Metabolically Healthy Obesity and Ischemic Heart Disease: A 10-Year Follow-Up of the Inter99 Study.

Context: Recent studies have suggested that a subgroup of obese individuals is not at increased risk of obesity-related complications. This subgroup has been referred to as metabolically healthy obese. Objective: To investigate whether obesity is a risk factor for development of ischemic heart disease (IHD) irrespective of metabolic health. Design: In all, 6238 men and women from the Danish prospective Inter99 study were followed during 10.6 (standard deviation = 1.7) years. Setting: General community. Participants: Participants were classified according to body mass index and four metabolic risk factors (low high-density lipoprotein cholesterol, elevated blood pressure, triglycerides, and fasting plasma glucose). Metabolically healthy individuals were defined as having no metabolic risk factors, and metabolically unhealthy individuals were defined as having a minimum of one. Main Outcome Measures: IHD. Results: During follow-up, 323 participants developed IHD. Metabolically healthy obese men had increased risk of IHD compared with metabolically healthy normal-weight men [hazard ratio (HR), 3.1; 95% confidence interval (CI), 1.1 to 8.2)]. The corresponding results for women were less pronounced (HR, 1.8; 95% CI, 0.7 to 4.8). Being metabolically healthy but overweight was not associated with higher risk of IHD in men (HR, 1.1; 95% CI, 0.5 to 2.4), and in women the risk was only slightly increased and insignificant (HR, 1.5; 95% CI, 0.8 to 3.0). A substantial proportion of metabolically healthy individuals became metabolically unhealthy after 5 years of follow-up. When these changes in exposure status were taken into account, slightly higher risk estimates were found. Conclusions: Being obese is associated with higher incidence of IHD irrespective of metabolic status, and we question the feasibility of denoting a subgroup of obese individuals as metabolically healthy.

Effectiveness of Liraglutide and Lixisenatide in the Treatment of Type 2 Diabetes: Real-World Evidence from The Health Improvement Network (THIN) Database in the United Kingdom.

INTRODUCTION: The glucagon-like peptide-1 receptor agonists liraglutide and lixisenatide are effective at reducing glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes mellitus (T2DM). Although liraglutide has demonstrated superior efficacy in head-to-head clinical trials, real-world evidence of comparative effectiveness is lacking. This observational study aimed to assess the effectiveness of liraglutide versus lixisenatide in UK clinical practice. METHODS: Electronic medical records from The Health Improvement Network (THIN) UK primary care database were analyzed. Patients aged ≥18 years, diagnosed with T2DM, and prescribed liraglutide or lixisenatide between 01 May 2013 and 31 December 2015 were included in the study. Adjusted linear regression models compared the difference in mean change in HbA1c, body mass index (BMI), and systolic blood pressure (SBP) after 12-month follow-up. The proportion of patients achieving glycemic control (HbA1c <6.5%, <7.0%, <7.5%); HbA1c reduction >1%; and weight reduction ≥3% within 12 months were determined. Cox proportional hazards modeling was used to evaluate the effect of treatment on time to achieving HbA1c and weight reduction targets. Healthcare resource use (HCRU) (GP, secondary care, hospitalizations) was compared using analysis of covariance. RESULTS: The primary outcome was assessed in 579 liraglutide and 213 lixisenatide new users. Fully adjusted linear regression indicated that liraglutide reduced HbA1c significantly more than lixisenatide (mean treatment difference -0.30; 95% CI -0.56, -0.04; p = 0.025). Compared to lixisenatide, liraglutide recipients were 2.5 times more likely to achieve HbA1c <6.5% (p = 0.0002). Liraglutide users were also more likely to achieve HbA1c <7.0% (HR 2.10; p < 0.0001), <7.5% (HR 1.65; p < 0.0001), and >1% HbA1c reduction (HR 1.29; p = 0.0002). BMI and SBP reductions were greater for the liraglutide group but results were not significant. HCRU was comparable between treatment groups. CONCLUSION: These results from the THIN database indicate that liraglutide treatment provided better outcomes related to glycemic control. FUNDING: Novo Nordisk.

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits.

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through genomewide association study of up to 30 884 adults of European ancestry from 21 studies, we confirmed and extended the list of previously identified loci associated with circulating IGF-I and IGFBP-3 concentrations (IGF1, IGFBP3, GCKR, TNS3, GHSR, FOXO3, ASXL2, NUBP2/IGFALS, SORCS2, and CELSR2). Significant sex interactions, which were characterized by different genotype-phenotype associations between men and women, were found only for associations of IGFBP-3 concentrations with SNPs at the loci IGFBP3 and SORCS2. Analyses of SNPs, gene expression, and protein levels suggested that interplay between IGFBP3 and genes within the NUBP2 locus (IGFALS and HAGH) may affect circulating IGF-I and IGFBP-3 concentrations. The IGF-I-decreasing allele of SNP rs934073, which is an eQTL of ASXL2, was associated with lower adiposity and higher likelihood of survival beyond 90 years. The known longevity-associated variant rs2153960 (FOXO3) was observed to be a genomewide significant SNP for IGF-I concentrations. Bioinformatics analysis suggested enrichment of putative regulatory elements among these IGF-I- and IGFBP-3-associated loci, particularly of rs646776 at CELSR2. In conclusion, this study identified several loci associated with circulating IGF-I and IGFBP-3 concentrations and provides clues to the potential role of the IGF axis in mediating effects of known (FOXO3) and novel (ASXL2) longevity-associated loci.

