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1.
Diabetologia ; 67(2): 301-311, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38095658

RESUMO

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 HbA1c 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.


Assuntos
Diabetes Mellitus Tipo 2 , Fraturas Ósseas , Hiperglicemia , Humanos , Idoso de 80 Anos ou mais , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Hiperglicemia/complicações , Glicemia/análise , Fatores de Risco , Fraturas Ósseas/epidemiologia , Fraturas Ósseas/complicações , Glucose , Análise da Randomização Mendeliana
2.
Cardiovasc Diabetol ; 23(1): 165, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730445

RESUMO

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 (ß-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.


Assuntos
Biomarcadores , Glicemia , Proteína C-Reativa , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Fatores de Risco de Doenças Cardíacas , Hiperglicemia , Análise da Randomização Mendeliana , Humanos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Proteína C-Reativa/análise , Proteína C-Reativa/metabolismo , Biomarcadores/sangue , Hiperglicemia/sangue , Hiperglicemia/epidemiologia , Hiperglicemia/diagnóstico , Hiperglicemia/mortalidade , Hiperglicemia/genética , Medição de Risco , Glicemia/metabolismo , Masculino , Dinamarca/epidemiologia , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/sangue , Feminino , Pessoa de Meia-Idade , Incidência , Regulação para Cima , Isquemia Miocárdica/sangue , Isquemia Miocárdica/genética , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/diagnóstico , Isquemia Miocárdica/mortalidade , Idoso , Prognóstico , Mediadores da Inflamação/sangue , Predisposição Genética para Doença , Fatores de Risco
3.
Diabetologia ; 64(7): 1492-1503, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33765180

RESUMO

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.


Assuntos
Controle Glicêmico/estatística & dados numéricos , Hiperglicemia/complicações , AVC Isquêmico/complicações , Glicemia/metabolismo , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/etiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/epidemiologia , Hiperglicemia/etiologia , Hipoglicemiantes/uso terapêutico , AVC Isquêmico/sangue , AVC Isquêmico/tratamento farmacológico , AVC Isquêmico/epidemiologia , Análise da Randomização Mendeliana , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia
4.
Clin Chem ; 67(1): 167-182, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33221847

RESUMO

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.


Assuntos
Glicemia/metabolismo , LDL-Colesterol/metabolismo , Doença Arterial Periférica/etiologia , Animais , Glicemia/análise , LDL-Colesterol/sangue , Células Endoteliais/metabolismo , Humanos , Análise da Randomização Mendeliana , Doença Arterial Periférica/sangue , Doença Arterial Periférica/genética , Doença Arterial Periférica/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco
5.
J Clin Gastroenterol ; 51(2): 145-150, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26974758

RESUMO

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.


Assuntos
Clostridioides difficile , Enterocolite Pseudomembranosa/terapia , Transplante de Microbiota Fecal/métodos , Trato Gastrointestinal Inferior/microbiologia , Trato Gastrointestinal Superior/microbiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Enterocolite Pseudomembranosa/microbiologia , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva , Resultado do Tratamento , Adulto Jovem
6.
Scand J Infect Dis ; 46(2): 89-97, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24354958

RESUMO

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.


Assuntos
Terapia Biológica/métodos , Infecções por Clostridium/terapia , Fezes/microbiologia , Prevenção Secundária , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
7.
CMAJ ; 185(4): E201-11, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23359047

RESUMO

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.


Assuntos
Método Duplo-Cego , Variações Dependentes do Observador , Avaliação de Resultados em Cuidados de Saúde/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos
8.
Cardiovasc Res ; 119(14): 2482-2493, 2023 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-37516996

RESUMO

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.


Assuntos
Isquemia Encefálica , Doenças Cardiovasculares , Diabetes Mellitus Tipo 2 , Insuficiência Cardíaca , Infarto do Miocárdio , Isquemia Miocárdica , Inibidores do Transportador 2 de Sódio-Glicose , Acidente Vascular Cerebral , Humanos , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/prevenção & controle , Glicemia , Transportador 2 de Glucose-Sódio , Isquemia Encefálica/complicações , Infarto do Miocárdio/genética , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Isquemia Miocárdica/genética , Insuficiência Cardíaca/complicações , Variação Genética , Sódio , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/complicações
9.
Atherosclerosis ; : 117236, 2023 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-37582673

RESUMO

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.

10.
Clin Nutr ; 42(11): 2124-2137, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37769369

RESUMO

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 ß-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.


Assuntos
Dieta Cetogênica , Doença de Depósito de Glicogênio Tipo V , Humanos , Doença de Depósito de Glicogênio Tipo V/metabolismo , Estudos Cross-Over , Método Simples-Cego , Músculo Esquelético , Corpos Cetônicos/metabolismo
11.
Front Genet ; 13: 840797, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35186049

RESUMO

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.

