24 results on '"Emanuelsson F"'
Search Results
2. Hyperglycemia, diabetes, and cardiovascular and all-cause mortality: An observational and Mendelian randomization study of the general population
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Emanuelsson, F., primary, Nordestgaard, B., additional, and Benn, M., additional
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- 2023
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3. Familial hypercholesterolemia, risk factors influencing diagnosis, and cardiovascular risk. An observational study of 106,507 individuals from the general population
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Toft-Nielsen, F., primary, Emanuelsson, F., additional, Benn, M., additional, and Nordestgaard, B., additional
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- 2023
- Full Text
- View/download PDF
4. High Glucose Levels And Risk Of Vascular Diseases – Observational And Mendelian Randomization Studies Of The General Population
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Emanuelsson, F., primary, Marott, S., additional, Tybjærg-Hansen, A., additional, Nordestgaard, B., additional, and Benn, M., additional
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- 2019
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5. High LDL cholesterol levels and risk of peripheral vascular diseases - A mendelian randomization study including 106,548 individuals from the general population
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Emanuelsson, F., primary, Nordestgaard, B.G., additional, Tybjærg-Hansen, A., additional, and Benn, M., additional
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- 2018
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6. Familial hypercholesterolaemia and risk of peripheral arterial disease and chronic kidney disease: The Copenhagen General Population Study
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Emanuelsson, F., primary, Nordestgaard, B.G., additional, and Benn, M., additional
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- 2018
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7. Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors
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Hrobjartsson, A., primary, Thomsen, A. S. S., additional, Emanuelsson, F., additional, Tendal, B., additional, Hilden, J., additional, Boutron, I., additional, Ravaud, P., additional, and Brorson, S., additional
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- 2012
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8. SGLT2-inhibition increases total, LDL, and HDL cholesterol and lowers triglycerides: Meta-analyses of 60 randomized trials, overall and by dose, ethnicity, and drug type.
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Bechmann LE, Emanuelsson F, Nordestgaard BG, and Benn M
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- Humans, Biomarkers blood, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 ethnology, Treatment Outcome, Cardiovascular Diseases prevention & control, Cardiovascular Diseases blood, Cardiovascular Diseases ethnology, Male, Female, Middle Aged, Dyslipidemias drug therapy, Dyslipidemias blood, Dyslipidemias ethnology, Dyslipidemias diagnosis, Blood Glucose metabolism, Blood Glucose drug effects, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Randomized Controlled Trials as Topic, Triglycerides blood, Cholesterol, HDL blood, Cholesterol, LDL blood
- Abstract
Background and Aims: Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type., Methods: PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models., Results: We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs., Conclusion: In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Børge Nordestgaard reports consultancies with Novo Nordisk. The other authors have no disclosures., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)
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- 2024
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9. Contributions of elevated CRP, hyperglycaemia, and type 2 diabetes to cardiovascular risk in the general population: observational and Mendelian randomization studies.
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Rolver MG, Emanuelsson F, Nordestgaard BG, and Benn M
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- Humans, Risk Assessment, Male, Denmark epidemiology, Female, Middle Aged, Incidence, Up-Regulation, Myocardial Ischemia blood, Myocardial Ischemia genetics, Myocardial Ischemia epidemiology, Myocardial Ischemia diagnosis, Myocardial Ischemia mortality, Aged, Prognosis, Inflammation Mediators blood, Genetic Predisposition to Disease, Risk Factors, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 mortality, Diabetes Mellitus, Type 2 epidemiology, Diabetes Mellitus, Type 2 genetics, Mendelian Randomization Analysis, C-Reactive Protein analysis, C-Reactive Protein metabolism, Biomarkers blood, Hyperglycemia blood, Hyperglycemia epidemiology, Hyperglycemia diagnosis, Hyperglycemia mortality, Hyperglycemia genetics, Blood Glucose metabolism, Heart Disease Risk Factors, Cardiovascular Diseases mortality, Cardiovascular Diseases genetics, Cardiovascular Diseases diagnosis, Cardiovascular Diseases epidemiology, Cardiovascular Diseases blood
