RESUMO
METHODS: Discovery Belux is an open-label, multicentre, randomised, phase IIIb, parallel group study comparing the efficacy of rosuvastatin (RSV) and atorvastatin (ATV) on changes in lipid levels and the achievement of European Atherosclerosis Society (EAS) lipid goals. Patients (> or = 18 years) with primary hypercholesterolaemia, with a low-density lipoprotein (LDL-C) level > 120 mg/dl (on treatment) or > 135 mg/dl (naive subjects), and with a statin indication, were randomised to receive RSV 10 mg/day or ATV 10 mg/day for 12 weeks. Patients not at goal after 12 weeks and receiving ATV 10 were further switched to RSV 10 mg for another 12 weeks. Patients not at goal with RSV 10 mg were further titrated to RSV 20 mg. RESULTS: 938 patients were randomised to the two treatment groups. After 12 weeks of treatment, a significantly greater percentage of patients receiving RSV 10 compared with ATV 10 achieved EAS LDL-C target goal (< 115 mg/dl) (85% vs. 67%). LDL-C was reduced by 47% and total cholesterol (TC) by 33% with RSV 10.This was 38% and 27% for ATV 10, respectively. After 24 weeks, an additional 57% of patients initially taking RSV 10 and uncontrolled, reached the target with RSV 20. In the patient group, initially taking ATV 10 and uncontrolled, 65% reached the target with RSV 10 after 24 weeks. Both treatments were well tolerated with a similar incidence of adverse events. In addition, a health economic analysis was performed. As RSV 10 is available at a lower cost in Belgium and as it is more effective, compared to ATV 10, it appeared to be the option of choice from a cost-effectiveness perspective. CONCLUSIONS: Rosuvastatin 10 mg treatment is significantly more effective than atorvastatin 10 mg at achieving European LDL-C goals, at lowering LDL-C and TC. These results were obtained with a similar safety profile. From a cost-effectiveness perspective RSV 10 is the preferred therapeutic option in comparison with ATV 10. Uptitration of uncontrolled patients to RSV 20 mg and switch from ATV 10 to RSV 10 allowed significantly more patients to reach the LDL-C and TC target goal.
Assuntos
Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipídeos/sangue , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , Atorvastatina , Bélgica , LDL-Colesterol/efeitos dos fármacos , Feminino , Indicadores Básicos de Saúde , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/economia , Hipercolesterolemia/fisiopatologia , Modelos Logísticos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Modelos Estatísticos , Rosuvastatina CálcicaRESUMO
Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans.
Assuntos
Mapeamento Cromossômico , Diabetes Mellitus Tipo 2/genética , Monoéster Fosfórico Hidrolases/genética , Regiões 3' não Traduzidas/genética , Animais , Sequência de Bases , Células CHO , Linhagem Celular , Estudos de Coortes , Cricetinae , Diabetes Mellitus Tipo 2/enzimologia , Amplificação de Genes , Genes Reporter , Genótipo , Humanos , Hibridização in Situ Fluorescente , Rim/embriologia , Rim/enzimologia , Luciferases/genética , Camundongos , Dados de Sequência Molecular , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases , Monoéster Fosfórico Hidrolases/metabolismo , Ratos , Proteínas Recombinantes/metabolismo , Valores de Referência , Deleção de Sequência , Transfecção , Domínios de Homologia de src/genéticaRESUMO
OBJECTIVE: A worldwide increase in the incidence of childhood type 1 diabetes has been observed. Because in various countries the majority of new type 1 diabetic patients are diagnosed in adulthood, we investigated whether the rising incidence of this disorder in children reflects a global increase in the incidence of diabetes or a shift toward earlier clinical presentation. RESEARCH DESIGN AND METHODS: The incidence of type 1 diabetes presenting before age 40 years was prospectively measured in the Antwerp district over a 12-year period (1989-2000). The completeness of ascertainment was evaluated by the capture-recapture method. Trends in incidence during the study period were analyzed by Poisson regression. RESULTS: The incidence of type 1 diabetes diagnosed before age 40 years remained constant over the 12-year period, averaging 9.9 cases per 100,000 individuals per year. The incidence was similar in both sexes under age 15 years, but a marked male excess was noted for adult-onset disease, in particular after age 20 years, resulting in a male-to-female ratio of 0.9 under age 15 years vs. 1.6 thereafter (P = 0.001). During the 12-year observation period, there was a significant tendency toward increasing incidence under age 15 years at the expense of a decreasing incidence between ages 15 and 40 years (P = 0.025). The annual increase in incidence averaged 1.8% under age 15 years and 5.0% under age 5 years (P = 0.06). CONCLUSIONS: Our results indicate that in Belgium, the increasing incidence of childhood type 1 diabetes-especially for children under age 5 years-is not attributable to a global increase in disease incidence, but rather to earlier clinical manifestation. The results suggest that an environmental factor may preferentially accelerate the subclinical disease process in young diabetes-prone subjects.
Assuntos
Diabetes Mellitus Tipo 1/epidemiologia , Adolescente , Adulto , Distribuição por Idade , Bélgica/epidemiologia , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Análise de Regressão , Distribuição por Sexo , Fatores de TempoRESUMO
We investigated inaugural disease phenotype in relation to the presence or absence of diabetes-associated autoantibodies and human leukocyte antigen (HLA) DQ risk genotypes in adult-onset diabetic patients. Blood samples and questionnaires were obtained from 1584 recent-onset Belgian Caucasian patients (age 15-39 yr at diagnosis of primary diabetes) who were recruited by the Belgian Diabetes Registry over an 11-yr period. At clinical diagnosis, antibody-positive patients (n = 1198) were on average younger and had more symptoms, a more acute disease onset, lower body mass index, and random C-peptide levels, but higher insulin needs, glycemia, and prevalence of ketonuria, HLA-DQ, and 5' insulin gene susceptibility genotypes (P < 0.001 vs. antibody-negative patients; n = 386). In antibody-positive patients, these characteristics did not differ according to HLA-DQ genotype. However, in antibody-negative subjects, we found that patients were younger (P = 0.001); had a lower body mass index (P < 0.001), higher insulin needs (P = 0.014), and amylasemia (P = 0.001); and tended to have a higher glycemia and lower C-peptide in the presence of susceptible HLA-DQ genotypes. Differences according to HLA-DQ genotype subsisted after careful age-matching. In conclusion, we found no relation between initial disease phenotype and HLA-DQ genotype in antibody-positive diabetic young adults. In contrast, antibody-negative patients displayed more type 1-like features when carrying susceptible HLA-DQ genotypes known to promote the development of antibody-positive diabetes. The overrepresentation of these susceptibility genotypes in antibody-negative patients suggests the existence of an immune-mediated disease process with as yet unidentified immune markers in a subgroup of seronegative patients.