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IN BRIEF Metformin, an established therapy for the treatment of type 2 diabetes, has demonstrated safety and effectiveness in the prevention or delay of type 2 diabetes in people at high risk. The Diabetes Prevention Program randomized clinical trial demonstrated that intensive lifestyle intervention and metformin therapy reduced progression to diabetes by 58 and 31%, respectively, compared to placebo in people at risk of type 2 diabetes. Although lifestyle intervention was beneficial in all groups, metformin had a selectively greater effect in those who were more obese, had a higher fasting glucose, had a history of gestational diabetes, or were younger. Long-term effects included an 18% diabetes reduction with metformin compared to placebo over 15 years, a reduction in microvascular complications among those who did not progress to diabetes (without difference among treatment arms), and suggestion by coronary calcium assessment of a possible impact on atherosclerosis in men. Although long-term follow-up to assess later-stage outcomes is underway, current efforts to address gaps in evidence and translation remain of significant public health interest.
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BACKGROUND: Impaired glucose tolerance is associated with increased rates of cardiovascular disease and conversion to type 2 diabetes mellitus. Interventions that may prevent or delay such occurrences are of great clinical importance. METHODS: We conducted a randomized, double-blind, placebo-controlled study to examine whether pioglitazone can reduce the risk of type 2 diabetes mellitus in adults with impaired glucose tolerance. A total of 602 patients were randomly assigned to receive pioglitazone or placebo. The median follow-up period was 2.4 years. Fasting glucose was measured quarterly, and oral glucose tolerance tests were performed annually. Conversion to diabetes was confirmed on the basis of the results of repeat testing. RESULTS: Annual incidence rates for type 2 diabetes mellitus were 2.1% in the pioglitazone group and 7.6% in the placebo group, and the hazard ratio for conversion to diabetes in the pioglitazone group was 0.28 (95% confidence interval, 0.16 to 0.49; P<0.001). Conversion to normal glucose tolerance occurred in 48% of the patients in the pioglitazone group and 28% of those in the placebo group (P<0.001). Treatment with pioglitazone as compared with placebo was associated with significantly reduced levels of fasting glucose (a decrease of 11.7 mg per deciliter vs. 8.1 mg per deciliter [0.7 mmol per liter vs. 0.5 mmol per liter], P<0.001), 2-hour glucose (a decrease of 30.5 mg per deciliter vs. 15.6 mg per deciliter [1.6 mmol per liter vs. 0.9 mmol per liter], P<0.001), and HbA(1c) (a decrease of 0.04 percentage points vs. an increase of 0.20 percentage points, P<0.001). Pioglitazone therapy was also associated with a decrease in diastolic blood pressure (by 2.0 mm Hg vs. 0.0 mm Hg, P=0.03), a reduced rate of carotid intima-media thickening (31.5%, P=0.047), and a greater increase in the level of high-density lipoprotein cholesterol (by 7.35 mg per deciliter vs. 4.5 mg per deciliter [0.4 mmol per liter vs. 0.3 mmol per liter], P=0.008). Weight gain was greater with pioglitazone than with placebo (3.9 kg vs. 0.77 kg, P<0.001), and edema was more frequent (12.9% vs. 6.4%, P=0.007). CONCLUSIONS: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema. (Funded by Takeda Pharmaceuticals and others; ClinicalTrials.gov number, NCT00220961.).