- Abstract
Objective: To investigate the contributions of low-grade inflammation measured by C-reactive protein (CRP), hyperglycaemia, and type 2 diabetes to risk of ischemic heart disease (IHD) and cardiovascular disease (CVD) death in the general population, and whether hyperglycaemia and high CRP are causally related., Research Design and Methods: Observational and bidirectional, one-sample Mendelian randomization (MR) analyses in 112,815 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study, and bidirectional, two-sample MR with summary level data from two publicly available consortia, CHARGE and MAGIC., Results: Observationally, higher plasma CRP was associated with stepwise higher risk of IHD and CVD death, with hazard ratios and 95% confidence intervals (95%CI) of 1.50 (1.38, 1.62) and 2.44 (1.93, 3.10) in individuals with the 20% highest CRP concentrations. The corresponding hazard ratios for elevated plasma glucose were 1.10 (1.02, 1.18) and 1.22 (1.01, 1.49), respectively. Cumulative incidences of IHD and CVD death were 365% and 592% higher, respectively, in individuals with both type 2 diabetes and plasma CRP ≥ 2 mg/L compared to individuals without either. Plasma CRP and glucose were observationally associated (β-coefficient: 0.02 (0.02, 0.03), p = 3 × 10
- 20 ); however, one- and two-sample MR did not support a causal effect of CRP on glucose (-0.04 (-0.12, 0.32) and - 0.03 (-0.13, 0.06)), nor of glucose on CRP (-0.01 (-0.08, 0.07) and - 0.00 (-0.14, 0.13))., Conclusions: Elevated concentrations of plasma CRP and glucose are predictors of IHD and CVD death in the general population. We found no genetic association between CRP and glucose, or vice versa, suggesting that lowering glucose pharmacologically does not have a direct effect on low-grade inflammation., (© 2024. The Author(s).)- Published
- 2024
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10. Hyperglycaemia, diabetes and risk of fragility fractures: observational and Mendelian randomisation studies.
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Emanuelsson F, Afzal S, Jørgensen NR, Nordestgaard BG, and Benn M
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- Humans, Aged, 80 and over, Blood Glucose analysis, Risk Factors, Glucose, Mendelian Randomization Analysis, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 genetics, Hyperglycemia complications, Fractures, Bone epidemiology, Fractures, Bone complications
- Abstract
Aims/hypothesis: Fragility fractures may be a complication of diabetes, partly caused by chronic hyperglycaemia. We hypothesised that: (1) individuals with hyperglycaemia and diabetes have increased risk of fragility fracture; (2) hyperglycaemia is causally associated with increased risk of fragility fracture; and (3) diabetes and fragility fracture jointly associate with the highest risk of all-cause mortality., Methods: In total, 117,054 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study (the Copenhagen studies) and 390,374 individuals from UK Biobank were included for observational and one-sample Mendelian randomisation (MR) analyses. Fragility fractures were defined as fractures at the hip, spine and arm (humerus/wrist), collected from national health registries. Summary data for fasting glucose and HbA
1c concentrations from 196,743 individuals in the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) were combined with data on fragility fractures from the Copenhagen studies in two-sample MR analyses., Results: Higher fasting and non-fasting glucose and HbA1c concentrations were associated with higher risk of any fragility fracture (p<0.001). Individuals with vs without diabetes had HRs for fragility fracture of 1.50 (95% CI 1.19, 1.88) in type 1 diabetes and 1.22 (1.13, 1.32) in type 2 diabetes. One-sample MR supported a causal association between high non-fasting glucose concentrations and increased risk of arm fracture in the Copenhagen studies and UK Biobank combined (RR 1.41 [1.11, 1.79], p=0.004), with similar results for fasting glucose and HbA1c in two-sample MR analyses (ORs 1.50 [1.03, 2.18], p=0.03; and 2.79 [1.12, 6.93], p=0.03, respectively). The corresponding MR estimates for any fragility fracture were 1.18 (1.00, 1.41), p=0.06; 1.36 (0.89, 2.09), p=0.15; and 2.47 (0.95, 6.43), p=0.06, respectively. At age 80 years, cumulative death was 27% in individuals with fragility fracture only, 54% in those with diabetes only, 67% in individuals with both conditions and 17% in those with neither., Conclusions/interpretation: Hyperglycaemia and diabetes are risk factors for fragility fracture and one- and two-sample MR analyses supported a causal effect of hyperglycaemia on arm fractures. Diabetes and previous fragility fracture jointly conferred the highest risk of death in the general population., (© 2023. The Author(s).)- Published
- 2024
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11. Genetic variation in solute carrier family 5 member 2 mimicking sodium-glucose co-transporter 2-inhibition and risk of cardiovascular disease and all-cause mortality: reduced risk not explained by lower plasma glucose.
