RESUMO
AIM: Glucose-lowering interventions in Type 2 diabetes mellitus have demonstrated reductions in microvascular complications and modest reductions in macrovascular complications. However, the degree to which targeting different HbA1c reductions might reduce risk is unclear. METHODS: Participant-level data for Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) participants with established cardiovascular disease were used in a Type 2 diabetes-specific simulation model to quantify the likely impact of different HbA1c decrements on complication rates. Ten-year micro- and macrovascular rates were estimated with HbA1c levels fixed at 86, 75, 64, 53 and 42 mmol/mol (10%, 9%, 8%, 7% and 6%) while holding other risk factors constant at their baseline levels. Cumulative relative risk reductions for each outcome were derived for each HbA1c decrement. RESULTS: Of 5717 participants studied, 72.0% were men and 74.2% White European, with a mean (sd) age of 66.2 (7.9) years, systolic blood pressure 134 (16.9) mmHg, LDL-cholesterol 2.3 (0.9) mmol/l, HDL-cholesterol 1.13 (0.3) mmol/l and median Type 2 diabetes duration 9.6 (5.1-15.6) years. Ten-year cumulative relative risk reductions for modelled HbA1c values of 75, 64, 53 and 42 mmol/mol, relative to 86 mmol/mol, were 4.6%, 9.3%, 15.1% and 20.2% for myocardial infarction; 6.0%, 12.8%, 19.6% and 25.8% for stroke; 14.4%, 26.6%, 37.1% and 46.4% for diabetes-related ulcer; 21.5%, 39.0%, 52.3% and 63.1% for amputation; and 13.6%, 25.4%, 36.0% and 44.7 for single-eye blindness. CONCLUSIONS: These simulated complication rates might help inform the degree to which complications might be reduced by targeting particular HbA1c reductions in Type 2 diabetes.
Assuntos
Doenças Cardiovasculares/complicações , Complicações do Diabetes/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hemoglobinas Glicadas/metabolismo , Hipoglicemiantes/uso terapêutico , Idoso , Amputação Cirúrgica/estatística & dados numéricos , Cegueira/epidemiologia , Cegueira/etiologia , Complicações do Diabetes/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Pé Diabético/epidemiologia , Pé Diabético/etiologia , Retinopatia Diabética/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Planejamento de Assistência ao Paciente , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologiaRESUMO
AIMS: To evaluate whether plasma glycated albumin, which provides an integrated measure of plasma glucose levels over the preceding 2-4 weeks, better reflects changes in postprandial glucose excursions than HbA1c . METHODS: People with suboptimum glycaemic control on dual oral therapy were enrolled in the Treating-to-Target-in-Type 2 diabetes (4-T) trial, in which participants were randomized to the addition of once-daily basal insulin, twice-daily biphasic insulin or thrice-daily prandial insulin. Glycated albumin levels were assayed enzymatically from baseline and 1-year fasting plasma samples. We evaluated robust correlations of glycated albumin and HbA1c both with fasting and postprandial glucose levels at these two time points, and with insulin-induced changes in the postprandial excursion. RESULTS: Requisite data were available for 625 of the participants in the 4-T trial. Their mean (±sd) age was 62 ± 10 years and body weight was 85.8 ± 15.9 kg, and their median (interquartile range) diabetes duration was 9 (6, 13) years. Partial correlations at baseline and 1 year between postprandial glucose excursions and glycated albumin/HbA1c , after adjusting for fasting glucose, were 0.27/0.15 and 0.22/0.18, respectively. Glycated albumin, compared with HbA1c , explained 66% more of the variation in postprandial glucose excursions at baseline. At 1 year, postprandial glucose excursions on basal, biphasic and prandial and insulin therapy were reduced by 0.43, 0.78 and 1.88 mmol/l, respectively. These reductions were associated with changes in both glycated albumin and HbA1c (P < 0.01), with a stronger association for glycated albumin. CONCLUSION: Changes in glycated albumin and HbA1c reflect changes in postprandial glucose excursions to a similar extent.