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Diabetes Mellitus Tipo 2/prevenção & controle , Intolerância à Glucose/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/uso terapêutico , Adolescente , Adulto , Glicemia/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Método Duplo-Cego , Edema/induzido quimicamente , Seguimentos , Intolerância à Glucose/complicações , Teste de Tolerância a Glucose , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/farmacologia , Resistência à Insulina , Estimativa de Kaplan-Meier , Tábuas de Vida , Pessoa de Meia-Idade , Pioglitazona , Modelos de Riscos Proporcionais , Tiazolidinedionas/efeitos adversos , Tiazolidinedionas/farmacologia , Aumento de Peso/efeitos dos fármacos , Adulto JovemRESUMO
The incidence and prevalence of diabetes mellitus have grown significantly throughout the world, due primarily to the increase in type 2 diabetes. This overall increase in the number of people with diabetes has had a major impact on development of diabetic kidney disease (DKD), one of the most frequent complications of both types of diabetes. DKD is the leading cause of end-stage renal disease (ESRD), accounting for approximately 50% of cases in the developed world. Although incidence rates for ESRD attributable to DKD have recently stabilized, these rates continue to rise in high-risk groups such as middle-aged African Americans, Native Americans, and Hispanics. The costs of care for people with DKD are extraordinarily high. In the Medicare population alone, DKD-related expenditures among this mostly older group were nearly $25 billion in 2011. Due to the high human and societal costs, the Consensus Conference on Chronic Kidney Disease and Diabetes was convened by the American Diabetes Association in collaboration with the American Society of Nephrology and the National Kidney Foundation to appraise issues regarding patient management, highlighting current practices and new directions. Major topic areas in DKD included (1) identification and monitoring, (2) cardiovascular disease and management of dyslipidemia, (3) hypertension and use of renin-angiotensin-aldosterone system blockade and mineralocorticoid receptor blockade, (4) glycemia measurement, hypoglycemia, and drug therapies, (5) nutrition and general care in advanced-stage chronic kidney disease, (6) children and adolescents, and (7) multidisciplinary approaches and medical home models for health care delivery. This current state summary and research recommendations are designed to guide advances in care and the generation of new knowledge that will meaningfully improve life for people with DKD.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Gerenciamento Clínico , Adolescente , Adulto , Ensaios Clínicos como Assunto , Comorbidade , Atenção à Saúde , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/terapia , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/epidemiologia , Nefropatias Diabéticas/terapia , Etnicidade , Humanos , Hipoglicemiantes/classificação , Hipoglicemiantes/uso terapêutico , Testes de Função Renal/métodos , Monitorização Fisiológica/métodos , Guias de Prática Clínica como Assunto , Prevalência , Fatores de RiscoRESUMO
OBJECTIVE: To determine whether changes in standard and novel risk factors during the Actos Now for Prevention of Diabetes trial explained the slower rate of carotid intima media thickness (CIMT) progression with pioglitazone treatment in persons with prediabetes. METHODS AND RESULTS: CIMT was measured in 382 participants at the beginning and up to 3 additional times during follow-up of the Actos Now for Prevention of Diabetes trial. During an average follow-up of 2.3 years, the mean unadjusted annual rate of CIMT progression was significantly (P=0.01) lower with pioglitazone treatment (4.76×10(-3) mm/year; 95% CI: 2.39×10(-3)-7.14×10(-3) mm/year) compared with placebo (9.69×10(-3) mm/year; 95% CI: 7.24×10(-3)-12.15×10(-3) mm/year). High-density lipoprotein cholesterol, fasting and 2-hour glucose, HbA(1c), fasting insulin, Matsuda insulin sensitivity index, adiponectin, and plasminogen activator inhibitor-1 levels improved significantly with pioglitazone treatment compared with placebo (P<0.001). However, the effect of pioglitazone on CIMT progression was not attenuated by multiple methods of adjustment for traditional, metabolic, and inflammatory risk factors and concomitant medications, and was independent of changes in risk factors during pioglitazone treatment. CONCLUSIONS: Pioglitazone slowed progression of CIMT, independent of improvement in hyperglycemia, insulin resistance, dyslipidemia, and systemic inflammation in prediabetes. These results suggest a possible direct vascular benefit of pioglitazone.
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Doenças das Artérias Carótidas/prevenção & controle , Diabetes Mellitus Tipo 2/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estado Pré-Diabético/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Adiponectina/sangue , Adulto , Idoso , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/etiologia , Progressão da Doença , Método Duplo-Cego , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Insulina/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Pioglitazona , Inibidor 1 de Ativador de Plasminogênio/sangue , Estado Pré-Diabético/sangue , Estado Pré-Diabético/complicações , Estado Pré-Diabético/diagnóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
Background: Coronavirus disease 2019 (COVID-19) pandemic public health measures such as stay-at-home and mandatory work-from-home orders have been associated with obesogenic lifestyle changes, increased risk of weight gain, and their metabolic sequelae. We sought to assess the impact of this pandemic on weight loss from a telemedicine-delivered very-low-carbohydrate intervention targeting nutritional ketosis (NKI). Methods: A total of 746 patients with a BMI ≥25kg/m2, enrolled between January and March 2020 and treated for at least 1 year with the NKI, were classified as pandemic cohort (PC). A separate cohort of 699 patients who received 1 year of the NKI in the preceding years, enrolled between January and March 2018, were identified as pre-pandemic cohort (Pre-PC). Demographic and clinical data were obtained from medical records to compare the cohorts and assess the outcomes. Using propensity score matching (PSM), balanced and matched groups of 407 patients in the Pre-PC and 407 patients in the PC were generated. Longitudinal change in absolute weight and percentage weight change from baseline to 1 year were assessed. Results: Weight significantly decreased in both PC and Pre-PC at 3, 6, 9, and 12 months. The weight loss trajectory was similar in both PC and Pre-PC with no significant weight differences between the two cohorts at 3, 6, 9, and 12 months. On an average, the PC lost 7.5% body weight while the Pre-PC lost 7.9% over 1 year, and the percent weight loss did not differ between the two cohorts (p = 0.50). Conclusion: A very-low-carbohydrate telemedicine intervention delivered comparable and medically significant weight loss independent of pandemic stress and lifestyle limitations.
