 2 DM was categorized as 10 years, 11 to 15 years, or 15 years. Duration of insulin use was categorized as 1 to 2 years, 3 to 4 years, or 4 years. Wald tests were used to assess linear trends for type 2 DM and insulin use durations, excluding the non type 2 DM group. To derive type 2 DM duration, participants who first reported DM on the 1982 questionnaire were initially assigned 10 years of duration, while participants who reported DM on the 1992 questionnaire, but not on the 1982 questionnaire, were assigned 5 years of duration. Once a participant indicated a DM diagnosis, duration was extended until the participant was diagnosed with CRC or was censored from the analysis. Duration of insulin use was ascertained initially using information from the 1992 questionnaire, which asked participants if they used insulin and, if so, for how many years insulin had been used. Insulin use duration was updated with each subsequent survey where a participant indicated whether insulin use had been initiated, had continued, or had stopped. Type 2 DM and insulin use (yes/no, and duration) were modeled as time-dependent variables, meaning that at the start of each time interval, coinciding with the completion of a new survey, participants type 2 DM and insulin use status were updated and exposure time was allocated to the appropriate groups. For example, a participant who first reported having type 2 DM in 2001 would contribute person-time in the proportional hazards model to the non-diabetes group from 1992 to 2001, whereas from 2001 onward, this participant would contribute person-time to the diabetes group. Covariates were selected at the onset of the study, based on their potential to confound or modify the association between type 2 DM and CRC risk. All covariate data were collected from the self-reported questionnaires. All covariates were modeled using baseline values, except colorectal endoscopy and family history of CRC, which were treated as time-dependent variables. The covariates included in the multivariate-adjusted models were body mass index (BMI; calculated as weight (kg) divided by height squared (m 2 ), defined according to World Health Organization criteria for obesity 24 : normal BMI: 18.5 to 25; overweight BMI: 25 to 30; obese BMI 30), education (high school or less, some college or vocational school, college graduate), physical activity (average metabolic equivalents of energy expenditure hours per week: 3.5, 3.5 to 4.5, 4.5 to 14, 14 to 19, 19), current use of nonsteroidal anti-inflammatory drugs (NSAID: yes, no), first-degree relative affected by CRC (yes, no), alcohol use (nondrinker, 1 drink per day, 1 drink per day, 1 drink per day, former drinker, unknown), and history of colorectal endoscopy (yes, no). In additional analyses, inclusion of red meat, total caloric intake, fat intake, glycemic index, BMI (continuous), fruit and vegetable intake, smoking status, marital status, race, and hormone use (women only), had no discernible effect on the relative risk estimates, and therefore were not included in the final multivariable models. Whether the association between type 2 DM and CRC risk differed by sex, age at baseline (younger than 63 years, 63 years or older), smoking status (never smoker, current or former smoker), BMI ( 30, 30), history of colorectal endoscopy procedure (never received endoscopy test, received test), current NSAID use (yes, no), family history of CRC (1 or more first-degree family members affected by CRC, no) and, among women, use of postmenopausal hormones (yes, no) was examined. Specifically, multiplicative interaction terms were created between type 2 DM and each potential modifier, and Cox models with and without the interaction terms were compared using -2 log likelihood ratio