Assuntos
Diabetes Mellitus Tipo 2/sangue , Hiperglicemia/sangue , Período Pós-Prandial , Albumina Sérica/fisiologia , Idoso , Biomarcadores/sangue , Insulinas Bifásicas/administração & dosagem , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Produtos Finais de Glicação Avançada , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/tratamento farmacológico , Insulina Detemir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial/efeitos dos fármacos , Albumina Sérica/metabolismo , Albumina Sérica GlicadaRESUMO
AIMS: Reduced aspirin efficacy has been demonstrated in people with Type 2 diabetes. Because increased platelet reactivity and/or turnover are postulated mechanisms, we examined whether higher and/or more frequent aspirin dosing might reduce platelet reactivity more effectively. METHODS: Participants with Type 2 diabetes (n = 24) but without known cardiovascular disease were randomized in a three-way crossover design to 2-week treatment periods with aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily. The primary outcome was platelet reactivity, assessed using the VerifyNow(™) ASA method. Relationships between platelet reactivity and aspirin dosing were examined using generalized linear mixed models with random subject effects. RESULTS: Platelet reactivity decreased from baseline with all doses of aspirin. Modelled platelet reactivity was more effectively reduced with aspirin 100 mg twice daily vs. 100 mg once daily, but not vs. 200 mg once daily. Aspirin 200 mg once daily did not differ from 100 mg once daily. Aspirin 100 mg twice daily was also more effective than once daily as measured by collagen/epinephrine-stimulated platelet aggregation and urinary thromboxane levels, with a similar trend measured by serum thromboxane levels. No episodes of bleeding occurred. CONCLUSIONS: In Type 2 diabetes, aspirin 100 mg twice daily reduced platelet reactivity more effectively than 100 mg once daily, and numerically more than 200 mg once daily. Clinical outcome trials evaluating primary cardiovascular disease prevention with aspirin in Type 2 diabetes may need to consider using a more frequent dosing schedule.
Assuntos
Aspirina/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Inibidores de Ciclo-Oxigenase/administração & dosagem , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Agregação Plaquetária/administração & dosagem , Adulto , Aspirina/efeitos adversos , Aspirina/uso terapêutico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Estudos Cross-Over , Inibidores de Ciclo-Oxigenase/efeitos adversos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/epidemiologia , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Resistência a Medicamentos , Inglaterra/epidemiologia , Feminino , Hemorragia/induzido quimicamente , Hemorragia/complicações , Hemorragia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Ativação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Risco , Medição de RiscoRESUMO
AIMS: To investigate whether metformin therapy alters circulating aromatic and branched-chain amino acid concentrations, increased levels amino acid concentrations, increased levels of which have been found to predict Type 2 diabetes. METHODS: In the Carotid Atherosclerosis: Metformin for Insulin Resistance (CAMERA) study (NCT00723307), 173 individuals without Type 2 diabetes, but with coronary disease, were randomized to metformin (n=86) or placebo (n=87) for 18 months. Plasma samples, taken every 6 months, were analysed using quantitative nuclear magnetic resonance spectroscopy. Ten metabolites consisting of eight amino acids [three branched-chain (isoleucine, leucine, valine), three aromatic (tyrosine, phenylalanine, histidine) and two other amino acids (alanine, glutamine)], lactate and pyruvate were quantified and analysed using repeated-measures models. On-treatment analyses were conducted to investigate whether amino acid changes were dependent on changes in weight, fat mass or insulin resistance estimated using homeostasis model assessment (HOMA-IR). RESULTS: Tyrosine decreased [-6.1 µmol/l (95% CI -8.5, -3.7); P<0.0001], while alanine [42 umol/l (95% CI 25, 59); P<0.0001] increased in the metformin-treated group compared with the placebo-treated group. Decreases in phenylalanine [-2.0 µmol/l (95% CI -3.6, -0.3); P=0.018] and increases in histidine [2.3 µmol/l (95% CI 0.1, 4.6); P=0.045] were also observed in the metformin group, although these changes were less statistically robust. Changes in these four amino acids were not accounted for by changes in weight, fat mass or HOMA-IR values. Levels of branched-chain amino acids, glutamine, pyruvate and lactate were not altered by metformin therapy. CONCLUSIONS: Metformin therapy results in a sustained and specific pattern of changes in aromatic amino acid and alanine concentrations. These changes are independent of any effects on weight and insulin sensitivity. Any causal link to metformin's unexplained cardiometabolic benefit requires further study.