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COVID-19 , Telemedicina , COVID-19/epidemiologia , Carboidratos , Humanos , Obesidade/epidemiologia , Obesidade/terapia , Pandemias , Pontuação de Propensão , Redução de PesoRESUMO
BACKGROUND: Rosiglitazone has several properties that may affect progression of atherosclerosis. The Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in Diabetes Patients With Cardiovascular History (APPROACH) study was undertaken to determine the effect of the thiazolidinedione rosiglitazone on coronary atherosclerosis as assessed by intravascular ultrasound compared with the sulfonylurea glipizide. METHODS AND RESULTS: This was a randomized, double-blind, controlled 18-month study in 672 patients aged 30 to 80 years with established type 2 diabetes mellitus treated by lifestyle, 1 oral agent, or submaximal doses of 2 oral agents who had at least 1 atherosclerotic plaque with 10% to 50% luminal narrowing in a coronary artery that had not undergone intervention during a clinically indicated coronary angiography or percutaneous coronary intervention. The primary outcome was change in percent atheroma volume in the longest and least angulated epicardial coronary artery that had not undergone intervention. Secondary outcomes included change in normalized total atheroma volume and change in total atheroma volume in the most diseased baseline 10-mm segment. Rosiglitazone did not significantly reduce the primary outcome of percent atheroma volume compared with glipizide (-0.64%; 95% confidence interval, -1.46 to 0.17; P=0.12). The secondary outcome of normalized total atheroma volume was significantly reduced by rosiglitazone compared with glipizide (-5.1 mm(3); 95% confidence interval, -10.0 to -0.3; P=0.04); however, no significant difference between groups was observed for the change in total atheroma volume within the most diseased baseline 10-mm segment (-1.7 mm(3); 95% confidence interval, -3.9 to 0.5; P=0.13). CONCLUSIONS: Rosiglitazone did not significantly decrease the primary end point of progression of coronary atherosclerosis more than glipizide in patients with type 2 diabetes mellitus and coronary atherosclerosis. Clinical Trial Registration- http://www.clinicaltrials.gov. Unique Identifier: NCT00116831.
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Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença da Artéria Coronariana/diagnóstico por imagem , Progressão da Doença , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Hemoglobinas Glicadas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Rosiglitazona , Tiazolidinedionas/efeitos adversos , Ultrassonografia de IntervençãoRESUMO
Impaired fasting glucose and impaired glucose tolerance reflect perturbations in glucose metabolism and define a prediabetic state in which risk for type 2 diabetes mellitus (T2DM) is increased. There is overlap between prediabetes and the metabolic syndrome, which itself increases the risk for T2DM and cardiovascular disease. The utility of medical interventions to prevent progression to diabetes in prediabetic individuals, many of whom also manifest metabolic syndrome, has been examined in several large clinical trials. Intensive lifestyle intervention consistently results in drastic reductions in the incidence of T2DM and reversal of metabolic syndrome. Additionally, pharmacotherapies-including metformin, acarbose, thiazolidinediones, glucagon-like peptide 1 receptor agonists, and renin-angiotensin inhibitors-also reduce diabetes incidence with variable effects on metabolic syndrome components. Taken together, we recommend that prediabetic patients undergo intensive lifestyle intervention, with the addition of pharmacotherapy based on the presence of specific features of the metabolic syndrome, for diabetes prevention.