tests. Results Select descriptive data for participants with and without type 2 DM at baseline are shown in Table 1. Compared to men and women without type 2 DM at baseline, participants with the disease were older, more obese, had less history of colorectal endoscopy, had less alcohol intake, had more current use of NSAID, and reported less physical activity. Among the 1567 men and 1242 women who were diagnosed with incident CRC between enrollment and the end of follow-up, 227 men and 108 women self-reported a diagnosis of type 2 DM, and 59 men and 26 women additionally reported insulin use. Among all participants with type 2 DM through to the end of the follow-up period, regardless of CRC status, 27% of men and 25% of women additionally reported insulin use. Associations between type 2 DM and risk of CRC overall and stratified by subsite in the colorectum (colon, rectum) and tumor stage (localized, regional or distant) were examined in men and women, separately (Table 2). For men, a history of type 2 DM was associated with a 24% higher risk of incident CRC compared to no history. This association did not meaningfully differ by subsite in the colorectum or by tumor stage. Among women, type 2 DM was not associated with any of the CRC outcomes. The interaction term for sex and type 2 DM, with CRC as the outcome, was not statistically significant (P-heterogeneity.08). For both men and women, the associa-

October 2010 TYPE 2 DIABETES AND COLORECTAL CANCER RISK 1141 Table 1. Age-Adjusted Percentages a and Means of Baseline Characteristics by Type 2 Diabetes Mellitus Status in the Cancer Prevention Study II Nutrition Cohort, 1992 2007 b Characteristic No type 2 DM (n 66,783), % Type 2 DM (n 6529), % No type 2 DM (n 76,857), % Type 2 DM (n 4806), % Mean age at baseline, y 63.9 65.1 62.1 63.2 Race c White 97.6 95.6 97.4 95.1 Black 1.1 2.5 1.4 3.3 Unknown, other, or not reported 1.3 1.9 1.2 1.7 Education level c,d Less than high school graduate 8.0 10.4 4.9 7.4 High school graduate 18.9 20.5 31.6 34.7 Vocational or technical school or Some college 25.5 28.0 31.3 31.7 or university Undergraduate or graduate degree 46.9 40.2 31.6 25.1 BMI e 18.5 0.5 0.5 1.9 0.9 18.5 to 25.0 35.9 25.9 51.5 29.7 25.0 to 30.0 48.9 47.6 30.8 33.8 30.0 to 35.0 11.1 18.5 10.3 20.7 35.0 2.1 5.8 3.9 13.0 Cigarette smoking status e Never 32.6 28.0 54.3 55.5 Current 9.2 9.1 8.5 7.8 Former 57.4 61.6 35.5 34.8 Family history of colorectal cancer c No 95.0 95.3 94.1 94.1 Yes 5.0 4.7 5.9 5.9 Endoscopy history f Never 28.9 27.6 37.4 35.5 Ever 48.0 39.8 44.0 38.7 Unknown 23.1 32.6 18.6 25.8 Alcohol use e Nondrinker 31.2 48.3 44.2 64.6 1 drink/day 39.1 31.4 38.9 23.1 1 drink/day 25.7 15.2 12.7 6.3 NSAID use e No current use 37.4 31.6 39.1 32.8 Current use 59.7 64.6 56.7 61.9 Total calorie intake (kcal/day) e Mean 1803.5 1797.8 1360.7 1377.3 MET hours of physical activity per week e,g Mean 13.3 11.8 12.1 11.1 BMI, body mass index (calculated as kg/m 2 ); DM, diabetes mellitus; MET, metabolic equivalents; NSAID, nonsteroidal anti-inflammatory drug. a Percentages were adjusted to the age distribution of the entire study population and may not sum to 100 due to missing data. b Some counts do not add to totals because of missing data. c Self-report via 1982 questionnaire. d Defined as highest completed level of education. e Self-report via baseline questionnaire. f Self-report via 1997 questionnaire. g Derived from responses to hours per week of 7 modes of activity (walking, jogging or running, lap swimming, tennis or racquetball, bicycling or stationary bike, aerobics or calisthenics, and dancing). tions were highly similar when colon cancer was further stratified by proximal and distal subsites (data not shown). Relative to not having a history of type 2 DM, the associations