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Bechmann LE, Emanuelsson F, Nordestgaard BG, and Benn M
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- Humans, Blood Glucose, Sodium-Glucose Transporter 2, Genetic Variation, Sodium, Cardiovascular Diseases diagnosis, Cardiovascular Diseases genetics, Cardiovascular Diseases prevention & control, Brain Ischemia complications, Stroke, Myocardial Infarction genetics, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Myocardial Ischemia genetics, Heart Failure complications, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 genetics, Diabetes Mellitus, Type 2 complications
- Abstract
Aims: Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality., Methods and Results: We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively., Conclusion: A functional genetic variant in SLC5A2, mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose., Competing Interests: Conflicts of interest: Børge Nordestgaard reports consultancies with Novo Nordisk. The other authors have no disclosures., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2023
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12. Can a modified ketogenic diet be a nutritional strategy for patients with McArdle disease? Results from a randomized, single-blind, placebo-controlled, cross-over study.
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Løkken N, Nielsen MR, Stemmerik MG, Ellerton C, Revsbech KL, Macrae M, Slipsager A, Krett B, Beha GH, Emanuelsson F, van Hall G, Quinlivan R, and Vissing J
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- Humans, Cross-Over Studies, Single-Blind Method, Muscle, Skeletal, Ketone Bodies metabolism, Glycogen Storage Disease Type V metabolism, Diet, Ketogenic
- Abstract
Background: McArdle disease is caused by myophosphorylase deficiency leading to blocked glycogenolysis in skeletal muscle. Consequently, individuals with McArdle disease have intolerance to physical activity, muscle fatigue, and pain. These symptoms vary according to the availability of alternative fuels for muscle contraction. In theory, a modified ketogenic diet (mKD) can provide alternative fuels in the form of ketone bodies and potentially boost fat oxidation., Methods: This randomized, single-blind, placebo-controlled, cross-over study aimed to investigate if a mKD improves exercise capacity in individuals with McArdle disease. Participants were randomized to follow a mKD (75-80% fat, 15% protein, 5-10% carbohydrates) or placebo diet (PD) first for three weeks, followed by a wash-out period, and then the opposite diet. The primary outcome was change in heart rate during constant-load cycling. Secondary outcomes included change in plasma metabolites, perceived exertion, indirect calorimetry measures, maximal exercise capacity, and patient-reported outcomes., Results: Fifteen out of 20 patients with genetically verified McArdle disease completed all study visits, and 14 were included in the data analyses. We found that the mKD induced a metabolic shift towards increased fat oxidation (∼60% increase), and a 19-fold increase in plasma β-hydroxybutyrate (p < 0.05). The mKD did not improve heart rate responses during constant-load cycling but did improve patient-reported outcomes and maximal exercise capacity (∼20% increase) compared to the PD., Conclusion: The mKD did not alleviate all McArdle disease-related symptoms but did induce some positive changes. To date, no satisfactory treatment options exist other than exercise training. To that end, a mKD can be a possible nutritional strategy for some individuals with McArdle disease who are motivated to undertake a restrictive diet., Clinical Trial Registration: clinical trials.gov: NCT04044508., Competing Interests: Conflicts of interest N.L. has received speaker honorarium from Nutricia, she reports no other conflicts of interest. The remaining authors report none., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
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- 2023
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13. Familial Hypercholesterolemia Prevalence Among Ethnicities-Systematic Review and Meta-Analysis.
