Selenium, antioxidants, cardiovascular disease, and all-cause mortality: a systematic review and meta-analysis of randomized controlled trials.
The American journal of clinical nutrition. 2020;112(6):1642-1652
Plain language summary
Oxidative damage is a shared characteristic in chronic diseases such as cardiovascular disease (CVD), diabetes, cancer and ageing. Antioxidants mitigate the impact of oxidants and have been widely investigated in ageing and disease. However, the evidence for supplementary antioxidants has been mixed and some authorities have advised against the use of certain single nutrients for the prevention of CVD or cancer. This systematic review and meta-analysis focused on selenium due to its vital role in the antioxidant system and associations of low selenium blood levels with increased risk of CVD, cancers and death. The study included 43 randomised controlled trials (RCTs) evaluating the effect of supplemental selenium and antioxidants with or without selenium and their impact on CVD risk, cancer and all-cause mortality. Overall supplemental selenium or antioxidants alone did not seem to be associated with CVD outcomes, cancer, CVD and cancer mortality, or all-cause mortality. On close examination, a decreased risk was seen for CVD mortality when antioxidants were combined with selenium, whilst antioxidant mixtures without selenium demonstrated an increased risk in all-cause mortality. The findings did not seem to be influenced by dietary selenium intake. The authors suggested that inclusion of selenium as part of an antioxidant mix could be key for an antioxidant associated risk reduction. However, in the absence of further long term studies, a balanced antioxidant-rich diet was advocated as the safest approach. In clinical practice, where antioxidant support beyond diet is warranted, supplemental antioxidant use should be concurrent with adequate selenium supplementation, with dose benefits of 50-200mcg observed.
BACKGROUND Antioxidants have been promoted for cardiovascular disease (CVD) risk reduction and for the prevention of cancer. Our preliminary analysis suggested that only when selenium was present were antioxidant mixtures associated with reduced all-cause mortality. OBJECTIVE We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to determine the effect of selenium supplementation alone and of antioxidant mixtures with or without selenium on the risk of CVD, cancer, and mortality. METHODS We identified studies using the Cochrane Library, Medline, and Embase for potential CVD outcomes, cancer, and all-cause mortality following selenium supplementation alone or after antioxidant supplement mixtures with and without selenium up to June 5, 2020. RCTs of ≥24 wk were included and data were analyzed using random-effects models and classified by the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS The meta-analysis identified 9423 studies, of which 43 were used in the final analysis. Overall, no association of selenium alone or antioxidants was seen with CVD and all-cause mortality. However, a decreased risk with antioxidant mixtures was seen for CVD mortality when selenium was part of the mix (RR: 0.77; 95% CI: 0.62, 0.97; P = 0.02), with no association when selenium was absent. Similarly, when selenium was part of the antioxidant mixture, a decreased risk was seen for all-cause mortality (RR: 0.90; 95% CI: 0.82, 0.98; P = 0.02) as opposed to an increased risk when selenium was absent (RR: 1.09; 95% CI: 1.04, 1.13; P = 0.0002). CONCLUSION The addition of selenium should be considered for supplements containing antioxidant mixtures if they are to be associated with CVD and all-cause mortality risk reduction. This trial was registered at https://www.crd.york.ac.uk/PROSPERO/ as CRD42019138268.
Metabolic signatures associated with Western and Prudent dietary patterns in women.
