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1.
Atherosclerosis ; 274: 41-46, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29751283

RESUMO

BACKGROUND AND AIMS: Patients with familial hypercholesterolaemia (FH) have an elevated risk of coronary heart disease (CHD). Here we compare changes in CHD mortality in patients with heterozygous (FH) pre 1992, before lipid-lowering therapy with statins was used routinely, and in the periods 1992-2008 and 2008-2016. METHODS: 1903 Definite (DFH) and 1650 Possible (PFH) patients (51% women) aged 20-79 years, recruited from 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2016 for 67,060 person-years. The CHD standardised mortality ratio (SMR) compared to the population in England and Wales was calculated (with 95% Confidence intervals). RESULTS: There were 585 deaths, including 252 from CHD. Overall, the observed 2.4-fold excess coronary mortality for treated DFH post-1991 was significantly higher than the 1.78 excess for PFH (35% 95% CI 3%-76%). In patients with DFH and established coronary disease, there was a significant excess coronary mortality in all time periods, but in men it was reduced from a 4.83-fold excess (2.32-8.89) pre-1992 to 4.66 (3.46-6.14) in 1992-2008 and 2.51 (1.01-5.17) post-2008, while in women the corresponding values were 7.23 (2.65-15.73), 4.42 (2.70-6.82) and 6.34 (2.06-14.81). Primary prevention in men with DFH resulted in a progressive reduction in coronary mortality over the three time-periods, with no excess mortality evident post-2008 (0.89 (0.29-2.08)), although in women the excess persisted (post-2008 3.65 (1.75-6.72)). CONCLUSIONS: The results confirm the benefit of statin treatment in reducing CHD mortality, but suggest that FH patients with pre-existing CHD and women with FH may not be treated adequately.


Assuntos
Colesterol/sangue , Doença das Coronárias/mortalidade , Doença das Coronárias/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/terapia , Prevenção Primária/métodos , Biomarcadores/sangue , Causas de Morte , Doença das Coronárias/sangue , Doença das Coronárias/diagnóstico , Seguimentos , Disparidades em Assistência à Saúde , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/mortalidade , Estudos Prospectivos , Fatores de Proteção , Sistema de Registros , Medição de Risco , Fatores de Risco , Fatores Sexuais , Fatores de Tempo , Resultado do Tratamento , Reino Unido/epidemiologia
2.
Diabetologia ; 55(7): 1971-7, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22453232

RESUMO

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 Tratamento
3.
Eur J Prev Cardiol ; 19(3): 474-83, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21460076

RESUMO

BACKGROUND: While evidence shows high-dose statins reduce cardiovascular events compared with moderate doses in individuals with acute coronary syndrome (ACS), many primary care trusts (PCT) advocate the use of generic simvastatin 40 mg/day for these patients. METHODS AND RESULTS: Data from 28 RCTs were synthesized using a mixed treatment comparison model. A Markov model was used to evaluate the cost-effectiveness of treatments taking into account adherence and the likely reduction in cost for atorvastatin when the patent expires. There is a clear dose-response: rosuvastatin 40 mg/day produces the greatest reduction in low-density lipoprotein cholesterol (56%) followed by atorvastatin 80 mg/day (52%), and simvastatin 40 mg/day (37%). Using a threshold of £20,000 per QALY, if adherence levels in general practice are similar to those observed in RCTs, all three higher dose statins would be considered cost-effective compared to simvastatin 40 mg/day. Using the net benefits of the treatments, rosuvastatin 40 mg/day is estimated to be the most cost-effective alternative. If the cost of atorvastatin reduces in line with that observed for simvastatin, atorvastatin 80 mg/day is estimated to be the most cost-effective alternative. CONCLUSION: Our analyses show that current PCT policies intended to minimize primary care drug acquisition costs result in suboptimal care.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/economia , Custos de Medicamentos , Medicamentos Genéricos/administração & dosagem , Medicamentos Genéricos/economia , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/economia , Prevenção Secundária/economia , Atorvastatina , Teorema de Bayes , Doenças Cardiovasculares/prevenção & controle , Ensaios Clínicos Fase III como Assunto , Análise Custo-Benefício , Prescrições de Medicamentos/economia , Fluorbenzenos/administração & dosagem , Fluorbenzenos/economia , Ácidos Heptanoicos/administração & dosagem , Ácidos Heptanoicos/economia , Humanos , Cadeias de Markov , Adesão à Medicação , Modelos Econômicos , Pirimidinas/administração & dosagem , Pirimidinas/economia , Pirróis/administração & dosagem , Pirróis/economia , Indicadores de Qualidade em Assistência à Saúde/economia , Anos de Vida Ajustados por Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosuvastatina Cálcica , Sinvastatina/administração & dosagem , Sinvastatina/economia , Sulfonamidas/administração & dosagem , Sulfonamidas/economia , Fatores de Tempo , Resultado do Tratamento
4.
Diabet Med ; 28(1): 100-8, 2011 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21166851