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Toft-Nielsen F, Emanuelsson F, and Benn M
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Background: Heterozygous familial hypercholesterolemia (FH) is a common genetic disorder leading to premature cardiovascular disease and death as a result of lifelong high plasma low-density lipoprotein cholesterol levels, if not treated early in life. The prevalence of FH varies between countries because of founder effects, use of different diagnostic criteria, and screening strategies. However, little is known about differences in FH prevalence according to ethnicity. We aimed to investigate the ethnic distribution of FH in diverse populations and estimate the prevalence of FH according to ethnicity. Methods: We performed a systematic review and meta-analysis, searching PubMed and Web of Science for studies presenting data on the prevalence of heterozygous FH among different ethnicities in non-founder populations. Studies with more than 100 individuals, relevant data on prevalence, ethnicity, and using the Dutch Lipid Clinical Network Criteria, Simon Broome, Making Early Diagnosis Prevents Early Death, genetic screening, or comparable diagnostic criteria were considered eligible for inclusion. Results: Eleven general population studies and two patient studies were included in a systematic review and 11 general population studies in a random-effects meta-analysis. The overall pooled FH prevalence was 0.33% or 1:303 in 1,169,879 individuals (95% confidence interval: 0.26-0:40%; 1:385-1:250). Included studies presented data on six ethnicities: black, Latino, white, Asian, brown, and mixed/other. Pooled prevalence was estimated for each group. The highest prevalence observed was 0.52% or 1:192 among blacks (0.34-0.69%; 1:294-1:145) and 0.48% or 1:208 among browns (0.31-0.74%; 1:323-1:135) while the lowest pooled prevalence was 0.25% or 1:400 among Asians (0.15-0.35; 1:500-1:286). The prevalence was 0.37% or 1:270 among Latino (0.24-0.69%; 1:417-1:145), 0.31% or 1:323 among white (0.24-0.41%; 1:417-1:244), and 0.32% or 1:313 among mixed/other individuals (0.13-0.52%; 1:769-1:192). Conclusion: The estimated FH prevalence displays a variation across ethnicity, ranging from 0.25% (1:400) to 0.52% (1:192), with the highest prevalence seen among the black and brown and the lowest among the Asian individuals. The differences observed suggest that targeted screening among subpopulations may increase the identification of cases and thus the opportunity for prevention., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Toft-Nielsen, Emanuelsson and Benn.)
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- 2022
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14. Impact of high glucose levels and glucose lowering on risk of ischaemic stroke: a Mendelian randomisation study and meta-analysis.
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Benn M, Emanuelsson F, Tybjærg-Hansen A, and Nordestgaard BG
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- Blood Glucose metabolism, Brain Ischemia epidemiology, Brain Ischemia etiology, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology, Humans, Hyperglycemia drug therapy, Hyperglycemia epidemiology, Hyperglycemia etiology, Hypoglycemic Agents therapeutic use, Ischemic Stroke blood, Ischemic Stroke drug therapy, Ischemic Stroke epidemiology, Mendelian Randomization Analysis, Risk Factors, Stroke epidemiology, Stroke etiology, Glycemic Control statistics & numerical data, Hyperglycemia complications, Ischemic Stroke complications
- Abstract
Aims/hypothesis: It is unclear whether glucose per se has a causal impact on risk of stroke and whether glucose-lowering drugs reduce this risk. This is important for the choice of treatment for individuals at risk. We tested the hypotheses that high plasma glucose has a causal impact on increased risk of ischaemic stroke, and that glucose-lowering drugs reduce this risk., Methods: Using a Mendelian randomisation design, we examined 118,838 individuals from two Copenhagen cohorts, the Copenhagen General Population Study and the Copenhagen City Heart Study, and 440,328 individuals from the MEGASTROKE study. Effects of eight glucose-lowering drugs on risk of stroke were summarised by meta-analyses., Results: In genetic, causal analyses, a 1 mmol/l higher plasma glucose had a risk ratio of 1.48 (95% CI 1.04, 2.11) for ischaemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (1.31, 2.18). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (0.77, 0.94) for glucagon-like peptide-1 receptor agonists and 0.82 (0.69, 0.98) for thiazolidinediones, while sulfonylureas, dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, α-glucosidase inhibitors, meglitinides and metformin individually lacked statistical evidence of an effect on stroke risk., Conclusions/interpretation: Genetically high plasma glucose has a causal impact on increased risk of ischaemic stroke. Treatment with glucose-lowering glucagon-like peptide-1 receptor agonists and thiazolidinediones reduces this risk. These results may guide clinicians in the treatment of individuals at high risk of ischaemic stroke.
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- 2021
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15. LDL-Cholesterol versus Glucose in Microvascular and Macrovascular Disease.
