Association of dairy intake with all-cause, cancer, and cardiovascular disease mortality in Japanese adults: a 25-year population-based cohort

Abstract Purpose The association between dairy intake and mortality remains uncertain, and evidence for the Japanese population is scarce. We aimed to investigate the association between dairy intake and all-cause, cancer, and cardiovascular disease (CVD) mortality in Japanese adults. Methods A total of 34,161 participants (16,565 men and 17,596 women) aged 40–64 years without a history of cancer, myocardial infarction, or stroke at baseline were included in the analysis, using data from the Miyagi Cohort Study initiated in 1990. Milk, yogurt, and cheese intake were obtained using a validated food frequency questionnaire. Total dairy intake was calculated as the sum of milk, yogurt, and cheese intake and then categorized by quartile. The outcomes were all-cause, cancer, and CVD mortality. Cox proportional hazards regression models were used to estimate multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality risks. Results During 750,016 person-years of follow-up, the total number of deaths was 6498, including 2552 deaths due to cancer and 1693 deaths due to CVD. There was no association between total dairy intake and all-cause, cancer, and CVD mortality for both men and women. We also examined the associations between subgroup dairy products and mortality. For milk and yogurt intake, our results suggest null associations. However, cheese intake was modestly associated with lower all-cause mortality in women; compared with non-consumers, the multivariable HRs (95%CIs) were 0.89 (0.81–0.98) for 1–2 times/month, 0.88 (0.78–1.00) for 1–2 times/week, and 0.89 (0.74–1.07) for 3 times/week or almost daily (p trend = 0.016). Conclusion Dairy intake was not associated with mortality in Japanese adults, except for limited evidence showing a modest association between cheese intake and a lower all-cause mortality risk in women.

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Dietary Inflammatory Index Is Associated with Risk of All-Cause and Cardiovascular Disease Mortality but Not with Cancer Mortality in Middle-Aged and Older Japanese Adults

Journal of Nutrition ◽

10.1093/jn/nxz085 ◽

2019 ◽

Vol 149 (8) ◽

pp. 1451-1459 ◽

Cited By ~ 7

Author(s):

Emiko Okada ◽

Toru Shirakawa ◽

Nitin Shivappa ◽

Kenji Wakai ◽

Koji Suzuki ◽

...

Keyword(s):

Cardiovascular Disease ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Dietary Inflammatory Index ◽

Digestive Cancer ◽

Inflammatory Index ◽

Japanese Adults ◽

Increased Risk ◽

Total Cancer ◽

Cvd Mortality

ABSTRACT Background The Dietary Inflammatory Index (DII) is a comprehensive, literature-derived index for assessing the effect of dietary constituents on inflammatory biomarkers. Several studies have shown an association between DII score and mortality, but there are limited prospective studies in Asian populations. Objectives The aim of this study was to investigate the association between DII score and risk of all-cause, total cardiovascular disease (CVD), stroke, coronary heart disease (CHD), total cancer, digestive cancer, and noncancer/non-CVD mortality in the Japanese population. Methods A total of 58,782 Japanese participants aged 40–79 y who were enrolled in the Japan Collaborative Cohort Study during 1988–1990 were included in the analysis. DII scores were calculated based on a food-frequency questionnaire. HRs and 95% CIs for mortality according to DII quintiles were estimated using Cox proportional hazards models. Results During the median follow-up period of 19.3 y, a total of 11,693 participants died. The multivariable HR for all-cause mortality for the highest compared with the lowest DII quintiles was 1.13 (95% CI: 1.05, 1.21). For CVD mortality, the highest multivariable HRs were 1.30 (95% CI: 1.13, 1.49), 1.29 (95% CI: 1.05, 1.59), and 1.30 (95% CI: 0.96, 1.76) for total CVD, stroke, and CHD, respectively. No significant associations were observed between DII and risk of total cancer, digestive cancer, and noncancer/non-CVD mortality. Conclusion Our findings suggest that a higher DII was associated with an increased risk of all-cause and CVD mortality among Japanese adults.

