One-year metabolic outcomes in patients with type 2 diabetes treated with exenatide in routine practice.

AIM: The study objective was to analyze, in everyday practice, the long-term metabolic effects of exenatide (for 9 and 12 months) in patients with type 2 diabetes not responding to treatments with metformin and sulphonylurea at maximum dosages. METHODS: A total of 299 type 2 diabetics were recruited from 14 centres specializing in diabetes care across Belgium. Main study endpoints were changes in HbA(1c), weight and waist circumference, and tolerability and compliance. Two patient cohorts were analyzed for effectiveness, with data available at 9 (n=90) and 12 (n=94) months of follow-up. RESULTS: Significant decreases in HbA(1c) of -1.3% and -1.6% were observed in the 9- and 12-month cohorts, respectively (P<0.001). The decrease in HbA(1c) was greater in patients with higher baseline levels (P<0.001), and the response was independent of baseline weight, body mass index (BMI), age, gender and diabetes duration. A progressive reduction of weight (4.9 kg) was also observed in the two cohorts at 9 and 12 months (P<0.001), with greater weight loss in patients with higher baseline BMI (P=0.046) and in female subjects (P=0.025). Waist circumference also decreased from baseline to endpoints. A correlation was observed between reduction in HbA(1c) and weight loss (P=0.019). Side effects, mainly of gastrointestinal origin, were reported in 33% (93/284 patients in the safety cohort). The rate of hypoglycaemia was 3.5%. Treatment was discontinued in 27% of patients (n=77) mainly due to drug inefficacy (53%, n=41) or adverse events (26%, n=20), or both (8%, n=6). CONCLUSION: Exenatide leads to long-term improvement of glycaemic control as well as weight loss in a majority of patients not responding to combined oral drug therapy in real-world clinical practice. However, no baseline factors predictive of response could be identified. Exenatide can be considered an effective treatment option in such patients, including those with high baseline HbA(1c) and long duration of diabetes.

In vitro effects of oestradiol on galanin gene expression in rat anterior pituitary cells.

While the pituitary galanin gene is highly responsive to oestrogen stimulation in vivo, in vitro effects of oestrogens on pituitary galanin gene expression have been less studied. We therefore examined the short-term effects of 17beta-oestradiol on galanin synthesis by dispersed rat anterior pituitary cell cultures and investigated the mechanisms by which oestrogens may modulate galanin gene expression. 17beta-oestradiol increased galanin mRNA expression in a dose-dependent manner, with a maximal increase observed at a concentration of 10-7 M. The 17beta-oestradiol (10-7 M)-induced increase in galanin mRNA expression varied from 3- to 20-fold (average 12-fold) depending upon the experiments and was also time-dependent, reaching significance after 6 h. A 1-h exposure of anterior pituitary cells to 17beta-oestradiol was sufficient to induce markedly galanin mRNA expression after 24 h (by 16-fold) and 48 h (by 25-fold). Tamoxifen administered simultaneously with or following 17beta-oestradiol treatment completely abolished the oestrogen-induced increase of galanin mRNA levels. Cycloheximide (10 microg/ml), a protein synthesis inhibitor, also blocked 17beta-oestradiol-induced galanin gene expression. Using transcription blockade by actinomycin D, we observed similar decreases of pituitary galanin mRNA concentrations, in the presence and absence of 17beta-oestradiol, implying no oestrogen effect on mRNA stability. We conclude that oestrogens stimulate rat pituitary galanin gene expression, mainly through a transcriptional mechanism, and that this effect requires persistent binding of the hormone to its nuclear receptor and newly synthesized protein intermediates.

Impact of genomics on drug discovery and clinical medicine.

Genomics, particularly high-throughput sequencing and characterization of expressed human genes, has created new opportunities for drug discovery. Knowledge of all the human genes and their functions may allow effective preventive measures, and change drug research strategy and drug discovery development processes. Pharmacogenomics is the application of genomic technologies such as gene sequencing, statistical genetics, and gene expression analysis to drugs in clinical development and on the market. It applies the large-scale systematic approaches of genomics to speed the discovery of drug response markers, whether they act at the level of the drug target, drug metabolism, or disease pathways. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to genetic and specific individual markers, selecting medications and dosages that are optimized for individual patients. The possibility of defining patient populations genetically may improve outcomes by predicting individual responses to drugs, and could improve safety and efficacy in therapeutic areas such as neuropsychiatry, cardiovascular medicine, endocrinology (diabetes and obesity) and oncology. Ethical questions need to be addressed and guidelines established for the use of genomics in clinical research and clinical medicine. Significant achievements are possible with an interdisciplinary approach that includes genetic, technological and therapeutic measures.

Temporary vena caval filtration. Preliminary clinical experience with removable vena caval filters.

Removable vena caval devices look attractive in order to prevent pulmonary embolism (PE) in high risk patients when anticoagulant therapy has to be discontinued for periods shorter than 14 days. We describe our preliminary experience about 10 consecutive patients. All patients were anticoagulated for recent venous thromboembolism and the indication of vena caval filtration was mainly a short-term contraindication to anticoagulation due to surgery (8 cases) or delivery (1 case). Gunther Tulip retrievable vena caval device was used. No clinical manifestation of PE occurred during the filtration period. No thrombosis was detected at the insertion site, nor was any filter thrombosis found at the time of retrieval. Eight out of ten filters were easily retrieved through internal jugular vein. In one patient, filter could not be removed due to device tilting; in two patients, permanent filtration was secondarily requested. These results suggest that temporary vena caval filtration is efficient and safe for preventing pulmonary embolism during a short-term discontinuation of anticoagulant therapy in high risk patients.

Pharmacological management of diabetes: recent progress and future perspective in daily drug treatment.

Glycaemic control in Type 1 diabetes has been proven efficient in preventing microvascular and neurological complications. The assumption that good control of hyperglycaemia may also have significant impact on alleviation of complications in Type 2 diabetes has gained growing support in recent years. Measures such as body weight reduction and exercise improve the metabolic defects, but pharmacological therapy is most frequently used. The sulphonylureas stimulate insulin secretion. Metformin and troglitazone increase glucose disposal and decrease hepatic glucose output without causing hypoglycaemia. Acarbose helps to spread the dietary carbohydrate challenge to endogenous insulin over time. These pharmacological treatments can improve blood glucose regulation in Type 2 diabetes patients. However, the key to strict glycaemic control with use of exogenous insulin lies in the creation of delivery methods that emulate physiologic insulin secretion. Insulin lispro, a recombinant insulin analogue, is identical to human insulin except for the transposition of proline and lysine at positions 28 and 29 in the C-terminus of the B chain. Evidence suggests that patients perceive their quality of life to be improved with insulin lispro when compared with regular human insulin, and that satisfaction with treatment is greater with the insulin analogue. Numerous new pharmacological approaches are under active investigation, with the aim of promoting insulin secretion, improving the action of insulin, or slowing carbohydrate absorption. With respect to continuous subcutaneous insulin infusion therapy and implantable pumps, despite that this approach is not widely utilised, it appears to bring us as close to achieving glycaemic control as is feasible with current treatment approaches. However, general application of such technology requires significant improvements in several areas, such as improvement of patency of catheter, pump failures due to early battery depletion incidents, and pump miniaturisation. Future perspective resides on insulin analogues with longer half-lives that would provide better basal insulin coverage in association with fast-acting analogues.