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Emanuelsson F and Benn M
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- Animals, Blood Glucose analysis, Cholesterol, LDL blood, Endothelial Cells metabolism, Humans, Mendelian Randomization Analysis, Peripheral Arterial Disease blood, Peripheral Arterial Disease genetics, Peripheral Arterial Disease physiopathology, Randomized Controlled Trials as Topic, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic genetics, Renal Insufficiency, Chronic physiopathology, Risk Factors, Blood Glucose metabolism, Cholesterol, LDL metabolism, Peripheral Arterial Disease etiology
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Background: The causal relationships between increased concentrations of low density lipoprotein (LDL)-cholesterol and glucose and risk of ischemic heart disease are well established. The causal contributions of LDL-cholesterol and glucose to risk of peripheral micro- and macrovascular diseases are less studied, especially in prediabetic stages and in a general population setting., Content: This review summarizes the current evidence for a causal contribution of LDL-cholesterol and glucose to risk of a spectrum of peripheral micro- and macrovascular diseases and reviews possible underlying disease mechanisms, including differences between vascular compartments, and finally discusses the clinical implications of these findings, including strategies for prevention and treatment., Summary: Combined lines of evidence suggest that LDL-cholesterol has a causal effect on risk of peripheral arterial disease and chronic kidney disease, both of which represent manifestations of macrovascular disease due to atherosclerosis and accumulation of LDL particles in the arterial wall. In contrast, there is limited evidence for a causal effect on risk of microvascular disease. Glucose has a causal effect on risk of both micro- and macrovascular disease. However, most evidence is derived from studies of individuals with diabetes. Further studies in normoglycemic and prediabetic individuals are warranted. Overall, LDL-cholesterol-lowering reduces risk of macrovascular disease, while evidence for a reduction in risk of microvascular disease is inconsistent. Glucose-lowering has a beneficial effect on risk of microvascular diseases and on risk of chronic kidney disease and estimated glomerular filtration rate (eGFR) in some studies, while results on risk of peripheral arterial disease are conflicting., (© American Association for Clinical Chemistry 2020. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2021
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16. Impact of Glucose Level on Micro- and Macrovascular Disease in the General Population: A Mendelian Randomization Study.
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Emanuelsson F, Marott S, Tybjærg-Hansen A, Nordestgaard BG, and Benn M
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- Aged, Denmark epidemiology, Diabetes Complications epidemiology, Diabetes Complications genetics, Female, Genotype, Humans, Male, Mendelian Randomization Analysis, Middle Aged, Myocardial Infarction blood, Myocardial Infarction epidemiology, Myocardial Infarction genetics, Peripheral Arterial Disease genetics, Peripheral Nervous System Diseases blood, Peripheral Nervous System Diseases epidemiology, Peripheral Nervous System Diseases genetics, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic epidemiology, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic genetics, Retinal Diseases blood, Retinal Diseases epidemiology, Retinal Diseases etiology, Retinal Diseases genetics, Risk Factors, Blood Glucose metabolism, Peripheral Arterial Disease blood, Peripheral Arterial Disease epidemiology
- Abstract
Objective: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population., Research Design and Methods: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank., Results: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m
2 , 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2 , and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level., Conclusions: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2 , PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2 ., (© 2020 by the American Diabetes Association.)- Published
- 2020
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17. Impact of LDL Cholesterol on Microvascular Versus Macrovascular Disease: A Mendelian Randomization Study.
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Emanuelsson F, Nordestgaard BG, Tybjærg-Hansen A, and Benn M
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- Aged, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Hypercholesterolemia drug therapy, Male, Mendelian Randomization Analysis, Middle Aged, Prospective Studies, Cholesterol, LDL blood, Hypercholesterolemia complications, Nervous System Diseases etiology, Peripheral Arterial Disease etiology, Renal Insufficiency, Chronic etiology, Retinal Diseases etiology
- Abstract
Background: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown., Objectives: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population., Methods: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed., Results: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m
2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2 ) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2 ) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2 ) through statin therapy., Conclusions: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
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18. Response to Letter to the Editor: "Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease".
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Emanuelsson F, Nordestgaard BG, and Benn M
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- Humans, Hyperlipoproteinemia Type II, Peripheral Arterial Disease, Renal Insufficiency, Chronic
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- 2019
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19. Familial Hypercholesterolemia and Risk of Peripheral Arterial Disease and Chronic Kidney Disease.