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Síndrome Metabólica/complicações , Síndrome Metabólica/tratamento farmacológico , Estado Pré-Diabético/complicações , Estado Pré-Diabético/tratamento farmacológico , Análise Custo-Benefício , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/economia , Diabetes Mellitus Tipo 2/prevenção & controle , Progressão da Doença , Humanos , Estilo de Vida , Síndrome Metabólica/epidemiologia , Estado Pré-Diabético/epidemiologiaRESUMO
BACKGROUND: Islet neogenesis associated protein (INGAP) has beta cell regenerating effects in experimental models. METHODS: Subjects with T1DM (N = 63) and T2DM (N = 126) received 300 or 600 mg/day of INGAP peptide in a 90 day, randomized, double-blind, placebo-controlled trial. RESULTS: In T1DM, on-treatment Arginine-stimulated C-peptide (AUC(0-30)) significantly increased from baseline in the 600 mg group (p = 0.0058 versus placebo); no significant changes were seen in the 300 mg group. In T2DM, stimulated C-peptide was significantly better preserved in the 600 mg group compared to placebo at day 120, 30 days after washout (p = 0.031 versus placebo), but did not reach statistical significance during treatment or in the 300 mg group. In T2DM, A1C decreased significantly more in the 600 mg group compared to placebo at day 90 (-0.94% versus -0.47%, respectively, p = 0.009) and day 120, 30 days after washout (-0.73% versus -0.24%, respectively, p = 0.013). This was accompanied by significant reductions in mean glucose. No difference from placebo was detected in the 300 mg group or in T1DM. Injection site reactions were the most common adverse event, occurring in 8 (36%) of placebo, 19 (90%) of 300 mg, and 15 (75%) of 600 mg groups (T1DM) and 14 (33%) of placebo, 27 (64%) of 300 mg, and 29 (69%) of 600 mg groups (T2DM). CONCLUSIONS: INGAP peptide increases C-peptide secretion in T1DM and improves glycaemic control in T2DM. Longer-term exposure, more frequent dosing, better tolerated formulations or combination with other therapies may be necessary to achieve optimal clinical response.
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Citocinas/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Adolescente , Adulto , Idoso , Análise de Variância , Antígenos de Neoplasias/fisiologia , Área Sob a Curva , Arginina/administração & dosagem , Arginina/metabolismo , Biomarcadores Tumorais/fisiologia , Glicemia/análise , Índice de Massa Corporal , Peptídeo C/sangue , Peptídeo C/metabolismo , Citocinas/efeitos adversos , Citocinas/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Jejum/sangue , Feminino , Glutamato Descarboxilase/imunologia , Hemoglobinas Glicadas/análise , Humanos , Injeções Subcutâneas , Insulina/uso terapêutico , Células Secretoras de Insulina/fisiologia , Lectinas Tipo C/fisiologia , Masculino , Pessoa de Meia-Idade , Proteínas Associadas a Pancreatite , Fragmentos de Peptídeos/efeitos adversos , Fragmentos de Peptídeos/imunologia , Proinsulina/sangue , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Regeneração , Resultado do Tratamento , Adulto JovemRESUMO
CONTEXT: Coronary artery disease (CAD) is the major cause of mortality and morbidity in patients with type 2 diabetes. But the utility of screening patients with type 2 diabetes for asymptomatic CAD is controversial. OBJECTIVE: To assess whether routine screening for CAD identifies patients with type 2 diabetes as being at high cardiac risk and whether it affects their cardiac outcomes. DESIGN, SETTING, AND PATIENTS: The Detection of Ischemia in Asymptomatic Diabetics (DIAD) study is a randomized controlled trial in which 1123 participants with type 2 diabetes and no symptoms of CAD were randomly assigned to be screened with adenosine-stress radionuclide myocardial perfusion imaging (MPI) or not to be screened. Participants were recruited from diabetes clinics and practices and prospectively followed up from August 2000 to September 2007. MAIN OUTCOME MEASURE: Cardiac death or nonfatal myocardial infarction (MI). RESULTS: The cumulative cardiac event rate was 2.9% over a mean (SD) follow-up of 4.8 (0.9) years for an average of 0.6% per year. Seven nonfatal MIs and 8 cardiac deaths (2.7%) occurred among the screened group and 10 nonfatal MIs and 7 cardiac deaths (3.0%) among the not-screened group (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.44-1.88; P = .73). Of those in the screened group, 409 participants with normal results and 50 with small MPI defects had lower event rates than the 33 with moderate or large MPI defects; 0.4% per year vs 2.4% per year (HR, 6.3; 95% CI, 1.9-20.1; P = .001). Nevertheless, the positive predictive value of having moderate or large MPI defects was only 12%. The overall rate of coronary revascularization was low in both groups: 31 (5.5%) in the screened group and 44 (7.8%) in the unscreened group (HR, 0.71; 95% CI, 0.45-1.1; P = .14). During the course of study there was a significant and equivalent increase in primary medical prevention in both groups. CONCLUSION: In this contemporary study population of patients with diabetes, the cardiac event rates were low and were not significantly reduced by MPI screening for myocardial ischemia over 4.8 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00769275.