Assuntos
Aminoácidos/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Metformina/uso terapêutico , Adulto , Aminoácidos de Cadeia Ramificada/sangue , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/tratamento farmacológico , Método Duplo-Cego , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , PlacebosRESUMO
AIMS: To estimate the immediate and long-term inpatient and non-inpatient costs for Type 2 diabetes-related complications. METHODS: The costs of all consultations, visits, admissions and procedures associated with diabetes-related complications during UK Prospective Diabetes Study post-trial monitoring in the period 1997-2007 were estimated using hospitalization records for 2791 patients in England and resource use questionnaires that were administered to 3589 patients across the UK. RESULTS: The estimated (95% CI) inpatient care costs (in 2012 pounds sterling) in the event year for the example of a 60-year-old man were: non-fatal ischaemic heart disease £9767 (£7038-£12 696); amputation £9546 (£6416-£13 463); non-fatal stroke £6805 (£3856-£10 278); non-fatal myocardial infarction £6379 (£4290-£8339); fatal stroke £3954 (£2012-£6428); fatal ischaemic heart disease £3766 (£746-£5512); heart failure £3191 (£1678-4903); fatal myocardial infarction £1521 (£647-£2670); and blindness in one eye £1355 (£415-£2655). In subsequent years, estimated (95% CI) costs ranged from £1792 (£1060-£2943) for amputations to £453 (£315-£691) for blindness in one eye. Costs of non-inpatient healthcare in the event year were: amputation £2699 (£1409-£4126); blindness in one eye £1790 (£878-£3056); non-fatal stroke £1019 (£770-£1499); nonfatal myocardial infarction £1963 (£794-£1157); heart failure £979 (£708-£1344); non-fatal ischaemic heart disease £864 (£718-£1014); and cataract extraction £700 (£619-£780). In each subsequent year, non-inpatient costs ranged from £1611 (£1193-£2116) for amputations to £654 (£572-£799) for ischaemic heart disease. CONCLUSIONS: Diabetic complications are associated with substantial immediate and long-term healthcare costs. Our comprehensive new estimates of these costs, derived from detailed recent UK Prospective Diabetes Study post-trial data, should aid researchers and health policy analyses.
Assuntos
Complicações do Diabetes/economia , Diabetes Mellitus Tipo 2/economia , Custos de Cuidados de Saúde/estatística & dados numéricos , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Custos Hospitalares/estatística & dados numéricos , Hospitalização/economia , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reino UnidoRESUMO
AIM: To investigate whether previous physical activity levels are associated with blood glucose levels in individuals with impaired glucose tolerance in the context of an international pharmaceutical trial. METHODS: Data were analysed from the NAVIGATOR trial, which involved 9306 individuals with impaired glucose tolerance and high cardiovascular risk from 40 different countries, recruited in the period 2002-2004. Fasting glucose, 2-h post-challenge glucose and physical activity (pedometer) were assessed annually. A longitudinal regression analysis was used to determine whether physical activity levels 2 years (t-2 ) and 1 year (t-1 ) previously were associated with levels of glucose, after adjusting for previous glucose levels and other patient characteristics. Those participants with four consecutive annual measures of glucose and two consecutive measures of physical activity were included in the analysis. RESULTS: The analysis included 3964 individuals. Change in physical activity from t-2 to t-1 and activity levels at t-2 were both associated with 2-h glucose levels after adjustment for previous glucose levels and baseline characteristics; however, the associations were weak: a 100% increase in physical activity was associated with a 0.9% reduction in 2-h glucose levels. In addition, previous physical activity only explained an additional 0.05% of the variance in 2-h glucose over the variance explained by the history of 2-h glucose alone (R(2) = 0.3473 vs. 0.3468). There was no association with fasting glucose. CONCLUSIONS: In the context of a large international clinical trial, previous physical activity levels did not meaningfully influence glucose levels in those with a high risk of chronic disease, after taking into account participants' previous trajectory of glucose control.