RESUMO

AIMS: To compare the renal effects of low- vs. high-dose atorvastatin in patients with Type 2 diabetes mellitus and optimally managed early renal disease. METHODS: We compared the 2-year progression of nephropathy in a double-blind randomized controlled trial of atorvastatin 80 mg/day (n = 60) vs. 10 mg/day (n = 59) in patients with Type 2 diabetes with microalbuminuria or proteinuria [mean (sd): age 64 years (10 years); HbA(1c) 7.7% (1.3%), 61 mmol/mol (10 mmol/mol); blood pressure 131/73 mmHg; renin-angiotensin system blocker use > 80%; dual blockade > 67%] recruited from diabetes clinics in Greater Manchester. RESULTS: Over (mean) 2.1 years of follow-up, the Modification of Diet in Renal Disease estimated glomerular filtration rate declined by 3 ml min(-1) 1.73 m(-2) in the combined group. The mean (95% CI) between-group difference during follow-up was not significant [2.2 ml min(-1) 1.73 m(-2) (-1.1 to 5.4 ml min(-1) 1.73: m(-2) ), P = 0.20] after adjusting for baseline differences in renal function; positive difference favours 80 mg dose. Similarly, there was no significant difference in creatinine clearance by Cockcroft and Gault [2.5 ml/min (-2.4 to 7.3 ml/min), P = 0.32]; serum creatinine/24-h urine collections [4.0 ml/min (-4.8 to 12.7 ml/min), P = 0.38]; cystatin C (P = 0.69); or 24-h urine protein or albumin excretion (P = 0.92; P = 0.93). We recorded no significant between-group differences in deaths or adverse events. CONCLUSIONS: In patients with Type 2 diabetes with early renal disease, we found no statistical difference in renal function between those taking high- or low-dose atorvastatin over 2 years. We cannot exclude a beneficial effect of < 1.6 ml min(-1) 1.73 m(-2) year(-1) on Modification of Diet in Renal Disease estimated glomerular filtration rate, or if blood pressure management or if renin-angiotensin system blocker use had not been optimized.


Assuntos
Anticolesterolemiantes/administração & dosagem , Diabetes Mellitus Tipo 2/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Ácidos Heptanoicos/administração & dosagem , Rim/efeitos dos fármacos , Pirróis/administração & dosagem , Albuminúria/metabolismo , Atorvastatina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/induzido quimicamente , Nefropatias Diabéticas/metabolismo , Método Duplo-Cego , Esquema de Medicação , Feminino , Taxa de Filtração Glomerular , Humanos , Rim/metabolismo , Falência Renal Crônica/induzido quimicamente , Falência Renal Crônica/metabolismo , Masculino , Pessoa de Meia-Idade , Placebos , Resultado do Tratamento , Reino Unido
5.
Atherosclerosis ; 211(2): 618-23, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20356595

RESUMO

OBJECTIVE: To examine all-cause and cardiovascular mortality in patients with severe hypertriglyceridaemia. METHODS: 337 patients aged less than 80 years (47 with diabetes, 75 women) with a fasting triglyceride concentration on at least two occasions of >5.0mmol/l were registered by 21 lipid clinics in the United Kingdom and followed prospectively between 1980 and 2008 for 4353 person-years. The standardised mortality ratio (SMR) was calculated by comparison with the general population. RESULTS: The mean untreated total cholesterol concentration was 9.8 (SD 3.6)mmol/l for men and 11.9 (7.2)mmol/l for women and the corresponding geometric mean triglyceride concentration was 12.6 (inter-quartile range 7.3, 21.6) and 15.7 (8.2, 29.2)mmol/l. There were 70 deaths, including 35 from CHD and 7 from stroke. The SMR for CHD was raised at 327 (95% confidence intervals 228, 455; p<0.0001) and remained elevated after excluding patients with diabetes at registration (SMR=287, 95% CI 190, 419; p<0.0001), and after excluding patients with CHD at registration (SMR=259, 95% CI 158, 400; p=0.0003). The increased SMR was most marked in younger men aged 40-59 years (SMR=544, 95% CI 304, 897; p<0.0001). The SMR for stroke for patients aged 20-79 years was raised at 262 (95% CI 105, 540; p=0.04), as was all-cause mortality at 164 (95% CI 129, 208; p<0.001). CONCLUSION: Severe hypertriglyceridaemia is associated with a substantially increased mortality from cardiovascular disease, even in the absence of diabetes. In addition to lowering triglyceride concentrations to reduce the risk of pancreatitis, treatment should aim to reduce the overall cardiovascular risk.


