Lege Artis Medicinae



NOVEMBER 19, 2006

Lege Artis Medicinae - 2006;16(11)

[Insulin aspart (B28 Asp-insulin), which is produced by recombinant DNA technology, is a fast-acting insulin analogue. Due to the aspartate for proline substitution at position 28 of the Bchain, the insulin molecule's tendency for selfassociation is diminished, therefore, insulin aspart rapidly dissociates into dimeric and monomeric forms and absorbs quickly and easily after subcutaneous administration. Compared to human regular insulin, insulin aspart has a faster onset of activity, a higher plasma peak and a shorter duration of action. Overall, the pharmacokinetic profile of insulin aspart better mimics the physiological postprandial insulin secretion. Therefore, insulin aspart can be used for prandial insulin substitution in order to decrease postprandial blood glucose excursion. It should be administered immediately before meals, but some observations suggest that it can also be used after finishing meal. This allows a more flexible lifestyle for patients. Insulin aspart can be used in both type 1 and type 2 diabetes. Compared to regular human insulin, a moderate decrease in the HbA1c values and fewer nocturnal hypoglycaemic events are expected from insulin aspart use. Insulin aspart is appropriate for pump treatment as well. It has recently been approved for use in pregnancy, whereas for children and adolescents the expected benefits should be weighed against the more modest clinical experience available. Similarly to other insulin analogues, results of long-term clinical investigations with insulin aspart with regard to the development of complications are not yet available.]



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[I Still Have So Much to Do... A Discussion with Éva Csatár MD]

VARGA Brigitta

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[Immunoglobulin E (IgE) plays a central role in the pathogenesis of the inflammation of the bronchial mucosa and airway hyperreactivity, which in turn produces the symptoms of allergic bronchial asthma. Omalizumab, the recently developed anti-IgE monoclonal antibody binds to the Cε3 region of the IgE molecule and thus prevents binding of the IgE to the surface of FCεRI receptor bearing cells (mast cells, basophils and antigen presenting dendritic cells). In the absence of cell-bound IgE, these cells are not activated and thus do not release inflammatory mediators and proinflammatory cytokines upon allergen exposition. Treatment with omalizumab significantly decreases the number of bronchial mucosal eosinophils and FCεRI positive cells, and the FCεRI receptor expression of the latter. Double blind controlled clinical studies have demonstrated that omalizumab treatment reduces the number of exacerbations and emergency room visits, the β2-agonist requirement and the dose of inhaled steroids, improves exspiratory airflow limitation, asthmatic symptoms and asthma-related quality of life in patients with moderate to severe allergic asthma. Low baseline FEV1, the use of high dose inhaled corticosteroids and a history of emergency asthma treatment in the past year are significant predictors of a better response to omalizumab. Omalizumab is tolerated well by patients. With the exception of local skin reactions, no significant difference in adverse events between patients taking omalizumab and control groups have been reported. According to the GINA (Global Initiative for Asthma) stepwise therapy protocol of asthma, omalizumab is indicated for severe asthmatics whose symptoms can not be controlled by inhaled corticosteroids and long-acting β2 agonists.]

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[The Great Binge Eating The Psychology and Symbols of Eating]

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[Rossini’s Mood Disorder]


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[Efficiency and safety of biphasic aspart insulin therapy in clinical studies]

GERŐ László

[Six-to-eight years after the diagnosis of type 2 diabetes the majority of patients require insulin treatment. Premixed insulin therapy provides an insulin profile that is closer to the physiological profile than that achieved by basal insulin supplementation and, in some cases, may serve as an alternative treatment in patients for whom intensified insulin therapy is unsuitable. However, if premixed human insulins are used, nocturnal hypoglycaemia occurs relatively frequently. Furthermore, patients must keep a lag-time of 30-45 minutes between the injection of insulin and eating. In contrast, if premixed insulin analogues are used, there is no need for such lag-time and both nocturnal and severe hypoglycaemia are less frequent than with human premixed therapy. The superiority of premixed insulin analogues compared with premixed human insulin therapy has been confirmed by a number of prospective, randomised controlled trials and retrospective analyses. The author summarises the results of these studies, emphasising the beneficial effects of premixed insulin analogues in the therapy of type 2 diabetes.]

