E. Cummins

Screening for hyperglycaemia in pregnancy: A rapid update for the National Screening Committee

BACKGROUND Screening for gestational diabetes has long been a controversial topic. A previous Health Technology Assessment (HTA) report reviewed literature on screening for gestational diabetes mellitus (GDM) and assessed the case for screening against the criteria set by the National Screening Committee. OBJECTIVE To update a previous HTA report which reviewed the literature on screening for GDM by examining evidence that has emerged since that last report, including the Australian Carbohydrate Intolerance Study in Pregnant Women (ACHOIS), the Maternal and Fetal Medicine Units Network (MFMUN) trial and the Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study. To review data on recent trends in maternal age at birth and on the prevalence of overweight and obesity and the effect on prevalence of GDM. DATA SOURCES A systematic review and meta-analysis of the literature was carried out. The bibliographic databases used were MEDLINE (1996 to January 2009), EMBASE (1996 to December 2009), the Cochrane Library 2008 issue 4, the Centre for Reviews and Dissemination database and the Web of Science. REVIEW METHODS For the review of treatment with oral drugs versus insulin, a full systematic review and meta-analysis was carried out. The results of the ACHOIS, MFMUN and HAPO studies were summarised and their implications discussed. Findings of a selection of other recent studies, relevant to the continuum issue, were summarised. Some recent screening studies were reviewed, including a particular focus on studies of screening earlier in pregnancy. RESULTS The HAPO results showed a linear relationship between plasma glucose and adverse outcomes - there is a continuum of risk with no clear threshold which could divide women into those with gestational diabetes and those without. There was good evidence from trials and the meta-analysis that women who fail to control hyperglycaemic in pregnancy on lifestyle measures alone can be safely and effectively be treated with oral agents, metformin or glibenclamide, rather than going directly to insulin. Evidence showed few differences in results between glibenclamide and insulin and metformin and insulin. The exceptions were that there was less maternal hypoglycaemia with glibenclamide, but less neonatal hypoglycaemia and lower birthweight with insulin, and there was less maternal weight gain with metformin. The ACHOIS and MFMUN trials showed reductions in perinatal complications among infants born to mothers who were provided with more intensive dietary advice, blood glucose monitoring and insulin when required. The HAPO study demonstrated adverse outcomes over a much wider range of blood glucose (BG) than the traditional definition of GDM. In the HAPO study, no one measure of BG came out as being clearly the best, although fasting plasma glucose (FPG) was as good as any, and had advantages of being more convenient than an oral glucose tolerance test (OGTT), but correlations between fasting and post-load levels were quite poor. Two screening strategies dominated; (1) selection by the American Diabetes Association criteria followed by the 75-g OGTT [incremental cost-effectiveness ratio (ICER) 3678 pounds], and (2) selection by high-risk ethnicity followed by the 75-g OGTT (ICER 21,739 pounds). Studies indicated that costs are about 1833 pounds higher for pregnancies complicated by gestational diabetes, suggesting that prevention would be worthwhile. LIMITATIONS Not all of the HAPO results have been published, and none of the reviewed economic studies resolved the most difficult issue - at what level of BG does intervention become cost-effective? CONCLUSIONS The evidence base has improved since the last HTA review in 2002. There is now good evidence for treatment of oral drugs instead of insulin and it looks increasingly as if FPG could be the test of choice. However some key uncertainties remain to be resolved, which can be done by further analysis of the already collected HAPO data and by using the UK model used in developing the NICE guidelines to assess the cost-effectiveness of intervention in each of the seven HAPO categories.