Adipocytokines, C-reactive protein, and cardiovascular disease: a population-based prospective study.

BACKGROUND: Being overweight or obese is associated with a greater risk of coronary heart disease and stroke compared with normal weight. The role of the specific adipose tissue-derived substances, called adipocytokines, in overweight- and obesity-related cardiovascular disease (CVD) is still unclear. OBJECTIVE: To investigate the associations of three adipose tissue-derived substances: adiponectin, leptin, and interleukin-6 with incident CVD in a longitudinal population-based study, including extensive adjustments for traditional and metabolic risk factors closely associated with overweight and obesity. C-reactive protein (CRP) was used as a proxy for interleukin-6. METHODS: Prospective population-based study of 6.502 participants, 51.9% women, aged 30-60 years, free of CVD at baseline, with a mean follow-up time of 11.4 years, equivalent to 74,123 person-years of follow-up. As outcome, we defined a composite outcome comprising of the first event of fatal and nonfatal coronary heart disease and fatal and nonfatal stroke. RESULTS: During the follow-up period, 453 composite CV outcomes occurred among participants with complete datasets. In models, including gender, age, smoking status, systolic blood pressure, treatment for hypertension, diabetes, body mass index (BMI), total cholesterol, high-density-lipoprotein cholesterol, homeostasis model assessment of insulin resistance, estimated glomerular filtration rate, adiponectin, leptin, and CRP, neither adiponectin (hazard ratio [HR] with 95% confidence interval [CI]: 0.97 [0.87-1.08] per SD increase, P = 0.60) nor leptin (0.97 [0.85-1.12] per SD increase, P = 0.70) predicted the composite outcome, whereas CRP was significantly associated with the composite outcome (1.19 [1.07-1.35] per SD increase, P = 0.002). Furthermore, in mediation analysis, adjusted for age and sex, CRP decreased the BMI-associated CV risk by 43% (95%CI 29-72). CONCLUSIONS: In this study, neither adiponectin nor leptin were independently associated with CVD, raising questions over their role in CVD. The finding that CRP was significantly associated with an increased risk of CVD and decreased the BMI-associated CVD risk substantially, could imply that interleukin-6-related pathways may play a role in mediating overweight- and obesity-related CVD.

Higher serum concentrations of N-terminal pro-B-type natriuretic peptide associate with prevalent hypertension whereas lower associate with incident hypertension.

BACKGROUND: The role of the natriuretic peptides (NPs) in hypertension is complex. Thus, a higher blood NP concentration is a robust marker of pressure-induced cardiac damage in patients with hypertension, whereas genetically elevated NP concentrations are associated with a reduced risk of hypertension and overweight individuals presumably at high risk of hypertension have lower NP concentrations. OBJECTIVE: To investigate the associations between serum N-terminal pro-B-type natriuretic peptide (NT-proBNP), used as a surrogate marker for active BNP, and prevalent as well as 5-year incident hypertension in a Danish general population sample. METHODS: Cross-sectional and prospective population-based study. RESULTS: At baseline, among 5,307 participants (51.3% women, mean age 46.0±7.9 years) with a complete set of data, we recorded 1,979 cases with prevalent hypertension (PHT). Among 2,389 normotensive participants at baseline with a complete set of data, we recorded 324 cases with incident hypertension (IHT) on follow-up 5 years later. In models adjusted for age, sex, lifestyle, social, dietary, anthropometric, pulmonic, lipid, metabolic and renal risk factors, as well as heart rate and baseline blood pressure (only incident model), one standard deviation increase in baseline log-transformed NT-proBNP concentrations was on one side associated with a 21% higher risk of PHT (odds ratio [OR]: 1.21 [95% confidence interval (CI): 1.13-1.30], P<0.001), and on the other side with a 14% lower risk of IHT (OR: 0.86 [95%CI:0.76-0.98], P = 0.020). CONCLUSIONS: Higher serum concentrations of NT-proBNP associate with PHT whereas lower concentrations associate with IHT. This suggests that a lower amount of circulating BNP, resulting in diminished vasodilation and natriuresis, could be involved in the pathogenesis of hypertension in its early stages.

Five-year weight changes associate with blood pressure alterations independent of changes in serum insulin.