Assuntos
Glicemia/metabolismo , Jejum , Intolerância à Glucose/metabolismo , Atividade Motora , Comportamento de Redução do Risco , Acelerometria , Actigrafia , Idoso , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Doenças Cardiovasculares , Estudos de Coortes , Cicloexanos/uso terapêutico , Feminino , Intolerância à Glucose/tratamento farmacológico , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Nateglinida , Fenilalanina/análogos & derivados , Fenilalanina/uso terapêutico , Estudos Prospectivos , Análise de Regressão , Fatores de Risco , Valsartana/uso terapêuticoRESUMO
AIMS: To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. METHODS: TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America. RESULTS: Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals. CONCLUSION: The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Fosfato de Sitagliptina/uso terapêutico , Fatores Etários , Idoso , Ásia/epidemiologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/terapia , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/complicações , Angiopatias Diabéticas/epidemiologia , Angiopatias Diabéticas/terapia , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/epidemiologia , Cardiomiopatias Diabéticas/terapia , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada/efeitos adversos , Europa (Continente)/epidemiologia , Feminino , Hospitalização , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , América Latina/epidemiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , América do Norte/epidemiologia , Fatores de Risco , Caracteres Sexuais , Fosfato de Sitagliptina/efeitos adversosRESUMO
AIMS: Evidence of ethnic differences in vascular complications of diabetes has been inconsistent. The aim of this study was to examine the relationship between ethnicity and long-term outcome in a large sample of individuals with newly diagnosed Type 2 diabetes. METHODS: In a prospective observational study of 4273 UK Prospective Diabetes Study participants followed for a median of 18 years, 3543 (83%) were White Caucasian, 312 (7%) Afro-Caribbean and 418 (10%) Asian Indian. Relative risks for predefined outcomes were assessed comparing Afro-Caribbean and Asian Indian with White Caucasian using accelerated failure time models, with adjustment for cardiovascular risk factors and other potentially confounding variables. RESULTS: During follow-up, 2468 (58%) participants had any diabetes-related end point, 1037 (24%) a myocardial infarction and 401 (9%) a stroke, and 1782 (42%) died. Asian Indian were at greater risk (relative risk, 95% confidence interval) for any diabetes-related end point (1.18, 1.07-1.29), but at lower risk of all-cause mortality (0.89, 0.80-0.97) and peripheral vascular disease (0.43, 0.23-0.82), vs. White Caucasian. Afro-Caribbean participants were at lower risk for all-cause mortality (0.84, 0.76-0.93), diabetes-related death (0.75, 0.64-0.88), myocardial infarction (0.55, 0.43-0.71) and peripheral vascular disease (0.55, 0.33-0.93) vs. White Caucasian. No ethnicity-related associations were found for stroke or microangiopathy. CONCLUSIONS: Asian Indian ethnicity is associated with the greatest burden of disease, but not with an increased risk of major vascular complications or death. Afro-Caribbean ethnicity is associated with reduced risk of all-cause and diabetes-related death, myocardial infarction and peripheral vascular disease, suggesting an ethnicity-specific protective mechanism.
Assuntos
Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etnologia , Etnicidade/estatística & dados numéricos , Adulto , Povo Asiático/estatística & dados numéricos , População Negra/estatística & dados numéricos , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Reino Unido/epidemiologia , Índias Ocidentais/etnologia , População Branca/estatística & dados numéricosRESUMO
Increased physical activity is known to be beneficial in people with type 2 diabetes mellitus (T2DM), but it is not known whether individuals change their activity levels after T2DM diagnosis. The present Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial, conducted in participants with impaired glucose tolerance at high cardiovascular risk, assessed ambulatory activity annually using research-grade pedometers. Oral glucose tolerance tests were performed annually and repeated to confirm T2DM diagnosis. This observational analysis used general linear models to compare step counts before and after T2DM diagnosis in the 2816 participants with the requisite data. Participants were relatively inactive at baseline, taking a median (interquartile range) of 5488 (3258-8361) steps/day, which decreased after T2DM diagnosis by a mean (s.e.) of 258 (64) steps/day (p < 0.0001); however, after adjusting for background trend for activity, step count after T2DM diagnosis was unchanged [mean (s.e.) of 103 (87) fewer steps/day; p = 0.23]. Awareness of T2DM diagnosis had no impact on the trajectory of activity established before the diagnosis.