The American journal of clinical nutrition. 2020;(2):268-283
BACKGROUND The Western dietary pattern (WD) is positively associated with risk of coronary artery disease (CAD) and cancer, whereas the Prudent dietary pattern (PD) may be protective. Foods may influence metabolite concentrations as well as oxidative stress and lipid dysregulation, biological mechanisms associated with CAD and cancer. OBJECTIVE The aim was to assess the association of 2 derived dietary pattern scores with serum metabolites and identify metabolic pathways associated with the metabolites. METHODS We evaluated the cross-sectional association between each dietary pattern (WD, PD) and metabolites in 2199 Women's Health Initiative (WHI) participants. With FFQ and factor analysis, we determined 2 dietary patterns consistent with WD and PD. Metabolites were measured with LC-tandem MS. Metabolite discovery among 904 WHI Observational Study (WHI-OS) participants was replicated among 1295 WHI Hormone Therapy Trial (WHI-HT) participants. We analyzed each of 495 metabolites with each dietary score (WD, PD) in linear regression models. RESULTS The PD included higher vegetables and fruit intake compared with the WD with higher saturated fat and meat intake. Independent of energy intake, BMI, physical activity, and other confounding variables, 45 overlapping metabolites were identified (WHI-OS) and replicated (WHI-HT) with an opposite direction of associations for the WD compared with the PD [false discovery rate (FDR) P < 0.05]. In metabolite set enrichment analyses, phosphatidylethanolamine (PE) plasmalogens were positively enriched for association with WD [normalized enrichment score (NES) = 2.01, P = 0.001, FDR P = 0.005], and cholesteryl esters (NES = -1.77, P = 0.005, FDR P = 0.02), and phosphatidylcholines (NES = -1.72, P = 0.01, P = 0.03) were negatively enriched for WD. PE plasmalogens were positively correlated with saturated fat and red meat. Phosphatidylcholines and cholesteryl esters were positively correlated with fatty fish. CONCLUSIONS Distinct metabolite signatures associated with Western and Prudent dietary patterns highlight the positive association of mitochondrial oxidative stress and lipid dysregulation with a WD and the inverse association with a PD.
Dietary Insulin Load and Cancer Recurrence and Survival in Patients With Stage III Colon Cancer: Findings From CALGB 89803 (Alliance).
Journal of the National Cancer Institute. 2019;(2):170-179
BACKGROUND Evidence suggests that diets inducing postprandial hyperinsulinemia may be associated with increased cancer-related mortality. The goal of this study was to assess the influence of postdiagnosis dietary insulin load and dietary insulin index on outcomes of stage III colon cancer patients. METHODS We conducted a prospective observational study of 1023 patients with resected stage III colon cancer enrolled in an adjuvant chemotherapy trial who reported dietary intake halfway through and six months after chemotherapy. We evaluated the association of dietary insulin load and dietary insulin index with cancer recurrence and survival using Cox proportional hazards regression adjusted for potential confounders; statistical tests were two-sided. RESULTS High dietary insulin load had a statistically significant association with worse disease-free survival (DFS), comparing the highest vs lowest quintile (adjusted hazard ratio [HR] = 2.77, 95% confidence interval [CI] = 1.90 to 4.02, Ptrend < .001). High dietary insulin index was also associated with worse DFS (highest vs lowest quintile, HR = 1.75, 95% CI = 1.22 to 2.51, Ptrend= .01). The association between higher dietary insulin load and worse DFS differed by body mass index and was strongest among patients with obesity (HR = 3.66, 95% CI = 1.88 to 7.12, Pinteraction = .04). The influence of dietary insulin load on cancer outcomes did not differ by mutation status of KRAS, BRAF, PIK3CA, TP53, or microsatellite instability. CONCLUSIONS Patients with resected stage III colon cancer who consumed a high-insulinogenic diet were at increased risk of recurrence and mortality. These findings support the importance of dietary management following resection of colon cancer, and future research into underlying mechanisms of action is warranted.
Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis: The CALGB 89803/Alliance Trial.
JAMA oncology. 2018;(6):783-790
Importance: The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. Objective: To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. Design, Setting, and Participants: This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. Exposures: We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. Main Outcomes and Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-free, recurrence-free, and overall survival. Results: Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99; P = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06; P = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76; P = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84; P = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94; P = .05 for trend). Conclusions and Relevance: Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. Trial Registration: clinicaltrials.gov Identifier: NCT00003835.
An Empirical Dietary Inflammatory Pattern Score Is Associated with Circulating Inflammatory Biomarkers in a Multi-Ethnic Population of Postmenopausal Women in the United States.