Assuntos
Doenças Cardiovasculares/mortalidade , Hipertrigliceridemia/sangue , Adulto , Doenças Cardiovasculares/epidemiologia , Estudos de Coortes , Doença das Coronárias/sangue , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/patologia , Estudos Prospectivos , Sistema de Registros , Risco , Triglicerídeos/metabolismo
6.
Atherosclerosis ; 209(2): 579-84, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19922937

RESUMO

INTRODUCTION: Coronary heart disease (CHD) is exceptionally prevalent amongst globally dispersed migrant groups originating from the Indian subcontinent, but the contribution of dyslipidaemia to their increased risk remains poorly defined. METHODS: Fasting lipids and lipoproteins, apolipoproteins (Apo), low density lipoprotein (LDL) diameter and oxidised LDL were measured amongst rural Indians in India (n=294) and their migrant contemporaries in the UK (n=242). The performance of qualitative and quantitative measures of lipid metabolism were compared in the discrimination of WHO defined metabolic risk and raised Framingham CHD risk scores (>15%) using Receiver Operating Characteristic (ROC) curves. RESULTS: LDL diameter was correlated with triglycerides (R(2)=0.12, P<0.001) and with high density lipoprotein (HDL) cholesterol levels (R(2)=0.15, P<0.001) in both groups. Migrants had less small dense LDL (95% CI: 12.5-14.2%) vs. rural Indians (15.7-17.2, P<0.05). On ROC analysis, triglycerides were the only consistent discriminators of metabolic and CHD risk scores (all P< or =0.001). Apo B was also a strong indicator of raised CHD risk scores. Irrespective of site, individuals with raised triglycerides also had higher total cholesterol and Apo B, denser LDL, lower HDL and more oxidised LDL (all P< or =0.01). DISCUSSION: Fasting triglycerides reflect both qualitative and quantitative aspects of lipid metabolism, and are a comprehensive discriminator of CHD risk in this South Asian population.


Assuntos
Doença das Coronárias/epidemiologia , Lipoproteínas LDL/sangue , Triglicerídeos/sangue , Adulto , Apolipoproteínas B/sangue , Povo Asiático , HDL-Colesterol/sangue , Doença das Coronárias/sangue , Feminino , Humanos , Índia/epidemiologia , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Migrantes , Reino Unido/epidemiologia
7.
J Hum Nutr Diet ; 22(3): 232-8, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19504738

RESUMO

BACKGROUND: The management of Type V hypertriglyceridaemia at some centres involves the use of a very low fat diet (15% energy as fat). There is no published research examining compliance with, or nutritional adequacy, of this treatment. This study assesses the nutritional adequacy of the diet and examines barriers and enablers to adherence. METHODS: Fifty-four eligible patients were invited to take part. Eight males and one female agreed to participate. One male later withdrew. The mean age of participants was 49.4 years (SD 12.9 years), their mean BMI was 30.4 kg m(-2) (SD 3.4 kg m(-2)) and their mean triglyceride level was 8.5 mmol L(-1) (SD 5.6 mmol L(-1)). To assess nutritional adequacy and compliance, 3-day dietary records and telephone based diet histories were used and analysed using CompEat. Patients' experience was investigated using semi-structured telephone based qualitative interviews. Qualitative data was recorded, transcribed and analysed using thematic analysis to allow elucidation of emerging themes. RESULTS: Fat accounted for 22.5% of dietary energy and compliance was considered difficult. Barriers included lack of accessible nutritional information, increased patient burden defined as inconvenience and the persistent awareness of potential or actual ill health, lack of appropriate food choices, other peoples' ignorance, lack of flavour and variety, a desire to broaden the palate, cost, social pressure and prior negative experiences with dietitians. Enablers to compliance included nutritional awareness, desire to maintain good health, building on their nutritional knowledge base, behaviour and lifestyle modification, developing a routine, the support of family and friends and supportive eating environments. CONCLUSION: Compliance could be improved through extensive education on labelling, eating during special occasions such as Christmas, birthdays and eating out.


Assuntos
Dieta com Restrição de Gorduras , Gorduras na Dieta , Ingestão de Energia , Hiperlipoproteinemia Tipo V/dietoterapia , Cooperação do Paciente , Adulto , Inquéritos sobre Dietas , Dieta com Restrição de Gorduras/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente/psicologia
8.
J Intern Med ; 265(5): 568-80, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19141093

RESUMO

OBJECTIVES: To study the evidence on the efficacy and safety of ezetimibe monotherapy for the treatment of primary (heterozygous familial and non-familial) hypercholesterolaemia. DESIGN: Systematic review and meta-analysis of randomized controlled trials (RCTs). METHODS: Eleven electronic bibliographic databases covering the biomedical, scientific and grey literature were searched from inception and supplemented by contact with experts in the field. Two reviewers independently determined the eligibility of RCTs, with a minimum treatment duration of 12 weeks, which compared ezetimibe monotherapy (10 mg per day) with placebo. RESULTS: In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid concentrations were used as indicators of clinical outcomes. A meta-analysis of eight randomized, double-blind, placebo-controlled trials (all 12 weeks) showed that ezetimibe monotherapy was associated with a statistically significant mean reduction in LDL cholesterol (from baseline to endpoint) of -18.58%, (95% CI: -19.67 to -17.48, P < 0.00001) compared with placebo. Significant (P < 0.00001) changes were also found in total cholesterol (-13.46%, 95% CI: -14.22 to -12.70), HDL cholesterol (3.00%, 95% CI: 2.06-3.94) and triglyceride levels (-8.06%, 95% CI: -10.92 to -5.20). Ezetimibe monotherapy appeared to be well tolerated with a safety profile similar to placebo. CONCLUSIONS: In a meta-analysis restricted to short-term trials in hypercholesterolaemia, significant potentially favourable changes in lipid and lipoprotein levels relative to baseline occurred with ezetimibe monotherapy. Further long-term studies with cardiovascular and other clinical outcome data are needed to assess the efficacy and safety of ezetimibe more fully.


Assuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Ezetimiba , Humanos , Hipercolesterolemia/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento , Triglicerídeos/sangue
9.
Diabetologia ; 52(2): 218-25, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18972097

RESUMO

AIMS/HYPOTHESIS: Controversy surrounds whether the ratio of apolipoprotein B (ApoB) to apolipoprotein A-I (ApoA-I) is the best lipoprotein discriminator of CHD risk in non-diabetic populations, but the issue has never been investigated in type 2 diabetes. METHODS: In 2,627 participants without known vascular disease in the Collaborative Atorvastatin Diabetes Study, ApoB, ApoA-I, LDL-cholesterol (LDLC) and HDL-cholesterol (HDLC) were assayed at baseline. RESULTS: There were 108 CHD and 59 stroke endpoints over 3.9 years. The ApoB:A-I ratio at baseline was the lipoprotein variable most closely predicting CHD risk both by comparison of the hazard ratio for a 1 SD change or tertiles of frequency distribution. The areas under the receiver-operator curve for the ApoB:ApoA-I and the LDLC to HDLC [corrected] ratios, although not significantly different from each other, were greater (p = 0.0005 and p = 0.0125 respectively) than that of non-HDLC:HDLC. The 27% decrease in the ApoB:ApoA-I ratio on atorvastatin predicted a 32% (95% CI 5.4-51.2%) risk reduction in CHD, close to the 36% decrease observed. Neither the ApoB:ApoA-I nor any other lipoprotein concentration or ratio predicted the stroke outcome. CONCLUSIONS/INTERPRETATION: Overall, the ApoB:ApoA-I ratio improved on the non-HDLC:HDLC ratio in predicting CHD, but, depending on the assessment chosen, its superiority over LDLC:HDLC may be marginal. The statin-induced decrease in stroke risk may not be lipoprotein mediated. TRIAL REGISTRATION: ClinicalTrials.gov NCT00327418. FUNDING: The study was supported by unrestricted grants from Diabetes UK, the Department of Health and Pfizer to the University of Manchester and to University College, London.


Assuntos
Apolipoproteínas/sangue , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/epidemiologia , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Adulto , Idoso , Apolipoproteína A-I/sangue , Atorvastatina , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Feminino , Frequência Cardíaca , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Fatores de Risco , Triglicerídeos/sangue
10.
Int J Clin Pract ; 62(9): 1322-31, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18793375

RESUMO

OBJECTIVE: To estimate 10-year cardiovascular disease (CVD) risk using the risk equation and risk categories of the Joint British Societies' Guidelines on Prevention of Cardiovascular Disease in Clinical Practice (2005). METHODS: A cross-sectional CVD screening programme was conducted in 35 towns in Great Britain. In total, 27,776 men and 43,261 women aged at least 18 years were screened. The estimated 10-year risk of CVD was calculated and directly standardised to the population of Great Britain. RESULTS: The age standardised combined prevalence of known CVD, diabetes, lipid-lowering or antihypertensive drug therapy, which preclude multifactorial risk assessment, was 18.0% for men and 18.1% for women. CVD risk was calculated for 56,863 individuals, and the age-standardised prevalence of an estimated 10-year CVD risk < 10% was 42.7% (95% CI: 42.2-43.1) for men and 60.4% (95% CI: 60.1-60.7) for women; 10% to < 20% was 19.6% (19.1-20.6) and 15.6% (15.2-15.9); and > or = 20% was 19.6% (19.1-20.0) and 6.0% (5.8-6.2) respectively. After aggregating known CVD, diabetes, antihypertensive or lipid-lowering drug therapy, or an estimated CVD risk of > or = 20%, the combined standardised prevalence of high CVD risk for individuals aged 50 years or more was 74.1% (73.5-74.8) for men (n = 14,787) and 45.5% (44.8-46.2) for women (n = 24,400). CONCLUSIONS: Using current risk thresholds, there is a substantial unmet need for primary prevention of CVD, particularly among middle-aged men. The results emphasise the scale of intervention that a strategy of individual risk assessment and pharmacological intervention requires.