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Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/etiologia , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/diagnóstico por imagem , Imagem de Perfusão do Miocárdio , Adenosina , Doença da Artéria Coronariana/mortalidade , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/mortalidade , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/etiologia , Compostos Radiofarmacêuticos , Tecnécio Tc 99m Sestamibi , VasodilatadoresRESUMO
CONTEXT: A past history of gestational diabetes mellitus (GDM) confers a very high risk of postpartum development of diabetes, particularly type 2 diabetes. OBJECTIVE: The Diabetes Prevention Program (DPP) sought to identify individuals with impaired glucose tolerance (IGT) and intervene in an effort to prevent or delay their progression to diabetes. This analysis examined the differences between women enrolled in DPP with and without a reported history of GDM. DESIGN: The DPP was a randomized, controlled clinical trial. SETTING: The study was a multicenter, National Institutes of Health-sponsored trial carried out at 27 centers including academic and Indian Health Services sites. PATIENTS: A total of 2190 women were randomized into the DPP and provided information for past history of GDM. This analysis addressed the differences between those 350 women providing a past history of GDM and those 1416 women with a previous live birth but no history of GDM. INTERVENTIONS: Subjects were randomized to either standard lifestyle and placebo or metformin therapy or to an intensive lifestyle intervention. MAIN OUTCOMES: The primary outcome was the time to development of diabetes ascertained by semiannual fasting plasma glucose and annual oral glucose tolerance testing. Assessments of insulin secretion and insulin sensitivity were also performed. RESULTS: Whereas entering the study with similar glucose levels, women with a history of GDM randomized to placebo had a crude incidence rate of diabetes 71% higher than that of women without such a history. Among women reporting a history of GDM, both intensive lifestyle and metformin therapy reduced the incidence of diabetes by approximately 50% compared with the placebo group, whereas this reduction was 49 and 14%, respectively in parous women without GDM. These data suggest that metformin may be more effective in women with a GDM history as compared with those without. CONCLUSIONS: Progression to diabetes is more common in women with a history of GDM compared with those without GDM history despite equivalent degrees of IGT at baseline. Both intensive lifestyle and metformin are highly effective in delaying or preventing diabetes in women with IGT and a history of GDM.
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Diabetes Mellitus/prevenção & controle , Diabetes Gestacional/prevenção & controle , Hipoglicemiantes/uso terapêutico , Estilo de Vida , Metformina/uso terapêutico , Adulto , Doenças Cardiovasculares/prevenção & controle , Método Duplo-Cego , Feminino , Intolerância à Glucose/complicações , Intolerância à Glucose/prevenção & controle , Humanos , Atividade Motora , Gravidez , Modelos de Riscos Proporcionais , Fatores de RiscoRESUMO
BACKGROUND: Rosiglitazone, a thiazolidinedione, has effects on insulin sensitivity and cardiovascular risk factors that may favorably impact the progression of coronary atherosclerosis. METHODS: APPROACH is a double-blind randomized clinical trial comparing the effects of the insulin sensitizer rosiglitazone with the insulin secretagogue glipizide on the progression of coronary atherosclerosis. Patients with type 2 diabetes and coronary artery disease undergoing clinically indicated coronary angiography or percutaneous coronary intervention are randomized to receive rosiglitazone or glipizide for 18 months using a titration algorithm designed to provide comparable glycemic control between treatment groups. The primary end point is change in percent atheroma volume from baseline to study completion in a nonintervened coronary artery, as measured by intravascular ultrasound. Cardiovascular events are adjudicated by an end point committee. RESULTS: A total of 672 patients were randomized. The mean age was 61 years, hemoglobin A(1c) (HbA(1c)) 7.2%, body mass index 29.5 kg/m(2), and median duration of diabetes 4.8 years. At baseline, approximately half of the participants were receiving oral antidiabetic monotherapy (53.9%) with 27.5% receiving dual combination therapy and 17.9% treated with diet and exercise alone. Approximately two thirds of the participants (68%) had dyslipidemia, 79.9% hypertension, and 24% prior myocardial infarction. CONCLUSIONS: APPROACH has fully enrolled a high-risk patient population and will compare the glucose-independent effects of rosiglitazone and glipizide on the progression of coronary atherosclerosis, as well as provide additional data on the cardiovascular safety of rosiglitazone in patients with type 2 diabetes and coronary artery disease.
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Doença da Artéria Coronariana/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/prevenção & controle , Hipoglicemiantes/uso terapêutico , Tiazolidinedionas/uso terapêutico , Adulto , Idoso , Doença da Artéria Coronariana/diagnóstico por imagem , Diabetes Mellitus Tipo 2/diagnóstico por imagem , Angiopatias Diabéticas/diagnóstico por imagem , Progressão da Doença , Método Duplo-Cego , Feminino , Glipizida/efeitos adversos , Glipizida/uso terapêutico , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Rosiglitazona , Tiazolidinedionas/efeitos adversos , Ultrassonografia de IntervençãoRESUMO
The incretin hormone glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors fill an unaddressed therapeutic gap in the treatment of type 2 diabetes mellitus (T2DM) by potentiating insulin secretion in pancreatic beta cells, suppressing glucagon secretion, delaying gastric emptying, and reducing appetite. The incretin therapies, alone or in combination with metformin and/or thiazolidinediones, yield improved glycemic control without risk of hypoglycemia and the potential for weight neutrality or even weight loss. New incretin-based approaches offer promising new strategies for treating T2DM by recruiting new, physiologically based mechanisms of action for glucoregulation in the context of a favorable safety profile.
