Liraglutide for the treatment of type 2 diabetes : a single technology appraisal

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 (STA) 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 glucoselowering 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 (GLP-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 Five of the six trials were published in full and one was then unpublished.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

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

The clinical effectiveness and cost-effectiveness of inhaled insulin in diabetes mellitus : a systematic review and economic evaluation

Background The two main types of diabetes are type 1 (formerly called insulin-dependent diabetes) and type 2 (formerly called non-insulin-dependent diabetes). In type 1, insulin is always required because the insulin-producing islet cells in the pancreas have been destroyed. In type 2, the pancreas can still produce insulin, and treatment is initially with diet and exercise, but the disease often progresses, with deteriorating control and rising blood glucose levels, and a need next for oral hypoglycaemic agents (OHAs), and later for insulin in about 30%. The aim of insulin therapy is to reduce blood glucose to normal levels, without going too low and causing hypoglycaemia. Insulin currently has to be given by injection. There are various types according to duration of action – short, intermediate and long. Short- and long-acting insulin both come in two forms: traditional and the newer analogues. The traditional form of short-acting insulin is known as soluble. It is given by injection using an insulin pen, or a syringe and needle. Insulin can also be given by continuous subcutaneous infusion by an insulin pump, usually only in selected patients with type 1 diabetes. Objective The aim was to review the clinical effectiveness and cost-effectiveness of a new technology, the inhaled insulin, Exubera® (Pfizer and Sanofi-Aventis in collaboration with Nektar Technologies), a short-acting insulin. Methods A systematic literature review was conducted and economic modelling carried out. Literature searches were done up to November 2005. The industry model, EAGLE, was used for modelling. Results Clinical effectiveness Nine trials of inhaled insulins were found, but only seven used the Exubera form of inhaled insulin. The other two used inhaled insulins that have not yet been licensed. There were five trials in type 1 and two in type 2 diabetes. Inhaled insulin is clinically effective, and is as good as short-acting soluble insulin in controlling blood glucose. The frequency of hypoglycaemia is similar. It works slightly more quickly than soluble insulin. None of the published trials compared it with short-acting analogues, which would have provided a better comparison since they also work slightly more rapidly than soluble. There is also a problem in most of the trials in that patients were on combinations of short-acting, and either long- or intermediate-acting insulin, and both were changed, making it more difficult to assess the effects of only the change from soluble to inhaled insulin. The only significant difference between inhaled and soluble insulin in the trials was in patient preference. Most patients preferred inhaled to injected short-acting insulin, and this has some effect on quality of life measures. However, there could be some bias operating in the trials. The control groups mostly used syringes and needles, rather than pens. As pens are more convenient, their use might have narrowed the patient satisfaction difference. The manufacturer, Pfizer, argues that this patient preference could lead to improved control in some type 1 patients, through improved compliance with treatment, and in some type 2 patients poorly controlled on oral agents, because a switch to insulin therapy would be more acceptable if people could use inhaled rather than injected insulin. These assertions are unproven. There were no trials of inhaled insulin against continuous subcutaneous insulin infusion (CSII). Safety Concern has been raised about the long-term effects of inhaled insulin in the lung. So far, no serious adverse effects have been seen, but until many thousands of people have used inhaled insulin for many years, one cannot rule out some uncommon or rare, but serious, adverse effects. Cost-effectiveness The manufacturer's model (EAGLE) appears to be a high-quality one. However, the results depend more on the assumptions fed into the model than on the model itself. The key assumptions are the size of the gain in quality of life utility from inhaling rather than injecting insulin, the effect of having an inhaled option on the willingness to start insulin among people with poor diabetic control on oral drugs, and the effect on glycaemic control. We consider that the assumptions used in the industry submission make the cost-effectiveness appear better than it really would be. The manufacturer's submission assumed utility gains of 0.036–0.075 in patients with type 1 diabetes, and 0.027–0.067 in those with type 2, based on an unpublished utility elicitation study sponsored by the manufacturer. We thought that these gains were optimistic and that gains of 0.02 or less were more likely, on average. However, patients with particular problems with injection sites might have more to gain, although they might also be a group with much to gain from CSII. A key factor is the cost of inhaled insulin. Much more insulin has to be given by inhaler than by injection, and so the cost of inhaled insulin is much higher than injected. The extra cost depends on dosage, but ranges from around £600 to over £1000 per patient per year. Conclusion The inhaled insulin, Exubera, appears to be effective and safe, but the cost is so much more that it is unlikely to be cost-effective