Assuntos
Doenças Cardiovasculares/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência , Medição de Risco , Fatores de Risco , Reino Unido/epidemiologia , Adulto Jovem
11.
Exp Physiol ; 93(1): 27-42, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-18165431

RESUMO

There has been a fascinating interplay between the discovery of some of the key enzymes, receptors and transporters in cholesterol biosynthesis and transfer and the development of drugs for the regulation of cholesterol metabolism. The discovery of the low-density lipoprotein (LDL) receptor led to the realization that circulating LDL cholesterol could be decreased when hepatic LDL receptor expression was stimulated by decreasing intrahepatic cholesterol levels. The first class of drugs which operate in this way were the bile-acid sequestrating agents, which, by interrupting the enterohepatic circulation of bile acids, deplete the liver of cholesterol used to replenish the pool of bile salts. Ezetimibe, which was developed to block cholesterol absorption from the intestine, led to the discovery of the Nieman-Pick C1-Like 1 sterol transporter channel. The statins, which have proved enormously successful in preventing cardiovascular disease, were discovered amongst fungal metabolites which inhibit hydroxyl methyl CoA reductase, the rate-limiting enzyme for hepatic cholesterol biosynthesis. Drugs which block enzymes at other stages of the cholesterol biosynthetic pathway, particularly the squalene synthase inhibitors, are entering the clinical phase of their development. Drugs which interfere with hepatic very low-density lipoprotein assembly in the liver, such as microsomal triglyceride transfer protein inhibitors and apolipoprotein B mRNA antisense oligonucleotides, are currently undergoing evaluation. Cholesteryl ester transfer protein (CETP) inhibitors, which decrease cholesteryl ester heteroexchange within the circulation, have undergone development to the point of clinical evaluation, and this will eventually settle the controversy about whether CETP is pro- or antiatherogenic.


Assuntos
Anticolesterolemiantes/farmacologia , Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B/biossíntese , Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Colesterol na Dieta/metabolismo , Farnesil-Difosfato Farnesiltransferase/antagonistas & inibidores , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Absorção Intestinal/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacologia , Receptores de LDL/efeitos dos fármacos , Receptores de LDL/fisiologia
12.
QJM ; 101(3): 231-6, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18204065

RESUMO

BACKGROUND: It has been reported that hypertension carries a greater risk of myocardial infarction (MI) in South Asians living in the UK than in the indigenous British population. This has been attributed to some specifically Asian susceptibility factor. DESIGN: Using a longitudinal approach, we investigated the relationship between coronary heart disease (CHD) risk factors amongst hypertension patients attending Sandwell and City Hospitals, and the onset of cardiovascular events over a 5-year follow-up period. RESULTS: A total of 350 Caucasian (83.7% male) and 104 South Asian (66.3% male) patients with hypertension [age 63.7 (7.6) years and 57.1 (11.1) years respectively, P < 0.001] were followed-up for a mean (SD) period of 64.7(12.1) months. There were 11 (6.4/1000 patient years) cases of MI in Caucasian patients vs. 11 (17.8/1000 patient years) in South Asians, with event-free survival times being significantly lower amongst South Asians (log-rank test P = 0.04). The prevalence of diabetes mellitus was 22.9% higher amongst South Asians (P < 0.001), whilst mean serum cholesterol and fasting triglyceride levels were higher amongst Caucasians (P = 0.001). There were no ethnic differences in HDL cholesterol concentrations, the use of tobacco, statin therapy or anti-platelet therapies (all P = NS), or in composite endpoint (MI, angina, peripheral vascular disease, stroke, revascularization or death; P = 0.74). On Cox regression analysis of all independent cardiovascular risk variables, associated treatments and ethnicity, MI risk was associated with diabetes mellitus (odds ratio 3.77, 95%CI 1.55-9.15, P = 0.003) but not ethnicity per se (P = 0.26). CONCLUSION: Increased risk of MI in hypertensive South Asians in the United Kingdom appears to be the result of a higher prevalence of diabetes mellitus. Further work is required to understand the pathophysiological basis with which diabetes increases CHD risk in this ethnic group.


Assuntos
Complicações do Diabetes/etnologia , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/etiologia , Anti-Hipertensivos/uso terapêutico , Povo Asiático , Colesterol/sangue , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/etnologia , Complicações do Diabetes/tratamento farmacológico , Diabetes Mellitus/tratamento farmacológico , Feminino , Seguimentos , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertensão/etnologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Razão de Chances , Modelos de Riscos Proporcionais , Fatores de Risco , Análise de Sobrevida , Triglicerídeos/sangue , População Branca
14.
Clin Endocrinol (Oxf) ; 67(5): 651-5, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17900299

