Background Diabetes is a multisystem disorder associated with a nearly twofold excess risk for a broad range of adverse cardiovascular outcomes including coronary heart disease, stroke, and ...cardiovascular death. Liraglutide is a human glucagon-like peptide receptor analog approved for use in patients with type 2 diabetes mellitus (T2DM). Study Design To formally assess the cardiovascular safety of liraglutide, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial was commenced in 2010. LEADER is a phase 3B, multicenter, international, randomized, double-blind, placebo-controlled clinical trial with long-term follow-up. Patients with T2DM at high risk for cardiovascular disease (CVD) who were either drug naive or treated with oral antihyperglycemic agents or selected insulin regimens (human NPH, long-acting analog, or premixed) alone or in combination with oral antihyperglycemics were eligible for inclusion. Randomized patients are being followed for up to 5 years. The primary end point is the time from randomization to a composite outcome consisting of the first occurrence of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Conclusions LEADER commenced in September 2010, and enrollment concluded in April 2012. There were 9,340 patients enrolled at 410 sites in 32 countries. The mean age of patients was 64.3 ± 7.2 years, 64.3% were men, and mean body mass index was 32.5 ± 6.3 kg/m2 . There were 7,592 (81.3%) patients with prior CVD and 1,748 (18.7%) who were high risk but without prior CVD. It is expected that LEADER will provide conclusive data regarding the cardiovascular safety of liraglutide relative to the current standard of usual care for a global population of patients with T2DM.
Summary Background No clinical trials have assessed the effects or cost-effectiveness of sequential screening strategies to detect new cases of type 2 diabetes. We used a mathematical model to ...estimate the cost-effectiveness of several screening strategies. Methods We used person-specific data from a representative sample of the US population to create a simulated population of 325 000 people aged 30 years without diabetes. We used the Archimedes model to compare eight simulated screening strategies for type 2 diabetes with a no-screening control strategy. Strategies differed in terms of age at initiation and frequency of screening. Once diagnosed, diabetes treatment was simulated in a standard manner. We calculated the effects of each strategy on the incidence of type 2 diabetes, myocardial infarction, stroke, and microvascular complications in addition to quality of life, costs, and cost per quality-adjusted life-year (QALY). Findings Compared with no screening, all simulated screening strategies reduced the incidence of myocardial infarction (3–9 events prevented per 1000 people screened) and diabetes-related microvascular complications (3–9 events prevented per 1000 people), and increased the number of QALYs (93–194 undiscounted QALYs) added over 50 years. Most strategies prevented a significant number of simulated deaths (2–5 events per 1000 people). There was little or no effect of screening on incidence of stroke (0–1 event prevented per 1000 people). Five screening strategies had costs per QALY of about US$10 500 or less, whereas costs were much higher for screening started at 45 years of age and repeated every year ($15 509), screening started at 60 years of age and repeated every 3 years ($25 738), or a maximum screening strategy (screening started at 30 years of age and repeated every 6 months; $40 778). Several strategies differed substantially in the number of QALYs gained. Costs per QALY were sensitive to the disutility assigned to the state of having diabetes diagnosed with or without symptoms. Interpretation In the US population, screening for type 2 diabetes is cost effective when started between the ages of 30 years and 45 years, with screening repeated every 3–5 years. Funding Novo Nordisk, Bayer HealthCare, and Pfizer.