Assuntos
Actigrafia , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/psicologia , Angiopatias Diabéticas/prevenção & controle , Monitorização Ambulatorial , Atividade Motora , Comportamento de Redução do Risco , Caminhada , Actigrafia/instrumentação , Glicemia/metabolismo , Pressão Sanguínea , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/terapia , Progressão da Doença , Exercício Físico , Feminino , Teste de Tolerância a Glucose , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Ambulatorial/instrumentação , Cooperação do Paciente , Educação de Pacientes como Assunto , Fatores de RiscoRESUMO
AIMS/HYPOTHESIS: The aim of this project was to build a new version of the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model (UKPDS-OM1), a patient-level simulation tool for predicting lifetime health outcomes of people with type 2 diabetes mellitus. METHODS: Data from 5,102 UKPDS patients from the 20 year trial and the 4,031 survivors entering the 10 year post-trial monitoring period were used to derive parametric proportional hazards models predicting absolute risk of diabetes complications and death. We re-estimated the seven original event equations and estimated new equations for diabetic ulcer and some second events. The additional data permitted inclusion of new risk factor predictors such as estimated GFR. We also developed four new equations for all-cause mortality. Internal validation of model predictions of cumulative incidence of all events and death was carried out and a contemporary patient-level dataset was used to compare 10 year predictions from the original and the new models. RESULTS: Model equations were based on a median 17.6 years of follow-up and up to 89,760 patient-years of data, providing double the number of events, greater precision and a larger number of significant covariates. The new model, UKPDS-OM2, is internally valid over 25 years and predicts event rates for complications, which are lower than those from the existing model. CONCLUSIONS/INTERPRETATION: The new UKPDS-OM2 has significant advantages over the existing model, as it captures more outcomes, is based on longer follow-up data, and more comprehensively captures the progression of diabetes. Its use will permit detailed and reliable lifetime simulations of key health outcomes in people with type 2 diabetes mellitus.
Assuntos
Diabetes Mellitus Tipo 2/fisiopatologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Avaliação de Resultados em Cuidados de Saúde , Estudos Prospectivos , Reino UnidoRESUMO
AIMS/HYPOTHESIS: In this study we aimed to replicate the previously reported association between the glycaemic response to metformin and the SNP rs11212617 at a locus that includes the ataxia telangiectasia mutated (ATM) gene in multiple additional populations. METHODS: Incident users of metformin selected from the Diabetes Care System West-Friesland (DCS, n = 929) and the Rotterdam Study (n = 182) from the Netherlands, and the CARDS Trial (n = 254) from the UK were genotyped for rs11212617 and tested for an association with both HbA(1c) reduction and treatment success, defined as the ability to reach the treatment target of an HbA(1c) ≤ 7 % (53 mmol/mol). Finally, a meta-analysis including data from literature was performed. RESULTS: In the DCS cohort, we observed an association between rs11212617 genotype and treatment success on metformin (OR 1.27, 95% CI 1.03, 1.58, p = 0.028); in the smaller Rotterdam Study cohort, a numerically similar but non-significant trend was observed (OR 1.45, 95% CI 0.87, 2.39, p = 0.15); while in the CARDS cohort there was no significant association. In meta-analyses of these three cohorts separately or combined with the previously published cohorts, rs11212617 genotype is associated with metformin treatment success (OR 1.24, 95% CI 1.04, 1.49, p = 0.016 and OR 1.25, 95% CI 1.33, 1.38, p = 7.8 × 10(-6), respectively). CONCLUSIONS/INTERPRETATION: A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetic patients from the Netherlands and the UK. This is the first robustly replicated common susceptibility locus found to be associated with metformin treatment response.