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Emanuelsson F, Nordestgaard BG, and Benn M
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- Aged, Ankle Brachial Index statistics & numerical data, Cholesterol blood, Cross-Sectional Studies, Denmark epidemiology, Female, Follow-Up Studies, Glomerular Filtration Rate, Humans, Hyperlipoproteinemia Type II diagnosis, Hyperlipoproteinemia Type II metabolism, Male, Middle Aged, Myocardial Infarction blood, Myocardial Infarction etiology, Myocardial Infarction metabolism, Peripheral Arterial Disease blood, Peripheral Arterial Disease etiology, Peripheral Arterial Disease metabolism, Prevalence, Prospective Studies, Renal Insufficiency, Chronic blood, Renal Insufficiency, Chronic etiology, Renal Insufficiency, Chronic metabolism, Risk Factors, Hyperlipoproteinemia Type II complications, Myocardial Infarction epidemiology, Peripheral Arterial Disease epidemiology, Renal Insufficiency, Chronic epidemiology
- Abstract
Context: Individuals with familial hypercholesterolemia (FH) have a high risk of coronary artery disease, but their risk of peripheral arterial disease (PAD) and chronic kidney disease (CKD) is unknown., Objective: In individuals with clinical FH, we tested the hypotheses (1) that the risks of PAD and CKD are elevated and (2) that low ankle-brachial index (ABI) and estimated glomerular filtration rate (eGFR) are associated with a high risk of myocardial infarction., Design and Setting: Prospective cohort study of the general population., Participants: A total of 106,172 individuals, of whom 7109 were diagnosed with FH., Main Outcome Measures: PAD, CKD, and myocardial infarction., Results: Compared with individuals with unlikely FH, multivariable adjusted ORs (95% CIs) of PAD were 1.84 (1.70 to 2.00) in those with possible FH and 1.36 (1.00 to 1.84) in individuals with probable/definite FH. For CKD, the corresponding ORs (95% CIs) were 1.92 (1.78 to 2.07) and 2.42 (1.86 to 3.26). Compared with individuals with unlikely FH and ABI >0.9, the multivariable adjusted hazard ratio (95% CI) of myocardial infarction was 4.60 (2.36 to 8.97) in those with possible/probable/definite FH and ABI ≤0.9. Compared with individuals with unlikely FH and eGFR ≥60 mL/min/1.73 m2, the corresponding value was 2.19 (1.71 to 2.82) in those with possible/probable/definite FH and eGFR <60 mL/min/1.73 m2., Conclusions: Individuals with clinical FH have increased risks of PAD and CKD, and low ABI and eGFR are associated with high risk of myocardial infarction. Consequently, individuals with FH should be screened for PAD and CKD, and ABI and eGFR may be used as prognostic tools in the management and treatment of FH to identify those at very high risk of myocardial infarction.
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- 2018
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20. Upper Versus Lower Gastrointestinal Delivery for Transplantation of Fecal Microbiota in Recurrent or Refractory Clostridium difficile Infection: A Collaborative Analysis of Individual Patient Data From 14 Studies.
- Author
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Furuya-Kanamori L, Doi SA, Paterson DL, Helms SK, Yakob L, McKenzie SJ, Garborg K, Emanuelsson F, Stollman N, Kronman MP, Clark J, Huber CA, Riley TV, and Clements AC
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Child, Child, Preschool, Enterocolitis, Pseudomembranous microbiology, Female, Humans, Infant, Male, Middle Aged, Recurrence, Treatment Outcome, Young Adult, Clostridioides difficile, Enterocolitis, Pseudomembranous therapy, Fecal Microbiota Transplantation methods, Lower Gastrointestinal Tract microbiology, Upper Gastrointestinal Tract microbiology
- Abstract
Goals: The aim of this study was to compare upper gastrointestinal (UGI) versus lower gastrointestinal (LGI) delivery routes of fecal microbiota transplantation (FMT) for refractory or recurrent/relapsing Clostridium difficile infection (CDI)., Background: FMT has been proven to be a safe and highly effective therapeutic option for CDI. Delivery, however, could be via the UGI or LGI routes, and it is unclear as to which route provides better clinical outcome., Study: A systematic search for studies that reported the use of FMT for CDI treatment was conducted. Individual patient data that included demographic (age and sex) and clinical (route of FMT delivery, CDI outcome after FMT, and follow-up time) information were obtained. Kaplan-Meier cumulative hazard curves and Cox proportional hazard models were used to assess clinical failure after FMT by the route of delivery., Results: Data from 305 patients treated with FMT (208 via LGI route and 97 via UGI route) for CDI were analyzed. At 30 and 90 days, the risk of clinical failure was 5.6% and 17.9% in the UGI group compared with 4.9% and 8.5% in the LGI delivery route group, respectively. A time-varying analysis suggested a 3-fold increase in hazard of clinical failure for UGI delivery (hazard ratio, 3.43; 95% confidence interval, 1.32-8.93) in the period after 30 days., Conclusions: FMT delivered via the LGI seems to be the most effective route for the prevention of recurrence/relapse of CDI. A randomized controlled trial is necessary to confirm whether FMT delivered via the LGI is indeed superior to that delivered via the UGI route.