OBJECTIVE: In overweight-related hypertension, the effect of weight changes on blood pressure (BP) is believed to be mediated by insulin. To test this hypothesis, we studied 5-year changes in weight, BP, and insulin in a general population of Danish adults (n = 3443; mean age 45.7 ±â€Š7.6 years). METHODS: We assessed the glucose-insulin metabolism by a standard oral glucose tolerance test. We divided the antihypertensive and antidiabetic medication-free participants into three groups: weight loss (n = 515), weight stable (n = 1778), and weight gain (n = 1150). RESULTS: Losing on average 6.5 kg body weight, the weight loss group experienced a 28.2% reduction [(95% confidence interval [CI] -31 to -25); P < 0.001] in fasting insulin and a 23.9% reduction [(95% CI -28 to -19); P < 0.001] in 2-h insulin. Gaining on average 6.4 kg, the weight gain group experienced a 12.5% increase [(95% CI 9 to 16); P < 0.001] in fasting insulin and 32.8% increase [(95% CI 28 to 38); P < 0.001] in 2-h insulin. Using linear regression adjusting for differences in sex, age, family history of hypertension, baseline BMI, SBP and DBP, lifestyle risk factors, and their 5-year changes, weight loss was associated with a decrease in SBP of -1.8 mmHg (95% CI -2.8 to -0.7), whereas weight gain with an increase in SBP of 1.9 mmHg (95% CI 1.2 to 2.6), both with P less than 0.001. Adding fasting insulin, 2-h insulin, Δfasting insulin, and Δ2-h insulin only marginally attenuated the association, and furthermore, none of the insulin variables was significantly associated with SBP or DBP (P ≥ 0.08). The results for changes in DBP were similar to SBP. CONCLUSION: Five-year weight changes associate with BP alterations independent of the insulin changes.

Overweight, adipocytokines and hypertension: a prospective population-based study.

OBJECTIVE: The adipocytokines, leptin, adiponectin, and interleukin-6, which stimulate liver C-reactive protein (CRP) production, are regarded as potential candidate intermediates between adipose tissue and overweight-induced hypertension. METHODS: We examined the associations between leptin, adiponectin, and CRP levels with both prevalent and 5-year incident hypertension (IHT) in a general population of Danish adults (n = 5,868, 51.3% women, mean age 45.8 ± 7.9 years). RESULTS: We recorded 2195 prevalent and 379 incident cases of hypertension. In models including leptin, CRP, adiponectin, sex, age, lifestyle risk factors, lipids, insulin, hemoglobin A1c, and in the incident model also baseline heart rate and blood pressure, only leptin of the three candidate intermediates was significantly associated with both prevalent and IHT [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.06-1.32, P = 0.002, and OR = 1.24, 95% CI 1.01-1.54, P = 0.044] for one standard deviation increase in log-transformed leptin levels, respectively. Log-transformed CRP was associated with prevalent (OR = 1.16, 95% CI 1.07-1.26, P < 0.001) but not IHT (OR = 0.98, 95% CI 0.84-1.14, P = 0.76). Log-transformed adiponectin was neither associated with prevalent nor IHT (OR = 0.94, 95% CI 0.87-1.02, P = 0.11 and OR = 0.93, 95% CI 0.80-1.08, P = 0.33). Comparing the lowest with the highest quintile of sex-specific BMI levels, there was an almost two-fold increase in IHT (OR = 1.89, 95% CI 1.10-3.25, P = 0.023) in the fully adjusted model. The population attributable risk estimate of IHT owing to overweight was 31%. CONCLUSION: Leptin, but not adiponectin or CRP, may play a mediating role in overweight-induced hypertension. However, as BMI was a strong independent predictor of hypertension, other factors than leptin must be involved in the pathogenesis of overweight-related hypertension.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization.

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

Indoor exposure to environmental cigarette smoke, but not other inhaled particulates associates with respiratory symptoms and diminished lung function in adults.

BACKGROUND AND OBJECTIVE: Exposure to particulate matter (PM) can induce airway inflammation and exacerbation of asthma. However, there is limited knowledge about the effects of exposure to indoor sources of PM. We investigated the associations between self-reported exposure to indoor sources of PM and lower airway symptoms and lung function. METHODS: A population-based cross-sectional study of 3471 persons aged 18-69 years was conducted. Information about exposure to indoor sources of PM and airway symptoms was obtained from a self-administered questionnaire. RESULTS: Exposure to wood stoves, candles and gas cookers was not significantly associated with an increased prevalence of lower respiratory symptoms or decreased lung function. In contrast, persons exposed to environmental tobacco smoke for >5 h/day had a significantly increased risk of 'wheeze' (OR 1.69, 95% CI: 1.24-2.30) and 'chronic cough' (OR 1.57, 95% CI: 1.12-2.20), as well as decreased lung function (FEV(1)% predicted), compared with those who were not exposed. Similar trends were observed in never smokers. CONCLUSIONS: In this cross-sectional study of an adult general population, self-reported exposure to environmental tobacco smoke, but not self-reported exposure to wood stoves, candles or gas cookers, appeared to be associated with an increased prevalence of lower airway symptoms and decreased lung function.