The Journal of nutrition. 2018;(5):771-780
BACKGROUND The empirical dietary inflammatory pattern (EDIP) score has been associated with concentrations of circulating inflammatory biomarkers in European Americans. OBJECTIVE We used the EDIP score, a weighted sum of 18 food groups that characterizes dietary inflammatory potential based on circulating concentrations of inflammatory biomarkers, to test the hypothesis that a pro-inflammatory dietary pattern is associated with inflammatory biomarker concentrations in a US multi-ethnic population. METHODS In this cross-sectional study, we calculated EDIP scores using baseline food frequency questionnaire data from 31,472 women, aged 50-79 y, in the Women's Health Initiative observational study and clinical trials. Circulating biomarkers outcomes at baseline were: C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor (TNF)-α, TNF receptor (TNFR) 1 and 2, and adiponectin. We used multivariable-adjusted linear regression analyses to estimate absolute concentrations and relative differences in biomarker concentrations, overall and in subgroups of race/ethnicity and BMI (body mass index) categories. RESULTS Independent of energy intake, BMI, physical activity, and other potential confounding variables, higher EDIP scores were significantly associated with higher (lower for adiponectin) absolute concentrations of all 6 biomarkers. On the relative scale, the percentage of difference in the concentration of biomarkers, among women in the highest compared to the lowest EDIP quintile, was: CRP, +13% (P-trend < 0.0001); IL-6, +15% (P-trend < 0.0001); TNF-α, +7% (P-trend = 0.0007); TNFR1, +4% (P-trend = 0.0009); TNFR2, +5% (P-trend < 0.0001); and adiponectin, -13% (P-trend <0.0001). These associations differed by racial/ethnic groups and by BMI categories. Whereas the absolute biomarker concentrations were lower among European-American women and among normal-weight women, the associations with diet were stronger than among women of African-American or Hispanic/Latino origin and among overweight and obese women. CONCLUSIONS Findings demonstrate the successful replication of an empirical hypothesis-oriented a posteriori dietary pattern score in a multi-ethnic population of postmenopausal women, with subgroup differences by race/ethnicity and body weight. Future research needs to apply the score in non-US populations.
Adherence to a Healthy Lifestyle is Associated With a Lower Risk of Diverticulitis among Men.
The American journal of gastroenterology. 2017;(12):1868-1876
OBJECTIVES Diverticulitis is a common disease with high clinical burden. We evaluated the joint contribution of multiple lifestyle factors to risks of incident diverticulitis. We also estimated the proportion of diverticulitis preventable by lifestyle modifications. METHODS We prospectively examined the association between lifestyle factors (red meat, dietary fiber intake, vigorous physical activity (activity with metabolic equivalent ≥6), body mass index (BMI), and smoking) and risk of diverticulitis among participants in the Health Professionals Follow-Up Study. RESULTS We documented 907 incident cases of diverticulitis during 757,791 person-years. High intake of red meat, low intake of dietary fiber, low vigorous physical activity, high BMI, and smoking were independently associated with increased risks of diverticulitis (all P<0.05). Low-risk lifestyle was defined as average red meat intake <51 g per day, dietary fiber intake in the top 40% of the cohort (about 23 g per day), vigorous physical activity in the highest 50% among participants with non-zero vigorous physical activity (roughly 2 h of exercise weekly), normal BMI between 18.5-24.9 kg m-2, and never-smoker. There was an inverse linear relationship between number of low-risk lifestyle factors and diverticulitis incidence (P for trend<0.001). Compared with men with no low-risk lifestyle factors, the multivariable relative risks of diverticulitis were 0.71 (95% confidence interval (CI): 0.59-0.87) for men with 1 low-risk lifestyle factor; 0.66 (95% CI: 0.55-0.81) for 2 low-risk factors; 0.50 (95% CI: 0.40-0.62) for 3 low-risk factors; 0.47 (95% CI: 0.35-0.62) for 4 low-risk factors, and 0.27 (95% CI: 0.15-0.48) for 5 low-risk factors. Adherence to a low-risk lifestyle could prevent 50% (95% CI: 20-71%) of incident diverticulitis. CONCLUSIONS Adherence to a low-risk lifestyle is associated with reduced incidence of diverticulitis.
Leucocyte telomere length, genetic variants at the TERT gene region and risk of pancreatic cancer.
OBJECTIVE Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer. DESIGN We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively. RESULTS Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023). CONCLUSIONS Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.
Prospective Study of Glycemic Load, Glycemic Index, and Carbohydrate Intake in Relation to Risk of Biliary Tract Cancer.
