Evidence review : liraglutide for the treatment of type 2 diabetes

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of liraglutide in the treatment of type 2 diabetes mellitus, based upon the manufacturer’s submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The manufacturer proposed the use of liraglutide as a second or third drug in patients with type 2 diabetes whose glycaemic control was unsatisfactory with metformin, with or without a second oral glucose-lowering drug. The submission included six manufacturer-sponsored trials that compared the efficacy of liraglutide against other glucose-lowering agents. Not all of the trials were relevant to the decision problem. The most relevant were Liraglutide Effects and Actions in Diabetes 5 (LEAD-5) (liraglutide used as part of triple therapy and compared against insulin glargine) and LEAD-6 [liraglutide in triple therapy compared against another glucagon-like peptide-1 agonist, exenatide]. Five of the six trials were published in full and one was then unpublished. Two doses of liraglutide, 1.2 and 1.8 mg, were used in some trials, but in the two comparisons in triple therapy, against glargine and exenatide, only the 1.8-mg dose was used. Liraglutide in both doses was found to be clinically effective in lowering blood glucose concentration [glycated haemoglobin (HbA1c)], reducing weight (unlike other glucose-lowering agents, such as sulphonylureas, glitazones and insulins, which cause weight gain) and also reducing systolic blood pressure (SBP). Hypoglycaemia was uncommon. The ERG carried out meta-analyses comparing the 1.2- and 1.8-mg doses of liraglutide, which suggested that there was no difference in control of diabetes, and only a slight difference in weight loss, insufficient to justify the extra cost. The cost-effectiveness analysis was carried out using the Center for Outcomes Research model. The health benefit was reported as quality-adjusted life-years (QALYs). The manufacturer estimated the cost-effectiveness to be £15,130 per QALY for liraglutide 1.8 mg compared with glargine, £10,054 per QALY for liraglutide 1.8 mg compared with exenatide, £10,465 per QALY for liraglutide 1.8 mg compared with sitagliptin, and £9851 per QALY for liraglutide 1.2 mg compared with sitagliptin. The ERG conducted additional sensitivity analyses and concluded that the factors that carried most weight were: in the comparison with glargine, the direct utility effects of body mass index (BMI) changes and SBP, with some additional contribution from HbA1c in the comparison with exenatide, HbA1c, with some additional effects from cholesterol and triglycerides in the comparison with sitagliptin, HbA1c and direct utility effects of BMI changes. The European Medicines Agency has approved liraglutide in dual therapy with other oral glucose-lowering agents. NICE guidance recommends the use of liraglutide 1.2 mg in triple therapy when glycaemic control remains or becomes inadequate with a combination of two oral glucose-lowering drugs. The use of liraglutide 1.2 mg in a dual therapy is indicated only in patients who are intolerant of, or have contraindications to, three oral glucose-lowering drugs. The use of liraglutide 1.8 mg was not approved by NICE. The ERG recommends research into the (currently unlicensed) use of liraglutide in combination with long-acting insulin

Chemical Bionics - a novel design approach using ion sensitive field effect transistors

In the late 1980s Carver Mead introduced Neuromorphic engineering in which various aspects of the neural systems of the body were modelled using VLSI1 circuits. As a result most bio-inspired systems to date concentrate on modelling the electrical behaviour of neural systems such as the eyes, ears and brain. The reality is however that biological systems rely on chemical as well as electrical principles in order to function. This thesis introduces chemical bionics in which the chemically-dependent physiology of specific cells in the body is implemented for the development of novel bio-inspired therapeutic devices. The glucose dependent pancreatic beta cell is shown to be one such cell, that is designed and fabricated to form the first silicon metabolic cell. By replicating the bursting behaviour of biological beta cells, which respond to changes in blood glucose, a bio-inspired prosthetic for glucose homeostasis of Type I diabetes is demonstrated. To compliment this, research to further develop the Ion Sensitive Field Effect Transistor (ISFET) on unmodified CMOS is also presented for use as a monolithic sensor for chemical bionic systems. Problems arising by using the native passivation of CMOS as a sensing surface are described and methods of compensation are presented. A model for the operation of the device in weak inversion is also proposed for exploitation of its physical primitives to make novel monolithic solutions. Functional implementations in various technologies is also detailed to allow future implementations chemical bionic circuits. Finally the ISFET integrate and fire neuron, which is the first of its kind, is presented to be used as a chemical based building block for many existing neuromorphic circuits. As an example of this a chemical imager is described for spatio-temporal monitoring of chemical species and an acid base discriminator for monitoring changes in concentration around a fixed threshold is also proposed