between insulin use and CRC were generally similar to the associations observed for type 2 DM overall (Table 3). In men, there was an approximately 36% higher risk of incident CRC associated with insulin use, which increased to 44% for risk of regional or distant tumors; whereas for women, insulin use was not associated with any of the CRC outcomes. All of the relative risk estimates were not statistically significant when comparing insulin users to participants with type 2 DM who did not use insulin (Table 3). Associations for duration of type 2 DM and insulin use with incident CRC are shown in Table 4. The Pearson

1142 CAMPBELL ET AL GASTROENTEROLOGY Vol. 139, No. 4 Table 2. Relative Risks and 95% Confidence Intervals for the Association Between Type 2 Diabetes Mellitus and Risk of Colorectal Cancer in the Cancer Prevention Study II Nutrition Cohort, 1992 2007 No type 2 DM Type 2 DM RR (95% CI) Age-adjusted RR Multivariable-adjusted (95% CI) a RR (95% CI) b Colorectal 1340/760,684 1.00 (referent) 227/93,994 1.33 (1.15 1.53) 1.24 (1.08 1.44) Colon 963/760,684 1.00 (referent) 166/93,994 1.32 (1.12 1.56) 1.23 (1.03 1.45) Rectal 377/760,684 1.00 (referent) 61/93,994 1.35 (1.03 1.77) 1.29 (0.98 1.70) Stage at diagnosis c,d Localized 572/760,684 1.00 (referent) 96/93,994 1.32 (1.06 1.64) 1.25 (1.00 1.56) Regional/distant 664/760,684 1.00 (referent) 113/93,994 1.33 (1.09 1.62) 1.24 (1.01 1.52) Colorectal 1134/938,024 1.00 (referent) 108/76,570 1.08 (0.88 1.31) 1.01 (0.82 1.23) Colon 887/938,024 1.00 (referent) 80/76,570 1.00 (0.80 1.26) 0.94 (0.74 1.18) Rectal 247/938,024 1.00 (referent) 28/76,570 1.36 (0.92 2.01) 1.28 (0.85 1.91) Stage at diagnosis c,d Localized 409/938,024 1.00 (referent) 41/76,570 1.12 (0.81 1.55) 1.07 (0.77 1.49) Regional/distant 640/938,024 1.00 (referent) 55/76,570 0.99 (0.75 1.30) 0.92 (0.69 1.21) CI, confidence interval; DM, diabetes mellitus; RR relative risk. a Relative risks adjusted for age at baseline. b Relative risks adjusted for age at baseline, education, body mass index in 1992, physical activity, nonsteroidal anti-inflammatory drug use, alcohol use, family history of colorectal cancer, and endoscopy history. c According to Surveillance Epidemiology and End Results (SEER) summary stage. d Those with unknown SEER summary stage were censored at diagnosis date. correlation coefficients for the association between type 2 DM duration and insulin use duration were 0.50 (P value.0001) and 0.58 (P value.0001) for men and women, respectively. Insulin use was more common among participants who reported 15 years of type 2 DM (52% of men, 56% of women) than among participants who reported 10 years of the disease (16% of men, 16% of women) (data not shown in Tables). Among men, risk of incident CRC increased progressively with duration of type 2 DM, from a null association for 10 years, to relative risks of 1.35 for 11 to 15 years, and 1.73 for 15 years (P trend.002). For women, the relative risks for the Table 3. Relative Risks and 95% Confidence Intervals for the Associations of Type 2 Diabetes Mellitus With and Without Insulin Use With Risk of Colorectal Cancer in the Cancer Prevention Study II Nutrition Cohort, 1992 2007 a No type 2 DM Type 2 DM with insulin use relative to no type 2 DM b Type 2 DM, by insulin-use status Type 2 DM without insulin use relative to no type 2 DM b Insulin use relative to no insulin use among type 2 DM cases/ person-years Multivariableadjusted RR (95%CI) cases/ person-years Multivariableadjusted RR (95% CI) cases/ person-years Multivariableadjusted RR (95% CI) Multivariableadjusted RR (95% CI) Colorectal 1340/760,684 1.00 (referent) 59/22,634 1.36 (1.05 1.78) 159/66,758 1.22 (1.04 1.45) 1.11 (0.82 1.51) Colon 963/760,684 1.00 (referent) 44/22,634 1.37 (1.01 1.86) 