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Nonfatal Stroke and All-Cause Mortality among Community-Dwelling Older Adults Living in Rural Ecuador: A Population-Based, Prospective Study

Journal of Neurosciences in Rural Practice ◽

10.4103/jnrp.jnrp_79_18 ◽

2018 ◽

Vol 09 (04) ◽

pp. 551-555

Author(s):

Oscar H. Del Brutto ◽

Robertino M. Mera ◽

Victor J. Del Brutto

Keyword(s):

Older Adults ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Rural Setting ◽

Nonfatal Stroke ◽

All Cause Mortality ◽

History Of ◽

Univariate Analyses

ABSTRACT Background: Stroke is a leading cause of disability in developing countries. However, there are no studies assessing the impact of nonfatal strokes on mortality in rural areas of Latin America. Using a population-based, prospective cohort study, we aimed to assess the influence of nonfatal strokes on all-cause mortality in older adults living in an underserved rural setting. Methods: Deaths occurring during a 5-year period in Atahualpa residents aged ≥60 years were identified from overlapping sources. Tests for equality of survivor functions were used to estimate differences between observed and expected deaths for each covariate investigated. Cox proportional hazards models were used to estimate Kaplan–Meier survival curves of variables reaching significance in univariate analyses. Results: Of 437 individuals enrolled over 5 years, follow-up was achieved in 417 (95%), contributing 1776 years of follow-up (average 4.3 ± 1.3 years). Fifty-one deaths were detected, for an overall cumulative 5-year mortality rate of 12.2% (8.9%–15.6%). Being older than 70 years of age, having poor physical activity, edentulism, and history of a nonfatal stroke were related to mortality in univariate analyses. A fully adjusted Cox proportional hazards model showed that having history of a nonfatal stroke (P = 0.024) and being older than 70 years of age (P = 0.031) independently predicted mortality. In contrast, obesity was inversely correlated with mortality (P = 0.047). Conclusions: A nonfatal stroke and increasing age increase the risk of all-cause mortality in inhabitants of a remote rural village. The body mass index is inversely related to death (obesity paradox).

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Association between incarceration and incident cardiovascular disease events: results from the CARDIA cohort study

BMC Public Health ◽

10.1186/s12889-021-10237-6 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Jordan Coleman ◽

Donald M. Lloyd-Jones ◽

Hongyan Ning ◽

Norrina B. Allen ◽

Catarina I. Kiefe ◽

...

Keyword(s):

Cardiovascular Disease ◽

Proportional Hazards ◽

White Men ◽

Incidence Rates ◽

Cox Proportional Hazards ◽

Study Objective ◽

Black And White ◽

All Cause Mortality ◽

History Of ◽

Incident Cardiovascular Disease

Abstract Background Incarceration has been associated with higher cardiovascular risk, yet data evaluating its association with cardiovascular disease events are limited. The study objective was to evaluate the association between incarceration and incident fatal and non-fatal cardiovascular disease (CVD) events. Methods Black and white adults from the community-based Coronary Artery Risk Development in Young Adult (CARDIA) study (baseline 1985–86, n = 5105) were followed through August 2017. Self-reported incarceration was measured at baseline (1985–1986) and Year 2 (1987–1988), and fatal and non-fatal cardiovascular disease events, including coronary heart disease, stroke, and heart failure, and all-cause mortality, were captured through 2017. Analyses were completed in September 2019. Cumulative CVD incidence rates and Cox proportional hazards were compared overall by incarceration status. An interaction between incarceration and race was identified, so results were also analyzed by sex-race groups. Results 351 (6.9%) CARDIA participants reported a history of incarceration. Over 29.0 years mean follow-up, CVD incidence rate was 3.52 per 1000 person-years in participants with a history of incarceration versus 2.12 per 1000 person-years in participants without a history of incarceration (adjusted HR = 1.33 [95% CI, 0.90–1.95]). Among white men, incarceration was associated with higher risk of incident cardiovascular disease (adjusted HR = 3.35 [95% CI, 1.54–7.29) and all-cause mortality (adjusted HR = 2.52 [95% CI, 1.32–4.83]), but these associations were not statistically significant among other sex-race groups after adjustment. Conclusions Incarceration was associated with incident cardiovascular disease rates, but associations were only significant in one sex-race group after multivariable adjustment.

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Co-Existence of Diabetes Mellitus And Pre-Existing Cardiovascular Disease, Diabetes Mellitus, And Pre-Existing Cardiovascular Disease And Mortality in Peritoneal Dialysis Patients

10.21203/rs.3.rs-35743/v1 ◽

2020 ◽

Author(s):

Xiaojiang Zhan ◽

Yueqiang Wen ◽

Qian Zhou ◽

Xiaoran Feng ◽

FenFen Peng ◽

...