Uued suunad GLP1 retseptori agonistide kasutamises diabeedi ravis

Väitekirja elektrooniline versioon ei sisalda publikatsiooneGlükagoonilaadne peptiid 1 (GLP1) on hormoon, mis vabaneb soolestikust vastusena söömisele. GLP1-l on erinevates elundsüsteemides mitmeid toimeid. See osaleb vere glükoositaseme regulatsioonis: stimuleerides insuliini ja inhibeerides glükagooni vabanemist veresuhkru tase langeb. GLP1 toimel aeglustub mao motoorika ja tühjenemine. Kesknärvisüsteemis reguleerib GLP1 söögiisu ning seeläbi kehakaalu. GLP1 füsioloogilistel toimetel põhineb ravimklassi GLP1 retseptori agonistide kasutamine. Need on laialdaselt kasutatavad diabeediravimid, mis lisaks veresuhkru taseme langetamisele vähendavad söögiisu ja alandavad kehakaalu. Ravimklass on võrdlemisi ohutu, kuna hüpoglükeemia risk on väike. Lisaks on kõrvaltoimed võrdlemisi kerged, sagedasemateks iiveldus ja oksendamine. GLP1 retseptori agonistide mõnede toimete suhtes kujuneb välja tolerantsus – näiteks mao motoorika aeglustumine väheneb ravimi kestval kasutusel. Samuti vähenevad ravimi korduval kasutamisel kõrvaltoimed, möödudes esimeste ravinädalatega. See, kas tolerantsus tekib ka GLP1 retseptori agonistide veresuhkru taset langetava toime suhtes, ei ole seni teada. GLP1 retseptori agoniste on kasutatud haruldaste ühe geeni rikkest põhjustatud suhkurtõve vormide puhul. Wolframi sündroom on geneetiline haigus, mille käigus arenevad 1. tüüpi diabeet, magediabeet ja silmanärvi kahjustus. Seni ei ole haigusel spetsiifilist ravi ja suhkruhaiguse tekkel kasutatakse tavaliselt insuliini süste. Käesolevas töös uurisime, kas GLP1 retseptori agoniste saaks kasutada Wolframi sündroomi puhul tekkiva suhkurtõve raviks. Uurimistöö eesmärkideks oli uurida GLP1 retseptori agonistide suhtes tekkivat tolerantsust hiirtel ja inimestel ning nende ravimite võimalikku toimet Wolframi sündroomi loommudelil. Eesmärkide saavutamiseks teostati loomkatseid hiirtel ning viidi läbi kliiniline uuring tervetel vabatahtlikel. Loomakatsete tulemused näitasid selget tolerantsuse teket hiirtel. Vastupidiselt loomkatsete tulemustele ei kujunenud aga tolerantsust välja inimeste puhul. Wolframi sündroomi loommudelis olid GLP1 retseptori agonistid efektiivsed veresuhkru langetajad, mis loob võimaluse nende kasutamiseks Wolframi sündroomi ravis.Glucagon-like peptide 1 (GLP1) is a peptide hormone secreted from the gastrointestinal tract in response to food ingestion. Moreover, GLP1 is secreted from the nervous system, where it functions as a neurotransmitter and, surprisingly, from the endocrine pancreas during metabolic stress. GLP1 regulates several biological functions in different organ systems. As one of the incretins, GLP1 stimulates in a glucose-dependent manner insulin secretion and inhibits that of glucagon, leading to a decrease in blood glucose levels. It decelerates gastric motility and emptying, regulates feeding behavior and body weight. GLP1 receptor agonists (GLP1RAs) have become a popular tool for treating type 2 diabetes, displaying positive impact beyond antihyperglycemic action. The key benefits of GLP1RAs include lower risk of hypoglycemia and modest weight loss. The adverse effects, most frequently nausea and vomiting, are generally mild and subside with time. One of the adverse effects of GLP1RA administration is decreased gastric motility. Interestingly, it is well known that this effect subsides with prolonged treatment. Thus, there is clear evidence that some effects of GLP1RAs are subject to tolerance development. It is logical to ask whether these drugs' core effects on glucose regulation may also be affected. GLP1RAs have been successfully used to treat certain forms of monogenic diabetes. We have asked whether a rare type of diabetes associated with Wolfram syndrome may respond to GLP1RAs. This study aimed to elucidate whether tolerance develops toward GLP1RAs’ glucose-lowering effects in mice and humans, and to investigate the drug class effect in the animal model of Wolfram syndrome. The results from our animal experiments demonstrated that the glucose lowering effect of GLP1RAs were clearly weaker after prolonged treatment. Unlike in mice, in the small clinical trial in healthy volunteers, the effects of GLP1RAs did not wane after 3 weeks of administration. Thus, tolerance toward GLP1RAs’ glucose lowering-effect developed in mice but not in humans. In the animal model of Wolfram syndrome, GLP1RAs potently decreased glucose levels and, therefore, may have potential in the treatment of patients with Wolfram syndrome.https://www.ester.ee/record=b546256

The treatment of hyperinsulinemic hypoglycaemia in adults: an update

Treatment of hyperinsulinemic hypoglycaemia (HH) is challenging due to the rarity of this condition and the difficulty of differential diagnosis. The aim of this article is to give an overview of the recent literature on the management of adult HH

Longitudinal imaging of pancreatic islets transplanted into the anterior chamber of the eye

