Efficacy and Safety of Lixisenatide Once Daily Versus Exenatide Twice Daily in Type 2 Diabetes Inadequately Controlled on Metformin: A 24-week,randomized, open-label,active-controlled study (GetGoal-X)

OBJECTIVE

To compare efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled with metformin.

RESEARCH DESIGN AND METHODS

Adults with diabetes inadequately controlled (HbA_1c 7–10%) with metformin were randomized to lixisenatide 20 μg once daily (n = 318) or exenatide 10 μg twice daily (n = 316) in a 24-week (main period), open-label, parallel-group, multicenter study. The primary objective was a noninferiority assessment of lixisenatide versus exenatide in HbA_1c change from baseline to week 24.

RESULTS

Lixisenatide once daily demonstrated noninferiority in HbA_1c reduction versus exenatide twice daily. The least squares mean change was −0.79% (mean decrease 7.97 to 7.17%) for lixisenatide versus −0.96% (mean decrease 7.96 to 7.01%) for exenatide, and treatment difference was 0.17% (95% CI, 0.033–0.297), meeting a predefined noninferiority upper CI margin of 0.4%. Responder rate (HbA_1c <7.0%) and improvements in fasting plasma glucose were comparable. Both agents induced weight loss (from 94.5 to 91.7 kg and from 96.7 to 92.9 kg with lixisenatide and exenatide, respectively). Incidence of adverse events (AEs) was similar for lixisenatide and exenatide, as was incidence of serious AEs (2.8 and 2.2%, respectively). Discontinuations attributable to AEs occurred in 33 lixisenatide (10.4%) and 41 exenatide (13.0%) patients. In the lixisenatide group, fewer participants experienced symptomatic hypoglycemia (2.5 vs. 7.9%; P < 0.05), with fewer gastrointestinal events (especially nausea; 24.5 vs. 35.1%; P < 0.05).

CONCLUSIONS

Add-on lixisenatide once daily in type 2 diabetes inadequately controlled with metformin demonstrated noninferior improvements in HbA_1c, with slightly lower mean weight loss, lower incidence of hypoglycemia, and better gastrointestinal tolerability compared with exenatide twice daily.The glucagon-like peptide-1 (GLP-1) receptor system has become an attractive target for type 2 diabetes therapies (1–5). GLP-1 receptor agonists increasingly have become established as effective therapeutic options in type 2 diabetes management (6,7).Glucose-lowering effects of GLP-1 receptor agonists are mediated by glucose-dependent stimulation of insulin release and inhibition of glucagon secretion, which decreases prandial blood glucose excursion and hepatic glucose production (1–5). Notably, GLP-1 receptor agonists achieve physiological blood glucose–insulin response with a low risk of hypoglycemia (as a result of their glucose-dependent action) (8), delay gastric emptying, and are associated with beneficial effects on weight and appetite reduction (9).Currently available GLP-1 receptor agonists include twice-daily and once-weekly formulations of exenatide, a once-daily formulation of liraglutide, and a once-daily formulation of lixisenatide. Both exenatide and liraglutide have been shown to improve glycemic control associated with beneficial effects on weight and a low risk of hypoglycemia (10,11). However, although exenatide and liraglutide share the same basic mechanisms, each has a distinct pharmacokinetic profile and molecular structure, with potential clinical implications in terms of efficacy against fasting plasma glucose (FPG) and postprandial plasma glucose, and in terms of regimen burden and safety. This has been demonstrated in a 26-week, randomized, parallel-group, open-label trial in adults with inadequately controlled type 2 diabetes who were assigned to receive additional liraglutide 1.8 mg once daily or additional exenatide 10 µg twice daily (11). Liraglutide reduced mean FPG more than did exenatide (−29.0 mg/dL vs. −10.8 mg/dL; P < 0.0001), whereas exenatide reduced postprandial plasma glucose increment after breakfast and dinner more than did liraglutide (breakfast: estimated treatment difference, 23.9 mg/dL; P < 0.0001; dinner: estimated treatment difference, 18.2 mg/dL; P = 0.0005) (11). These findings suggest that liraglutide and exenatide should not be used interchangeably, but instead should be prescribed on an individual basis according to the glycemic requirements of each patient.Lixisenatide is a once-daily prandial GLP-1 receptor agonist for the treatment of type 2 diabetes that was approved by the European Medicines Agency in February 2013 (12,13). It is a 44–amino-acid peptide that is amidated at the COOH terminal amino acid and shares some structural elements with the GLP-1 receptor agonist exenatide; the primary difference is the addition of six lysine residues at the C terminus (13). A 13-week, randomized, double-blind, placebo-controlled, dose-ranging study that evaluated the dose-dependent effects of lixisenatide (5, 10, 20, or 30 µg once daily or twice daily) found that lixisenatide 20 µg administered once daily provided the best efficacy-to-tolerability ratio, with no additional benefits with any of the twice-daily doses (14). Lixisenatide 20 μg once daily subsequently has been shown to significantly improve glycemic control, with low rates of hypoglycemia and beneficial weight effects, when administered as monotherapy (15), as add-on therapy to oral agents (14,16–18), and in combination with basal insulin with or without oral antidiabetic therapy (19–21).In the current study, we report the results from a head-to-head study (GetGoal-X) that compared the benefit/risk profile of lixisenatide once daily versus exenatide twice daily in patients with type 2 diabetes inadequately controlled with metformin monotherapy.     