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- 2017
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21. Bias due to lack of patient blinding in clinical trials. A systematic review of trials randomizing patients to blind and nonblind sub-studies.
- Author
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Hróbjartsson A, Emanuelsson F, Skou Thomsen AS, Hilden J, and Brorson S
- Subjects
- Humans, Bias, Double-Blind Method, Randomized Controlled Trials as Topic, Single-Blind Method
- Abstract
Background: Blinding patients in clinical trials is a key methodological procedure, but the expected degree of bias due to nonblinded patients on estimated treatment effects is unknown., Methods: Systematic review of randomized clinical trials with one sub-study (i.e. experimental vs control) involving blinded patients and another, otherwise identical, sub-study involving nonblinded patients. Within each trial, we compared the difference in effect sizes (i.e. standardized mean differences) between the sub-studies. A difference <0 indicates that nonblinded patients generated a more optimistic effect estimate. We pooled the differences with random-effects inverse variance meta-analysis, and explored reasons for heterogeneity., Results: Our main analysis included 12 trials (3869 patients). The average difference in effect size for patient-reported outcomes was -0.56 (95% confidence interval -0.71 to -0.41), (I(2)=60%, P=0.004), i.e. nonblinded patients exaggerated the effect size by an average of 0.56 standard deviation, but with considerable variation. Two of the 12 trials also used observer-reported outcomes, showing no indication of exaggerated effects due lack of patient blinding. There was a larger effect size difference in 10 acupuncture trials [-0.63 (-0.77 to -0.49)], than in the two non-acupuncture trials [-0.17 (-0.41 to 0.07)]. Lack of patient blinding also increased attrition and use of co-interventions: ratio of control group attrition risk 1.79 (1.18 to 2.70), and ratio of control group co-intervention risk 1.55 (0.99 to 2.43)., Conclusions: This study provides empirical evidence of pronounced bias due to lack of patient blinding in complementary/alternative randomized clinical trials with patient-reported outcomes., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2014
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22. Observer bias in randomized clinical trials with time-to-event outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.
- Author
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Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Rasmussen JV, Hilden J, Boutron I, Ravaud P, and Brorson S
- Subjects
- Humans, Single-Blind Method, Observer Variation, Randomized Controlled Trials as Topic methods, Research Design
- Abstract
Background: We wanted to evaluate the impact of nonblinded outcome assessors on estimated treatment effects in time-to-event trials., Methods: Systematic review of randomized clinical trials with both blinded and nonblinded assessors of the same time-to-event outcome. Two authors agreed on inclusion of trials and outcomes. We compared hazard ratios based on nonblinded and blinded assessments. A ratio of hazard ratios (RHR)<1 indicated that nonblinded assessors generated more optimistic effect estimates. We pooled RHRs with inverse variance random-effects meta-analysis., Results: We included 18 trials. Eleven trials (1969 patients) with subjective outcomes provided hazard ratios, RHR 0.88 (0.69 to 1.12), (I2=44%, P=0.06), but unconditional pooling was problematic because of qualitative heterogeneity. Four atypical cytomegalovirus retinitis trials compared experimental oral administration with control intravenous administration of the same drug, resulting in bias favouring the control intervention, RHR 1.33 (0.98 to 1.82). Seven trials of cytomegalovirus retinitis, tibial fracture and multiple sclerosis compared experimental interventions with standard control interventions, e.g. placebo, no-treatment or active control, resulting in bias favouring the experimental intervention, RHR 0.73 (0.57 to 0.93), indicating an average exaggeration of nonblinded hazard ratios by 27% (7% to 43%)., Conclusions: Lack of blinded outcome assessors in randomized trials with subjective time-to-event outcomes causes high risk of observer bias. Nonblinded outcome assessors typically favour the experimental intervention, exaggerating the hazard ratio by an average of approximately 27%; but in special situations, nonblinded outcome assessors favour control interventions, inducing a comparable degree of observer bias in the reversed direction., (© The Author 2014; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)
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- 2014
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23. Faecal microbiota transplantation and bacteriotherapy for recurrent Clostridium difficile infection: a retrospective evaluation of 31 patients.