RESUMO

OBJECTIVE: Serum testosterone measurement is an integral part of the endocrine assessment of men. Little is known about its variation in relation to migration. We examined within a South Asian group the effect of migration to the UK on androgen levels. DESIGN: Circulating testosterone and SHBG concentrations were measured in 97 Gujarati men resident in India and in 79 men from the same villages of origin living in Birmingham, UK. Free testosterone was calculated by Vermeulen's method. Insulin sensitivity (HOMA-S) was determined from paired fasting plasma intact insulin and glucose values. RESULTS: Circulating testosterone was significantly lower in UK Gujarati men (17.2 nmol/l [15.7-18.7]) vs. Indian Gujarati men (21.7 [20.0-23.5]) (P = 0.0002) (age-adjusted median [95% CI]). There was no difference by migration status in circulating free testosterone. Sex hormone binding globulin (SHBG) levels were lower in UK migrants (16.8 nmol/l [15.5-18.1]) than in nonmigrants (21.9 nmol/l [20.5-23.3]) (P < 0.0001). Testosterone level correlated positively with insulin sensitivity (HOMA-S) (rho 0.16, P = 0.04). In multivariate analysis, total testosterone was independently and positively associated with logSHBG (normalized beta (beta) = 0.29, P = 0.002) and independently and negatively with waist circumference (beta = -0.19, P = 0.04), in a model also including height, age, migration status, leptin and fasting insulin. CONCLUSION: Lower circulating testosterone in UK Gujarati men and its association with markers of insulin sensitivity suggest a profound influence of body composition change with migration on testosterone levels. The lower SHBG in this group restores parity in free testosterone. Account should be taken of SHBG in interpreting testosterone levels in men, as well as in women.


Assuntos
Povo Asiático , Emigração e Imigração , Testosterona/sangue , Envelhecimento , Biomarcadores/sangue , Glicemia/análise , Composição Corporal , Estatura , Estudos de Casos e Controles , Inglaterra , Humanos , Índia/etnologia , Insulina/sangue , Resistência à Insulina , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Leptina/sangue , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Globulina de Ligação a Hormônio Sexual/análise
15.
Diabet Med ; 24(12): 1313-21, 2007 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17894827

RESUMO

AIMS: Patients with Type 2 diabetes have an elevated risk of stroke. The role of lipid levels and diabetes-specific factors in risk prediction of stroke is unclear, and estimates of efficacy of lipid-lowering therapy vary between trials. We examined predictors of stroke and the effect of atorvastatin on specific stroke subtypes in Type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS) [a trial of 2838 participants with mean low-density lipoprotein cholesterol < 4.14 mmol/l, no history of macrovascular disease and randomized to atorvastatin 10 mg daily or placebo]. METHODS: Median follow-up was 3.9 years. Cox regression models were used to estimate the effect of atorvastatin on stroke rate and risk of stroke associated with baseline risk factors. Risk factors that predicted stroke in univariate models were examined in a multivariable model. RESULTS: Independent risk factors predicting stroke were age [10-year increments; hazard ratio (HR) 2.3, P < 0.001], microalbuminuria (albumin : creatinine ratio > 2.5 mg/mmol; HR 2.0, P = 0.007) and glycaemic control (HbA(1c) > 10%; HR 2.7, P = 0.007). Women were at lower risk of stroke (HR 0.3, P = 0.004). Lipids did not predict stroke. Of 60 first strokes, 47 were non-haemorrhagic, 13 were indeterminate and none was definitely haemorrhagic. Atorvastatin treatment was associated with 50% reduction in non-haemorrhagic stroke (95% confidence interval 9%-72%P = 0.024), similar to the 48% reduction (11%-69%) for all strokes combined. CONCLUSIONS: Diabetes-specific risk factors are important predictors of stroke in Type 2 diabetes. Despite the lack of association between baseline lipids and first stroke, there was a reduction of 50% of non-haemorrhagic strokes associated with atorvastatin treatment in the CARDS population.


Assuntos
Anticolesterolemiantes/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/prevenção & controle , Ácidos Heptanoicos/uso terapêutico , Pirróis/uso terapêutico , Acidente Vascular Cerebral/prevenção & controle , Adulto , Idoso , Atorvastatina , Pressão Sanguínea , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/análise , Humanos , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Acidente Vascular Cerebral/etiologia
16.
Biomarkers ; 12(2): 188-202, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17536768

RESUMO

Previously we reported that in sheep dippers exposed to organophosphates the frequency of paraoxonase (PON1) polymorphisms differed between those with or without self-reported ill health. We have now examined whether polymorphisms in other genes involved in xenobiotic metabolism alter disease risk in this population. There were elevated but non-significant risks associated with the CYP2D6 WT genotype (odds ratio (OR) 1.47, 95% CI 0.83-2.60), or a GSTP1*B or *C allele (OR 1.37, 95% CI 0.88-2.01) or being GSTM1*2/GSTT1*2 homozygous (OR 1.61, 95% CI 0.74-3.48). Similar results were generally obtained after the exclusion of subjects to obtain a more homogenous case-referent population: for double null GSTM1 and GSTT1 homozygotes the OR was 2.06 (95% CI 0.85-2.04). In those also likely to have been exposed to diazinon, risks associated with a GSTP1*B or *C allele (OR 1.82, 95% CI 0.92-3.63) or a GSTM1*2/GSTT1*2 homozygous (OR 2.60, 95% CI 0.72-10.42) were elevated but not to a significant extent. Risk associated with PON1 genotype and phenotype varied with CYP2D6 and GSTP1 genotype but not consistently with a priori hypotheses. Further work is necessary to delineate more clearly pathways of organophosphate activation and non-PON1 pathways of detoxification and to confirm whether CYP and GST polymorphisms alter disease risk in populations exposed to organophosphates.