The effectiveness and cost-effectiveness of computed tomography screening for coronary artery disease : systematic review

Coronary heart disease (CHD) is one of the main causes of mortality and morbidity in the UK and other Western countries. The disease can be asymptomatic until the first event, which may be a fatal myocardial infarction (heart attack). Half of all heart attacks occur in people who have had no prior warning of coronary disease, and almost half will die from the first attack. Risk scores based on well-known factors such as age, blood pressure, smoking, cholesterol and diabetes have been used to assess risk, but are imperfect: not all high-risk people develop heart disease, and many low-risk people do. Indeed, depending on which cut-off is used to define high risk, most heart attacks occur in low-risk people, because the number of people at low risk is much greater than the number at high risk. There is therefore a need for a better way of identifying those at risk so that they can treat themselves with lifestyle measures, or receive drug therapy such as statins and antihypertensive drugs as appropriate. Computed tomography (CT) is a form of radiological imaging that can detect calcium deposits in the coronary arteries. This calcification is a marker for CHD, and so CT imaging could be a way of detecting asymptomatic but serious CHD. CT is quick and non-invasive, but does involve a relatively large radiation dose

Clinical and cost-effectiveness of autologous chondrocyte implantation for cartilage defects in knee joints : systematic review and economic evaluation

Objective: To support a review of the guidance issued by the National Institute for Health and Clinical Excellence (NICE) in December 2000 by examining the current clinical and cost-effectiveness evidence on autologous cartilage transplantation. Data sources: Electronic databases. Review methods: Evidence on clinical effectiveness was obtained from randomised trials, supplemented by data from selected observational studies for longer term results, and for the natural history of chondral lesions. Because of a lack of long-term results on outcomes such as later osteoarthritis and knee replacement, only illustrative modelling was done, using a range of assumptions that seemed reasonable, but were not evidence based. Results: Four randomised controlled trials were included, as well as observational data from case series. The trials studied a total of 266 patients and the observational studies up to 101 patients. Two studies compared autologous chondrocyte implantation (ACI) with mosaicplasty, the third compared ACI with microfracture, and the fourth compared matrix-guided ACI (MACI®) with microfracture. Follow-up was 1 year in one study, and up to 3 years in the remaining three studies. The first trial of ACI versus mosaicplasty found that ACI gave better results than mosaicplasty at 1 year. Overall, 88% had excellent or good results with ACI versus 69% with mosaicplasty. About half of the biopsies after ACI showed hyaline cartilage. The second trial of ACI versus mosaicplasty found little difference in clinical outcomes at 2 years. Disappointingly, biopsies from the ACI group showed fibrocartilage rather than hyaline cartilage. The trial of ACI versus microfracture also found only small differences in outcomes at 2 years. Finally, the trial of MACI versus microfracture contained insufficient long-term results at present, but the study does show the feasibility of doing ACI by the MACI technique. It also suggested that after ACI, it takes 2 years for full-thickness cartilage to be produced. Reliable costs per quality-adjusted life-year (QALY) could not be calculated owing to the absence of necessary data. Simple short-term modelling suggests that the quality of life gain from ACI versus microfracture would have to be between 70 and 100% greater over 2 years for it to be more cost-effective within the £20,000–30,000 per QALY costeffectiveness thresholds. However, if the quality of life gains could be maintained for a decade, increments relative to microfracture would only have to be 10–20% greater to justify additional treatment costs within the cost-effectiveness band indicated above. Follow-up from the trials so far has only been up to 2 years, with longer term outcomes being uncertain. Conclusions: There is insufficient evidence at present to say that ACI is cost-effective compared with microfracture or mosaicplasty. Longer term outcomes are required. Economic modelling using some assumptions about long-term outcomes that seem reasonable suggests that ACI would be cost-effective because it is more likely to produce hyaline cartilage, which is more likely to be durable and to prevent osteoarthritis in the longer term (e.g. 20 years). Further research is needed into earlier methods of predicting long-term results. Basic science research is also needed into factors that influence stem cells to become chondrocytes and to produce high-quality cartilage, as it may be possible to have more patients developing hyaline cartilage after microfracture. Study is also needed into cost-effective methods of rehabilitation and the effect of early mobilisation on cartilage growth