116/66,758 1.20 (0.99 1.47) 1.13 (0.79 1.61) Rectal 377/760,684 1.00 (referent) 15/22,634 1.34 (0.80 2.26) 43/66,758 1.28 (0.93 1.77) 1.05 (0.58 1.90) Stage at diagnosis c,d Localized 572/760,684 1.00 (referent) 21/22,634 1.17 (0.75 1.81) 70/66,758 1.28 (0.99 1.64) 0.96 (0.59 1.58) Regional/distant 664/760,684 1.00 (referent) 31/22,634 1.44 (1.00 2.07) 78/66,758 1.20 (0.95 1.53) 1.14 (0.75 1.75) Colorectal 1134/938,024 1.00 (referent) 26/19,809 0.95 (0.64 1.41) 77/53,051 1.03 (0.82 1.31) 0.94 (0.60 1.48) Colon 887/938,024 1.00 (referent) 21/19,809 0.97 (0.62 1.49) 56/53,051 0.94 (0.71 1.24) 1.04 (0.62 1.73) Rectal 247/938,024 1.00 (referent) 5/19,809 0.88 (0.36 2.16) 21/53,051 1.39 (0.88 2.19) 0.65 (0.24 1.75) Stage at diagnosis c,d Localized 409/938,024 1.00 (referent) 10/19,809 1.02 (0.54 1.93) 29/53,051 1.08 (0.74 1.59) 0.91 (0.44 1.89) Regional/distant 640/938,024 1.00 (referent) 15/19,809 0.98 (0.59 1.65) 38/53,051 0.91 (0.68 1.27) 1.12 (0.61 2.05) CI, confidence interval; DM, diabetes mellitus; RR, relative risk. a Relative risks adjusted for age at baseline, education, BMI in 1992, physical activity, nonsteroidal anti-inflammatory drug use, alcohol use, family history of colorectal cancer, and endoscopy history. b Some counts do not add up to totals because of missing information on insulin use. c According to Surveillance Epidemiology and End Results (SEER) summary stage. d Those with unknown SEER summary stage were censored at diagnosis date.

October 2010 TYPE 2 DIABETES AND COLORECTAL CANCER RISK 1143 Table 4. Relative Risks and 95% Confidence Intervals for the Associations of Duration of Type 2 Diabetes Mellitus and Insulin Use With Risk of Colorectal Cancer in the Cancer Prevention Study II Nutrition Cohort, 1992 2007 Multivariable-adjusted RR (95% CI) a Multivariable-adjusted RR (95% CI) a Duration of type 2 DM, y b No type 2 DM 1340/760,684 1.00 (referent) 1134/938,024 1.00 (referent) 10 111/68,828 1.06 (0.87 1.29) 59/57,115 0.92 (0.71 1.21) 11 15 65/12,755 1.35 (1.05 1.73) 32/9,835 1.28 (0.90 1.83) 15 51/12,374 1.73 (1.30 2.30) 17/9,488 0.91 (0.56 1.48) P trend c.002.30 Duration of insulin use, y d No type 2 DM 1340/760,684 1.00 (referent) 1134/938,024 1.00 (referent) 1 2 11/5,568 1.08 (0.59 1.95) 8/4,728 1.25 (0.62 2.50) 3 4 10/3,382 1.49 (0.80 2.78) 3/2,964 0.70 (0.23 2.19) 4 33/12,859 1.31 (0.92 1.85) 15/11,356 0.90 (0.54 1.51) P trend e.64.58 CI, confidence interval; DM, diabetes mellitus; RR, relative risk. a Adjusted for age at baseline, education, body mass index in 1992, physical activity, nonsteroidal anti-inflammatory drug use, alcohol use, family history of colorectal cancer, and endoscopy history. b Models exclude participants with unknown duration of diabetes. c Calculated with Wald 2 statistic based on models with a continuous term for type 2 DM duration with a median duration value for each category (median values were 3.4 years, 12.0 years, and 19.7 years, respectively). Trend tests included only participants with type 2 DM. d Models exclude participants with unknown duration of insulin use and participants with type 2 DM, not using insulin. e Calculated with Wald 2 statistic based on models with a continuous term for insulin-use duration for each category (i.e., 1, 2, 3 to denote 1 2 years, 3 4 years, and 4 years, respectively). Trend tests included only insulin users. type 2 DM duration variable all had confidence intervals that overlapped one. For men and women, the relative risks for duration of insulin use, relative to not having type 2 DM, were not statistically significant, although it should be noted that there were considerably fewer insulin users who developed CRC (54 men, 26 women) than participants with type 2 DM overall who developed CRC (227 men, 108 women). There was weak evidence