12.
Diabetes Care ; 43(4): 894-902, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32054721

RESUMO

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 m2, 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.


Assuntos
Glicemia/metabolismo , Doença Arterial Periférica/sangue , Doença Arterial Periférica/epidemiologia , Idoso , Dinamarca/epidemiologia , Complicações do Diabetes/epidemiologia , Complicações do Diabetes/genética , Feminino , Genótipo , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/genética , Doença Arterial Periférica/genética , Doenças do Sistema Nervoso Periférico/sangue , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/genética , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/genética , Doenças Retinianas/sangue , Doenças Retinianas/epidemiologia , Doenças Retinianas/etiologia , Doenças Retinianas/genética , Fatores de Risco
13.
J Am Coll Cardiol ; 74(11): 1465-1476, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31514949

RESUMO

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 m2 (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.


Assuntos
LDL-Colesterol , Hipercolesterolemia/complicações , Doenças do Sistema Nervoso/etiologia , Doença Arterial Periférica/etiologia , Insuficiência Renal Crônica/etiologia , Doenças Retinianas/etiologia , Idoso , LDL-Colesterol/sangue , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Estudos Prospectivos
14.
J Clin Endocrinol Metab ; 103(12): 4491-4500, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085243

RESUMO

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.


Assuntos
Hiperlipoproteinemia Tipo II/complicações , Infarto do Miocárdio/epidemiologia , Doença Arterial Periférica/epidemiologia , Insuficiência Renal Crônica/epidemiologia , Idoso , Índice Tornozelo-Braço/estatística & dados numéricos , Colesterol/sangue , Estudos Transversais , Dinamarca/epidemiologia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/metabolismo , Doença Arterial Periférica/sangue , Doença Arterial Periférica/etiologia , Doença Arterial Periférica/metabolismo , Prevalência , Estudos Prospectivos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/metabolismo , Fatores de Risco
16.
Int J Epidemiol ; 43(4): 1272-83, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24881045

RESUMO

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.


Assuntos
Viés , Método Duplo-Cego , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Simples-Cego , Humanos
17.
Int J Epidemiol ; 43(3): 937-48, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24448109

RESUMO

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.


Assuntos
Variações Dependentes do Observador , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Projetos de Pesquisa , Humanos , Método Simples-Cego
18.
BMJ ; 344: e1119, 2012 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-22371859

RESUMO

OBJECTIVE: To evaluate the impact of non-blinded outcome assessment on estimated treatment effects in randomised clinical trials with binary outcomes. DESIGN: Systematic review of trials with both blinded and non-blinded assessment of the same binary outcome. For each trial we calculated the ratio of the odds ratios--the odds ratio from non-blinded assessments relative to the corresponding odds ratio from blinded assessments. A ratio of odds ratios <1 indicated that non-blinded assessors generated more optimistic effect estimates than blinded assessors. We pooled the individual ratios of odds ratios with inverse variance random effects meta-analysis and explored reasons for variation in ratios of odds ratios with meta-regression. We also analysed rates of agreement between blinded and non-blinded assessors and calculated the number of patients needed to be reclassified to neutralise any bias. DATA SOURCES: PubMed, Embase, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, HighWire Press, and Google Scholar. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Randomised clinical trials with blinded and non-blinded assessment of the same binary outcome. RESULTS: We included 21 trials in the main analysis (with 4391 patients); eight trials provided individual patient data. Outcomes in most trials were subjective--for example, qualitative assessment of the patient's function. The ratio of the odds ratios ranged from 0.02 to 14.4. The pooled ratio of odds ratios was 0.64 (95% confidence interval 0.43 to 0.96), indicating an average exaggeration of the non-blinded odds ratio by 36%. We found no significant association between low ratios of odds ratios and scores for outcome subjectivity (P=0.27); non-blinded assessor's overall involvement in the trial (P=0.60); or outcome vulnerability to non-blinded patients (P=0.52). Blinded and non-blinded assessors agreed in a median of 78% of assessments (interquartile range 64-90%) in the 12 trials with available data. The exaggeration of treatment effects associated with non-blinded assessors was induced by the misclassification of a median of 3% of the assessed patients per trial (1-7%). CONCLUSIONS: On average, non-blinded assessors of subjective binary outcomes generated substantially biased effect estimates in randomised clinical trials, exaggerating odds ratios by 36%. This bias was compatible with a high rate of agreement between blinded and non-blinded outcome assessors and driven by the misclassification of few patients.


Assuntos
Variações Dependentes do Observador , Avaliação de Resultados em Cuidados de Saúde/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Método Duplo-Cego , Humanos , Razão de Chances , Método Simples-Cego , Resultado do Tratamento
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