Perspective from a Younger Generation -- The Astro-Spectroscopy of Gisbert Winnewisser

Gisbert Winnewisser's astronomical career was practically coextensive with the whole development of molecular radio astronomy. Here I would like to pick out a few of his many contributions, which I, personally, find particularly interesting and put them in the context of newer results.Comment: 14 pages. (Co)authored by members of the MPIfR (Sub)millimeter Astronomy Group. To appear in the Proceedings of the 4th Cologne-Bonn-Zermatt-Symposium "The Dense Interstellar Medium in Galaxies" eds. S. Pfalzner, C. Kramer, C. Straubmeier, & A. Heithausen (Springer: Berlin

Exenatide prolonged-release suspension for injection in combination with oral antidiabetic therapy for the treatment of type 2 diabetes

Prolonged-release exenatide in triple therapy regimens (that is, in combination with metformin and a sulphonylurea, or metformin and a thiazolidinedione) is recommended as a treatment option for people with type 2 diabetes as described in 'Type 2 diabetes: the management of type 2 diabetes (NICE clinical guideline 87); that is, when control of blood glucose remains or becomes inadequate (HbA1c ≥ 7.5% [59 mmol/mol] or other higher level agreed with the individual), and the person has: a body mass index (BMI) ≥ 35 kg/m2 in those of European family origin (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight or a BMI < 35 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related comorbidities

Newer agents for blood glucose control in type 2 diabetes : systematic review and economic evaluation

Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH, but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes. Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis. The gliptins are similar to the glitazones in glycaemic control and costs, and appeared to have fewer long-term side effects. Therefore, it appears, as supported by recent NICE guidelines, that NPH should be the preferred first-line insulin for the treatment of type 2 diabetes. More economic analysis is required to establish when it becomes cost-effective to switch from NPH to a long-acting analogue. Also, long-term follow-up studies of exenatide and the gliptins, and data on combined insulin and exenatide treatment, would be useful

Self-monitoring of blood glucose in type 2 diabetes : systematic review

The evidence suggested that SMBG is of limited clinical effectiveness in improving glycaemic control in people with T2DM on oral agents, or diet alone, and is therefore unlikely to be cost-effective. SMBG may lead to improved glycaemic control only in the context of appropriate education - both for patients and health-care professionals - on how to respond to the data, in terms of lifestyle and treatment adjustment. Also, SMBG may be more effective if patients are able to self-adjust drug treatment. Further research is required on the type of education and feedback that are most helpful, characteristics of patients benefiting most from SMBG, optimal timing and frequency of SMBG, and the circumstances under which SMBG causes anxiety and/or depression

Clinical effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes : systematic review and economic evaluation

Based on the totality of evidence, using observational studies to supplement the limited data from randomised trials against best MDI, CSII provides some advantages over MDI in T1DM for both children and adults. However, there was no evidence that CSII is better than analogue-based MDI in T2DM or in pregnancy. Further trials with larger numbers and longer durations comparing CSII and optimised MDI in adults, adolescents and children are needed. In addition, there should be a trial of CSII versus MDI with similar provision of structured education in both arms. A trial is also needed for pregnant women with pre-existing diabetes, to investigate using CSII to the best effect