of possible effect modification by family history of CRC. In analyses of men and women combined, the relative risk of CRC for participants with type 2 DM was 1.91 among participants with a family history of CRC, whereas among participants without a family history of CRC the comparable relative risk was 1.12 (P-heterogeneity.09) (Table 5). There was little evidence that the association between type 2 DM Table 5. Relative Risks and 95% Confidence Intervals for the Association Between Type 2 Diabetes Mellitus and Risk of Colorectal Cancer, Stratified by Family History of Colorectal Cancer in the Cancer Prevention Study II Nutrition Cohort, 1992 2007 No family history of colorectal cancer in 1992 Family history of colorectal cancer in 1992 Multivariable-adjusted RR (95% CI) a Multivariable-adjusted RR (95% CI) a P interaction with family history b and women combined No type 2 DM 2311/1,605,246 1.00 (referent) 143/93,461 1.00 (referent) Type 2 DM 309/161,734 1.12 (0.99 1.26) 26/8829 1.91 (1.24 2.94).09 No type 2 DM 1268/722,269 1.00 (referent) 72/38,415 1.00 (referent) Type 2 DM 212/89,773 1.21 (1.05 1.41) 15/4221 1.91 (1.06 3.45).26 No type 2 DM 1063/882,978 1.00 (referent) 71/55,045 1.00 (referent) Type 2 DM 97/71,962 0.95 (0.77 1.18) 11/4608 1.89 (0.97 3.65).15 CI, confidence interval; DM, diabetes mellitus; RR, relative risk. a Adjusted for age at baseline, education, body mass index in 1992, physical activity, nonsteroidal anti-inflammatory drug use, alcohol use, endoscopy history, and sex (in combined models only). b Calculated from 2 log likelihood ratio test comparing models with and without an interaction term between type 2 DM and the family history variable.

1144 CAMPBELL ET AL GASTROENTEROLOGY Vol. 139, No. 4 and risk of incident CRC differed by subgroups according to age at enrollment, history of colorectal endoscopy, smoking status, BMI, NSAID use, or postmenopausal hormone use (data not shown, P heterogeneity 0.4 for all subgroup comparisons). Discussion In this large, prospective cohort of US adults, type 2 DM was associated with moderately higher risk of incident CRC among men. The increased risk associated with insulin use was not markedly greater than that of type 2 DM without insulin use. Among women, there was no evidence that type 2 DM or insulin use was associated with any of the CRC outcomes. These findings provide at least partial support for the hypothesis that hyperinsulinemia, 2,3 hyperglycemia, 3 or related cofactors, are associated with higher CRC risk. These findings also support recent observations that the association may be more prominent in men than in women, 5 9 and raise the possibility of a stronger association among individuals with a family history of CRC, a finding that could have clinical relevance if confirmed by other large studies. An earlier study from the CPS-II cohort of 1.2 million participants, with follow-up through to 1998, showed similar relative risks of colon cancer mortality among men (RR: 1.20; 95% CI: 1.06 1.37) and women (RR: 1.24; 95% CI: 1.07 1.43) who reported having diabetes mellitus in 1982. 25 Similarly, studies from the Nurses Health Study 10 and the Iowa s Health Study, 26 with follow-up through to 1994 and 1999, respectively, further supported a moderately higher risk of CRC incidence among women that had type 2 DM. Consistent with these earlier studies, a 2005 meta-analysis 4 of CRC incidence reported almost identical summary estimates for men (summary RR: 1.29; 95% CI: 1.15 1.44) and women (summary RR: 1.33; 95% CI: 1.23 1.44). Intriguingly, all studies 5 9 of type 2 DM and CRC published since the 2005 meta-analysis 4 in which men and women were analyzed separately in the same study suggest that the association among women is either attenuated relative