Assuntos
Arildialquilfosfatase/genética , Citocromo P-450 CYP2D6/genética , Predisposição Genética para Doença , Glutationa S-Transferase pi/genética , Exposição Ocupacional/efeitos adversos , Organofosfatos/efeitos adversos , Polimorfismo Genético , Agricultura , Animais , Genótipo , Glutationa Transferase/genética , Humanos , Inseticidas/efeitos adversos , Carneiro Doméstico
17.
Diabetologia ; 50(4): 733-40, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17265034

RESUMO

AIMS/HYPOTHESIS: We estimated the cost-effectiveness of atorvastatin treatment in the primary prevention of cardiovascular disease in patients with type 2 diabetes using data from the Collaborative Atorvastatin Diabetes Study (CARDS). SUBJECTS AND METHODS: A total of 2,838 patients, who were aged 40 to 75 years and had type 2 diabetes without a documented history of cardiovascular disease and without elevated LDL-cholesterol, were recruited from 32 centres in the UK and Ireland and randomly allocated to atorvastatin 10 mg daily (n = 1,428) or placebo (n = 1,410). These subjects were followed-up for a median period of 3.9 years. Direct treatment costs and effectiveness were analysed to provide estimates of cost per endpoint-free year over the trial period for alternative definitions of endpoint, and of cost per life-year gained and cost per quality-adjusted life-year (QALY) gained over a patient's lifetime. RESULTS: Over the trial period, the incremental cost-effectiveness ratio (ICER) was estimated to be 7,608 pounds per year free of any CARDS primary endpoint; the ICER was calculated to be 4,896 pounds per year free of any cardiovascular endpoint and 4,120 pounds per year free of any study endpoint. Over lifetime, the incremental cost per life-year gained was 5,107 pounds and the cost per QALY was 6,471 pounds (costs and benefits both discounted at 3.5%). CONCLUSIONS/INTERPRETATION: Primary prevention of cardiovascular disease with atorvastatin is a cost-effective intervention in patients with type 2 diabetes, with the ICER for this intervention falling within the current acceptance threshold ( 20,000 pounds per QALY) specified by the National Institute for Health and Clinical Excellence (NICE).


Assuntos
Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/tratamento farmacológico , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Ácidos Heptanoicos/farmacologia , Pirróis/farmacologia , Adulto , Idoso , Atorvastatina , Análise Custo-Benefício , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Econômicos , Prevenção Primária , Anos de Vida Ajustados por Qualidade de Vida
18.
Diabet Med ; 24(2): 145-53, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17257276

RESUMO

OBJECTIVE: To determine whether pancreatic B-cell function varies in different populations with similar genetic backgrounds but different environments. RESEARCH DESIGN/METHODS: We compared a specific migrant Gujarati community in the UK (n = 205) with people still resident in the same villages of origin in Gujarat, India (n = 246). Pancreatic B-cell function (HOMA-B) was determined and the influence of age, migration and other factors was explored. RESULTS: As anticipated, there was an age-related decline in log(HOMA-B) in both groups. However, the age-related fall in log(HOMA-B) was more pronounced in the UK than in Gujarat (normalized beta-0.29 vs. -0.14, P for difference = 0.03). The decline of HOMA-B with age persisted after adjustment for body mass index (UK beta = -0.31; Gujarat beta = -0.16, P = 0.015, P < 0.001). There was no significant change in insulin sensitivity (HOMA-S) with age at either site, although insulin sensitivity was lower in the UK. Fasting non-estrified fatty acid (NEFA) levels rose with age in the UK but not in Gujarat (P = 0.003 for difference in gradients). In multiple linear regression analysis, lower log(HOMA-B) was independently associated with higher fasting log(NEFA) levels; normalized beta = -0.24, P < 0.001, age; beta = -0.16, P = 0.005, higher log(insulin-like growth factor binding protein-1); beta = -0.19, P = 0.007 and lower body mass index; beta = 0.26, P = 0.001. This model accounted for 25% of the variability in HOMA-B. CONCLUSIONS: HOMA-B as a measure of B-cell function declines more rapidly with age in the migrant UK group than in Gujarat. This may be a direct consequence of chronically higher NEFA exposure in the UK group.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Células Secretoras de Insulina/fisiologia , Fatores Etários , Aminoácidos/fisiologia , Índice de Massa Corporal , Cromo/fisiologia , Emigração e Imigração , Inglaterra/etnologia , Feminino , Humanos , Índia/etnologia , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Ácidos Nicotínicos/fisiologia
19.
J Med Genet ; 43(12): 943-9, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17142622