Abstract Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes mellitus (T2DM), reduced glycosylated hemoglobin (HbA1c ) and weight in 30-week placebo-controlled ...trials. Some patients were followed up in open-label extensions to provide ‘real-world’ exenatide clinical experience. Objective: The purpose of this study was to examine the metabolic effects of 2 years of exenatide treatment in patients with T2DM. Methods: For this interim analysis, data were pooled from patients who completed 1 of three 30-week, multicenter, double-blind, placebo-controlled trials and their open-label extensions. In the initial trials, subjects were randomized to BID 5-pg exenatide, 10-pg exenatide, or placebo for 30 weeks. All subjects who enrolled in the extension phase then received 5-pg exenatide BID for 4 weeks, followed by open-label treatment with 10-pg exenatide BID. Subjects continued their existing metformin and/or sulfonylurea regimens. Analyses were conducted on data from all subjects who had the opportunity to achieve 2 years of exenatide exposure, irrespective of their treatment arm in the 30-week placebo-controlled trials. Results: A total of 974 patients entered the open-label, extension phase of the trial. Two hundred eighty-three subjects (mean SD age, 57 10 years; mean SD weight, 100 119 kg; sex, 63% male; mean SD body mass index, 34 6 kg/m2; mean SD HbA1c , 8.3% 1.0%1 completed 2 years of exenatide treatment. Reductions in mean (SE) HbA1c from baseline to week 30 (−0.9% 0.1%) were sustained through 2 years (−1.1% 0.1%; P < 0.05 vs baseline), with 50% of the population achieving HbA1c ≤ 7%. At week 30, exenatide was associated with a significant reduction in mean (SD) body weight from baseline (−2.1 0.2 kg), with progressive reductions after 2 years (−4.7 0.3 kg; P < 0.001 vs baseline). Patients with normal baseline alanine aminotransferase (ALT) (132/283 47%; normal: female ≤19 IU/L; male ≤30 IU/L) had no significant ALT change. However, patients with elevated ALT at baseline (151/283 53%) had a mean (SEM) reduction of ALT (−11 1 IU/L from baseline 38 1 IU/1,; P < 0.05) and 39% achieved normal ALT by week 104. Patients with elevated ALT at baseline lost significantly more weight than patients with normal ALT at baseline ( P = 0.04). However, weight change was minimally correlated with baseline ALT ( r = −0.09) or ALT change ( r = 0.31). Also, homeostasis model assessment of the β-cell function (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. The most frequently reported adverse event was mild-to-moderate nausea. Conclusions: In these patients with T2DM, adjunctive exenatide treatment for 2 years was generally well tolerated and resulted in a sustained reduction of HbA1c , progressive reduction in weight, and improvements in HOMA-B, blood pressure, and the hepatic injury biomarkers, AST and ALT.
Summary Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight ...reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of exenatide to that of a twice daily dose. Methods A 30-week, randomised, non-inferiority study compared a long-acting release formulation of exenatide 2 mg administered once weekly to 10 μg exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A1c HbA1c 8·3% SD 1·0, mean fasting plasma glucose 9 SD 2 mmol/L, weight 102 SD 20 kg, diabetes duration 6·7 SD 5·0 years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA1c at 30 weeks. This study is registered with ClinicalTrials.gov , number NCT00308139. Findings At 30 weeks, the patients given exenatide once a week had significantly greater changes in HbA1c than those given exenatide twice a day (−1·9 SE 0·1% vs −1·5 0·1%, 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039). Interpretation Exenatide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight. Funding Amylin Pharmaceuticals Inc and Eli Lilly and Company.
Background Prior randomized trials suggested that revascularization of diabetic patients by coronary artery bypass grafting (CABG) produced results superior to balloon angioplasty. The introduction ...of drug-eluting stents (DESs) calls into question the relevance of past studies to the current era. The FREEDOM Trial is designed to determine whether CABG or percutaneous coronary intervention (PCI) is the superior approach for revascularization of diabetic patients. Study Design The FREEDOM Trial is a multicenter, open-label prospective randomized superiority trial of PCI versus CABG in at least 2000 diabetic patients in whom revascularization is indicated. Consenting diabetic patients with multivessel disease will be randomized on a 1:1 basis to either CABG or multivessel stenting using DESs and observed at 30 days, 1 year, and annually for up to 5 years. At the discretion of the primary physician or interventionalists, patients randomized to the PCI/DES arm will receive any approved DESs. The primary outcome measure is the composite of all-cause mortality, nonfatal myocardial infarction, or stroke. Patients will be observed for a mean of 4 years. Implications At present, coronary revascularization with CABG surgery is the treatment of choice in diabetic patients with multivessel coronary artery disease. Drug-eluting stents have shown promising preliminary results in the diabetic population. The FREEDOM Trial is an international study designed to define the optimal revascularization strategy for the diabetic patient with multivessel coronary disease.
Patients with type 2 diabetes mellitus die of cardiovascular disease (CVD) at rates 2–4 times higher than patients without diabetes but with similar demographic characteristics. The prevalence of ...diabetes is increasing in the United States and, thus, the prevention of CVD in patients with diabetes poses an urgent public health challenge. The objective of this report is to review the current knowledge base for the prevention of CVD in patients with diabetes, with particular emphasis on the control of glycemia, lipids, and blood pressure. Epidemiologic analyses suggest that each 1% increase in glycosylated hemoglobin increases the risk for CVD by approximately 18%; however, evidence from the randomized trials that have examined whether glucose lowering reduces this risk is conflicting. Randomized trials have shown that lowering low-density lipoprotein cholesterol reduces CVD event rates by 17%–43% in patients with diabetes. Limited data support a role for lowering triglycerides and increasing high-density lipoprotein cholesterol in the prevention of CVD. Evidence from clinical trials shows that reducing systolic blood pressure to <140 mm Hg results in 30%–60% reductions in CVD events; however, epidemiologic evidence suggests that lowering to optimal systolic blood pressure levels (<120 mm Hg) may be additionally beneficial. Important questions regarding prevention of CVD in patients with diabetes remain unresolved, including the benefits of near-normal glycemic control, comprehensive therapy for diabetes-related dyslipidemia, and optimal blood pressure control. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial will test hypotheses to address these unanswered questions.