to men 5 or altogether null 6 9 (of note, all but one 7 of these recent studies were conducted among Asian populations). The current finding that type 2 DM is associated with higher risk of CRC among men but not women is in agreement with these more recent studies. Possible explanations for recent sex differences in the association between diabetes and CRC could relate to sex differences in the use of metformin and degree of glucose control. Metformin is used as first-line treatment for type 2 DM and its use is associated with a lower risk of CRC. 13,27 Metformin has become more commonly used among women than among men since the late 1990s, 28 the period coinciding with these recent sex differences. This attenuated risk among women may also relate to better glucose control during this period. National Health and Nutrition Examination Survey data suggest that women with type 2 DM, but not men, have statistically significantly improved hemoglobin A1c (a marker of glucose control) in the period from 1999 to 2004. 29 It is plausible that these population trends in metformin use and improved glucose control are connected, although we are unaware of direct population level data to support this link. Maintaining normal blood glucose and insulin levels are likely key factors in CRC prevention, independent of type 2 DM status. A recent meta-analysis of epidemiologic studies suggested that biomarkers of glucose control and endogenous insulin are quite consistently associated with risk of CRC. 30 Many of the studies included in the meta-analysis excluded participants who reported type 2 DM. A relatively small study, 31 nested within a large European cohort, suggested that hemoglobin A1c, and not self-reported type 2 DM, was associated with higher risk of CRC. Relevant to these findings, a recent study showed that telomere length in colon epithelial tissue, a marker of susceptibility to colon carcinogenesis, did not differ between patients who had well-controlled type 2 DM and age-matched participants without type 2 DM. 32 Collectively, these results suggest that glucose control or degree of insulinemia, and not DM by itself, is influencing colorectal carcinogenesis. Few studies have assessed the association between insulin use and CRC risk. Among men in this study, the increased risk of CRC associated with insulin use (RR: 1.36) was not markedly greater than that associated with type 2 DM, not using insulin (RR: 1.22). Among women, insulin use was not associated with risk of CRC. These results with respect to insulin use differ from those of 2 previous retrospective studies from the United Kingdom. 12,14 In a retrospective cohort analysis of the UK General Research Practice Database, Yang and colleagues reported a 2.1-fold higher risk of CRC among type 2 DM patients that had ever used insulin relative to type 2 DM patients who did not use insulin, in statistical models that controlled for sex and age. 12 In a similar study, Currie and colleagues reported a 1.7-fold increased risk of CRC among type 2 DM patients who used insulin relative to type 2 DM patients who used metformin. 14 The current results are more consistent with those of a recent US study, conducted with data from a large pharmacy claims database, 13 where there was a null association between insulin monotherapy and risk of CRC. We are not aware of a clear explanation for these discordant results, although differences in study design and study populations may play some role. Although this study had a relatively large number of participants who used insulin and later developed CRC (n 85) compared with the previous studies on this topic 12 14 (n 18 12 ), statistical power to detect modest associations between duration of insulin-use and CRC risk was still quite limited.