Keyword(s):

Diabetes Mellitus ◽

Cardiovascular Disease ◽

Peritoneal Dialysis ◽

Proportional Hazards ◽

Multinomial Logistic Regression ◽

Cox Proportional Hazards ◽

Control Group ◽

All Cause Mortality ◽

Study Population ◽

Cvd Mortality

Abstract Background: Little is known over the effect of co-existence of diabetes mellitus (DM) and pre-existing cardiovascular disease (CVD), DM, and pre-existing CVD on mortality among continuous ambulatory peritoneal dialysis (CAPD) patients.Methods: A retrospective study, with 2939 incident Chinese CAPD patients from five facilities between January 1, 2005 and December 31, 2018, was conducted. The primary and secondary outcomes were all-cause and CVD mortality. The association between these interesting comorbidities and mortality was evaluated using the Cox proportional hazards regression.Results: Over a median of 35.1 months of follow-up, 519 (17.7%) patients died, with 258 (8.8%) CVD mortality. Hypertension was independently associated with co-existence of DM and pre-existing CVD using multinomial logistic regression (odd ratio 13.72, 95% CI 6.14 to 30.63). After adjusting for confounding factors, DM plus CVD, DM, and pre-existing CVD groups had a higher risk of all-cause mortality (HR 2.85, 95% CI 2.18 to 3.72; HR 1.89, 95% CI 1.50 to 2.38; and HR 1.43, 95% CI 1.07 to 1.92) and CVD mortality (HR 2.79, 95% CI 1.91 to 4.08; HR 1.88, 95% CI 1.35 to 2.61; and HR 1.82, 95% CI 1.23 to 2.68), respectively, compared to the control group. Compared with those pre-existing CVD patients, DM patients had 1.44 (95%CI 1.04 to 1.98)-time and 1.11 (95%CI 0.72 to 1.71) risk of all-cause and CVD mortality, respectively. There was no significant interaction between DM and CVD on all-cause and CVD mortality (β=0.203, P=0.292; β=0.281, P=0.123) in the study population. Conclusions: CAPD patients with co-existence of DM and pre-existing CVD at baseline are at highest risk of all-cause and CVD mortality, followed sequentially by DM patients and pre-existing CVD patients, with hypertension as a powerful predictor for co-existence of DM and pre-existing CVD. DM patients have a higher risk of all-cause mortality and similar risk of CVD mortality compared with pre-existing CVD patients.

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Higher Dietary Non-enzymatic Antioxidant Capacity Is Associated with Decreased Risk of All-Cause and Cardiovascular Disease Mortality in Japanese Adults

Journal of Nutrition ◽

10.1093/jn/nxz145 ◽

2019 ◽

Cited By ~ 2

Author(s):

Ikuko Kashino ◽

Tetsuya Mizoue ◽

Mauro Serafini ◽

Shamima Akter ◽

Norie Sawada ◽

...

Keyword(s):

Cardiovascular Disease ◽

Antioxidant Capacity ◽

Large Scale ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Antioxidant Power ◽

Enzymatic Antioxidant ◽

Japanese Adults ◽

All Cause Mortality ◽

Specific Mortality

ABSTRACT Background Few studies have assessed associations of non-enzymatic antioxidant capacity (NEAC) in the overall diet with all-cause or specific mortality, and their results have been inconsistent. Objectives The present study investigated the association between dietary NEAC and all-cause or cause-specific mortality. Methods The study was a large-scale population-based prospective cohort study in Japan consisting of 42,520 men and 50,207 women aged 44–76 y, who had no history of cancer, stroke, ischemic heart disease, or chronic liver disease. We evaluated FFQ-based dietary NEAC with use of published databases in which the NEACs of individual foods were analyzed by ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity (ORAC) assays. Dietary NEAC was calculated by multiplying the estimated NEAC with the consumed amount and summing up those values for all foods, and was categorized in quartiles. We identified death and cause of death with use of residential registry and death certificates. HRs and 95% Cls for death from the second survey, which was conducted from April 1995 to December 2014 were estimated with Cox proportional hazards regression analysis. Results After 1,498,308 person-years of follow-up, 12,978 total deaths occurred. The multivariable-adjusted HRs (95% Cls) for all-cause mortality for the highest compared with the lowest quartile of FRAP and ORAC were 0.85 (0.80, 0.89) and 0.84 (0.79, 0.89), respectively. Dietary NEACs were inversely associated with mortality from cardiovascular disease (CVD), but not from cancer. The multivariable-adjusted HRs (95% Cls) for CVD for the highest compared with the lowest quartile of FRAP and ORAC were 0.83 (0.75, 0.92) and 0.79 (0.70, 0.89), respectively. Conclusions Higher dietary NEACs from FRAP and ORAC were associated with lower risk of all-cause mortality and mortality from CVD in Japanese adults.

