Metformin use is not associated with reduced risk of older onset inflammatory bowel disease: a Danish nationwide population-based study.

BACKGROUND: Metformin has pleiotropic effects including anti-inflammatory properties and effects on the gut microbiome. It is primarily used in the older population, where the occurrence of inflammatory bowel disease (IBD) is increasing. The aim of this study was to examine whether metformin protects against development of IBD. METHODS: In the setting of a Danish nationwide population-based cohort, we conducted a nested case-control study using a new-user active comparator design. For each patient with IBD, we selected 10 IBD-free individuals matched on age, sex, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) of IBD. Adjustment included educational level, other immune-mediated inflammatory diseases, and use of dipeptidyl peptidase (DPP)-4 inhibitors and statins. RESULTS: Among 302,863 IBD-free new users of oral glucose-lowering drugs, we identified 1271 patients who developed IBD and 12,676 matched IBD-free individuals. Mean age at IBD diagnosis was 66 (SD, 11) years. We found no association between ever use of metformin and risk of IBD, Crohn's disease or ulcerative colitis, adjusted OR 0.95 (95% CI 0.78-1.15), 0.87 (95% CI 0.60-1.26), and 1.04 (95% CI 0.83-1.31), respectively. Neither was the cumulative dose of metformin or the treatment duration with metformin associated with risk of IBD. CONCLUSIONS: In this population-based study, we report that despite anti-inflammatory effects and a notable impact on the gut microbiome, metformin use is not associated with reduced risk of older onset IBD.

Bariatric Surgery and Risk of New-onset Inflammatory Bowel Disease: A Nationwide Cohort Study.

BACKGROUND AND AIMS: The aim of this study was to examine the risk of new-onset inflammatory bowel disease [IBD] following bariatric surgery. METHODS: We conducted a nationwide population-based prospective cohort study of the entire Danish population 18 to 60 years of age, alive, and residing in Denmark, from 1996 to 2018. Bariatric surgery was included as a time-dependent variable, and Cox proportional hazards regression models were used to estimate hazard ratios [HRs] of IBD. We used a model adjusting for age, sex, and birth cohort and a multifactor-adjusted model additionally including educational status and number of obesity-related comorbidities. RESULTS: We followed 3 917 843 individuals of whom 15 347 had a bariatric surgery, for development of new-onset IBD. During 106 420 person-years following bariatric surgery, 100 IBD events occurred [incidence rate 0.940/1000 person-years]. During 55 553 785 person-years without bariatric surgery, 35 294 events of IBD occurred [incidence rate 0.635/1000 person-years]. This corresponded to a multifactor-adjusted hazard ratio [HR] of 1.15 (95% confidence interval[CI], 0.94-1.40) for IBD. Multifactor-adjusted HRs of Crohn's disease [CD] and ulcerative colitis [UC] were 1.85 [95% CI, 1.40-2.44] and 0.81 [95% CI, 0.61-1.08], respectively. Among women, the multifactor-adjusted HR for CD was 2.18 [95% CI, 1.64-2.90]. When limiting the study population to individuals with a diagnosis of overweight/obesity, bariatric surgery remained associated with increased risk of CD, multifactor-adjusted HR 1.59 [95% CI, 1.18-2.13]. CONCLUSIONS: This nationwide cohort study shows that bariatric surgery is associated with increased risk of development of new-onset CD, but not of UC. The underlying mechanisms remain elusive.

Current European guidelines for management of cardiovascular disease: Is medical treatment in nearly half a population realistic?

Background Health checks of the general population are widely used to prevent cardiovascular diseases, but are the current clinical guidelines from the European Society of Cardiology (ESC) suitable for screening the general population? Design A cross-sectional, population-based study of 978 men and women aged 40-65 years examined in 2010-2011 was used to estimate the proportion of the general Danish population fulfilling the criteria from the clinical guidelines from the ESC on medical treatment and lifestyle intervention to prevent cardiovascular disease. Methods The ESC criteria for medical treatment and lifestyle intervention were applied to a general population using information on previous cardiovascular diseases, known diabetes, urinalbumin, smoking, total cholesterol, systolic and diabolic blood pressure, low-density lipoprotein cholesterol and a multifactor risk score (SCORE). Results A total of 12.5% fulfilled the criteria for immediate medical treatment to prevent cardiovascular diseases. Furthermore, 30.4% are recommended for medical treatment if an initial lifestyle intervention fails summing to 42.9% eligible for medical treatment. The majority (79%) of persons aged 60-65 years are eligible for medical treatment, while close to half (44.9%) of all persons aged 50-59 years are recommended for medical treatment. Conclusion If ESC's guidelines were followed in Denmark, a conservative estimate shows that medical preventive treatment would involve nearly half the general population aged 40-65 years. The use of these guidelines in screening of the general population can be questioned as realistic and suitable.