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

OBJECTIVES To examine whether or not self-monitoring of blood glucose (SMBG) is worthwhile, in terms of glycaemic control, hypoglycaemia, quality of life (QoL) and cost per quality-adjusted life-year (QALY), in people with type 2 diabetes (T2DM) who were not treated with insulin or who were on basal insulin in combination with oral agents. DATA SOURCES Literature searched included systematic reviews published since 1996, and a systematic review and meta-analyses of randomised controlled trials (RCTs) identified from the reviews, and from searches for more recent trials, along with review of qualitative and economic studies. Search strategies were limited to the English language and to articles published since 1996, and included: databases searched from 1996 to April 2009 - The Cochrane Library, MEDLINE, EMBASE, PsycINFO, Web of Science - limited to meeting abstracts; and websites. REVIEW METHODS The intervention was self-testing of blood glucose with a meter and test strips. Studies included adult patients with T2DM on any oral treatment or combination of regimens, including lifestyle, oral agents or once-daily basal insulin. Existing systematic reviews of SMBG were summarised and results compared. Evidence synthesis of all of the studies meeting the inclusion criteria was carried out using a narrative review. Data were analysed by outcome and subgroups. HbA1c data from RCTs were summarised using a meta-analysis. Heterogeneity was calculated using the chi-squared and I2 methods. The following analyses were carried out: SMBG compared to self-monitoring of urine glucose, SMBG versus no SMBG, more intensive SMBG versus less intensive SMBG, and more intensive SMBG versus no SMBG. Available qualitative data gained from in-depth interview studies, repeated interviews, and questionnaire and survey data were summarised. RESULTS The review identified 30 RCTs, although few were of high quality. Ten trials comparing SMBG with no SMBG showed statistically significant reduction in HbA1C of 0.21%, which may not be considered clinically significant. A similar, though not statistically significant difference, was shown where SMBG with education was compared to SMBG without education or feedback. RCTs showed no consistent effect on hypoglycaemic episodes and no impact on medication changes. Review of cost-effectiveness studies showed that costs of SMBG per annum vary considerably (10-259 pounds). Although some studies assert that SMBG may lead to savings in health-care costs which may offset the costs of testing, the best analysis to date (DiGEM - Diabetes Glycaemic Education and Monitoring) concluded that SMBG was not cost-effective. Qualitative studies revealed that there was a lack of education in how to interpret and use the data from SMBG, and that failure to act on the results was common. CONCLUSIONS 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.

Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation.

BACKGROUND Irritable bowel syndrome (IBS) is common, and causes pain, bloating and diarrhoea and/or constipation. It is a troublesome condition that reduces the quality of life but causes no permanent damage. Inflammatory bowel disease (IBD) comprises mainly ulcerative colitis (UC) and Crohns disease (CD). Both cause serious complications and may lead to sections of the bowel having to be removed, although this is more common with CD. The presenting symptoms of IBS and IBD can be similar. Distinguishing them on clinical signs and symptoms can be difficult. Until recently, colonoscopy was often required to rule out IBD. In younger people, > 60% of colonoscopies showed no abnormality. Faecal calprotectin (FC) is a protein released by the white blood cells, neutrophils, found in inflamed areas of the bowel in IBD. Determining the level of FC in stool samples may help distinguish IBS from IBD. OBJECTIVE To review the value of FC for distinguishing between IBD and non-IBD. DATA SOURCES Sources included MEDLINE, EMBASE, The Cochrane Library, Web of Science, websites of journals and the European Crohns and Colitis Organisation (conference abstracts 2012 and 2013), and contact with experts. REVIEW METHODS Systematic review and economic modelling. Review Manager (RevMan) version 5.2 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen, Denmark) was used for most analysis, with statistical analyses done in Stata version 12 (StataCorp LP, College Station, TX, USA). Forest plots and receiver operating characteristic curves were produced. Quality Assessment of Diagnostic Accuracy Studies was used for quality assessment. Economic modelling was done in Microsoft Excel 2010 (Microsoft Corporation, Redmond, WA, USA). LIMITATIONS Studies were often small, most used only one calprotectin cut-off level, and nearly all came from secondary care populations. RESULTS Twenty-eight studies provided data for 2 × 2 tables and were included in meta-analyses, with seven in the most important comparison in adults (IBS vs. IBD) and eight in the key comparison in paediatrics (IBD vs. non-IBD). Most studies used laboratory enzyme-linked immunosorbent assay (ELISA) tests. For distinguishing between IBD and IBS in adults, these gave pooled sensitivity of 93% and specificity of 94% at FC cut-off level of 50 µg/g. Sensitivities at that cut-off ranged from 83% to 100%, and specificities from 60% to 100%. For distinguishing between IBD and non-IBD in paediatric populations with ELISA tests, sensitivities ranged from 95% to 100% at cut-off of 50 µg/g and specificities of 44-93%. Few studies used point-of-care testing but that seemed as reliable as ELISA, though perhaps less specific. The evidence did not provide any grounds for preferring one test over others on clinical effectiveness grounds. FC testing in primary care could reduce the need for referral and colonoscopies. Any quality-adjusted life-year gains are likely to be small because of the low prevalence of IBD and the high sensitivities of all of the tests, resulting in few false negatives with IBD. However, considerable savings could accrue. Areas of uncertainty include the optimum management of people with borderline results (50-150 µg/g), most of whom do not have IBD. Repeat testing may be appropriate before referral. CONCLUSIONS Faecal calprotectin can be a highly sensitive way of detecting IBD, although there are inevitably trade-offs between sensitivity and specificity, with some false positives (IBS with positive calprotectin) if a low calprotectin cut-off is used. In most cases, a negative calprotectin rules out IBD, thereby sparing most people with IBS from having to have invasive investigations, such as colonoscopy. STUDY REGISTRATION PROSPERO CRD 42012003287. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Systematic review of the clinical effectiveness and cost-effectiveness, and economic evaluation, of denosumab for the treatment of bone metastases from solid tumours