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Diabetes Mellitus Tipo 2/tratamento farmacológico , Incretinas/uso terapêutico , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Exenatida , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Peptídeo 1 Semelhante ao Glucagon/uso terapêutico , Receptor do Peptídeo Semelhante ao Glucagon 1 , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/metabolismo , Secreção de Insulina , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/metabolismo , Ilhotas Pancreáticas/patologia , Liraglutida , Peptídeos/uso terapêutico , Receptores de Glucagon/agonistas , Resultado do Tratamento , Peçonhas/uso terapêuticoRESUMO
OBJECTIVE: The aim of this study was to examine the glucose-lowering effect of exenatide over 24 hours in patients with type 2 diabetes with inadequate glycemic control using metformin, with or without a thiazolidinedione (TZD). METHODS: This randomized, double-blind, 2-arm, parallel-group, placebo-controlled, 2-week study was conducted in patients with type 2 diabetes with inadequate glycemic control, despite metformin with or without a TZD. Patients underwent a baseline and a week-2 (study end) 24-hour admission during which serial serum glucose measurements were taken. Preprandial and postprandial concentrations of triglycerides and free fatty acids were also measured. Meals provided for each patient were identical at the baseline and week-2 assessments. Following the baseline admission, patients were randomized to receive SC injections of either exenatide (5 microg BID for 1 week, then 10 microg BID for the next week) or placebo (volume equivalent) for 14 days. RESULTS: A total of 30 patients (19 women [63%], 11 men [37%]; mean [SD] age, 52.6 [11.2] years; weight, 94.3 [23.0] kg; body mass index, 34.2 [6.1] kg/m(2); glycosylated hemoglobin value, 8.0% [0.9%]; diabetes duration, 8.7 [5.6] years; race, Hispanic 18 [60%], white 10 [33%], black 2 [7%]) were eligible. Seventeen patients (57%) were randomized to treatment with exenatide and 13 patients (43%) received placebo. Concurrent antidiabetic medications were metformin only (n = 19 [63%]) and metformin plus a TZD (n = 11 [37%]). All postbaseline values were least squares mean (SE). After 2 weeks (study end), the 24-hour time-average glucose values were 7.0 (0.2) and 8.8 (0.3) mmol/L for exenatide-treated and placebo-administered patients, respectively (P < 0.001). The glucose values for patients treated with exenatide were lower compared with those in patients who received placebo 2 hours after the morning meal (6.6 [0.4] vs 12.0 [0.5] mmol/L; P < 0.001), the midday meal (8.8 [0.5] vs 11.8 [0.6] mmol/L; P = 0.001), and the evening meal (6.8 [0.4] vs 11.3 [0.4] mmol/L; P < 0.001). The mean durations of patient exposure to glucose concentrations >7.8 and >11.1 mmol/L were significantly shorter for the exenatide group compared with the placebo group (>7.8 mmol/L: 6.8 [0.9] vs 14.1 [1.1] hours; >11.1 mmol/L: 1.0 [0.7] vs 4.7 [0.8] hours; both, P < 0.001). After 2 weeks, the postprandial triglyceride excursions after the morning and evening meals for patients treated with exenatide were significantly lower compared with those treated with placebo. There was no apparent effect on free fatty acid concentrations. CONCLUSIONS: In these patients with type 2 diabetes, exenatide was associated with significantly reduced glucose concentrations at multiple time points during 24 hours, with the greatest effect seen on postprandial glucose concentrations. In addition, exenatide was associated with decreased overall hyperglycemic exposure and significantly decreased postprandial triglyceride excursions. These results are consistent with those seen in other studies that reported the effectiveness of exenatide in controlling hyperglycemia in patients with type 2 diabetes.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Peptídeos/uso terapêutico , Peçonhas/uso terapêutico , Diabetes Mellitus Tipo 2/metabolismo , Método Duplo-Cego , Exenatida , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-PrandialRESUMO
CONTEXT: Individuals with diabetes are at increased risk for cardiovascular disease (CVD), but more aggressive targets for risk factor control have not been tested. OBJECTIVE: To compare progression of subclinical atherosclerosis in adults with type 2 diabetes treated to reach aggressive targets of low-density lipoprotein cholesterol (LDL-C) of 70 mg/dL or lower and systolic blood pressure (SBP) of 115 mm Hg or lower vs standard targets of LDL-C of 100 mg/dL or lower and SBP of 130 mm Hg or lower. DESIGN, SETTING, AND PARTICIPANTS: A randomized, open-label, blinded-to-end point, 3-year trial from April 2003-July 2007 at 4 clinical centers in Oklahoma, Arizona, and South Dakota. Participants were 499 American Indian men and women aged 40 years or older with type 2 diabetes and no prior CVD events. INTERVENTIONS: Participants were randomized to aggressive (n=252) vs standard (n=247) treatment groups with stepped treatment algorithms defined for both. MAIN OUTCOME MEASURES: Primary end point was progression of atherosclerosis measured by common carotid artery intimal medial thickness (IMT). Secondary end points were other carotid and cardiac ultrasonographic measures and