Associations of genetic determinants of serum vitamin B12 and folate concentrations with hay fever and asthma: a Mendelian randomization meta-analysis.

BACKGROUND/OBJECTIVES: Studies of the effect of vitamin B12 and folate on the risk of asthma and hay fever have shown inconsistent results that may be biased by reverse causation and confounding. We used a Mendelian randomization approach to examine a potential causal effect of vitamin B12 and folate on hay fever, asthma, and selected biomarkers of allergy by using 11 vitamin B12-associated single-nucleotide polymorphisms (SNPs) and 2 folate-associated SNPs as unconfounded markers. SUBJECTS/METHODS: We included 162,736 participants from 9 population-based studies including the UK Biobank. Results were combined in instrumental variable and meta-analyses and effects expressed as odds ratios (ORs) or estimates with 95% confidence interval (CI). RESULTS: Using genetic proxies for B12 and folate, instrumental variable analyses did not show evidence for associations between serum B12 and hay fever: OR = 1.02 (95% CI: 0.98, 1.05), asthma: OR = 0.99 (95% CI: 0.95, 1.04), allergic sensitization: OR = 1.02 (95% CI: 0.74, 1.40), or change in serum IgE: 10.0% (95% CI: -9.6%, 29.6%) per 100 pg/ml B12. Similarly, there was no evidence for association between serum folate and hay fever: OR = 0.74 (95% CI: 0.45, 1.21), asthma: OR = 0.80 (95% CI: 0.43, 1.49), or allergic sensitization: OR = 1.92 (95% CI: 0.11, 33.45), but there was a statistically significant association with change in serum IgE: 2.0% (95% CI: 0.43%, 3.58%) per 0.1 ng/ml serum folate. CONCLUSIONS: Our results did not support the hypothesis that levels of vitamin B12 and folate are causally related to hay fever, asthma, or biomarkers of allergy, but we found evidence of a positive association between serum folate and serum total IgE.

Investigating the causal effect of smoking on hay fever and asthma: a Mendelian randomization meta-analysis in the CARTA consortium.

Observational studies on smoking and risk of hay fever and asthma have shown inconsistent results. However, observational studies may be biased by confounding and reverse causation. Mendelian randomization uses genetic variants as markers of exposures to examine causal effects. We examined the causal effect of smoking on hay fever and asthma by using the smoking-associated single nucleotide polymorphism (SNP) rs16969968/rs1051730. We included 231,020 participants from 22 population-based studies. Observational analyses showed that current vs never smokers had lower risk of hay fever (odds ratio (OR) = 0·68, 95% confidence interval (CI): 0·61, 0·76; P < 0·001) and allergic sensitization (OR = 0·74, 95% CI: 0·64, 0·86; P < 0·001), but similar asthma risk (OR = 1·00, 95% CI: 0·91, 1·09; P = 0·967). Mendelian randomization analyses in current smokers showed a slightly lower risk of hay fever (OR = 0·958, 95% CI: 0·920, 0·998; P = 0·041), a lower risk of allergic sensitization (OR = 0·92, 95% CI: 0·84, 1·02; P = 0·117), but higher risk of asthma (OR = 1·06, 95% CI: 1·01, 1·11; P = 0·020) per smoking-increasing allele. Our results suggest that smoking may be causally related to a higher risk of asthma and a slightly lower risk of hay fever. However, the adverse events associated with smoking limit its clinical significance.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Psychological consequences of screening for cardiovascular risk factors in an un-selected general population: results from the Inter99 randomised intervention study.