October 2010 TYPE 2 DIABETES AND COLORECTAL CANCER RISK 1145 Few studies have assessed the association between type 2 DM duration and risk of CRC. 7,10,11,26 Similar to the current study, Limburg and colleagues 7 reported progressively higher relative risks of CRC with longer duration type 2 DM among men. These results emphasize the need for diligent adherence to recommended guidelines for CRC early detection among men with longstanding type 2 DM. Also similar to the current study, Limburg and colleagues 7 reported consistently null associations with type 2 DM duration among women. Two earlier cohort studies among women, 10,26 however, reported higher relative risks for the intermediate duration categories than either of their respective shorter or longer duration categories. As hypothesized previously, 10,26 if hyperinsulinemia is a key mediator for this association, risk of CRC may diminish with long-term type 2 DM as cells in the pancreas are expected to produce insufficient levels of endogenous insulin relative to the prediabetes state. 33 Limburg and colleagues 7 reported that clinically confirmed type 2 DM was associated with a 1.8-fold increased risk of CRC among men who were current or former cigarette smokers, whereas there was a null association among men who were never smokers. In the current study, there was no evidence of effect modification by smoking status. However, there was a stronger association between type 2 DM and CRC among men and women who reported a family history of CRC (RR: 1.91) than among men and women with no reported family history of CRC (RR: 1.12). To our knowledge, these are the first data to suggest that family history of CRC may modify the association between type 2 DM and CRC. This study has some limitations. First, type 2 DM and insulin use were self-reported. Because many patients with type 2 DM do not know they have the disease, 34 self-reports of type 2 DM may lead to attenuated risk estimates. We observed good agreement between selfreports and medical record data for type 2 DM in a random sample of participants in this study, although medical records clearly will not capture persons with undiagnosed type 2 DM. Other studies have indicated good validity of self-reported type 2 DM with direct measures of fasting glucose. 35 Other limitations to this study include the lack of detailed pharmacologic data on diabetes therapy, including metformin use and degree of glucose control. This study also has several strengths, including its prospective design, long duration of followup, large sample size, verified cancer outcomes, and repeatedly updated information on covariates, diabetes status, and insulin use. In conclusion, this study supports an association of type 2 DM and insulin use with CRC incidence among men, but not women. Reasons for the sex differences are unclear, but may relate to temporal trends in the use of diabetic drugs and glucose control. Further investigation of the molecularly defined CRC subtypes, including microsatellite instability status, associated with type 2 DM may also be informative in this regard. These results also suggest that insulin use is unlikely to substantially increase risk of CRC among patients with type 2 DM. Colorectal cancer prevention strategies for patients with type 2 DM should emphasize adherence to guidelines intended for the general population, including smoking cessation, weight management, physical activity, and regular early detection exams. References 1. World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR, 2007. 2. 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Kuriki K, Hirose K, Tajima K. Diabetes and cancer risk for all and specific sites among Japanese men and women. Eur J Cancer Prev 2007;16:83 89. 9. Ren X, Zhang X, Gu W, et al. Type 2 diabetes mellitus associated with increased risk for colorectal cancer: evidence from an international ecological study and population-based risk analysis in China. Public Health 2009;123:540 544. 10. Hu FB, Manson JE, Liu S, et al. Prospective study of adult onset diabetes mellitus (type 2) and risk of colorectal cancer in women. J Natl Cancer Inst 1999;91:542 547. 11. Yang YX, Hennessy S, Lewis JD. Type 2 diabetes mellitus and the risk of colorectal cancer. Clin Gastroenterol Hepatol 2005;3: 587 594. 12. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044 1050. 13. Oliveria SA, Koro CE, Ulcickas Yood M, Sowell M. Cancer incidence among patients treated with antidiabetic pharmacotherapy. Diabetes Metab Syndr Clin Res Rev 2008;2:47 57. 14. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009; 52:1766 1777. 15. Tran TT, Medline A, Bruce WR. Insulin promotion of colon tumors in rats. Cancer Epidemiol Biomarkers Prev 1996;5:1013 1015. 16. Tran TT, Naigamwalla D, Oprescu AI, et al. Hyperinsulinemia, but not other factors associated with insulin resistance, acutely enhances colorectal epithelial proliferation in vivo. Endocrinology 2006;147:1830 1837. 17. National Institute of Diabetes and Digestive and Kidney Diseases. National Diabetes Statistics, 2007 fact sheet. Bethesda, MD: US Department of Health and Human Services, National Institutes of Health, 2008.

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