clinical events. RESULTS: Mean target LDL-C and SBP levels for both groups were reached and maintained. Mean (95% confidence interval) levels for LDL-C in the last 12 months were 72 (69-75) and 104 (101-106) mg/dL and SBP levels were 117 (115-118) and 129 (128-130) mm Hg in the aggressive vs standard groups, respectively. Compared with baseline, IMT regressed in the aggressive group and progressed in the standard group (-0.012 mm vs 0.038 mm; P < .001); carotid arterial cross-sectional area also regressed (-0.02 mm(2) vs 1.05 mm(2); P < .001); and there was greater decrease in left ventricular mass index (-2.4 g/m(2.7) vs -1.2 g/m(2.7); P = .03) in the aggressive group. Rates of adverse events (38.5% and 26.7%; P = .005) and serious adverse events (n = 4 vs 1; P = .18) related to blood pressure medications were higher in the aggressive group. Clinical CVD events (1.6/100 and 1.5/100 person-years; P = .87) did not differ significantly between groups. CONCLUSIONS: Reducing LDL-C and SBP to lower targets resulted in regression of carotid IMT and greater decrease in left ventricular mass in individuals with type 2 diabetes. Clinical events were lower than expected and did not differ significantly between groups. Further follow-up is needed to determine whether these improvements will result in lower long-term CVD event rates and costs and favorable risk-benefit outcomes. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00047424.
Assuntos
Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Pressão Sanguínea , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/complicações , Adulto , Anti-Hipertensivos/uso terapêutico , Aterosclerose/etnologia , Artéria Carótida Primitiva/diagnóstico por imagem , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Humanos , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Hipertrofia Ventricular Esquerda/complicações , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipolipemiantes/uso terapêutico , Indígenas Norte-Americanos , Masculino , Pessoa de Meia-Idade , UltrassonografiaRESUMO
Hypoglycemia is the limiting factor in controlling glucose levels in Diabetes. Rather than being a side effect, hypoglycemia is the mechanism of action for insulin therapy, with a very narrow therapeutic window. Until recently, regulatory bodies listed hypoglycemia only as an adverse effect of therapy; however, one insulin preparation is now recognized and labelled as reducing the risk of severe hypoglycemia. This paper describes internationally agreed upon definitions for hypoglycemia and proposed regulatory approaches for recognition and labeling of diabetes therapies to facilitate personalized care.
Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemia/diagnóstico , Hipoglicemiantes/efeitos adversos , Insulina/efeitos adversos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Humanos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêuticoRESUMO
Cardiovascular disease (CVD) burden remains the predominant cause of mortality and morbidity in the United States and in most of the developed world. The ongoing twin epidemics of obesity and type 2 diabetes mellitus provide a groundswell source for sustaining this trend for the foreseeable future (increasing the prevalence of CVD by 2-4 times), unless radical changes are made in public health policy. Oral hypoglycemic agents (OHAs) remain a mainstay for management of type 2 diabetes in most practice settings. Although these agents are primarily prescribed to achieve better glycemic control, it is important to evaluate what effects they have on cardiovascular risk and whether there are significant differences in effects among the different OHAs. This review presents the available data on the effects of the various OHAs on cardiovascular risk surrogates and actual events in retrospective and prospective study design settings.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Administração Oral , Benzamidas/farmacologia , Biguanidas/farmacologia , Inibidores de Glicosídeo Hidrolases , Humanos , Fatores de Risco , Compostos de Sulfonilureia/farmacologia , Tiazolidinedionas/farmacologiaRESUMO
This randomised, double-blind, parallel-group study assessed the effects of addition of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, tesaglitazar, for 24 weeks to the therapeutic regimen of 392 poorly controlled (glycosylated haemoglobin [HbA1C] 7.5-10%) insulin-treated, type 2 diabetes patients. At 24 weeks, tesaglitazar 0.5 mg resulted in a 0.66% (95% confidence intervals: -0.85, -0.47; p<0.0001) reduction from baseline in HbA1C, and reduced fasting plasma glucose (p<0.0001) and daily insulin dose (p=0.014) versus placebo. After 24 weeks, tesaglitazar caused greater improvements from baseline in triglycerides (p<0.0001), high-density lipoprotein cholesterol (HDL-C) (p<0.001), non-HDL-C (p<0.05), apolipoprotein (apo)A-I (p<0.05) and apoB levels (p<0.01) than placebo. Tesaglitazar was generally well tolerated but was associated with a greater increase in serum creatinine level than placebo. The clinical development of tesaglitazar is no longer continuing; its effects on the glucose and lipid abnormalities of type 2 diabetes suggest that the concept of dual PPARalpha/gamma agonism is worthy of further investigation.