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Risk and Timing of Cardiovascular Disease After Androgen-Deprivation Therapy in Men With Prostate Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2014.59.1792 ◽

2015 ◽

Vol 33 (11) ◽

pp. 1243-1251 ◽

Cited By ~ 121

Author(s):

Sean O'Farrell ◽

Hans Garmo ◽

Lars Holmberg ◽

Jan Adolfsson ◽

Pär Stattin ◽

...

Keyword(s):

Prostate Cancer ◽

Cardiovascular Disease ◽

Androgen Deprivation Therapy ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Androgen Deprivation ◽

Gnrh Agonists ◽

Cvd Risk ◽

Comparison Cohort ◽

Using Data

Purpose Findings on the association between risk of cardiovascular disease (CVD) and the duration and type of androgen-deprivation therapy (ADT) in men with prostate cancer (PCa) are inconsistent. Methods By using data on filled drug prescriptions in Swedish national health care registers, we investigated the risk of CVD in a cohort of 41,362 men with PCa on ADT compared with an age-matched, PCa-free comparison cohort (n = 187,785) by use of multivariable Cox proportional hazards regression models. Results From 2006 to 2012, 10,656 men were on antiandrogens (AA), 26,959 were on gonadotropin-releasing hormone (GnRH) agonists, and 3,747 underwent surgical orchiectomy. CVD risk was increased in men on GnRH agonists compared with the comparison cohort (hazard ratio [HR] of incident CVD, 1.21; 95% CI, 1.18 to 1.25; and orchiectomy: HR, 1.16; 95% CI, 1.08 to 1.25). Men with PCa on AA were at decreased risk (HR of incident CVD, 0.87; 95% CI, 0.82 to 0.91). CVD risk was highest during the first 6 months of ADT in men who experienced two or more cardiovascular events before therapy, with an HR of CVD during the first 6 months of GnRH agonist therapy of 1.91 (95% CI, 1.66 to 2.20), an HR of CVD with AA of 1.60 (95% CI, 1.24 to 2.06), and an HR of CVD with orchiectomy of 1.79 (95% CI, 1.16 to 2.76) versus the comparison cohort. Conclusion Our results support that there should be a solid indication for ADT in men with PCa so that benefit outweighs potential harm; this is of particular importance among men with a recent history of CVD.

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Cardiovascular Safety and Possible Benefit of a 5-Alpha Reductase Inhibitor among Benign Prostatic Hyperplasia Patients, A Nationally Representative Cohort of Korean Men

Journal of Clinical Medicine ◽

10.3390/jcm8050733 ◽

2019 ◽

Vol 8 (5) ◽

pp. 733

Author(s):

Jooyoung Chang ◽

Seulggie Choi ◽

Kyuwoong Kim ◽

Sang Min Park

Keyword(s):