- Author
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Emanuelsson F, Claesson BE, Ljungström L, Tvede M, and Ung KA
- Subjects
- Adult, Aged, Female, Humans, Male, Middle Aged, Retrospective Studies, Treatment Outcome, Biological Therapy methods, Clostridium Infections therapy, Feces microbiology, Secondary Prevention
- Abstract
Background: Recurrent Clostridium difficile infection (CDI) is a significant problem due to its increased incidence and severity. Failure rates for standard antibiotic therapies are high. In our hospital, faecal microbiota transplantation (FMT), or instillation of a culture mixture of known enteric bacteria in saline as rectal bacteriotherapy (RBT), has long been used as 'rescue therapy' in patients with recurrent disease, in whom repeated courses of standard antibiotic treatment have failed. We wanted to evaluate the effectiveness of FMT and RBT for recurrent CDI., Methods: The records of 31 patients treated with either FMT or RBT for recurrent CDI were reviewed retrospectively. FMT was based on faecal donation by a close relative and RBT on a defined saline mixture of 10 individually cultured enteric bacterial strains originally isolated from healthy persons. Both types of instillation were carried out through a rectal catheter. FMT (500 ml) was given as 1 installation. RBT (200 ml) was given as 2 or 3 installations with an interval of 2 days between courses. Treatment success was defined as a sustained loss of symptoms and discontinuation of diarrhoea within 3 days., Results: Of 31 patients, 23 (74%) responded successfully to the treatment: 16 of 23 (70%) receiving FMT and 7 of 8 (88%) receiving RBT., Conclusion: We found FMT to be effective in patients with recurrent CDI. RBT based on a predefined bacterial suspension was as effective as or better than FMT based on faecal donation; however, multiple installations may be needed.
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- 2014
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24. Observer bias in randomized clinical trials with measurement scale outcomes: a systematic review of trials with both blinded and nonblinded assessors.
- Author
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Hróbjartsson A, Thomsen AS, Emanuelsson F, Tendal B, Hilden J, Boutron I, Ravaud P, and Brorson S
- Subjects
- Double-Blind Method, Observer Variation, Outcome Assessment, Health Care methods, Randomized Controlled Trials as Topic methods
- Abstract
Background: Clinical trials are commonly done without blinded outcome assessors despite the risk of bias. We wanted to evaluate the effect of nonblinded outcome assessment on estimated effects in randomized clinical trials with outcomes that involved subjective measurement scales., Methods: We conducted a systematic review of randomized clinical trials with both blinded and nonblinded assessment of the same measurement scale outcome. We searched PubMed, EMBASE, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press and Google Scholar for relevant studies. Two investigators agreed on the inclusion of trials and the outcome scale. For each trial, we calculated the difference in effect size (i.e., standardized mean difference between nonblinded and blinded assessments). A difference in effect size of less than 0 suggested that nonblinded assessors generated more optimistic estimates of effect. We pooled the differences in effect size using inverse variance random-effects meta-analysis and used metaregression to identify potential reasons for variation., Results: We included 24 trials in our review. The main meta-analysis included 16 trials (involving 2854 patients) with subjective outcomes. The estimated treatment effect was more beneficial when based on nonblinded assessors (pooled difference in effect size -0.23 [95% confidence interval (CI) -0.40 to -0.06]). In relative terms, nonblinded assessors exaggerated the pooled effect size by 68% (95% CI 14% to 230%). Heterogeneity was moderate (I(2) = 46%, p = 0.02) and unexplained by metaregression., Interpretation: We provide empirical evidence for observer bias in randomized clinical trials with subjective measurement scale outcomes. A failure to blind assessors of outcomes in such trials results in a high risk of substantial bias.
- Published
- 2013
- Full Text
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