Factors associated to temporal artery biopsy result in suspects of giant cell arteritis: a retrospective,multicenter, case–control study

Purpose: To evaluate the positivity rate of temporal artery biopsies (TAB) performed in suspects of giant cell arteritis (GCA) and to study the epidemiological and clinical factors associated to the biopsy result. Methods: A retrospective, multicenter, case–control study was performed, including three hundred and thirty‐five patients who underwent TAB for a suspicion of GCA from 2001 to 2010. Clinical, epidemiological and pathology data were recovered from the patients’ clinical records. Histologic diagnosis of GCA was made when active inflammation or giant cells were found in the arterial wall. Results: Eighty‐one biopsies (24.2%) were considered positive for GCA. Clinical factors independently associated to TAB result in a logistic regression analysis were temporal cutaneous hyperalgesia (OR = 10.8; p < 0.001), jaw claudication (OR = 4.6; p = 0.001), recent‐onset headache (OR = 4.4; p = 0.001), decreased temporal pulse (OR = 2.8; p = 0.02), pain and stiffness in neck and shoulders (OR = 2.3; p = 0.05), unintentional weight loss (OR = 1.33; p = 0.003) and age (OR = 1.085; p = 0.004). Other factors such as length of the surgical specimen (OR = 1.079; p = 0.028) and erythrocyte sedimentation rate (OR = 1.042; p < 0.001) were also statistically significant. The model was accurate (C‐index = 0.921), reliable (p_{Hosmer–Lemeshow} = 0.733) and consistent in the bootstrap sensitivity analysis. No significant association was detected between TAB result and number of days of previous systemic corticosteroid treatment (p = 0.146). However, an association was observed between TAB result and the total accumulated dose of previous systemic corticotherapy (p = 0.043). Conclusions: Exhaustive anamnesis and clinical examination remain of paramount importance in the diagnosis of GCA. To improve the yield of TAB, it should be performed specially in older patients with GCA‐compatible clinic. TAB could be avoided in patients with an isolated elevation of acute phase reactants, without GCA‐compatible clinic.     

Usefulness of pneumococcal antigen detection in pleural effusion for the rapid diagnosis of infection by Streptococcus pneumoniae

Pleural effusion is increasingly reported in children. Standard culture of blood or pleural fluid is frequently negative and molecular diagnosis by polymerase chain reaction is not available in all hospitals. The Binax NOW Streptococcus pneumoniae Antigen test (Binax, Portland, USA) is a rapid immunochromatographic test (ICT) for the detection of the C polysaccharide antigen. We evaluated the Binax NOW test on the pleural fluid of 73 children hospitalized with pleural effusion over a period of 4 years. In our sample, the sensitivity and specificity of ICT were high (88% and 71%, respectively), with a positive predictive value of 96%. Detection of the pneumococcal antigen in pleural fluid by ICT is easy and quick, and enables us to identify the pneumococcal origin of the effusion, thus, making the treatment of complicated pneumonia suitably and early.     