BACKGROUND Denosumab offers an alternative, or additional, treatment for the prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumours. OBJECTIVES The aim of this review was to assess the clinical effectiveness and cost-effectiveness of denosumab, within its licensed indication, for the prevention of SREs in patients with bone metastases from solid tumours. DATA SOURCES Databases searched were MEDLINE (1948 to April 2011), EMBASE (1980 to March 2011), The Cochrane Library (all sections; Issue 1, 2011) and Web of Science with Conference Proceedings (1970 to May 2011). REVIEW METHODS Only randomised controlled trials (RCTs) assessing denosumab, bisphosphonates (BPs) or best supportive care (BSC) in patients with bone metastases were included. Systematic reviews and observational studies were used for safety and quality-of-life assessments. Study quality was assessed using the Cochrane risk of bias tool. Studies suitable for meta-analysis were synthesised using network meta-analysis (NMA). A systematic review was conducted for cost, quality-of-life and cost-effectiveness studies. The results of this informed the cost-utility modelling. This principally estimated the cost-effectiveness of denosumab relative to zoledronic acid for when BPs are currently recommended and relative to BSC when BPs are not recommended or are contraindicated. RESULTS A literature search identified 39 studies (eight suitable for NMA). Denosumab was effective in delaying time to first SRE and reducing the risk of multiple SREs compared with zoledronic acid. Generally speaking, denosumab was similar to zoledronic acid for quality of life, pain, overall survival and safety. The NMA demonstrated that denosumab was more effective in delaying SREs than placebo, but was limited by numerous uncertainties. Cost-utility modelling results for denosumab relative to zoledronic acid were driven by the availability of the patient access scheme (PAS) for denosumab. Without this, denosumab was not estimated to be cost-effective compared with zoledronic acid. With it, the cost-effectiveness ranged between dominance for breast and prostate cancer, to between £5400 and £15,300 per quality-adjusted life-year (QALY) for other solid tumours (OSTs) including non-small cell lung cancer (NSCLC) and £12,700 per QALY for NSCLC. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. Denosumab was not estimated to be cost-effective compared with BSC. LIMITATIONS Only subgroup data were available for denosumab for NSCLC, and OSTs excluding NSCLC. The NMA was subject to numerous uncertainties. Owing to small patient gains estimated, the cost-effectiveness of denosumab was very sensitive to the zoledronic acid price. CONCLUSION Denosumab, compared with zoledronic acid and placebo, is effective in delaying SREs, but is similar with regard to quality of life and pain. Cost-effectiveness showed that without the PAS denosumab was not estimated to be cost-effective relative to either zoledronic acid or BSC. With the PAS, denosumab was estimated to be cost-effective relative to zoledronic acid but not BSC. STUDY REGISTRATION PROSPERO number CRD42011001418. FUNDING The National Institute for Health Research Health Technology Assessment programme.

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 manufacturers 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.