BACKGROUND: Concerns that general health checks, including screening for risk factors to ischemic heart disease (IHD), have negative psychological consequences seem widely unfounded; however, previous studies are only based on self-reports from participants. AIM: To investigate if risk factor screening in healthy adults leads to mental distress in the study population, independent of participation. METHODS: The Inter99 study (1999 - 2006) was a randomised intervention in the general population, aiming to prevent IHD by a healthier lifestyle. We included the whole study population, independent of participation (n = 60,915). We merged data with information on the use of psychotropic medication and/or hospitalisation due to psychiatric diagnoses, as retrieved from national registers in Denmark, 4 years before and 5 years after the study began. We conducted analyses using generalised estimating equations. RESULTS: There was no significant difference between the intervention and control groups in their use of antipsychotics, hypnotics/sedatives, antidepressants or anxiolytics. As regards admission to the hospital with mental disorders, no significant difference was seen. These findings were true based on a yearly basis, and when investigating both short-term and a long-term effects of the intervention. There was no interaction with socioeconomic status. Of the 918 persons with a psychiatric diagnosis before the study start, 303 (33%) were re-admitted in the intervention period. Pre-screening of psychological status did not influence the psychological impact of screening. CONCLUSIONS: This large, randomised intervention study supports that screening for risk factors to IHD does not increase mental distress, not even in the mentally or socioeconomically most vulnerable persons. This study included the whole Inter99 study population not only study participants.

Differential cross-sectional associations of work- and leisure-time sitting, with cardiorespiratory and muscular fitness among working adults.

OBJECTIVES: Sedentary behavior is increasingly recognized as a risk factor for cardiovascular and metabolic morbidity and mortality. Recent studies suggest that sitting during work and leisure time may affect markers of cardiometabolic health, differently. However, little is known about associations' between sitting time and cardiorespiratory and muscular fitness among adults. The aim of the present study was to examine associations between work- and leisure-time sitting, and key markers of cardiorespiratory and muscular fitness among working adults. METHODS: Working adults (N=2544) aged 18-69 from Health2006, a Danish population-based study, were included in this cross-sectional study. Sitting time during work and leisure time along with sociodemographic and behavioral covariates, including physical activity, were self-reported. Participants underwent a health examination with assessment of cardiorespiratory fitness (step test estimated VO 2Max, systolic and diastolic blood pressure) and muscular fitness (handgrip strength, lower limb extension power). Associations were explored by linear regression. Results Leisure-time sitting time was significantly (P<0.05) and inversely associated with VO 2Max, systolic blood pressure and handgrip strength among adults <50 years. There were no significant associations between sitting time at work and any of the markers of cardiorespiratory and muscular fitness. CONCLUSION: Work- and leisure-time sitting were differentially associated with cardiorespiratory and muscular fitness among working adults. This suggests that the domain in which sitting time is accrued should be considered when further investigating the relationship between sedentary behaviors and various healthy outcomes. In particular, caution should be exercised when labeling occupational sitting a danger per se for health.

Separate and joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors in working adults: a cross-sectional study.

BACKGROUND: The workplace is a main setting for prolonged sitting for some occupational groups. Convincing evidence has recently accumulated on the detrimental cardio-metabolic health effects of leisure-time sitting. Yet, much less is known about occupational sitting, and the potential health risk attached compared to leisure-time sitting. OBJECTIVE: To explore the separate and joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors in working adults. METHODS: All working adults (N = 2544) from the Health2006, a Danish population-based study, were included in this cross-sectional study. Participants reported hours of sitting during work, during leisure-time along with socio-demographic and behavioral characteristics, including physical activity. Cardio-metabolic risk factors (waist circumference, body mass index, body fat percentage, total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides, insulin, hemoglobin A1c and plasma glucose) were measured. Associations were explored by linear regression for leisure-time, occupational, and overall sitting time. RESULTS: Statistically significant (p<.05) detrimental associations of leisure-time sitting were observed with all cardio-metabolic risk factors, except hemoglobin A1c and plasma glucose. Similarly, occupational sitting time was significantly detrimentally associated with HDL cholesterol, triglycerides, and insulin. For categories of sitting time, a joint adverse association of sitting much during both work-time and leisure-time was observed. CONCLUSION: The associations of occupational sitting time with cardio-metabolic risk factors were fewer and weaker compared to leisure-time sitting. Yet, the joint associations of occupational and leisure-time sitting with cardio-metabolic risk factors were higher than the separate. Our findings amplify the need for further focus in this area prior to making assumptions about equivalent health risks across sedentary behaviors. To our knowledge, this is the first study to contrast the deleterious associations of prolonged occupational and leisure-time sitting, both separately and jointly.