Cardiovascular Disease ◽

Benign Prostatic Hyperplasia ◽

Proportional Hazards ◽

Population Based ◽

Cox Proportional Hazards ◽

Prostatic Hyperplasia ◽

Cumulative Exposure ◽

Primary Study ◽

Unexpected Finding ◽

Nationally Representative

Several studies suggest that 5-alpha reductase inhibitors (5ARIs) may be associated with elevated risk of cardiovascular disease (CVD). We investigated the association of 5ARI exposure and CVD incidence using the National Health Insurance Service-Health Screening Cohort, a nationally representative population-based sample of Koreans. We calculated the 4-year cumulative exposure to 5ARI for 215,003 men without prior 5ARI use. Participants were followed from January 1st, 2008 to December 31st, 2015. A subcohort of newly diagnosed benign prostatic hyperplasia (BPH) patients during 2004–2010 was also analyzed. The primary study outcome was CVD and secondary outcomes were myocardial infarction (MI) or stroke. Hazard ratios (HRs) were estimated using Cox proportional hazards models adjusted for conventional risk factors. In both the main cohort and BPH subcohort, the use of any 5ARI did not increase the risk of cardiovascular disease (HR = 1.06; 95% CI = 0.91–1.23; HR = 0.95; 95% CI = 0.88–1.03; respectively). Furthermore, as an unexpected finding, a dose-analysis among the BPH subcohort showed that the highest tertile of 5ARI exposure reduced the risk of CVD (HR = 0.82; 95% CI = 0.72–0.92; p-trend = 0.001), MI (HR = 0.69; 95% CI = 0.50–0.95), and stroke (HR = 0.84; 95% CI = 0.72–0.98) compared to non-users. Among men and BPH patients, 5ARI did not increase the risk of CVD. Among BPH patients, 5ARI use may reduce the risk CVD.

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Dietary Omega-3 Fatty Acid Intake and Mortality in CKD Population: A 1999–2014 NHANES Analysis

American Journal of Nephrology ◽

10.1159/000520027 ◽

2021 ◽

pp. 1-10

Author(s):

Wei-Lan Li ◽

Nan-Hui Zhang ◽

Shu-Wang Ge ◽

Gang Xu

Keyword(s):

Cardiovascular Disease ◽

Fatty Acid ◽

Proportional Hazards ◽

Early Death ◽

Cox Proportional Hazards ◽

Omega 3 ◽

Pufa Intake ◽

Dietary Recall ◽

Cox Proportional Hazards Models ◽

All Cause Mortality

Introduction: High risk of early death, especially contributed to cardiovascular disease, exists in patients who have chronic kidney disease (CKD). And the burden of cardiovascular disease is able to be lightened by an increase in omega-3 polyunsaturated fatty acid (omega-3 PUFA). A diet high in omega-3 PUFA in the general population is protective, although it is inconclusive about its beneficial role in the CKD population. Methods: From the 1999 to 2014 National Health and Nutrition Examination Surveys (NHANES), we can collect 2,990 participants who suffered from CKD, who were classified into 4 groups: <0.86, 0.87–1.30, 1.31–1.92, and 1.93–9.65 g/day based on NHANES 24-h dietary recall questionnaire dietary omega-3 PUFA. Moreover, their mortality details were available to be obtained by linking NHANES to the National Death Index. The associations between dietary omega-3 PUFA and mortality were evaluated by constructing multivariable Cox proportional hazards models. Results: Over 8 years of a median follow-up, 864 deaths were recorded. The adjusted hazard ratios (95% confidence interval) for all-cause mortality of the diseased people with CKD in the 2nd (0.87–1.30 g/day), 3rd (0.87–1.30 g/day), and 4th (1.93–9.65 g/day) quartiles of dietary omega-3 PUFA were 0.94 (0.72, 1.23), 0.74 (0.54, 1.02), and 0.67 (0.48, 0.93), respectively, versus those with the lowest quartile of dietary omega-3 PUFA intake (<0.86 g/day) (p for trend = 0.011). Conclusion: There may be a inverse relation of dietary omega-3 PUFA intake and all-cause mortality in patients with CKD. Therefore, an increase of dietary omega-3 PUFA may be encouraged to be used clinically in patients with CKD.

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Abstract 17: Association of Race and Sex with Cardiovascular Disease and Non-Cardiovascular Disease Mortality: The REasons for Geographic and Racial Differences in Stroke study

Circulation ◽

10.1161/circ.135.suppl_1.17 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Gabriel S Tajeu ◽