Assuntos
Replicação do DNA/genética , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Polimorfismo de Nucleotídeo Único , Idoso , Estudos de Coortes , Replicação do DNA/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Relação Dose-Resposta a Droga , Feminino , Estudo de Associação Genômica Ampla , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: Observational studies suggest that metformin may reduce cancer risk by approximately one-third. We examined cancer outcomes and all-cause mortality in published randomised controlled trials (RCTs). METHODS: RCTs comparing metformin with active glucose-lowering therapy or placebo/usual care, with minimum 500 participants and 1-year follow-up, were identified by systematic review. Data on cancer incidence and all-cause mortality were obtained from publications or by contacting investigators. For two trials, cancer incidence data were not available; cancer mortality was used as a surrogate. Summary RRs, 95% CIs and I (2)statistics for heterogeneity were calculated by fixed effects meta-analysis. RESULTS: Of 4,039 abstracts identified, 94 publications described 14 eligible studies. RRs for cancer were available from 11 RCTs with 398 cancers during 51,681 person-years. RRs for all-cause mortality were available from 13 RCTs with 552 deaths during 66,447 person-years. Summary RRs for cancer outcomes in people randomised to metformin compared with any comparator were 1.02 (95% CI 0.82, 1.26) across all trials, 0.98 (95% CI 0.77, 1.23) in a subgroup analysis of active-comparator trials and 1.36 (95% CI 0.74, 2.49) in a subgroup analysis of placebo/usual care comparator trials. The summary RR for all-cause mortality was 0.94 (95% CI 0.79, 1.12) across all trials. CONCLUSIONS/INTERPRETATION: Meta-analysis of currently available RCT data does not support the hypothesis that metformin lowers cancer risk by one-third. Eligible trials also showed no significant effect of metformin on all-cause mortality. However, limitations include heterogeneous comparator types, absent cancer data from two trials, and short follow-up, especially for mortality.
Assuntos
Diabetes Mellitus/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Neoplasias/mortalidade , Adulto , Idoso , Complicações do Diabetes/complicações , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Taxa de SobrevidaRESUMO
AIM: Informing a person of their individual risk of developing a disease in the future may be sufficient to provide the person with the impetus to adopt risk reducing behaviours. The aim of this study was to determine if a personalised 10-year cardiovascular disease (CVD) risk estimate can increase physical activity and other risk reduction behaviours in adults at high risk of CVD. METHODS: Pilot 2 × 2 factorial randomised controlled trial conducted in Oxfordshire, UK including 194 adults at increased CVD risk (10-year CVD risk ≥ 20%) recruited from four general practices. Main outcome measure at one month was physical activity measured by accelerometer. RESULTS: Median (IQR) age was 62.3 (54.9, 66.1) years, 67% were men and 19% had known diabetes. Mean (SD) total accelerometer counts per day was 297 × 10(-3) (110 × 10(-3) ) and activity of moderate or greater intensity was undertaken for 53 (22) minutes per day. In the 185 (95%) participants attending follow-up an increase in physical activity was not seen. There was a non-significant 0.5% (p = 0.56) greater increase in accelerometer counts in those receiving personalised CVD risk estimates. No significant within or between group changes were seen at one month in estimated 10-year CVD risk. A net 7% decrease in mean LDL cholesterol (p = 0.004) was seen in the intervention group despite similar increases in new prescriptions for lipid lowering therapies. CONCLUSION: In adults at increased risk of CVD provision of personalised 10-year CVD risk estimates did not appear to increase physical activity or estimated CVD risk over a one-month period.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Reino Unido/epidemiologiaRESUMO
AIM: To explore participants' experiences of intensifying insulin therapy during the Treating to Target in Type 2 Diabetes (4-T) trial. METHODS: In-depth interviews were conducted with 41 trial participants who had had their insulin therapy intensified during this trial. Data were analysed using an inductive, thematic approach. RESULTS: The vast majority of participants were receptive towards intensifying treatment. Whilst some were happy simply to follow health professionals' recommendations, others saw taking two types of insulin as a more effective way of controlling their diabetes. Post-intensification, participants sought to remember to take their additional injections by developing injection-related strategies and daily routines. The need to inject insulin whilst in public often arose more frequently following intensification and was a consistent source of anxiety. Those who were worried about injecting in public sought to avoid having to do so; for example, by injecting in toilets or by advancing or delaying the timing of their injections. CONCLUSIONS: IT was not increasing the number of daily injections per se which was problematic for the participants who had agreed to have their insulin therapies intensified, but the increased likelihood of having to inject insulin in public. Addressing concerns about injecting in public places may help promote adherence to intensified insulin regimens.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/psicologia , Esquema de Medicação , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Cooperação do PacienteRESUMO