Electromiografía laríngea en el diagnóstico y tratamiento de los trastornos de la voz

Introduction and objectivesLaryngeal electromyography, together with clinical evaluation, is a valuable tool in voice disorder management. It assesses the integrity of laryngeal nerves and muscles, contributing to the diagnosis of many diseases, especially laryngeal movement disorders. Our purpose was to describe the experience of the first Spanish series with laryngeal electromyography in evaluating voice disorders.MethodsA prospective study was designed to evaluate laryngeal movement disorders with laryngeal electromyography. Both the cricothyroid and thyroarytenoid muscles were tested routinely and, in some cases, the posterior cricoarytenoid muscle. The laryngeal electromyography technique and result interpretation were performed by a laryngologist and a neurophysiologist.ResultsWe included 110 patients, with the most common symptom being dysphonia. Laryngeal electromyography was performed in 85% of cases. Primary diagnosis before electromyography was laryngeal immobility. Positive predictive value for diagnosis in cases of paralysis was 88%.ConclusionsLaryngeal electromyography is a useful adjunct, together with clinical evaluation, for diagnosis and management of motion abnormalities in the larynx in patients who present with dysphonia.     

Bcl-2 protects murine erythroleukemia cells from p53-dependent and -independent radiation-induced cell death

To better understand the molecular basis of radiation-inducedcell death, we studied the role of the bcl-2 oncogene and thep53 tumor suppressor gene in this process. A temperature-sensitivemutant of murine p53 (p53Va-l35) and/or bcl-2 was transfectedinto murine erythroleukemia cells (MEL, DP16-1, which are nullin p53). We demonstrate that radiation-induced cell death occursby both p53-dependent and -independent pathways and overexpressionof bcl-2 modulates both pathways. When viability was measured24 h post-radiation, cells that had been briefly exposed towtp53 immediately after X-ray irradiation had decreased survivalas compared to unirradiated cells expressing wtp53 or X-rayirradiated DP16-1 cells. However, at later times X-ray irradiatedparental DP16-1 cells also had decreased survival compared tothe unirradiated control. This decrease in survival began 48h following radiation. Bcl-2 prevented radiation-induced celldeath in DP16-1 cells expressing wtp53 and delayed radiation-inducedcell death in DP16-1 cells without wtp53. X-ray irradiated cellsexpressing wtp53 displayed microscopic and biochemical characteristicsconsistent with cell death due to apoptosis. DP16-1 cells whichwere untransfected or co-transfected with wtp53 and bcl-2 displayedcharacteristics of cells undergoing necrosis. These resultssuggest that radiation-induced cell death occurs by both p53-dependentand p53-independent pathways. The p53-dependent pathway resultsin cell death via apoptosis and occurs approximately 24 h followingradiation. The p53-independent pathway does not appear to involveapoptosis and occurs at a later time, starting 48 h after X-rayexposure. Thus, bcl-2 protects cells from p53-dependent radiation-inducedapoptotic cell death and attenuates p53-independent radiation-inducedcell death.     

Aqueous and hydroalcoholic extracts of Black Maca (Lepidium meyenii) improve scopolamine-induced memory impairment in mice.

Lepidium meyenii Walp. (Brassicaceae), known as Maca, is a Peruvian hypocotyl growing exclusively between 4,000 and 4,500 m altitude in the central Peruvian Andes, particularly in Junin plateau. Previously, Black variety of Maca showed to be more beneficial than other varieties of Maca on learning and memory in ovariectomized mice on the water finding test. The present study aimed to test two different doses of aqueous (0.50 and 2.00 g/kg) and hydroalcoholic (0.25 and 1.00 g/kg) extracts of Black Maca administered for 35 days on memory impairment induced by scopolamine (1mg/kg body weight i.p.) in male mice. Memory and learning were evaluated using the water Morris maze and the step-down avoidance test. Brain acetylcholinesterase (AChE) and monoamine oxidase (MAO) activities in brain were also determined. Both extracts of Black Maca significantly ameliorated the scopolamine-induced memory impairment as measured in both the water Morris maze and the step-down avoidance tests. Black Maca extracts inhibited AChE activity, whereas MAO activity was not affected. These results indicate that Black Maca improves scopolamine-induced memory deficits.