Background Peroxisome proliferator–activated receptors (PPARs) regulate transcription of genes involved in glucose uptake, lipid metabolism, and inflammation. Aleglitazar is a potent dual PPAR ...agonist with insulin-sensitizing and glucose-lowering actions and favorable effects on lipid profiles and biomarkers of cardiovascular risk. The AleCardio trial examines whether the addition of aleglitazar to standard medical therapy reduces the risk of cardiovascular morbidity and mortality in patients with type 2 diabetes mellitus and recent acute coronary syndrome. Study Design AleCardio is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. A total of 7,228 patients were randomized to aleglitazar 150 μg or placebo daily in addition to standard medical therapy. The primary efficacy end point is time to the first event of cardiovascular death, myocardial infarction, or stroke. Principal safety end points are hospitalization due to heart failure and changes in renal function. Treatment will continue until 7,000 patients are followed up for at least 2.5 years and 950 primary end point events are adjudicated. Conclusions AleCardio will establish whether the PPAR-α/γ agonist aleglitazar improves cardiovascular outcomes in patients with diabetes and high-risk coronary disease.
Objectives To characterize lipids and lipoproteins in a diverse school-based cohort and identify features associated with discordance between low-density lipoprotein cholesterol (LDL-C) and LDL ...particle (LDL-P). Study design Sixth-grade children enrolled in the HEALTHY trial (n = 2384; mean age 11.3 ± 0.6 years; 54.2% female) were evaluated for standard lipids, lipoprotein particles measured by nuclear magnetic resonance, and homeostatic model of insulin resistance. Characteristics of subgroups with values of LDL-C and LDL-P discordant by >20 percentile units, an amount reasoned to be clinically significant, were compared. Results Four-hundred twenty-eight (18%) of children were in the LDL-P < LDL-C subgroup and 375 (16%) in the LDL-P > LDL-C subgroup. Those with LDL-P > LDL-C had significantly greater body mass index, waist circumference, homeostatic model of insulin resistance, triglycerides, systolic and diastolic blood pressure, and reflected a greater Hispanic ethnic composition but fewer of black race than both the concordant (LDL-P ≅ LDL-C) and opposite discordant (LDL-P < LDL-C) subgroups. Conclusions There is as much lipoprotein cholesterol compositional heterogeneity in sixth graders as has been described in adults and a discordant atherogenic phenotype of LDL-P > LDL-C, common in obesity, is often missed when only LDL-C is considered. Conversely, many children with moderate-risk cholesterol measures (75th to 99th percentile) have a lower LDL-P burden.
Diabetes and periodontal therapy Pihlstrom, Bruce L; Buse, John B
The Journal of the American Dental Association (1939),
12/2014, Letnik:
145, Številka:
12
Journal Article
Objective To examine whether longitudinal changes in relative weight category (as indicated by change in body mass index BMI classification group) were associated with changes in nuclear magnetic ...resonance (NMR)−derived lipoprotein particles among US youth. Study design Secondary analysis of data from a clustered randomized controlled trial. BMI and fasting blood samples were obtained from 2069 participants at the start of the 6th grade and end of the 8th grade. BMI was categorized as normal weight, overweight, or obese at both time points. Lipoprotein particle profiles were measured with NMR spectroscopy at both time points. Regression models were used to examine changes in relative weight group and change in lipoprotein variables. Results A total of 38% of participants changed relative weight category (BMI group) during the 2.5-year study period. Low-density lipoprotein (LDL) cholesterol and non−high-density lipoprotein (HDL) cholesterol decreased almost universally, but more with improved BMI category. There were adverse effects on LDL size and total LDL particles, HDL size, and cholesterol for participants who remained obese or whose relative weight group worsened. Changes in relative category had no impact on HDL particles. Conclusion Improvement in relative weight group from 6th to 8th grade was associated with favorable changes in non-HDL cholesterol, very low-density lipoprotein size, LDL size, HDL size, and LDL particles but had no effect on HDL particles. Findings indicate that an improvement in relative weight group between 6th and 8th grade had an effect on NMR-derived particles sizes and concentrations among a large group of adolescents, which overrepresented low-income minorities.
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