RESUMO

AIMS: To determine the relative frequency of mutations in three different genes (low-density lipoprotein receptor (LDLR), APOB, PCSK9), and to examine their effect in development of coronary heart disease (CHD) in patients with clinically defined definite familial hypercholesterolaemia in UK. PATIENTS AND METHODS: 409 patients with familial hypercholesterolaemia patients (158 with CHD) were studied. The LDLR was partially screened by single-strand conformational polymorphism (SSCP) (exons 3, 4, 6-10 and 14) and by using a commercial kit for gross deletions or rearrangements. APOB (p.R3500Q) and PCSK9 (p.D374Y) were detected by specific assays. Coding exons of PCSK9 were screened by SSCP. RESULTS: Mutations were detected in 253 (61.9%) PATIENTS: 236 (57.7%) carried LDLR, 10 (2.4%) carried APOB p.Q3500 and 7 (1.7%) PCSK9 p.Y374. No additional mutations were identified in PCSK9. After adjusting for age, sex, smoking and systolic blood pressure, compared to those with no detectable mutation, the odds ratio of having CHD in those with an LDLR mutation was 1.84 (95% CI 1.10 to 3.06), for APOB 3.40 (0.71 to 16.36), and for PCSK9 19.96 (1.88 to 211.5; p = 0.001 overall). The high risk in patients carrying LDLR and PCSK9 p.Y374 was partly explained by their higher pretreatment cholesterol levels (LDLR, PCSK9 and no mutation, 10.29 (1.85), 13.12 and 9.85 (1.90) mmol/l, respectively, p = 0.001). The post-statin treatment lipid profile in PCSK9 p.Y374 carriers was worse than in patients with no identified mutation (LDL-C, 6.77 (1.82) mmol/l v 4.19 (1.26) mmol/l, p = 0.001, HDL-C 1.09 (0.27) mmol/l v 1.36 (0.36) mmol/l, p = 0.03). CONCLUSIONS: The higher CHD risk in patients carrying PCSK9 p.Y347 or a detected LDLR mutation supports the usefulness of DNA testing in the diagnosis and management of patients with familial hypercholesterolaemia. Mutations in PCSK9 appear uncommon in patients with familial hypercholesterolaemia in UK.


Assuntos
Doença das Coronárias/genética , Hiperlipoproteinemia Tipo II/genética , Lipídeos/sangue , Adulto , Apolipoproteínas B/genética , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença das Coronárias/sangue , Análise Mutacional de DNA , Feminino , Frequência do Gene , Humanos , Hiperlipoproteinemia Tipo II/sangue , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Mutação/genética , Razão de Chances , Polimorfismo Conformacional de Fita Simples , Pró-Proteína Convertase 9 , Pró-Proteína Convertases , Receptores de LDL/genética , Fatores de Risco , Serina Endopeptidases/genética , Reino Unido
20.
Qual Saf Health Care ; 15(5): 339-43, 2006 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17074870

RESUMO

OBJECTIVE: To use population impact measures to help prioritise the National Service Framework (NSF) strategies recommended by the UK government for reducing the population burden of coronary heart disease (CHD). DESIGN: Modelling study. SETTING: Primary care. DATA SOURCES: Published data on incidence, baseline risk and prevalence of risk factors for CHD and the proportion treated, eligible for treatment, and adhering to the different interventions. Data from meta-analyses and systematic reviews for relative risk and relative risk reduction associated with different risk factors and interventions. MAIN OUTCOME MEASURES: Population impact measures for the decline in the prevalence of a risk factor and the increased uptake of interventions expressed as number of CHD events prevented in the population. RESULTS: If lifestyle targets for primary prevention are met, 73 522 (95% CI 54,117 to 95,826) CHD events would be prevented per year, with the greatest gain coming from reduced cholesterol and blood pressure levels. In those at high risk of developing CHD, achieving target levels for lifestyle interventions would prevent 4410 (95% CI 1993 to 8014) CHD events and for pharmacological treatments 2008 (95% CI 790 to 3627) CHD events. For patients with established CHD, achieving NSF targets will result in the prevention of 3067 (95% CI 1572 to 5878) CHD events through improved drug treatment and 1103 (95% CI 179 to 2097) events through lifestyle interventions. CONCLUSION: Current strategies focus largely on secondary prevention, but many more cardiovascular events would be prevented by meeting the government's public health and primary prevention targets than targeting people at high risk or those with established heart disease.


Assuntos
Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Atenção Primária à Saúde/normas , Medição de Risco , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/prevenção & controle , Hipertensão/epidemiologia , Hipertensão/prevenção & controle , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Vigilância da População , Prevalência , Prevenção Primária , Fatores de Risco , Medicina Estatal , Reino Unido/epidemiologia
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