AIM: No differences in patient health status as measured by the EuroQol-5 Dimension (EQ-5D) questionnaire were observed at 1 year between groups randomized to addition of biphasic, prandial or basal insulin to oral therapy in the treat-to-target in type 2 diabetes trial. We further investigated insulin treatment satisfaction between groups. METHODS: Seven hundred and eight patients with suboptimal glycated haemoglobin levels (7.0-10.0%) taking maximally tolerated doses of metformin and sulphonylurea were randomized to biphasic insulin aspart twice-daily, prandial insulin aspart three times daily or basal insulin detemir once-daily (twice if required). At 1 year self-completed Insulin Treatment Satisfaction Questionnaires (ITSQ) were administered. Lower scores indicated lower treatment satisfaction. We tested for differences between the three groups for the ITSQ total score and for each of the five ITSQ domain scores adjusting for age, gender, ethnicity and education. RESULTS: All 22 ITSQ subscales were completed by 554 (78.2%) patients. Their mean (s.d.) age was 61.5 (9.4) years, body weight 86.1 (16) kg and median (IQR) diabetes duration 9 (6-13) years. Sixty-five percent (358) were male. Median (IQR) 1-year ITSQ total score was lower in patients allocated to prandial therapy (76.5, 68.0-88.6) than in patients allocated to biphasic insulin (83.3, 74.2-90.2) or basal insulin (84.1, 73.5-93.2). With the exception of 'perceived glycaemic control', 1-year adjusted ITSQ scores were significantly different between groups for each of the ITSQ domains, with lower scores for prandial insulin compared with the basal or biphasic groups. Median (IQR) ITSQ scores were lower in patients with a gain in body mass index (BMI) > 1.23 kg/m² over 1 year (79.5, 69.7-89.4) compared to those with a lesser or no gain in BMI (84.1, 74.2-92.4) and in those with occurrence of hypoglycaemia (79.5, 69.7-88.6) compared to those with no hypoglycaemia (84.1, 73.7-93.2). CONCLUSION: Specific measurement of insulin treatment satisfaction identifies differences between regimens used to intensify treatment for type 2 diabetes. Impact of treatment on lifestyle needs to be considered as a factor in the choice of an insulin regimen.
Assuntos
Glicemia/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Insulinas Bifásicas/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Esquema de Medicação , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/efeitos dos fármacos , Humanos , Hipoglicemiantes/administração & dosagem , Insulina/administração & dosagem , Insulina Aspart/uso terapêutico , Masculino , Metformina/administração & dosagem , Pessoa de Meia-Idade , Satisfação do Paciente , Compostos de Sulfonilureia/administração & dosagem , Inquéritos e Questionários , Resultado do TratamentoRESUMO
AIMS/HYPOTHESIS: We compared the effect of biphasic, basal or prandial insulin regimens on glucose control, clinical outcomes and adverse events in people with type 2 diabetes. METHODS: We searched the Cochrane Library, MEDLINE, EMBASE and major American and European conference abstracts for randomised controlled trials up to October 2008. A systematic review and meta-analyses were performed. RESULTS: Twenty-two trials that randomised 4,379 patients were included. Seven trials reported both starting insulin dose and titration schedules. Hypoglycaemia definitions and glucose targets varied. Meta-analyses were performed pooling data from insulin-naive patients. Greater HbA(1c) reductions were seen with biphasic and prandial insulin, compared with basal insulin, of 0.45% (95% CI 0.19-0.70, p = 0.0006) and 0.45% (95% CI 0.16-0.73, p = 0.002), respectively, but with lesser reductions of fasting glucose of 0.93 mmol/l (95% CI 0.21-1.65, p = 0.01) and 2.20 mmol/l (95% CI 1.70-2.70, p < 0.00001), respectively. Larger insulin doses at study end were reported in biphasic and prandial arms compared with basal arms. No studies found differences in major hypoglycaemic events, but minor hypoglycaemic events for prandial and biphasic insulin were inconsistently reported as either higher than or equivalent to basal insulin. Greater weight gain was seen with prandial compared with basal insulin (1.86 kg, 95% CI 0.80-2.92, p = 0.0006). CONCLUSIONS/INTERPRETATION: Greater HbA(1c) reduction may be obtained in type 2 diabetes when insulin is initiated using biphasic or prandial insulin rather than a basal regimen, but with an unquantified risk of hypoglycaemia. Studies with longer follow-up are required to determine the clinical relevance of this finding.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 2/metabolismo , Hemoglobinas Glicadas/metabolismo , HumanosRESUMO