The American journal of gastroenterology. 2016;111(6):891-6
OBJECTIVES Diets that induce a high glycemic response might increase the risk of biliary tract cancer (BTC). We evaluated the hypothesis that diets with high glycemic load (GL) and high glycemic index (GI), which are measures of the glycemic effect of foods, are associated with an increased incidence of BTC. METHODS We used data from a population-based prospective study of 76,014 Swedish adults (age 45-83 years; 57% men) who were free of cancer and had completed a food-frequency questionnaire in the autumn of 1997. Incident cancer cases were ascertained by linkage with the Swedish Cancer Registry. Data were analyzed using Cox proportional hazards regression models. RESULTS During a mean follow-up of 13.3 years (1,010,777 person-years), we identified 140 extrahepatic BTC cases (including 77 gallbladder cancers) and 23 intrahepatic BTC cases. A high dietary GL was associated with an increased risk of BTC. The multivariable relative risks for the highest versus lowest quartile of dietary GL were 1.63 (95% confidence interval (95% CI), 1.01-2.63) for extrahepatic BTC, 2.14 (95% CI, 1.06-4.33) for gallbladder cancer, and 3.46 (95% CI, 1.22-9.84) for intrahepatic BTC. Dietary GI was statistically significantly positively associated with risk of extrahepatic BTC and gallbladder cancer. We observed no statistically significant association between carbohydrate intake and BTC risk, although all associations were positive. CONCLUSION Although these data do not prove a causal relationship, they are consistent with the hypothesis that high-GL and high-GI diets are associated with an increased risk of BTC.
Postdiagnostic Statin Use and the Risk of Lethal Prostate Cancer in the Health Professionals Follow-up Study.
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2015;(10):1638-40
BACKGROUND Observational studies suggest potential chemopreventive benefits of statins on prostate cancer outcomes, but data on the impact of postdiagnostic use are sparse. METHODS We examined the association of postdiagnostic statin use and risk of lethal prostate cancer (metastases or prostate cancer death, N = 242) among 3,949 men diagnosed with localized prostate cancer from the Health Professionals Follow-Up Study between 1992 and 2008 and followed through 2010 (33,302 person years). We used Cox proportional hazards regression models to estimate relative risks and 95% confidence intervals (CI), adjusting for age, time period, time from diagnosis to questionnaire, body mass index, vigorous physical activity, smoking, aspirin use, clinical stage, PSA at diagnosis, Gleason score, primary treatment, and comorbidities. RESULTS We found no statistically significant association between postdiagnostic current use of statins or duration of statin usage and the outcome of lethal prostate cancer [N = 242 cases; multivariate HR = 0.97 (95% CI, 0.72-1.31) for current use yes/no; HR = 0.85 (95% CI, 0.59-1.22) for 1 to 5 years of use, 0.96 (95% CI, 0.66-1.38) for 6+ years of use vs. never use]. CONCLUSIONS We observed little evidence that statin usage after diagnosis of localized prostate cancer reduces risk of progression to metastatic disease or prostate cancer-specific death. IMPACT These results do not support statins as a chemopreventive agent for prostate cancer progression.
Effects of Vitamin D Supplementation on C-peptide and 25-hydroxyvitamin D Concentrations at 3 and 6 Months.
Scientific reports. 2015;:10411
The link between African-Americans' disproportionate rates of diabetes, obesity and vitamin D deficiency may be marked by C-peptide as an indicator of insulin secretion. We hypothesize that vitamin D supplementation will increase C-peptide, a marker of insulin secretion. During 3 winters from 2007-2010, 328 healthy African-Americans (median age, 51 years) living in Boston, MA were randomized into a 4-arm, double-blind trial for 3 months of placebo, 1000, 2000, or 4000 IU of vitamin D3. The differences in non-fasting C-peptide between baseline and 3 months were -0.44 ng/mL for those receiving placebo, -0.10 ng/mL for those receiving 1000 IU/d, 0 ng/mL for those receiving 2000 IU/d, 1.24 ng/mL for those receiving 4000 IU/d (C-peptide increased 0.42 ng/mL for each additional 1000 IU/d of vitamin D3, p < 0.001). Vitamin D supplementation increased C-peptide in overweight African-Americans and may be compatible with other recommendations for diabetes prevention and management including weight loss and increased physical activity.