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[Insulin detemir is a neutral, soluble, long-acting insulin analogue in which the amino acid threonineB30 has been removed and the LysB29 acylated with a 14-carbon fatty acid. The fatty acid modification allows insulin detemir to dihexamerisate and reversibly bind to human albumin upon administration. This brand new principle (self association and albumin binding) ensures slow absorption and a prolonged and consistent metabolic effect without a marked peak for up to 24 hours in patients both with type 1 and type 2 diabetes mellitus. Results of large clinical trials have shown that detemir can be efficiently used as basal insulin, supplemented with human regular insulin or aspart insulin taken before the main meals, in both type 1 and type 2 diabetes. Available data clearly demonstrate that the use of this insulin is associated with decreased variability of the fasting blood glucose values. In some of the studies the risk of (mostly nocturnal) hypoglycaemic episodes also dropped. It is important to note that patients using insulin detemir gained less or no weight compared to the group of patients treated with neutral protamine Hagedorn (NPH) insulin. Evaluation of long-term and wide-spread application of detemir needs further observations. Such trials are being conducted worldwide.]

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[Biosimilar insulins on the horizon]


[Nowadays human insulins and insulin analogues are exclusively used in the clinical practice, when insulin therapy is needed. The patents of human insulins are expired and will expire soon for glargine, the first long-acting, basal insulin analogue preparation. The reliable production of biosimilar insulins is a new challenge for the pharmaceutical industry. Independently developed insulins with appreciable clinical efficacy have already become available in some countries where the quality criteria of regulatory process in place are less strict than in the European Union. The first approval for true biosimilar insulin, i.e. for biosimilar glargine was given in Europe in 2014. In this article, the characteristics of biosimilar insulins, especially the difficulties in the manufacturing process are reviewed in comparison with generic drugs. It is of note that potential efficacy and safety differences may occur due to even minor changes in the production, formulation and storage of the biological drugs. Therefore, biosimilarity should be investigated by detailed comparative pharmacokinetic and pharmacodynamic studies. Moreover, similar clinical efficacy and safety should be documented by randomized, comparative clinical trials. The potential impact of altered immunologic profile of biosimilar insulins should also be carefully monitored. ]

LAM Extra for General Practicioners



[Administration of the alpha-glucosidase enzyme inhibitor acarbose leads to a prolonged absorption of carbohydrates, which has a smoothing effect on blood glucose excursions, and results in a more even daily blood glucose profile. The glucose lowering effect is mainly due to the reduction of postprandial blood glucose levels. Non-glycaemic effects of acarbose, including those on blood pressure, lipids and the coagulation system are also clearly beneficial. According to the available data, the preparation also reduces cardiovascular risk. If used as a monotherapy, acarbose does not cause hypoglycaemia. Flatulence and diaorrhea represent the main side effects. From a professional point of view, acarbose should be given if postprandial blood glucose excursions exceed 2.2 mmol/l.]

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[Switching from human basal insulin to once daily insulin detemir in type 2 diabetic patients treated by basal-bolus regimen - Results from the LEONCET2, an observational, prospective, multicenter study]


[Insulin analogues have been developed in order to overcome some drawbacks of human insulins. Switching from a human insulin-based basal- bolus regimen to once daily detemir could result in improved metabolism and increased safety of the therapy. We assessed the effects of switching from human NPH-insulin to once daily detemir insulin in patients with type 2 diabetes mellitus treated with a basal-bolus insulin regimen. We evaluated the data of 1,474 patients with diabetes (age: 59.1±9.8 years, body weight 89.6±8.6 kg, BMI 31.6±5.4 kg/m2) in an observational, prospective, 24-week, multicenter study. All patients were treated with a basal-bolus regimen consisting of human NPH as basal insulin and a human or analogue insulin as bolus insulin. After enrollment, patients received once daily detemir insulin instead of NPH-insulin, while treatment with bolus insulin was continued. Patients were examined at weeks 12 and 24. By week 24, the mean HbA1c value, irrespective of BMI-categories, decreased significantly (p<0.0001) from 8.63±1.01% by 0.79±0.63%. Fasting blood glucose level decreased from 8.86±1.78 mmol/l to 7.09±1.31 mmol/l; p<0.0001). The target level of HbA1c (<7.0%) was reached by 194 patients (13.1%). The patients’ body weight decreased significantly by week 12 (-0.69±2.00 kg; p<0.0001) and by week 24 (-1.28±2.80 kg; p<0.0001). The changes were more pronounced in higher than in lower BMI-categories (p for trend <0.0001). The mean daily doses of basal insulin were increased from 0.28 IU/kg to 0.33 IU/kg while those of bolus insulins were not changed. The rate of severe hypoglycaemic events decreased significantly (p=0.048) from 2.95 [daytime 1.02, nocturnal 1.93] to 0.06 [daytime 0.04, nocturnal 0.02] episodes/patient-year. In patients with type 2 diabetes mellitus treated with basal-bolus regimen, switching from human basal insulin to once daily insulin detemir results in a significantly improved metabolism, as well as fewer hypoglycaemic events and decreased body weight. Nevertheless, the low rate of patients reaching the glycaemic target implicates that some factors other than an appropriate basal insulin substitution have a role in achieving an optimal metabolic control.]