Monika M Safford ◽

George Howard ◽

Rikki M Tanner ◽

Paul Muntner

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Racial Differences ◽

Proportional Hazards ◽

Cox Proportional Hazards ◽

Hazard Ratio ◽

Cvd Risk ◽

Hazard Ratios ◽

Stroke Study ◽

Cvd Mortality

Introduction: Black Americans have higher rates of cardiovascular disease (CVD) mortality compared with whites. Differences in sociodemographic, psychosocial, CVD, and other risk factors may explain increased mortality risk. Methods: We analyzed data from 29,015 REasons for Geographic and Racial Differences in Stroke study participants to determine factors that may explain the higher hazard ratio for CVD and non-CVD mortality in blacks compared with whites. Cause of death was adjudicated by trained investigators. Within age-sex sub-groups, we used Cox proportional hazards regression with progressive adjustment to estimate black:white hazard ratios. Results: Overall, 41.0% of participants were black, and 54.9% were women. Over a mean follow-up of 7.1 years (maximum 12.3 years), 5,299 participants died (1,797 CVD and 3,502 non-CVD deaths). Among participants < 65 years of age, the age and region adjusted black:white hazard ratio for CVD mortality was 2.28 (95% CI: 1.68-3.10) and 2.32 (95% CI: 1.80-3.00) for women and men, respectively, and for participants ≥ 65 was 1.54 (95% CI: 1.30-1.82) and 1.35 (95% CI: 1.16-1.57) for women and men, respectively ( Table ). The higher black:white hazard ratios for CVD mortality were no longer statistically significant after multivariable adjustment, with the largest attenuation occurring with sociodemographic and CVD risk factor adjustment. Among participants < 65 years of age, the age and region adjusted black:white hazard ratios for non-CVD mortality were 1.51 (95% CI: 1.24-1.85) and 1.76 (95% CI: 1.46-2.13) for women and men, respectively, and for participants ≥ 65 was 1.12 (95% CI: 1.00-1.26) and 1.34 (95% CI: 1.20-1.49) for women and men, respectively. The higher black:white hazard ratios for non-CVD mortality were attenuated after adjustment for sociodemographics. Conclusions: Black:white differences are larger for CVD than non-CVD causes of death. The increased CVD mortality for blacks compared with whites is primarily explained by sociodemographic and CVD risk factors.

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Effects of metformin and sulfonylureas on overall and colorectal cancer-specific mortality.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2599 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2599-2599

Author(s):

Susan Spillane ◽

Kathleen Bennett ◽

Linda Sharp ◽

Thomas Ian Barron

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Proportional Hazards ◽

Early Stage ◽

Population Based ◽

Cox Proportional Hazards ◽

Stage I ◽

Early Stage Disease ◽

All Cause Mortality ◽

Specific Mortality

2599 Background: Preclinical studies have suggested a role for metformin in the treatment of colorectal cancer (CRC). Associations between metformin versus sulfonylurea exposure and mortality (all-cause and colorectal cancer specific) are assessed in this population-based study of patients with a diagnosis of stage I-IV CRC. Methods: National Cancer Registry Ireland records were linked to prescription claims data and used to identify a cohort of patients with incident TNM stage I-IV CRC diagnosed 2001-2006. From this cohort, 2 patient groups were identified and compared for outcomes - those who received a prescription for metformin +/- a sulfonylurea (MET) or a prescription for sulfonylurea alone (SUL) in the 90 days pre CRC diagnosis. Adjusted hazard ratios (HR) with 95% confidence intervals (CI) were estimated using Cox proportional hazards models adjusted for age, sex, stage, grade, site, comorbidities, year of diagnosis, and insulin, aspirin or statin exposure. Analyses were repeated stratifying by stage and site. Results: 5,617 patients with stage I-IV CRC were identified, of whom 369 received a prescription for metformin or a sulfonylurea in the 90 days pre diagnosis (median follow-up 1.6 years; MET: n=257; SUL: n=112). In adjusted analyses metformin exposure was associated with a 28% lower risk of all-cause mortality relative to sulfonylurea exposure (HR 0.72, 95% CI 0.53-0.98) and a non-significant 24% reduction in CRC-specific mortality (HR 0.76, 95% CI 0.52-1.13). In analyses stratified by site, in colon cancer, metformin exposure was associated with a significant one-third reduction in all-cause mortality (HR 0.66, 95% CI 0.46-0.95) and a non-significant reduction in site-specific mortality (HR 0.64, 95% CI 0.40-1.02). No mortality benefit was observed for rectal cancer. The association between metformin exposure and reduced mortality was strongest for stage I/II disease (all-cause mortality: HR 0.56, 95% CI 0.32-0.98; CRC-specific mortality: HR 0.48, 95% CI 0.21-1.11). Conclusions: Pre-diagnosis metformin exposure in CRC patients was associated with a significant reduction in mortality relative to sulfonylurea exposure. This benefit was greatest in patients with colon cancer and early stage disease.

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