AIMS/HYPOTHESIS: The aim of this study was to investigate the impact of using a non-diabetes-specific cardiovascular disease (CVD) risk calculator to determine eligibility for statin therapy according to current UK National Institute for Health and Clinical Excellence (NICE) guidelines for those patients with type 2 diabetes who are at an increased risk of CVD (10 year risk >or=20%). METHODS: The 10 year CVD risks were estimated using the UK Prospective Diabetes Study (UKPDS) Risk Engine and the Framingham equation for 4,025 patients enrolled in the Lipids in Diabetes Study who had established type 2 diabetes and LDL-cholesterol <4.1 mmol/l. RESULTS: The mean (SD) age of the patients was 60.7 (8.6) years, blood pressure 141/83 (17/10) mmHg and the total cholesterol:HDL-cholesterol ratio was 3.9 (1.0). The median (interquartile range) diabetes duration was 6 (3-11) years and the HbA(1c) level was 8.0% (7.2-9.0%). The cohort comprised 65% men, 91% whites, 4% Afro-Caribbeans, 5% Asian Indians and 15% current smokers. More patients were classified as being at high risk by the UKPDS Risk Engine (65%) than by the Framingham CVD equation (63%) (p < 0.0001). The Framingham CVD equation classified fewer men and people aged <50 years old as high risk (p < 0.0001). There was no difference between the UKPDS Risk Engine and Framingham classification of women at high risk (p = 0.834). CONCLUSIONS/INTERPRETATION: These results suggest that the use of Framingham-derived rather than UKPDS Risk Engine-derived CVD risk estimates would deny about one in 25 patients statin therapy when applying current NICE guidelines. Thus, under these guidelines the choice of CVD risk calculator is important when assessing CVD risk in patients with type 2 diabetes, particularly for the identification of the relatively small proportion of younger people who require statin therapy.
Assuntos
Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/tratamento farmacológico , Humanos , Seleção de Pacientes , Medição de RiscoRESUMO
The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hiperglicemia/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Algoritmos , Ensaios Clínicos Controlados como Assunto , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/psicologia , Europa (Continente) , Hiperglicemia/prevenção & controle , Hiperglicemia/psicologia , Hipoglicemiantes/efeitos adversos , Estilo de Vida , Sociedades Médicas , Estados UnidosRESUMO
AIMS/HYPOTHESIS: The aim of the study was to examine the impact of statin or omega-3-acid ethyl esters 90 (omega-3 EE90; omega-3-acid ethyl esters 90 refers to a mixture of ethyl esters of n-3 fatty acids) on estimated cardiovascular disease (CVD) risk in community-based people with type 2 diabetes but without known CVD and not taking lipid-lowering therapy. METHODS: A central computer randomised 800 patients in 59 UK general practices to atorvastatin (n = 401, 20 mg/day) or placebo (n = 399) and omega-3 EE90 (n = 397, 2 g/day) or placebo (n = 403) in a concealed factorial manner. Participants with LDL-cholesterol <2.6 mmol/l, triacylglycerol <1.5 mmol/l and estimated 10-year CVD risk <20% were compared at 4 months. RESULTS: Mean (SD) age was 63.5 (11.7) years, HbA(1c) 6.9 (1.1) % and known diabetes duration (median [interquartile range]) was 4 (2-8) years. Fifty-seven per cent were men, 90% white and 74% had an estimated 10-year CVD risk >or=20%. Of 732 patients with 4-month data, more allocated atorvastatin (n = 371) compared with placebo (n = 361) achieved LDL-cholesterol <2.6 mmol/l (91% vs 24%, p < 0.001) and had estimated 10-year CVD risks <20% (38% vs 26%, p < 0.001). No differences were seen between those allocated omega-3 EE90 (n = 371) compared with placebo (n = 361) for participants achieving triacylglycerol <1.5 mmol/l (65% vs 60%, p = 0.18) or estimated 10-year CVD risks <20% (34% vs 30%, p = 0.18). There were no side effects of note. CONCLUSIONS/INTERPRETATION: Many community-based diabetic patients without known CVD remain at high CVD risk despite statin treatment and require additional risk-reduction strategies. The impact of omega-3 EE90 on CVD risk will remain uncertain until clinical endpoint trial results are available. TRIAL REGISTRATION: ISRCT no. 76737502.
Assuntos
Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Idoso , Atorvastatina , Pressão Sanguínea , Tamanho Corporal , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Angiopatias Diabéticas/prevenção & controle , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , PlacebosRESUMO
AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.