Diabetes is a growing health problem associated with substantial health and socioeconomic costs. Current medications address hyperglycaemia and related complications, but a definitive cure for diabetes remains elusive. Pharmacotherapy with the potential to restore β-cell function is urgently needed. To this end, it is vital that we achieve a better understanding of islet function in both health and disease states. While major breakthroughs in diabetes research have traditionally resulted from in vitro experimentation, the crucial role of the pancreatic internal milieu is being increasingly recognised. The islet in the eye imaging platform is the first experimental tool which allows for the longitudinal and direct investigation of β-cell function in a non-invasive manner. This thesis describes the application of this imaging platform to three divergent areas of islet research. Firstly the physiology of co-ordinated insulin secretion is examined. Pulsatile insulin secretion is physiologically relevant and is impaired in diabetes. The imaging platform is used to establish, for the first time in vivo, that the calcium waves that underlie insulin secretion arise from the co-ordinated activity of a heterogeneous group of β-cells. Obesity is the greatest risk factor for developing Type 2 diabetes. The effects of high fat diet on islet calcium dynamics are incompletely understood. Hyperglucagonaemia is traditionally thought of as a contributing factor to diabetes disease progression. Emerging evidence however suggests that glucagon signalling has beneficial effects on food intake and energy expenditure. More recently, the insulin potentiating effects of intra-islet glucagon has been suggested. The imaging platform is developed to investigate the longitudinal effects of high fat diet and the subsequent weight-loss independent effects of a synthetic glucagon analogue on islet function. Together, these two studies investigate the utility of the islet in the eye imaging platform to better our understanding of intercellular β-cell calcium dynamics in the acute and in a more chronic setting. Islet transplantation has not provided a reliable cure for patients with Type 1 diabetes, due to a relative lack of suitable donors but, more importantly, because the majority of patients fail to achieve long term insulin independence. The reasons for transplant failure are manifold and poorly 9 understood, although engraftment failure is a major issue. There is a clear need to improve transplant success rates, especially if this can be achieved in line with a more reliable supply of β-cells/islets (for example stem-cell derived therapies). The last experimental chapter aims to investigate the effects of epidermal growth factor receptor (EGFR) overexpression in β-cells and whether this treatment improves islet engraftment. In particular, this chapter focuses on the angiogenesis of newly transplanted islets and whether the islet in eye platform is capable of longitudinally monitoring this process.Open Acces

Challenges and Opportunities in Design of Control Algorithm for Artificial Pancreas

With discovery of the insulin, Type-1 diabetes converted from a fatal and acute to a chronic disease which includes micro-vascular complications which range from Kidney disease to stroke and micro-vascular complications such as retinopathy, nephropathy and neuropathy. Artificial pancreas is a solution to improve the quality of life for people with this very fast growing disease in the world and to reduce the costs. Despite technological advances e.g., in subcutaneous sensors and actuators for insulin injection, modeling of blood glucose dynamics and control algorithms still need significant improvement. In this paper, we investigate challenges and opportunities for development of efficient algorithm for designing robust artificial pancreas. We discuss the state of the art and summarize clinical and in silico assessment results. We contrast conventional integer order system approach with a newly proposed fractal control and summarize its benefits

Systemic inflammation, body composition, and physical performance in old community-dwellers

Background Chronic inflammation, changes in body composition, and declining physical function are hallmarks of the ageing process. The aim of the present study was to provide a preliminary characterisation of the relationship among these age-related phenomena via multivariate modelling. Methods Thirty-five old adults (OAs) and 17 young adults (YAs) were enrolled. The volume of skeletal muscle, subcutaneous adipose tissue (SAT), and intermuscular adipose tissue (IMAT) of the thigh was quantified by three-dimensional magnetic resonance imaging. Muscle strength was measured by knee extension strength testing. In OAs, physical performance was further assessed via the Short Physical Performance Battery (SPPB). Multi-block partial least squares-discriminant analysis (PLS-DA) was employed to explore the relationship among inflammatory profiles and functional and imaging parameters. Double cross-validation procedures were used to validate the predictive ability of the PLS-DA model. Results The optimal complexity of the PLS-DA model was found to be two latent variables. The proportion of correct classification was 92.3% in calibration (94.1% in YAs and 91.4% in OAs), 84.6% in internal validation (95.3% in YAs and 78.5% in OAs), and 82.6% in external validation (94% in YAs and 76.9% in OAs). Relative to YAs, OAs were characterised by smaller muscle volume, greater IMAT volume, lower muscle strength, and higher levels of myeloperoxidase, P-selectin, soluble intercellular adhesion molecule 1, and vascular cell adhesion molecule 1. Compared with OAs with SPPB >8, those scoring 8 were characterised by smaller muscle volume, greater SAT volume, lower muscle strength, and higher levels of interleukin 1 beta, 6, 10, 12, 13, tumour necrosis factor alpha, and granulocyte-macrophage colony-stimulating factor. Conclusions Multi-block PLS-DA identified distinct patterns of relationships among circulating cytokines and functional and imaging parameters in persons of different ages and varying levels of physical performance. The longitudinal implementation of such an innovative strategy could allow for the tracking of health status over time, the early detection of deviations in health trajectories, and the monitoring of response to treatments