Assuntos
Alcanossulfonatos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , PPAR alfa/agonistas , PPAR gama/agonistas , Fenilpropionatos/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Alcanossulfonatos/efeitos adversos , Glicemia/efeitos dos fármacos , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/metabolismo , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Hemoglobinas Glicadas/metabolismo , Humanos , Hipoglicemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenilpropionatos/efeitos adversos , Fatores de Tempo , Triglicerídeos/sangueRESUMO
OBJECTIVE: To estimate the proportion of U.S. adults with diabetes who meet American Diabetes Association (ADA) clinical practice recommendations. RESEARCH DESIGN AND METHODS: Using data from the 1999-2002 National Health and Nutrition Examination Survey, 998 adults aged >/=18 years with self-reported diabetes were identified. The proportion of adults with diabetes meeting ADA recommendations for HbA(1c) (A1C), HDL cholesterol, LDL cholesterol, triglycerides, blood pressure, renal function, nutrient intake, smoking, pneumococcal vaccination, and physical activity was estimated. RESULTS: Among U.S. adults with diabetes in 1999-2002, 49.8% had A1C <7%; 27.4, 36.0, and 65.0% were classified as low risk for HDL cholesterol, LDL cholesterol, and triglycerides, respectively. Nearly 40% met blood pressure recommendations, 66% had normal renal function, and daily nutrient recommendations for protein, saturated fat, unsaturated fat, and fiber were met by 64.0, 48.3, 28.3, and 18.3%, respectively. Although >81% of the sample reported not smoking at the time of the exam, only 38.2% reported ever having had a pneumococcal immunization, and 28.2% reported getting the recommended level of physical activity. Race, age, duration of diabetes, and education affected achievement of ADA recommendations. CONCLUSIONS: Achievement of ADA clinical practice recommendations is far from adequate in U.S. adults with diabetes.
Assuntos
Diabetes Mellitus/reabilitação , Inquéritos Epidemiológicos , Inquéritos Nutricionais , Adulto , Idoso , Albuminúria/urina , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Creatinina/urina , Diabetes Mellitus/tratamento farmacológico , Feminino , Hemoglobinas Glicadas/análise , Humanos , Hipertensão/epidemiologia , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto/normas , Fumar/epidemiologia , Triglicerídeos/sangue , Estados Unidos/epidemiologia , Instituições Filantrópicas de SaúdeRESUMO
OBJECTIVE: The Diabetes Prevention Program (DPP) lifestyle intervention is a cost-effective strategy to prevent type 2 diabetes, but it is unclear how this intervention could be financed. We explored whether this intervention could be offered in a way that allows return on investment for private health insurers while remaining attractive for consumers, employers, and Medicare. RESEARCH DESIGN AND METHODS: We used the DPP and other published reports to build a Markov simulation model to estimate the lifetime progression of disease, costs, and quality of life for adults with impaired glucose tolerance. The model assumed a health-payer perspective and compared DPP lifestyle and placebo interventions. Primary outcomes included cumulative incidence of diabetes, direct medical costs, quality-adjusted life-years (QALYs), and cost per QALY gained. RESULTS: Compared with placebo, providing the lifestyle intervention at age 50 years could prevent 37% of new cases of diabetes before age 65, at a cost of $1,288 per QALY gained. A private payer could reimburse $655 (24%) of the $2,715 in total discounted intervention costs during the first 3 intervention years and still recover all of these costs in the form of medical costs avoided. If Medicare paid up to $2,136 in intervention costs over the 15-year period before participants reached age 65, it could recover those costs in the form of future medical costs avoided beginning at age 65. CONCLUSIONS: Cost-sharing strategies to offer the DPP lifestyle intervention for eligible people between ages 50 and 64 could provide financial return on investment for private payers and long-term benefits for Medicare.